(EAU) European Association of Urology Guidelines 2017
(EAU) European Association of Urology Guidelines 2017
(EAU) European Association of Urology Guidelines 2017
Association
of Urology
Guidelines
2017 edition
European Association of Urology Guidelines 2017
Introduction
We are honoured to present the 2017 edition of the European Association of Urology (EAU) Guidelines. The
EAU Guidelines are the most comprehensive continuously updated guidelines, available for urologists and
related specialities, produced by a dedicated Guidelines Office involving approximately 300 international
experts. The EAU guidelines are recognised worldwide as an important resource to assist clinicians in their
everyday practice, they are currently available in more than 30 languages and endorsed by more than 55
national and scientific societies throughout Europe and the world. Furthermore, this year we are delighted to
announce the inclusion of two new topics, Renal Transplantation and Thromboprophylaxis.
Clinical practice guidelines not only play a pivotal role in health care practice, but are also a vital resource for
the advancement of medical education. The EAU Guidelines Office are committed to actively pursuing effective
collaborations both within the EAU and externally which help to further the medical education of young
clinicians. A key example of this is the EAU Guidelines Office systematic review programme, the success of
which is measurable in the numerous European Urology publications it has produced to date. In this endeavour
the EAU Guidelines Office is exceptionally grateful for the continued support and active collaboration of
Prof. Dr. J. Catto editor-in-chief of European Urology. Other highly productive collaborations include the hosting
of multiple European School of Urology courses on changes in the guidelines and evidence-based medicine
methodology for which the continued support of Prof. Dr. J. Palou has been invaluable. In the coming year we
will continue to build upon and grow these collaborations.
Adherence to national and international clinical guidelines is sub-optimal throughout Europe therefore, the
development of clinical guidelines must fundamentally be supported by an effective dissemination and
implementation strategy. Dissemination should be an active process in which tailor-made information is
actively imparted to the appropriate audience/users. Effective implementation of clinical guidelines involves
the identification of barriers to knowledge transfer, or more importantly, the identification of the optimum
interventions to limit or overcome such barriers. During the course of 2017 both the EAU Guidelines Social
Media (SoMe) and IMpact Assessment of Guidelines Implementation and Education (IMAGINE) groups will
continue to actively drive these processes forward, allowing for the continued optimisation of urological
healthcare resources ultimately, focused on improving patient outcomes.
Moving forward, as of 2018, the EAU Guidelines will begin to adopt a modified version of the Grading of
Recommendations Assessment, Development and Evaluation (GRADE) approach to measure the quality of
evidence of studies included in the guidelines and to grade guidelines recommendations. The strength of
each recommendation will be determined by the balance between desirable and undesirable consequences
of alternative interventions, the quality of evidence for each intervention as well as the nature and variability
of patients’ values and preferences. The strength of each recommendation will be represented by the words
‘strong’ or ‘weak’. The panels will provide both ‘strong’ and ‘weak’ recommendations ‘for’ or ‘against’ each
intervention. This system will be introduced across all EAU Guidelines, in a staged process, the aim being to
provide transparency between the underlying evidence and a given recommendation.
The yearly publication of the EAU Guidelines would not be possible without the unwavering support of the
EAU Executive Committee and Management team, our highly valued Guidelines Panels and young Guidelines
Associates, our EAU membership and every user of the Guidelines globally. So, on behalf of the EAU
Guidelines Office Board, thank you for your support and inspiration.
We hope you enjoy using the 2017 update of the EAU Guidelines!
Prof.Dr. J. N’Dow Prof.Dr. A. Bjartell, Prof.Dr. A. Briganti Prof.Dr. M. De Santis Prof.Dr. T. Knoll
Aberdeen (UK) Malmö (SE) Milan (IT) Coventry (UK) Sindelfingen (DE)
(chair)
Prof.Dr. M.J. Ribal Prof.Dr. R. Sylvester Prof.Dr. T. Loch Prof.Dr. H. Van Poppel
Barcelona (ES) Brussels (BE) Flensburg (DE) Leuven (BE)
(ex-officio) (ex-officio)
The EAU Guidelines Office has set up dedicated Committees responsible for critical aspects of guidelines
development.
EAU Guidelines Office Methods Committee EAU Guidelines Office IMAGINE Group (IMpact
Prof.Dr. R. Sylvester, Brussels (BE) (chair) Assessment of Guidelines Implementation and
Prof.Dr. S. Canfield, Houston (TX, USA) Education)
Dr. L. Marconi, Coimbra (PT) Prof.Dr. A. Briganti, Milan (IT) (chair)
Dr. C. Yuhong Yuan, Hamilton (ON, CN) Dr. G. Gandaglia, Milan (IT)
Dr. I. Omar, Aberdeen (UK) (ex-officio) Dr. S. MacLennan, Aberdeen (UK)
Dr. S. MacLennan, Aberdeen (UK) Dr. S.J. MacLennan, Aberdeen (UK)
Prof.Dr. J. N’Dow, Aberdeen (UK) (ex-officio) Dr. L. Marconi, Coimbra (PT)
Prof.Dr. M. Trapero-Bertran, Barcelona (ES)
EAU Guidelines Office Dissemination Committee Prof.Dr. L. Vale, Newcastle (UK)
Prof.Dr. M.J. Ribal, Barcelona (ES) (chair Prof.Dr. J. N’Dow, Aberdeen (UK) (ex-officio)
Prof.Dr. M. Rouprêt, Paris (FR)
Dr. S. Loeb, New York (NY) USA EAU Guidelines Office CONFIDENCE Committee
Dr. I. van Oort, Nijmegen (NL) (CONsensus FindIng DEvelopmeNt CommitteE)
Prof.Dr. A. Bex, Amsterdam (NL) (chair)
EAU Guidelines Office Associates Programme Dr. G. Athanasiadis, Aberdeen (UK)
Prof.Dr. T. Knoll, Sindelfingen (DE) (chair) Dr. M. Bruins, Nijmegen (NL)
Dr. L. Marconi, Coimbra (PT) Prof.Dr. J. N’Dow, Aberdeen (UK) (ex-officio)
Dr. V. Hernández, Madrid (ES)
Dr. M. Bruins, Nijmegen (NL)
Clinical guidelines development is one of the core activities of the European Association of Urology (EAU), with
the 2017 Guidelines covering the majority of the urological field. The EAU clinical guidelines, which are updated
based on systematic reviews of the available clinical evidence, are developed to support clinicians in making
informed decisions in their care of patients.
The Guidelines Office (GO), consisting of more than 300 clinicians, is responsible for the production of these
documents. Their efforts are supported by a number of expert Committees, each with specific tasks and
responsibilities.
Independently of these SRs, each Guideline Panel has undertaken a separate systematic search, tailored to
their individual guideline. These are broad searches (Scope/Horizon searches) which are developed to:
• ensure that the available clinical evidence is identified in a structured unbiased fashion;
• ensure that significant data are not missed;
• inform on the need to update guidelines documents;
• identify gaps in the literature and prioritise future systematic review activities.
The results of these searches are selected and assessed in a structured fashion by Guideline Associates
and Guideline Panel members, although no detailed evidence summaries are produced.The search histories
are available online in the Appendices and Publications sections of each guideline topic (www.uroweb.org/
guidelines/).
To allow for a transparent assessment of how recommendation statements have been developed, a Summary
of Evidence (SOE) table will be provided for each recommendation within the guidelines which will address a
number of key elements:
1. The overall quality of the evidence which exists for the recommendation;
2. The magnitude of the effect (individual or combined effects);
3. The certainty of the results (precision, consistency, heterogeneity and other statistical or study related
factors);
4. The balance between desirable and undesirable outcomes;
5. The impact of patient values and preferences on the intervention;
6. The certainty of those patient values and preferences.
These key elements in the SOE tables are the basis which panels use to define the strength of each
recommendation. The strength of each recommendation will no longer be represented by alphabetic
characters, but rather by the words ‘strong’ or ‘weak’ [9]. The panels will provide both ‘strong’ and ‘weak’
recommendations ‘for’ or ‘against’ recommending an action based on the information found in the SOE tables.
The strength of each recommendation is determined by the balance between desirable and undesirable
consequences of alternative management strategies, the quality of the evidence (including certainty of
estimates), and nature and variability of patient values and preferences.
References
1. Atkins, D., et al. Grading quality of evidence and strength of recommendations. BMJ, 2004. 328: 1490.
2. Guyatt, G., et al. Grading strength of recommendations and quality of evidence in clinical guidelines: report from an
american college of chest physicians task force. Chest, 2006. 129: 174.
3. Guyatt, G.H., et al. What is "quality of evidence" and why is it important to clinicians? BMJ, 2008. 336: 995.
4. Guyatt, G.H., et al. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations.
BMJ, 2008. 336: 924.
5. Moher, D., et al. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. J Clin
Epidemiol, 2009. 62: 1006.
Furthermore, the EAU Guidelines Office is most grateful for the continued support of the European Board of
Urology.
Associates:
Mr. R. Robinson, Manchester (UK)
Associates:
Dr. S. Goonewarde, London (UK)
Dr. B. Parsons, London (UK)
Associates:
Dr. R. Boissier, Marseille (FR)
Dr. C. Fraser Taylor, London (UK)
Dr. V. Hevia, Madrid (ES)
Dr. R.H. Zakri, Folkestone (UK)
Reviewers were identified based on their expert knowledge within the urological field and bordering specialities.
The EAU Guidelines Office Board is most grateful for their time and diligence in providing complete and
extensive reviews of the individual EAU Guidelines. Whenever feasible, feedback from lay reviewers and patient
advocacy groups has been sought.
Prostate Cancer
Testicular Cancer
Penile Cancer
Urinary Incontinence
Neuro-Urology
Male Infertility
Male Hypogonadism
Urological Infections
Urolithiasis
Paediatric Urology
Urological Trauma
Renal Transplantation
Thromboprophylaxis
Abbreviations
EAU Guidelines on
Non-muscle-invasive
Bladder Cancer
(TaT1 and CIS)
M. Babjuk (Chair), M. Burger (Vice-Chair), E. Compérat,
P. Gontero, A.H. Mostafid, J. Palou, B.W.G. van Rhijn,
M. Rouprêt, S.F. Shariat, R. Sylvester, R. Zigeuner
Guidelines Associates: O. Capoun, D. Cohen,
V. Hernández, V. Soukup
2. METHODS 6
2.1 Data Identification 6
2.2 Review 6
2.3 Future goals 6
5. DIAGNOSIS 10
5.1 Patient history 10
5.2 Signs and symptoms 10
5.3 Physical examination 10
5.4 Imaging 10
5.4.1 Computed tomography urography and intravenous urography 10
5.4.2 Ultrasound (US) 10
5.5 Urinary cytology 11
5.6 Urinary molecular marker tests 11
5.7 Potential application of urinary cytology and markers 11
5.7.1 Screening of the population at risk of bladder cancer 11
5.7.2 Exploration of patients after haematuria or other symptoms
suggestive of bladder cancer (primary detection) 12
5.7.3 Surveillance of non-muscle-invasive bladder cancer 12
5.7.3.1 Follow-up of high-risk non-muscle-invasive bladder cancer 12
5.7.3.2 Follow-up of low/intermediate-risk non-muscle-invasive
bladder cancer 12
5.8 Cystoscopy 12
5.9 Summary of evidence and recommendations for the primary
assessment of non-muscle-invasive bladder cancer 13
5.10 Transurethral resection of TaT1 bladder tumours 13
5.10.1 Strategy of the procedure 13
5.10.2 Surgical and technical aspects of tumour resection 13
5.10.2.1 Surgical strategy of resection 13
5.10.2.2 Evaluation of resection quality 13
5.10.2.3 Monopolar and bipolar resection 13
5.10.2.4 Office-based fulguration and laser vaporisation 13
5.10.2.5 Resection of small papillary bladder tumours at the time
of transurethral resection of the prostate 14
2 NON-MUSCLE-INVASIVE BLADDER CANCER (TAT1 AND CIS) - LIMITED UPDATE MARCH 2017
5.10.3 Bladder and prostatic urethral biopsies and incidental papillary tumours
during transurethral resection of the prostate 14
5.11 New methods of tumour visualisation 14
5.11.1 Photodynamic diagnosis (fluorescence cystoscopy) 14
5.11.2 Narrow-band imaging 14
5.12 Second resection 15
5.13 Pathology report 15
5.14 Summary of evidence and recommendations for transurethral
resection of the bladder, biopsies and pathology report 15
7. DISEASE MANAGEMENT 20
7.1 Counselling of smoking cessation 20
7.2 Adjuvant treatment 20
7.2.1 Intravesical chemotherapy 20
7.2.1.1 A single, immediate, post-operative intravesical
instillation of chemotherapy 20
7.2.1.2 Additional adjuvant intravesical chemotherapy instillations 20
7.2.1.3 Options for improving efficacy of intravesical chemotherapy 21
7.2.1.3.1 Adjustment of pH, duration of instillation,
and drug concentration 21
7.2.1.3.2 Device-assisted intravesical chemotherapy 21
7.2.1.4 Summary of evidence - intravesical chemotherapy 21
7.2.2 Intravesical BCG immunotherapy 21
7.2.2.1 Efficacy of BCG 21
7.2.2.2 BCG strain 22
7.2.2.3 BCG toxicity 22
7.2.2.4 Optimal BCG schedule 23
7.2.2.5 Optimal dose of BCG 24
7.2.2.6 Indications for BCG 24
7.2.2.7 Summary of evidence - BCG treatment 24
7.2.3 Combination therapy 24
7.2.4 Specific aspects of treatment of Carcinoma in situ 24
7.2.4.1 Treatment strategy 24
7.2.4.2 Cohort studies on intravesical BCG or chemotherapy 25
7.2.4.3 Prospective randomised trials on intravesical BCG or chemotherapy 25
7.2.4.4 Treatment of CIS in prostatic urethra and upper urinary tract 25
7.2.4.5 Summary of evidence – treatment of carcinoma in situ 25
7.3 Treatment of failure of intravesical therapy 27
7.3.1 Failure of intravesical chemotherapy 27
7.3.2 Recurrence and failure after intravesical BCG immunotherapy 27
7.3.3 Treatment of BCG failure and recurrences after BCG 27
7.3.4 Summary of evidence - treatment failure of intravesical therapy 27
7.4 Radical cystectomy for NMIBC 28
7.5 Recommendations for adjuvant therapy in TaT1 tumours and for therapy
of carcinoma in situ 29
7.6 Treatment recommendations in TaT1 tumours and carcinoma in situ
according to risk stratification 30
7.7 Treatment recommendations for BCG failure and recurrences
after BCG 30
NON-MUSCLE-INVASIVE BLADDER CANCER (TAT1 AND CIS) - LIMITED UPDATE MARCH 2017 3
8. FOLLOW-UP OF PATIENTS WITH NON-MUSCLE-INVASIVE BLADDER CANCER 30
8.1 Summary of evidence and recommendations for follow-up of patients after
transurethral resection of the bladder for non-muscle-invasive bladder cancer 31
9. REFERENCES 32
4 NON-MUSCLE-INVASIVE BLADDER CANCER (TAT1 AND CIS) - LIMITED UPDATE MARCH 2017
1. INTRODUCTION
1.1 Aim and scope
This overview represents the updated European Association of Urology (EAU) guidelines for Non-muscle-
invasive Bladder Cancer (NMIBC), TaT1 and carcinoma in situ (CIS). The information presented is limited to
urothelial carcinoma, unless specified otherwise. The aim is to provide practical recommendations on the
clinical management of NMIBC with a focus on clinical presentation and recommendations.
Separate EAU guidelines documents are available addressing upper tract urothelial carcinoma
(UTUC) [1], muscle-invasive and metastatic bladder cancer (MIBC) [2], and primary urethral carcinoma [3]. It
must be emphasised that clinical guidelines present the best evidence available to the experts, but following
guideline recommendations will not necessarily result in the best outcome. Guidelines can never replace
clinical expertise when making treatment decisions for individual patients, but rather help to focus decisions -
also taking personal values and preferences/individual circumstances of patients into account. Guidelines are
not mandates and do not purport to be a legal standard of care.
Changes in recommendations
NON-MUSCLE-INVASIVE BLADDER CANCER (TAT1 AND CIS) - LIMITED UPDATE MARCH 2017 5
Section 5.14: Additional information has been included.
Recommendations for transurethral resection of the bladder (TURB) and/or biopsies and
pathology report
Perform en-block resection or resection in fractions (exophytic part of the tumour, the underlying B
bladder wall and the edges of the resection area). The presence of detrusor muscle in the specimen is
required in all cases except for TaG1/LG tumours.
Perform a second TURB in the following situations: A
• after (suspicion of) incomplete initial TURB (in the case of any doubt about completeness of a
TURB);
• if there is no muscle in the specimen after initial resection, with exception of TaLG/G1 tumours
and primary CIS;
• In T1 tumours.
Register the results of a second TURB as it reflects the quality of the initial resection. A
Recommendations for adjuvant therapy in TaT1 tumours and for therapy of CIS GR
In patients with bacillus Calmette-Guérin failure, who are not candidates of radical cystectomy due to C
comorbidities, use preservation strategies (device-assisted instillations of chemotherapy, intravesical
chemotherapy, intravesical immunotherapy).
Recommendations for follow-up of patients after transurethral resection of the bladder for GR
NMIBC
In patients initially diagnosed with TaLG/G1-2 bladder cancer, use ultrasound of the bladder during C
surveillance in case cystoscopy is not possible, or refused by the patient.
2. METHODS
2.1 Data Identification
For the 2017 NMIBC Guidelines, new and relevant evidence has been identified, collated and appraised
through a structured assessment of the literature.
A broad and comprehensive scoping exercise covering all areas of the NMIBC Guidelines was
performed. Excluded from the search were basic research studies, case series, reports and editorial comments.
Only articles published in the English language, addressing adults, were included. The search was restricted
to articles published between June 1st 2015 and April 22nd 2016. Databases covered by the search included
Pubmed, Ovid, EMBASE and the Cochrane Central Register of Controlled Trials and the Cochrane Database of
Systematic Reviews. After deduplication, a total of 973 unique records were identified, retrieved and screened
for relevance. A detailed search strategy is available on line:
https://uroweb.org/guideline/non-muscle-invasive-bladder-cancer/?type=appendices-publications.
Recommendations in this text are assessed according to their level of evidence (LE) and Guidelines are given
a grade of recommendation (GR), according to a classification system modified from the Oxford Centre for
Evidence-Based Medicine Levels of Evidence [5]. Additional methodology information can be found in the
general Methodology section of this print, and online at the EAU website: http://uroweb.org/guidelines/. A list of
Associations endorsing the EAU Guidelines can also be viewed on line at the above address.
2.2 Review
Chapter 7, Disease Management was peer reviewed prior to publication in 2016. All other chapters of the
NMIBC Guidelines were peer-reviewed in 2015.
3.2 Aetiology
Tobacco smoking is the most important risk factor for BC, accounting for approximately 50% of cases
[8, 9, 11] (LE: 3). Tobacco smoke contains aromatic amines and polycyclic aromatic hydrocarbons, which are
renally excreted.
Occupational exposure to aromatic amines, polycyclic aromatic hydrocarbons and chlorinated
hydrocarbons is the second most important risk factor for BC, accounting for about 10% of all cases. This type
of occupational exposure occurs mainly in industrial plants, which process paint, dye, metal and petroleum
products [8, 9, 12, 13]. In developed industrial settings, these risks have been reduced by work-safety
guidelines, therefore, chemical workers no longer have a higher incidence of BC compared to the general
population [8, 12, 13].
While family history seems to have little impact [14] and, to date, no overt significance of any
genetic variation for BC has been shown, genetic predisposition has an influence on the incidence of BC via its
impact on susceptibility to other risk factors [8, 15, 16].
Although the significance of fluid intake is uncertain, the chlorination of drinking water and
subsequent levels of trihalomethanes are potentially carcinogenic, also exposure to arsenic in drinking water
increases risk [8, 17] (LE: 3). The association between personal hair dye use and risk remains uncertain; an
increased risk has been suggested in users of permanent hair dyes with a slow NAT2 acetylation phenotype [8].
Dietary habits seem to have little impact [18-20].
Exposure to ionizing radiation is connected with increased risk; weak association was also
suggested for cyclophosphamide and pioglitazone [8, 17] (LE: 3). Schistosomiasis, a chronic endemic cystitis
based on recurrent infection with a parasitic trematode, is also a cause of BC [8] (LE: 3).
3.3 Pathology
The information presented in this text is limited to urothelial carcinoma, unless otherwise specified.
Summary of evidence LE
Worldwide, bladder cancer is the eleventh most commonly diagnosed cancer. 2a
Several risk factors connected with the risk of bladder cancer diagnosis have been identified. 3
NON-MUSCLE-INVASIVE BLADDER CANCER (TAT1 AND CIS) - LIMITED UPDATE MARCH 2017 7
4. STAGING AND CLASSIFICATION SYSTEMS
4.1 Definition of non-muscle-invasive bladder cancer
Papillary tumours confined to the mucosa and invading the lamina propria are classified as stage Ta and
T1, respectively, according to the Tumour, Node, Metastasis (TNM) classification system [21]. Flat, high-
grade tumours that are confined to the mucosa are classified as CIS (Tis). These tumours can be treated by
transurethral resection of the bladder (TURB), eventually in combination with intravesical instillations and
are therefore grouped under the heading of NMIBC for therapeutic purposes. However, molecular biology
techniques and clinical experience have demonstrated the highly malignant potential of CIS and T1 lesions as
compared to Ta lesions. The terms “NMIBC” and “superficial BC” are therefore suboptimal descriptions.
T - Primary tumour
TX Primary tumour cannot be assessed
T0 No evidence of primary tumour
Ta Non-invasive papillary carcinoma
Tis Carcinoma in situ: ‘flat tumour’
T1 Tumour invades subepithelial connective tissue
T2 Tumour invades muscle
T2a Tumour invades superficial muscle (inner half)
T2b Tumour invades deep muscle (outer half)
T3 Tumour invades perivesical tissue
T3a Microscopically
T3b Macroscopically (extravesical mass)
T4 Tumour invades any of the following: prostate stroma, seminal vesicles, uterus, vagina, pelvic wall,
abdominal wall
T4a Tumour invades prostate stroma, seminal vesicles, uterus or vagina
T4b Tumour invades pelvic wall or abdominal wall
N – Regional lymph nodes
NX Regional lymph nodes cannot be assessed
N0 No regional lymph node metastasis
N1 Metastasis in a single lymph node in the true pelvis (hypogastric, obturator, external iliac, or presacral)
N2 Metastasis in multiple regional lymph nodes in the true pelvis (hypogastric, obturator, external iliac, or
presacral)
N3 Metastasis in common iliac lymph node(s)
M - Distant metastasis
M0 No distant metastasis
M1a Non-regional lymph nodes
M1b Other distant metastases
4.3 T1 subclassification
The depth and extent of invasion into the lamina propria (T1 substaging) has been demonstrated to be of
prognostic value in retrospective cohort studies [22, 23] (LE: 3). Its use is recommended by the most recent
2016 World Health Organization (WHO) classification [24]. The optimal system to substage T1 remains to be
defined.
8 NON-MUSCLE-INVASIVE BLADDER CANCER (TAT1 AND CIS) - LIMITED UPDATE MARCH 2017
Table 4.2: WHO grading in 1973 and in 2004 [25, 26]
The prognostic value of both WHO 1973 and 2004 grading systems has been confirmed. Attempts to
demonstrate better prognostic value of one over the other, however, have yielded controversial results [27-29].
(LE: 2a). Moreover, the 2004 WHO system have not been fully incorporated into prognostic models yet.
Figure 4.1: Stratification of tumours according to grade in the WHO 1973 and 2004 classifications [30]*
• Urothelial proliferation of uncertain malignant potential (flat lesion without atypia or papillary aspects).
• Reactive atypia (flat lesion with atypia).
• Atypia of unknown significance.
• Urothelial dysplasia.
• Urothelial CIS is always high grade.
NON-MUSCLE-INVASIVE BLADDER CANCER (TAT1 AND CIS) - LIMITED UPDATE MARCH 2017 9
4.7 Further pathology parameters
According to a meta-analysis of retrospective trials, the presence of lymphovascular invasion (LVI) in TURB
specimens is connected with an increased risk of pathological upstaging [38] (LE: 3). Lymphovascular invasion
has been reported as an unfavourable prognostic factor in T1 tumours [38] (LE: 3). Some variants of urothelial
carcinoma (micropapillary, plasmocytoid, nested, sarcomatoid, microcystic, squamous and adeno variants,
have a worse prognosis than classical urothelial carcinoma [2, 39-46] (LE: 3).
Molecular markers, particularly FGFR3 mutation status, are promising but need further validation
[47-51].
Summary of evidence LE
The depth of invasion (staging) is classified according to the TNM classification. 2a
Papillary tumours confined to the mucosa and invading the lamina propria are classified as stage Ta 2a
and T1, respectively. Flat, high-grade tumours that are confined to the mucosa are classified as CIS
(Tis).
T1 and CIS, as compared to Ta, have high malignant potential, the term non-muscle-invasive bladder 3
cancer (NMIBC) is therefore a suboptimal description.
For histological classification of NMIBC, both the WHO 1973 and 2004 grading systems are used. 2a
Recommendations GR
Use the 2017 TNM system for classification of the depth of tumour invasion (staging). A
Use both the 1973 and 2004/2016 WHO grading systems for histological classification. A
Do not use the term “superficial bladder cancer”. A
Mention the tumour stage and grade whenever the terminology NMIBC is used in individual cases. A
5. DIAGNOSIS
5.1 Patient history
A comprehensive patient history is mandatory.
5.4 Imaging
5.4.1 Computed tomography urography and intravenous urography
Computed tomography (CT) urography is used to detect papillary tumours in the urinary tract, indicated by
filling defects or hydronephrosis.
Intravenous urography (IVU) is an alternative if CT is not available [53] (LE: 3), but particularly
in muscle-invasive tumours of the bladder and in UTUCs, CT urography gives more information than IVU
(including status of lymph nodes and neighbouring organs).
The necessity to perform a baseline CT urography or IVU once a bladder tumour has been detected
is questionable due to the low incidence of significant findings obtained [54-56] (LE: 2a). The incidence of
UTUCs is low (1.8%), but increases to 7.5% in tumours located in the trigone [55] (LE: 2b). The risk of UTUC
during follow up increases in patients with multiple- and high-risk tumours [57] (LE: 3).
10 NON-MUSCLE-INVASIVE BLADDER CANCER (TAT1 AND CIS) - LIMITED UPDATE MARCH 2017
The diagnosis of CIS cannot be made with imaging methods (CT urography, IVU or US) (LE: 4).
A standardised reporting system redefining urinary cytology diagnostic categories was published in 2016 by
the Paris Working Group [62]:
• Adequacy of urine specimens (Adequacy);
• Negative for high-grade urothelial carcinoma (Negative);
• Atypical urothelial cells (AUC);
• Suspicious for high-grade urothelial carcinoma (Suspicious);
• High-grade urothelial carcinoma (HGUC);
• Low-grade urothelial neoplasia (LGUN).
Urine collection should respect the recommendation provided in Section 5.9. One cytospin slide from the
sample is usually sufficient [63]. In patients with suspicious cytology repeat investigation is advised [64] (LE: 3).
NON-MUSCLE-INVASIVE BLADDER CANCER (TAT1 AND CIS) - LIMITED UPDATE MARCH 2017 11
reported [79]. The low incidence of BC in the general population and the short lead-time impair feasibility and
cost-effectiveness [77, 79]. Routine screening for BC is not recommended [80].
5.7.2 Exploration of patients after haematuria or other symptoms suggestive of bladder cancer
(primary detection)
It is generally accepted that none of the currently available tests can replace cystoscopy. However, urinary
cytology or markers can be used as an adjunct to cystoscopy to detect invisible tumours, particularly CIS. In
this setting, sensitivity for high-grade tumours and specificity are particularly important. Urinary cytology is
highly specific, but urinary markers lack such high specificity and are not recommended for primary detection.
5.8 Cystoscopy
The diagnosis of papillary BC ultimately depends on cystoscopic examination of the bladder and histological
evaluation of sampled tissue by either cold-cup biopsy or resection. Carcinoma in situ is diagnosed by a
combination of cystoscopy, urine cytology, and histological evaluation of multiple bladder biopsies [84].
Cystoscopy is initially performed as an outpatient procedure. A flexible instrument with topical intra-urethral
anaesthetic lubricant instillation results in better compliance compared to a rigid instrument, especially in men
[85].
12 NON-MUSCLE-INVASIVE BLADDER CANCER (TAT1 AND CIS) - LIMITED UPDATE MARCH 2017
5.9 Summary of evidence and recommendations for the primary assessment of
non-muscle-invasive bladder cancer
Summary of evidence LE
The diagnosis of bladder cancer depends on cystoscopy examination. 1
Urinary cytology has high sensitivity in high-grade tumours including carcinoma in situ. 2b
Recommendations GR
Take a patient history. A
Renal and bladder ultrasound may be used during the initial work-up in patients with haematuria. C
At the time of the initial diagnosis of non-muscle-invasive bladder cancer (NMIBC), perform computed B
tomography urography (or intravenous urography [IVU]) in selected cases (e.g., tumours located in the
trigone, multiple or high-risk tumours).
Perform cystoscopy in all patients with symptoms suggestive of bladder cancer. It cannot be replaced A
by cytology or by any other non-invasive test.
Cystoscopy should describe all macroscopic features of the tumour (site, size, number and C
appearance) and mucosal abnormalities. A bladder diagram is recommended (see Figure 5.1).
Voided urine cytology is advocated as an adjunct to cystoscopy to detect high-grade tumour. C
Perform cystoscopy on fresh urine with adequate fixation. Morning urine is not suitable because of the C
frequent presence of cytolysis.
Repeat urine cytology in patients with suspicious initial cytology results. C
NON-MUSCLE-INVASIVE BLADDER CANCER (TAT1 AND CIS) - LIMITED UPDATE MARCH 2017 13
5.10.2.5 Resection of small papillary bladder tumours at the time of transurethral resection of the prostate
(TURP)
Only limited, retrospective, data exist on the outcome of incidentally detected papillary bladder tumour during
cystoscopy as the initial step of TURP. Provided these tumours are papillary by aspect, rather small and
not extensively multifocal, it seems feasible to resect these tumours and continue with the resection of the
prostate. However, no exact risk-assessment can be provided [100, 101].
5.10.3 Bladder and prostatic urethral biopsies and incidental papillary tumours during transurethral
resection of the prostate
Carcinoma in situ can present as a velvet-like, reddish, area indistinguishable from inflammation, or it may not
be visible at all. For this reason, the strategy of taking biopsies from abnormal urothelium and biopsies from
normal-looking mucosa (random/mapping biopsies) is recommended (see Section 5.14). The indication for
random biopsies reflects the very low likelihood of detecting CIS, especially in low-risk tumours (< 2%) [102]
(LE: 2a). The risk increases in patients with high-risk tumours and with positive cytology [103].
If equipment is available, photodynamic diagnosis (PDD) is a useful tool to target the biopsy (see
Section 5.11.1).
Involvement of the prostatic urethra and ducts in men with NMIBC has been reported. Palou et
al. [104] showed that in 128 men with T1G3 BC, the incidence of CIS in the prostatic urethra was 11.7% (LE:
2b). The risk of prostatic urethra or duct involvement is higher if the tumour is located at the trigone or bladder
neck, in the presence of bladder CIS and multiple tumours [105] (LE: 3). Based on this observation, a biopsy
from the prostatic urethra is necessary in some cases (see recommendation in Section 5.14) [104, 106].
14 NON-MUSCLE-INVASIVE BLADDER CANCER (TAT1 AND CIS) - LIMITED UPDATE MARCH 2017
5.12 Second resection
The significant risk of residual tumour after initial TURB of TaT1 lesions has been demonstrated [86] (LE: 2a).
Persistent disease after resection of T1 tumours has been observed in 33-55% of patients, after resection
of TaG3 tumour in 41.4% [121-124]. Moreover, the tumour is often understaged in the initial resection. The
likelihood that muscle-invasive disease is detected by second resection of initially T1 tumour ranges from 1.3-
25%, and increases to 45% if there was no muscle in the initial resection [109, 125-128]. This risk increased to
50% in some radical cystectomy (RC) series, although these studies only enrolled selected patients [129-131]
(LE: 2a). Treatment of a TaT1 high-grade tumour and a T2 tumour is completely different; correct staging is
therefore important. It has been demonstrated that a second TURB can increase recurrence-free survival [121,
122] (LE: 2a), improve outcomes after BCG treatment [132] (LE: 3) and provide prognostic information [127,
129, 133] (LE: 3).
In a retrospective evaluation of a large multi-institutional cohort of 2,451 patients with BCG-
treated T1G3/HG tumours (second resection was performed in 935 patients), the second resection improved
recurrence-free survival (RFS), progression-free survival (PFS) and overall survival (OS) only in patients without
muscle in the specimen from initial resection [134] (LE:3).
Retrospective evaluation showed that a second resection performed 14-42 days after initial resection provides
longer RFS and PFS comparing to second resection performed after 43-90 days [135] (LE:3). Based on
these arguments, a second TURB is recommended in selected cases two-six weeks after initial resection (for
recommendations on patient selection, see Section 5.14).
The results of the second resection (residual tumours and understaging) reflect the quality of the
initial TURB. As the goal is to improve the quality of the initial TURB, the results of the second resection should
be recorded.
Summary of evidence LE
Transurethral resection of the bladder (TURB) followed by pathology investigation of the obtained 1
specimen(s) is an essential step in the treatment of NMIBC.
The absence of detrusor muscle in the specimen is associated with a significantly higher risk of 2b
residual disease and tumour understaging.
In patients with a history of small, TaLG/G1 tumours, fulguration of small papillary recurrences on an 3
outpatient basis is feasible and safe.
A second TURB can detect residual tumours and tumour understaging, increase recurrence-free 2
survival, improve outcomes after BCG treatment and provide prognostic information.
Recommendations GR
In patients suspected of having bladder cancer, perform a TURB followed by pathology investigation A
of the obtained specimen(s) as a diagnostic procedure and initial treatment step.
Perform TURB systematically in individual steps: C
• bimanual palpation under anaesthesia;
• insertion of the resectoscope, under visual control with inspection of the whole urethra;
• inspection of the whole urothelial lining of the bladder;
• biopsy from the prostatic urethra (if indicated);
• cold-cup bladder biopsies (if indicated);
• resection of the tumour;
• recording of findings in the surgery report/record;
• precise description of the specimen for pathology evaluation.
NON-MUSCLE-INVASIVE BLADDER CANCER (TAT1 AND CIS) - LIMITED UPDATE MARCH 2017 15
Performance of individual steps
Perform en-block resection or resection in fractions (exophytic part of the tumour, the underlying B
bladder wall and the edges of the resection area). The presence of detrusor muscle in the specimen is
required in all cases except for TaG1/LG tumours.
Avoid cauterisation as much as possible during TURB to avoid tissue deterioration. C
Take biopsies from abnormal-looking urothelium. Biopsies from normal-looking mucosa (trigone, B
bladder dome, and right, left, anterior and posterior bladder wall) are recommended when cytology is
positive or when high-risk exophytic tumour is expected (non-papillary appearance). If equipment is
available, perform fluorescence-guided (PDD) biopsies.
Take biopsy of the prostatic urethra in cases of bladder neck tumour, when bladder carcinoma in situ C
is present or suspected, when there is positive cytology without evidence of tumour in the bladder,
or when abnormalities of the prostatic urethra are visible. If biopsy is not performed during the initial
procedure, it should be completed at the time of the second resection.
Take the biopsy from abnormal areas in the prostatic urethra and from the precollicular area (between C
the 5 and 7 o’clock position) using a resection loop. In primary non-muscle-invasive tumours when
stromal invasion is not suspected, cold-cup biopsy with forceps can be used.
Refer the specimens from different biopsies and resection fractions to the pathologist in separate C
containers and label them separately.
The TURB protocol must describe tumour appearance, all steps of the procedure, as well as the C
extent and completeness of resection.
In patients with positive cytology, but negative cystoscopy, exclude an upper tract urothelial C
carcinoma, CIS in the bladder (random biopsies or PDD-guided biopsies) and tumour in the prostatic
urethra (prostatic urethra biopsy).
Perform a second TURB in the following situations: A
• after (suspicion of) incomplete initial TURB (in the case of any doubt about completeness of a
TURB);
• if there is no muscle in the specimen after initial resection, with the exception of TaLG/G1 tumours
and primary CIS;
• in T1 tumours.
If indicated, perform a second TURB within two-six weeks after initial resection. This second TURB C
should include resection of the primary tumour site.
Register the results of a second TURB as it reflects the quality of the initial resection. A
Inform the pathologist of prior treatments (intravesical therapy, radiotherapy, etc.). A
Pathological report
The pathological report should specify tumour location, tumour grade, depth of tumour invasion, A
presence of CIS, and whether the detrusor muscle is present in the specimen.
The pathological report should specify the presence of lymphovascular invasion or unusual (variant) C
histology.
In difficult cases, consider an additional review by an experienced genitourinary pathologist. B
16 NON-MUSCLE-INVASIVE BLADDER CANCER (TAT1 AND CIS) - LIMITED UPDATE MARCH 2017
6. PREDICTING DISEASE RECURRENCE AND
PROGRESSION
6.1 TaT1 tumours
In order to predict, separately, the short- and long-term risks of disease recurrence and progression in
individual patients, the EORTC Genito-Urinary Cancer Group has developed a scoring system and risk tables
[137]. The basis for these tables are individual patient data from 2,596 patients diagnosed with TaT1 tumours,
who were randomised into seven EORTC trials. Patients with CIS alone were not included. Seventy-eight
percent of patients received intravesical treatment, mostly chemotherapy. However, they did not undergo a
second TURB or receive maintenance BCG.
The scoring system is based on the six most significant clinical and pathological factors which are
shown in Table 6.1. It also illustrates the weights applied to various factors for calculating the total scores for
recurrence and progression. Table 6.2 shows the total scores stratified, into four categories that reflect various
probabilities of recurrence and progression at one and five years [137] (LE: 2a).
Table 6.1: Weighting used to calculate disease recurrence and progression scores
Table 6.2: Probability of recurrence and disease progression according to total score
NON-MUSCLE-INVASIVE BLADDER CANCER (TAT1 AND CIS) - LIMITED UPDATE MARCH 2017 17
Progression score Probability of Probability of progression at 5 years
progression at 1 year
% (95% CI) % (95% CI)
0 0.2 (0-0.7) 0.8 (0-1.7)
2-6 1 (0.4-1.6) 6 (5-8)
7-13 5 (4-7) 17 (14-20)
14-23 17 (10-24) 45 (35-55)
NB: Electronic calculators for Tables 6.1 and 6.2, which have been updated for the Apple and Android
phones and tablets, are available at http://www.eortc.be/tools/bladdercalculator/.
A scoring model for BCG-treated patients that predicts the short- and long-term risks of recurrence and
progression has been published by the Club Urológico Español de Tratamiento Oncológico (CUETO) (Spanish
Urological Oncology Group). It is based on an analysis of 1,062 patients from four CUETO trials that compared
different intravesical BCG treatments. Patients received twelve instillations over five to six months. No
immediate post-operative instillation or second TURB was performed in these patients. The scoring system is
based on the evaluation of seven prognostic factors:
• gender;
• age;
• prior recurrence status;
• number of tumours;
• T category;
• associated CIS;
• tumour grade.
Using these tables, the calculated risk of recurrence is lower than that obtained by the EORTC tables. For
progression, probability is lower only in high-risk patients [138] (LE: 2a). The lower risks in the CUETO tables
may be attributed to the use of BCG in this sample, which is a more effective instillation therapy. The CUETO
risk calculator is available at: http://www.aeu.es/Cueto.html.
The prognostic value of the EORTC scoring system has been confirmed by data from the CUETO
patients treated with BCG and by long-term follow up in an independent patient population [139, 140] (LE: 2a).
In 1,812 intermediate- and high-risk patients without CIS treated with one to three years of maintenance BCG,
the EORTC found that the prior disease-recurrence rate and number of tumours were the most important
prognostic factors for disease recurrence, stage and grade were the most important prognostic factors for
disease progression and disease-specific survival, while age and grade were the most important prognostic
factors for OS. T1G3 patients do poorly, with one- and five-year disease-progression rates of 11.4% and
19.8%, respectively. Using these data the new EORTC risk groups and nomograms for BCG treated patients
were designed [141] (LE: 2a).
18 NON-MUSCLE-INVASIVE BLADDER CANCER (TAT1 AND CIS) - LIMITED UPDATE MARCH 2017
The response to intravesical treatment with BCG or chemotherapy is an important prognostic factor
for subsequent progression and death caused by BC [138-140, 144]. Approximately 10-20% of complete
responders eventually progress to muscle-invasive disease, compared with 66% of non-responders [150, 151]
(LE: 2a).
Summary of evidence LE
The EORTC scoring system and risk tables predict the short- and long-term risks of disease 2a
recurrence and progression in individual patients with non-muscle-invasive bladder cancer (NMIBC).
In patients treated with BCG, the CUETO scoring model predicts the short- and long-term risks of 2a
disease recurrence and progression.
In patients receiving BCG maintenance: prior recurrence rate and number of tumours are the most 2a
important prognostic factors for disease recurrence.
Stage and grade are the most important prognostic factors for disease progression and disease 2a
specific survival.
Patient age and grade are the most important prognostic factors for overall survival. 2a
NON-MUSCLE-INVASIVE BLADDER CANCER (TAT1 AND CIS) - LIMITED UPDATE MARCH 2017 19
Recommendations GR
Stratify patients into three risk groups according to Table 6.3. B
Apply the EORTC risk tables and calculator for the prediction of the risk of tumour recurrence and B
progression in different intervals after transurethral resection of the bladder, in individual patients.
Use the CUETO risk tables and the new EORTC risk groups for the prediction of the risk of tumour B
recurrence and progression in individual patients treated with bacillus Calmette-Guérin.
7. DISEASE MANAGEMENT
7.1 Counselling of smoking cessation
It has been confirmed that smoking increases the risk of tumour recurrence and progression [152, 153] (LE:
3). While it is still controversial whether smoking cessation in BC will favourably influence the outcome of BC
treatment, patients should be counselled to stop smoking due to the general risks connected with tobacco
smoking [154-157] (LE: 3).
20 NON-MUSCLE-INVASIVE BLADDER CANCER (TAT1 AND CIS) - LIMITED UPDATE MARCH 2017
corresponds to an absolute difference of 13-14% in the number of patients with recurrence. Contrary to these
findings, two meta-analyses have demonstrated that BCG therapy may reduce the risk of tumour progression
[175, 176] (LE: 1a) (see Section 7.2.2.1). Moreover, BCG maintenance therapy appears to be significantly better
in preventing recurrences than chemotherapy [177-179] (see Section 7.2.2.1) (LE: 1a). However, BCG causes
significantly more side effects than chemotherapy [179] (LE: 1a).
The length and frequency of chemotherapy instillations is still controversial. A systematic review
of RCTs, comparing different schedules of intravesical chemotherapy instillations, concluded that the ideal
duration and intensity of the schedule remains undefined because of conflicting data [172]. The available
evidence does not support treatment longer than one year (LE: 3).
Summary of evidence LE
In patients with non-muscle-invasive bladder cancer and a prior low recurrence rate (≤ to one 1a
recurrence per year) and in those with an EORTC recurrence score < 5, a single instillation (SI)
significantly reduces the recurrence rate compared to transurethral resection of the bladder alone.
In intermediate-risk patients, SI might have an impact on recurrence even when further adjuvant 3
instillations are given.
Further chemotherapy instillations after SI improve recurrence-free survival in intermediate-risk 2a
patients.
NON-MUSCLE-INVASIVE BLADDER CANCER (TAT1 AND CIS) - LIMITED UPDATE MARCH 2017 21
of 27% in the odds of progression with BCG maintenance treatment. The size of the reduction was similar
in patients with TaT1 papillary tumours and in those with CIS [176]. A recent RCT with long-term observation
has demonstrated significantly fewer distant metastases and better overall- and disease-specific survival in
patients treated with BCG compared to epirubicin [178] (LE: 1b). On the contrary, a meta-analysis of individual
patient data was not able to confirm any statistically significant difference between MMC and BCG for
progression, survival and cause of death [177].
The conflicting results in the outcomes of these studies can be explained by different patient
characteristics, duration of follow-up, methodology and statistical power. However, most studies showed a
reduction in the risk of progression in high- and intermediate-risk tumours if BCG was applied including a
maintenance schedule.
Two other meta-analyses have suggested a possible bias in favour of BCG arising from the inclusion
of patients previously treated with intravesical chemotherapy [192]. In the most recent meta-analysis, however,
BCG maintenance was more effective than MMC, both in patients previously treated and not previously treated
with chemotherapy [177] (LE: 1a). It was demonstrated that BCG was less effective in patients > 70 years of
age, but still more effective than epirubicin in a cohort of elderly patients [193] (LE: 1a).
22 NON-MUSCLE-INVASIVE BLADDER CANCER (TAT1 AND CIS) - LIMITED UPDATE MARCH 2017
Table 7.1: M
anagement options for side effects associated with intravesical bacillus Calmette-Guérin
(BCG) [206-209]
Management options for local side effects (modified from International Bladder Cancer Group)
Symptoms of cystitis Phenazopyridine, propantheline bromide, or non-steroidal anti-inflammatory drugs
(NSAIDs)
If symptoms improve within a few days: continue instillations
If symptoms persist or worsen:
a. Postpone the instillation
b. Perform a urine culture
c. Start empirical antibiotic treatment
If symptoms persist even with antibiotic treatment:
a. With positive culture: adjust antibiotic treatment according to sensitivity
b. With negative culture: quinolones and potentially analgesic anti-
inflammatory instillations once daily for 5 days (repeat cycle if necessary)
[207].
If symptoms persist: anti-tuberculosis drugs + corticosteroids.
If no response to treatment and/or contracted bladder: radical cystectomy.
Haematuria Perform urine culture to exclude haemorrhagic cystitis, if other symptoms present.
If haematuria persists, perform cystoscopy to evaluate presence of bladder tumour.
Symptomatic Symptoms rarely present: perform urine culture.
granulomatous Quinolones.
prostatitis If quinolones are not effective: isoniazid (300 mg/day) and rifampicin (600 mg/day)
for three months.
Cessation of intravesical therapy.
Epididymo-orchitis Perform urine culture and administer quinolones.
[208] Cessation of intravesical therapy.
Orchidectomy if abscess or no response to treatment.
Management options for systemic side effects
General malaise, fever Generally resolve within 48 hours, with or without antipyretics.
Arthralgia and/or Rare complication and considered autoimmune reaction.
arthritis Arthralgia: treatment with NSAIDs.
Arthritis: NSAIDs.
If no/partial response, proceed to corticosteroids, high-dose quinolones or anti-
tuberculosis drugs [209].
Persistent Permanent discontinuation of BCG instillations.
high-grade fever Immediate evaluation: urine culture, blood tests, chest X-ray.
(> 38.5°C for > 48 h) Prompt treatment with more than two antimicrobial agents while diagnostic
evaluation is conducted.
Consultation with an infectious diseases specialist.
BCG sepsis Prevention: initiate BCG at least 2 weeks post-transurethral resection of the bladder
(if no signs and symptoms of haematuria).
Cessation of BCG.
For severe infection:
• High-dose quinolones or isoniazid, rifampicin and ethambutol 1.2 g daily for 6
months.
• Early, high-dose corticosteroids as long as symptoms persist.
• Consider an empirical non-specific antibiotic to cover Gram-negative bacteria
and/or Enterococcus.
Allergic reactions Antihistamines and anti-inflammatory agents.
Consider high-dose quinolones or isoniazid and rifampicin for persistent symptoms.
Delay therapy until reactions resolve.
NON-MUSCLE-INVASIVE BLADDER CANCER (TAT1 AND CIS) - LIMITED UPDATE MARCH 2017 23
weeks to 27 over three years [211]. The EORTC meta-analysis was unable to determine which BCG
maintenance schedule was the most effective [176]. In their meta-analysis, Böhle et al. concluded that at least
one year of maintenance BCG is required to obtain superiority of BCG over MMC for prevention of recurrence
or progression [175] (LE: 1a).
The optimal number of induction instillations and the optimal frequency and duration of
maintenance instillations is not fully known. Moreover, it can be different in each individual patient [212]. In a
RCT of 1,355 patients, the EORTC has shown that when BCG is given at full dose, three years’ maintenance
(three-weekly instillations 3, 6, 12, 18, 24, 30 and 36 months) reduces the recurrence rate compared to one
year in high- but not in intermediate-risk patients. There were no differences in progression or OS. In the three-
year arm, however, 36.1% of patients did not complete the three-year schedule [213] (LE: 1b). In a RCT of 397
patients CUETO suggested that in high-risk tumours, the maintenance schedule with only one instillation every
three months for three years may be suboptimal [214] (LE: 1b).
Summary of evidence LE
In patients with intermediate- and high-risk tumours, intravesical bacillus Calmette-Guérin (BCG) 1a
after TURB reduces the risk of tumour recurrence; it is more effective than TURB alone or TURB +
intravesical chemotherapy.
For optimal efficacy, BCG must be given in a maintenance schedule. 1a
Three-year maintenance is more effective than one year to prevent recurrence in patients with high- 1a
risk tumours, but not in patients with intermediate-risk tumours.
24 NON-MUSCLE-INVASIVE BLADDER CANCER (TAT1 AND CIS) - LIMITED UPDATE MARCH 2017
situ must be followed by further treatment, either intravesical BCG instillations or RC (LE: 4). Tumour-specific-
survival rates after immediate RC for CIS are excellent, but as many as 40-50% of patients might be over
treated [146] (LE: 3).
Summary of evidence LE
Carcinoma in situ (CIS) cannot be cured by an endoscopic procedure alone. 4
Compared to intravesical chemotherapy, bacillus Calmette-Guérin treatment of CIS increases the 1b
complete response rate, the overall percentage of patients who remain disease free, and reduces the
risk of tumour progression.
NON-MUSCLE-INVASIVE BLADDER CANCER (TAT1 AND CIS) - LIMITED UPDATE MARCH 2017 25
Flowchart 7.1: Treatment strategy in primary or recurrent tumour(s) without previous BCG*
TURB
Incomplete resection or no muscle (except Macroscopically complete resection and Muscle invasive tumour
for monofocal TaG1/LG) or T1 or G3/HG TaG1-2/LG with muscle in the specimen or in
(except for primary CIS) TaG1/LG even without muscle or in primary CIS
Low-risk tumour (primary solitary Intermediate-risk tumour High-risk tumour (T1 or Tis or G3/HG
TaG1/LG < 3 cm) or multiple and recurrent and > 3 cm
TaG1-2/LG)
Cystoscopy (GR: A) at 3 mo Primary or recurrent tumour without previous chemotherapy: Highest-risk tumour (T1G3/HG+CIS,
Intravesical BCG for 1 yr (6 weekly and 3 weekly at 3, 6 and T1G3/HG+CIS in prostatic urethra,
If negative, cystoscopy (GR: A) at 12 12 mo) or intravesical chemotherapy for up to 12 mo (GR: A) multiple T1G3/HG, T1G3/HG > 3 cm,
mo and then yearly for 5 yr (GR: C) micropapillary variant)
Recurrent tumour with previous chemotherapy: Intravesical
BCG for 1 yr (6 weekly and 3 weekly at 3, 6 and 12 mo) (GR: A),
in late recurrence of small TaG1/LG consider repeating
Positive or suspect cystoscopy intravesical Chemotherapy
during follow-up
In all cases: Cystoscopy (GR: A) and cytology (GR: B) at 3 mo No Yes
If negative, cystoscopy and cytology at 3-6 mo intervals until
5 yr and then yearly (GR: C) Explain the risk and
consider radical cystectomy
Tiny Larger or
papillary non papilary
recurrence recurrence
Intravesical BCG for 1-3 yr (GR: A)
Office fulguration
or surveillance Positive cytology with no visible tumour
in the bladder during follow-up
Follow-up: TURB + biopsies from abnormal looking Re-check upper tract (GR: B)
cystoscopy (GR: A) mucosa (GR: B), bladder random
Schedule: biopsies if indicated* (GR: C), prostatic Bladder random biopsies (GR: B), prostatic urethra biopsy in men (GR: B),
individual (GR: C) urethra biopsy if indicated* (GR: C) if available use PDD (GR: B)
Consider
pathological report
26 NON-MUSCLE-INVASIVE BLADDER CANCER (TAT1 AND CIS) - LIMITED UPDATE MARCH 2017
7.3 Treatment of failure of intravesical therapy
7.3.1 Failure of intravesical chemotherapy
Patients with NMIBC recurrence after a chemotherapy regimen can benefit from BCG instillations. Prior
intravesical chemotherapy has no impact on the effect of BCG instillation [177] (LE: 1a).
7.3.2 Recurrence and failure after intravesical bacillus Calmette-Guérin (BCG) immunotherapy
Categories of unsuccessful treatment with intravesical BCG are presented in Table 7.2.
BCG failure
Whenever a MIBC is detected during follow-up.
BCG-refractory tumour:
1. If high-grade, non-muscle-invasive papillary tumour is present at three months [229]. Further conservative
treatment with BCG is associated with increased risk of progression [150, 230] (LE: 3).
2. If CIS (without concomitant papillary tumour) is present at both three and six months. If patients with CIS
present at three months, an additional BCG course can achieve a complete response in > 50% of cases
[31] (LE: 3).
3. If high-grade tumour appears during BCG therapy*.
High-grade recurrence after BCG. Recurrence of high-grade/grade 3 (WHO 2004/1973) tumour after
completion of BCG maintenance, despite an initial response [231] (LE: 3).
BCG intolerance
Severe side effects that prevent further BCG instillation before completing treatment [206].
* Patients with low-grade recurrence during or after BCG treatment are not considered to be a BCG failure.
Summary of evidence LE
Prior intravesical chemotherapy has no impact on the effect of bacillus Calmette-Guérin (BCG) 1a
instillation.
Treatments other than radical cystectomy must be considered oncologically inferior in patients with 3
BCG failure.
NON-MUSCLE-INVASIVE BLADDER CANCER (TAT1 AND CIS) - LIMITED UPDATE MARCH 2017 27
Flowchart 7.2: Treatment strategy in recurrence during or after intravesical BCG*
TURB
BCG refractory tumour: G3/HG tumour > 1 yr after G1-2/LG tumour Muscle invasive tumour
G3/HG tumour at 3 mo, completion of BCG treatment
G3/HG tumour during BCG
treatment, persistent CIS
at 6 mo Consider individual situation (age, comorbidities etc.)
Muscle invasive No or
or G3/HG G1-2/LG
tumour tumour
Repeat course of intravesical BCG for 1-3 yr (GR: C) In selected TaG1/LG (small, solitary etc.)
consider intravesical chemotherapy (GR: C)
In muscle- Cystoscopy (GR: A) and cytology (GR: B) at 3 mo
invasive BC
respect MIBC If negative, cystoscopy and cytology at 3-6 mo
guidelines intervals until 5 yr and then yearly (GR: C),
CT-IVU or IVU yearly (GR: C)
Eligible for radical cystectomy? Recurrence during follow-up Positive cytology with no visible tumour
in the bladder during follow-up
Yes No
Re-check upper tract (GR: B)
BCG = bacillus Calmette-Guérin; CIS = carcinoma in situ; HG = high-grade; IVU = intravenous urography;
LG = low-grade; PDD = photodynamic diagnosis; TURB = transurethral resection of the bladder.
There are several reasons to consider immediate RC for selected patients with NMIBC:
• The staging accuracy for T1 tumours by TURB is low with 27-51% of patients being upstaged to muscle-
invasive tumour at RC [106, 130, 243-246] (LE: 3).
• Some patients with NMIBC experience disease progression to muscle-invasive disease (Table 6.2).
Patients who experience disease progression to muscle-invasive stage, have a worse prognosis than those
who present with ‘primary’ muscle-invasive disease [247, 248].
The potential benefit of RC must be weighed against its risks, morbidity, and impact on quality of life. It
is reasonable to propose immediate RC in those patients with NMIBC who are at highest risk of disease
28 NON-MUSCLE-INVASIVE BLADDER CANCER (TAT1 AND CIS) - LIMITED UPDATE MARCH 2017
progression (see Section 7.6) [46, 104, 137, 138, 249] (LE: 3).
The benefits and risks of immediate and delayed RC should be discussed with patients, in a shared
decision-making process. Individual additional prognostic factors in T1 tumours mentioned in Sections 4.7
and 6.4 should be considered. Early RC is strongly recommended in patients with BCG-refractory tumours, as
mentioned above. A delay in RC may lead to decreased disease-specific survival [250] (LE: 3).
In patients in whom RC is performed before progression to MIBC, the five-year disease-free survival
rate exceeds 80% [251-253] (LE: 3).
7.5 Recommendations for adjuvant therapy in TaT1 tumours and for therapy of
carcinoma in situ
GR
Counsel smokers with confirmed non-muscle-invasive bladder cancer (NMIBC) to stop smoking. B
The type of further therapy after transurethral resection of the bladder (TURB) should be based on the A
risk groups shown in Table 6.3 and Section 7.6.
In patients with tumours presumed to be at low risk and in those presumed to be at intermediate risk A
with previous low recurrence rate (≤ one recurrence per year) and expected EORTC recurrence score <
5, one immediate chemotherapy instillation is recommended.
In patients with intermediate-risk tumours (with or without immediate instillation), one-year full-dose A
bacillus Calmette-Guérin (BCG) treatment (induction plus three-weekly instillations at 3, 6 and 12
months), or instillations of chemotherapy (the optimal schedule is not known) for a maximum of one
year is recommended. The final choice should reflect the individual patient’s risk of recurrence and
progression as well as the efficacy and side effects of each treatment modality.
In patients with high-risk tumours, full-dose intravesical BCG for one-three years (induction plus A
three-weekly instillations at 3, 6, 12, 18, 24, 30 and 36 months), is indicated. The additional beneficial
effect of the second and third years of maintenance should be weighed against its added costs and
inconveniences.
In patients with CIS in the epithelial lining of the prostatic urethra, transurethral resection of the C
prostate followed by intravesical instillation of BCG can be offered.
Discuss immediate radical cystectomy with patients at highest risk of tumour progression (see Section C
7.6).
Offer radical cystectomy (RC) to patients with BCG failure (see Section 7.7). B
In patients with BCG failure, who are not candidates for RC due to comorbidities, use preservation C
strategies (device-assisted instillations of chemotherapy, intravesical chemotherapy, intravesical
immunotherapy).
Intravesical chemotherapy
When given, a single immediate instillation of chemotherapy should be administered within 24 hours C
after TURB, preferably within two hours.
A single immediate instillation of chemotherapy should be omitted in any case of overt or suspected C
bladder perforation or bleeding requiring bladder irrigation.
Give clear instructions to the nursing staff to control the free flow of the bladder catheter at the end of C
the immediate instillation.
The optimal schedule of further intravesical chemotherapy instillation and its duration is not defined, it C
should not exceed one year.
If intravesical chemotherapy is given, it is advised to use the drug at its optimal pH and to maintain the B
concentration of the drug by reducing fluid intake before and during instillation.
The length of individual instillation should be one-two hours. C
BCG intravesical immunotherapy
Absolute contraindications of BCG intravesical instillation are: C
• during the first two weeks after TURB;
• in patients with visible haematuria;
• after traumatic catheterisation;
• in patients with symptomatic urinary tract infection.
The management of side effects after BCG intravesical instillation should reflect their type and grade C
(see Table 7.1).
NON-MUSCLE-INVASIVE BLADDER CANCER (TAT1 AND CIS) - LIMITED UPDATE MARCH 2017 29
7.6 Treatment recommendations in TaT1 tumours and carcinoma in situ according to
risk stratification
When planning the follow-up schedule and methods, the following aspects should be considered:
• The prompt detection of muscle-invasive and HG/G3 non-muscle-invasive recurrence is crucial because
a delay in diagnosis and therapy can be life-threatening.
30 NON-MUSCLE-INVASIVE BLADDER CANCER (TAT1 AND CIS) - LIMITED UPDATE MARCH 2017
• Tumour recurrence in the low-risk group is nearly always low stage and LG/G1. Small, TaLG/G1 papillary
recurrence does not present an immediate danger to the patient and early detection is not essential
for successful therapy [254, 255] (LE: 2b). Fulguration of small papillary recurrences on an outpatient
basis could be a safe option that reduces the therapeutic burden [98] (LE: 3). Some authors have even
defended temporary surveillance in selected cases [255-257] (LE: 3).
• The first cystoscopy after TURB at three months is an important prognostic indicator for recurrence and
progression [144, 150, 258-260] (LE: 1a). Therefore, the first cystoscopy should always be performed
three months after TURB in all patients with TaT1 tumours and CIS.
• In tumours at low risk, the risk of recurrence after five recurrence-free years is low [259] (LE: 3).
• Discontinuation of cystoscopy or its replacement with less-invasive methods can be considered [260].
• In tumours originally intermediate- or high risk, recurrences after ten years tumour-free are not unusual
[261] (LE: 3). Therefore, life-long follow-up is recommended [260].
• The follow-up strategy must reflect the risk of extravesical recurrence (prostatic urethra in men and UUT
in both genders)
• The risk of UUT recurrence increases in patients with multiple- and high-risk tumours [57] (LE: 3).
• Positive urine test results have a positive impact on the quality of follow-up cystoscopy [83] (LE: 1b)
supporting the adjunctive role of urine tests during follow-up.
• In patients initially diagnosed with TaLG/G1-2 BC, ultrasound of the bladder may be a mode of
surveillance in case cystoscopy is not possible or refused by the patient [262].
No non-invasive method can replace endoscopy. Follow-up is therefore based on regular cystoscopy (see
Section 5.7). There is a lack of randomised studies investigating the possibility of safely reducing the frequency
of follow-up cystoscopy.
As CIS is often not visible, multiple biopsies may be necessary in selected cases to confirm the
efficacy of intravesical treatment in patients treated for CIS [84]. The recommendations for follow-up are mainly
based on retrospective data (see Section 8.1).
Summary of evidence LE
The first cystoscopy after transurethral resection of the bladder at 3 months is an important prognostic 1a
indicator for recurrence and progression.
The risk of upper urinary tract (UUT) recurrence increases in patients with multiple- and high-risk 3
tumours.
Recommendations GR
Base follow-up of TaT1 tumours and carcinoma in situ (CIS) on regular cystoscopy. A
Patients with low-risk Ta tumours should undergo cystoscopy at three months. If negative, subsequent C
cystoscopy is advised nine months later, and then yearly for five years.
Patients with high-risk tumours should undergo cystoscopy and urinary cytology at three months. If C
negative, subsequent cystoscopy and cytology should be repeated every three months for a period of
two years, and every six months thereafter until five years, and then yearly.
Patients with intermediate-risk Ta tumours should have an in-between (individualised) follow-up C
scheme using cystoscopy and cytology.
Regular (yearly) upper tract imaging (computed tomography-intravenous urography [CT-IVU] or IVU) is C
recommended for high-risk tumours.
Endoscopy under anaesthesia and bladder biopsies should be performed when office cystoscopy B
shows suspicious findings or if urinary cytology is positive.
Consider random (R)-biopsies or photodynamic diagnosis (PDD)-guided biopsies after intravesical C
treatment (at three or six months) in patients with CIS.
During follow-up in patients with positive cytology and no visible tumour in the bladder, R-biopsies B
or PDD-guided biopsies (if equipment is available) and investigation of extravesical locations (CT
urography, prostatic urethra biopsy) are recommended.
In patients initially diagnosed with TaLG/G1-2 bladder cancer, use ultrasound of the bladder during C
surveillance in case cystoscopy is not possible or refused by the patient.
NON-MUSCLE-INVASIVE BLADDER CANCER (TAT1 AND CIS) - LIMITED UPDATE MARCH 2017 31
9. REFERENCES
1. Rouprêt, M., et al. Guidelines on Upper Urinary Tract Urothelial Cell Carcinoma. EAU Guidelines
2017. Edn presented at the 32nd EAU Annual Congress London.
2. Witjes, J., et al. EAU Guidelines on Muscle-invasive and Metastatic Bladder Cancer. EAU Guidelines
2017. Edn presented at the 32nd EAU Annual Congress London.
3. Gakis, G., et al. Guidelines on Primary Urethral Carcinoma. EAU Guidelines 2017. Edn presented at
the 32nd EAU Annual Congress London.
4. Babjuk, M., et al. EAU Guidelines on Non-Muscle-invasive Urothelial Carcinoma of the Bladder:
Update 2016. Eur Urol, 2016. 71: 447.
https://www.ncbi.nlm.nih.gov/pubmed/27324428
5. Phillips, B. Oxford Centre for Evidence-based Medicine Levels of Evidence. Updated by Jeremy
Howick March 2009. 1998.
http://www.cebm.net/oxford-centre-evidence-based-medicine-levels-evidence-march-2009/
6. Hernandez, V., et al. Is there a difference between the 2004 WHO grading system and the 1973
WHO grading system for NMIBC in terms of prognostic performance?. PROSPERO International
prospective register of systematic reviews, 2015.
http://www.crd.york.ac.uk/PROSPERO/display_record.asp?ID=CRD42015025045
7. Ferlay J., et al. GLOBOCAN 2012 v1.0: Estimated cancer incidence, mortality and prevalence
worldwide in 2012. 2013. 2015.
http://globocan.iarc.fr/Default.aspx
8. Burger, M., et al. Epidemiology and risk factors of urothelial bladder cancer. Eur Urol, 2013. 63: 234.
https://www.ncbi.nlm.nih.gov/pubmed/22877502
9. Chavan, S., et al. International variations in bladder cancer incidence and mortality. Eur Urol, 2014.
66: 59.
https://www.ncbi.nlm.nih.gov/pubmed/24451595
10. Comperat, E., et al. Clinicopathological characteristics of urothelial bladder cancer in patients less
than 40 years old. Virchows Arch, 2015. 466: 589.
https://www.ncbi.nlm.nih.gov/pubmed/25697540
11. Freedman, N.D., et al. Association between smoking and risk of bladder cancer among men and
women. JAMA, 2011. 306: 737.
https://www.ncbi.nlm.nih.gov/pubmed/21846855
12. Colt, J.S., et al. A case-control study of occupational exposure to metalworking fluids and bladder
cancer risk among men. Occup Environ Med, 2014. 71: 667.
https://www.ncbi.nlm.nih.gov/pubmed/25201311
13. Pesch, B., et al. Screening for bladder cancer with urinary tumor markers in chemical workers with
exposure to aromatic amines. Int Arch Occup Environ Health, 2013.
https://www.ncbi.nlm.nih.gov/pubmed/24129706
14. Egbers, L., et al. The prognostic value of family history among patients with urinary bladder cancer.
Int J Cancer, 2015. 136: 1117.
https://www.ncbi.nlm.nih.gov/pubmed/24978702
15. Corral, R., et al. Comprehensive analyses of DNA repair pathways, smoking and bladder cancer risk
in Los Angeles and Shanghai. Int J Cancer, 2014. 135: 335.
https://www.ncbi.nlm.nih.gov/pubmed/24382701
16. Figueroa, J.D., et al. Identification of a novel susceptibility locus at 13q34 and refinement of
the 20p12.2 region as a multi-signal locus associated with bladder cancer risk in individuals of
European ancestry. Hum Mol Genet, 2016. 25: 1203.
https://www.ncbi.nlm.nih.gov/pubmed/26732427
17. Steinmaus, C., et al. Increased lung and bladder cancer incidence in adults after in utero and early-
life arsenic exposure. Cancer Epidemiol Biomarkers Prev, 2014. 23: 1529.
https://www.ncbi.nlm.nih.gov/pubmed/24859871
18. Buckland, G., et al. Adherence to the Mediterranean diet and risk of bladder cancer in the EPIC
cohort study. Int J Cancer, 2014. 134: 2504.
https://www.ncbi.nlm.nih.gov/pubmed/24226765
19. Liu, H., et al. Fruit and vegetable consumption and risk of bladder cancer: an updated meta-analysis
of observational studies. Eur J Cancer Prev, 2015. 24: 508.
https://www.ncbi.nlm.nih.gov/pubmed/25642791
32 NON-MUSCLE-INVASIVE BLADDER CANCER (TAT1 AND CIS) - LIMITED UPDATE MARCH 2017
20. Vieira, A.R., et al. Fruits, vegetables, and bladder cancer risk: a systematic review and meta-
analysis. Cancer Med, 2015. 4: 136.
https://www.ncbi.nlm.nih.gov/pubmed/25461441
21. TNM classification of malignant tumors. UICC International Union Against Cancer. 8th edn. Brierley
JD, Gospodarowicz M, Wittekind C (Eds). 2017, Wiley-Blackwell.
http://www.uicc.org/resources/tnm/publications-resources
22. Orsola, A., et al. Initial high-grade T1 urothelial cell carcinoma: feasibility and prognostic significance
of lamina propria invasion microstaging (T1a/b/c) in BCG-treated and BCG-non-treated patients. Eur
Urol, 2005. 48: 231.
https://www.ncbi.nlm.nih.gov/pubmed/15963635
23. van Rhijn, B.W., et al. A new and highly prognostic system to discern T1 bladder cancer substage.
Eur Urol, 2012. 61: 378.
https://www.ncbi.nlm.nih.gov/pubmed/22036775
24. Moch, H., et al., WHO Classification of Tumours of the Urinary System and Male Genital Organs. 4th
ed. ed, ed. O. H. 2016, Lyon, France
http://apps.who.int/bookorders/anglais/detart1.jsp?codlan=1&codcol=70&codcch=4008
25. Sauter G, A.F., et al., Tumours of the urinary system: non-invasive urothelial neoplasias. In: WHO
classification of classification of tumours of the urinary system and male genital organs., 2004,
IARCC Press: Lyon.
http://publications.iarc.fr/Book-And-Report-Series/Who-Iarc-Classification-Of-Tumours/Who-
Classification-Of-Tumours-Of-The-Urinary-System-And-Male-Genital-Organs-2016
26. Epstein, J.I., et al. The World Health Organization/International Society of Urological Pathology
consensus classification of urothelial (transitional cell) neoplasms of the urinary bladder. Bladder
Consensus Conference Committee. Am J Surg Pathol, 1998. 22: 1435.
https://www.ncbi.nlm.nih.gov/pubmed/9850170
27. van Rhijn, B.W., et al. The pathologist’s mean grade is constant and individualizes the prognostic
value of bladder cancer grading. Eur Urol, 2010. 57: 1052.
https://www.ncbi.nlm.nih.gov/pubmed/19765886
28. May, M., et al. Prognostic accuracy of individual uropathologists in noninvasive urinary bladder
carcinoma: a multicentre study comparing the 1973 and 2004 World Health Organisation
classifications. Eur Urol, 2010. 57: 850.
https://www.ncbi.nlm.nih.gov/pubmed/19346063
29. Otto, W., et al. The WHO classification of 1973 is more suitable than the WHO classification of 2004
for predicting survival in pT1 urothelial bladder cancer. BJU Int, 2011. 107: 404.
https://www.ncbi.nlm.nih.gov/pubmed/20707791
30. MacLennan, G.T., et al. Histologic grading of noninvasive papillary urothelial neoplasms. Eur Urol,
2007. 51: 889.
https://www.ncbi.nlm.nih.gov/pubmed/17095142
31. Sylvester, R.J., et al. High-grade Ta urothelial carcinoma and carcinoma in situ of the bladder.
Urology, 2005. 66: 90.
https://www.ncbi.nlm.nih.gov/pubmed/16399418
32. Lamm, D., et al. Updated concepts and treatment of carcinoma in situ. Urol Oncol, 1998. 4: 130.
https://www.ncbi.nlm.nih.gov/pubmed/21227218
33. Witjes, J.A., et al. Review pathology in a diagnostic bladder cancer trial: effect of patient risk
category. Urology, 2006. 67: 751.
https://www.ncbi.nlm.nih.gov/pubmed/16566990
34. van Rhijn, B.W., et al. Pathological stage review is indicated in primary pT1 bladder cancer. BJU Int,
2010. 106: 206.
https://www.ncbi.nlm.nih.gov/pubmed/20002439
35. Comperat, E., et al. An interobserver reproducibility study on invasiveness of bladder cancer using
virtual microscopy and heatmaps. Histopathology, 2013. 63: 756.
https://www.ncbi.nlm.nih.gov/pubmed/24102813
36. Mangrud, O.M., et al. Reproducibility and prognostic value of WHO1973 and WHO2004 grading
systems in TaT1 urothelial carcinoma of the urinary bladder. PLoS One, 2014. 9: e83192.
https://www.ncbi.nlm.nih.gov/pubmed/24409280
37. Luchey, A.M., et al. Change in Management Based on Pathologic Second Opinion Among Bladder
Cancer Patients Presenting to a Comprehensive Cancer Center: Implications for Clinical Practice.
Urology, 2016. 93: 130.
https://www.ncbi.nlm.nih.gov/pubmed/27041469
NON-MUSCLE-INVASIVE BLADDER CANCER (TAT1 AND CIS) - LIMITED UPDATE MARCH 2017 33
38. Cho, K.S., et al. Lymphovascular invasion in transurethral resection specimens as predictor of
progression and metastasis in patients with newly diagnosed T1 bladder urothelial cancer. J Urol,
2009. 182: 2625.
https://www.ncbi.nlm.nih.gov/pubmed/19836779
39. Comperat, E., et al. Micropapillary urothelial carcinoma of the urinary bladder: a clinicopathological
analysis of 72 cases. Pathology, 2010. 42: 650.
https://www.ncbi.nlm.nih.gov/pubmed/21080874
40. Kaimakliotis, H.Z., et al. Plasmacytoid variant urothelial bladder cancer: is it time to update the
treatment paradigm? Urol Oncol, 2014. 32: 833.
https://www.ncbi.nlm.nih.gov/pubmed/24954925
41. Willis, D.L., et al. Micropapillary bladder cancer: current treatment patterns and review of the
literature. Urol Oncol, 2014. 32: 826.
https://www.ncbi.nlm.nih.gov/pubmed/24931270
42. Beltran, A.L., et al. Clinicopathological characteristics and outcome of nested carcinoma of the
urinary bladder. Virchows Arch, 2014. 465: 199.
https://www.ncbi.nlm.nih.gov/pubmed/24878757
43. Soave, A., et al. Does the extent of variant histology affect oncological outcomes in patients with
urothelial carcinoma of the bladder treated with radical cystectomy? Urol Oncol, 2015. 33: 21 e1.
https://www.ncbi.nlm.nih.gov/pubmed/25465301
44. Masson-Lecomte, A., et al. Oncological outcomes of advanced muscle-invasive bladder cancer with
a micropapillary variant after radical cystectomy and adjuvant platinum-based chemotherapy. World
J Urol, 2015. 33: 1087.
https://www.ncbi.nlm.nih.gov/pubmed/25179011
45. Seisen, T., et al. Impact of histological variants on the outcomes of nonmuscle invasive bladder
cancer after transurethral resection. Curr Opin Urol, 2014. 24: 524.
https://www.ncbi.nlm.nih.gov/pubmed/25051021
46. Willis, D.L., et al. Clinical outcomes of cT1 micropapillary bladder cancer. J Urol, 2015. 193: 1129.
https://www.ncbi.nlm.nih.gov/pubmed/25254936
47. Burger, M., et al. Prediction of progression of non-muscle-invasive bladder cancer by WHO 1973
and 2004 grading and by FGFR3 mutation status: a prospective study. Eur Urol, 2008. 54: 835.
https://www.ncbi.nlm.nih.gov/pubmed/18166262
48. Fristrup, N., et al. Cathepsin E, maspin, Plk1, and survivin are promising prognostic protein markers
for progression in non-muscle invasive bladder cancer. Am J Pathol, 2012. 180: 1824.
https://www.ncbi.nlm.nih.gov/pubmed/22449953
49. Palou, J., et al. Protein expression patterns of ezrin are predictors of progression in T1G3 bladder
tumours treated with nonmaintenance bacillus Calmette-Guerin. Eur Urol, 2009. 56: 829.
https://www.ncbi.nlm.nih.gov/pubmed/18926620
50. van Rhijn, B.W., et al. The FGFR3 mutation is related to favorable pT1 bladder cancer. J Urol, 2012.
187: 310.
https://www.ncbi.nlm.nih.gov/pubmed/22099989
51. Remy, E., et al. A Modeling Approach to Explain Mutually Exclusive and Co-Occurring Genetic
Alterations in Bladder Tumorigenesis. Cancer Res, 2015. 75: 4042.
https://www.ncbi.nlm.nih.gov/pubmed/26238783
52. Ramirez, D., et al. Microscopic haematuria at time of diagnosis is associated with lower disease
stage in patients with newly diagnosed bladder cancer. BJU Int, 2016. 117: 783.
https://www.ncbi.nlm.nih.gov/pubmed/26435378
53. Nolte-Ernsting, C., et al. Understanding multislice CT urography techniques: Many roads lead to
Rome. Eur Radiol, 2006. 16: 2670.
https://www.ncbi.nlm.nih.gov/pubmed/16953373
54. Goessl, C., et al. Is routine excretory urography necessary at first diagnosis of bladder cancer? J
Urol, 1997. 157: 480.
https://www.ncbi.nlm.nih.gov/pubmed/8996338
55. Palou, J., et al. Multivariate analysis of clinical parameters of synchronous primary superficial
bladder cancer and upper urinary tract tumor. J Urol, 2005. 174: 859.
https://www.ncbi.nlm.nih.gov/pubmed/16093970
56. Holmang, S., et al. Long-term followup of a bladder carcinoma cohort: routine followup urography is
not necessary. J Urol, 1998. 160: 45.
https://www.ncbi.nlm.nih.gov/pubmed/9628602
34 NON-MUSCLE-INVASIVE BLADDER CANCER (TAT1 AND CIS) - LIMITED UPDATE MARCH 2017
57. Millan-Rodriguez, F., et al. Upper urinary tract tumors after primary superficial bladder tumors:
prognostic factors and risk groups. J Urol, 2000. 164: 1183.
https://www.ncbi.nlm.nih.gov/pubmed/10992362
58. Hilton, S., et al. Recent advances in imaging cancer of the kidney and urinary tract. Surg Oncol Clin
N Am, 2014. 23: 863.
https://www.ncbi.nlm.nih.gov/pubmed/25246053
59. Yafi, F.A., et al. Prospective analysis of sensitivity and specificity of urinary cytology and other
urinary biomarkers for bladder cancer. Urol Oncol, 2015. 33: 66 e25.
https://www.ncbi.nlm.nih.gov/pubmed/25037483
60. Tetu, B. Diagnosis of urothelial carcinoma from urine. Mod Pathol, 2009. 22 Suppl 2: S53.
https://www.ncbi.nlm.nih.gov/pubmed/19494853
61. Raitanen, M.P., et al. Differences between local and review urinary cytology in diagnosis of bladder
cancer. An interobserver multicenter analysis. Eur Urol, 2002. 41: 284.
https://www.ncbi.nlm.nih.gov/pubmed/12180229
62. Rosenthal DL., et al., The Paris System for Reporting Urinary Cytology. 2016, Switzerland.
http://www.springer.com/us/book/9783319228631
63. Burton, J.L., et al. Demand management in urine cytology: a single cytospin slide is sufficient.
J Clin Pathol, 2000. 53: 718.
https://www.ncbi.nlm.nih.gov/pubmed/11041065
64. Nabi, G., et al. Suspicious urinary cytology with negative evaluation for malignancy in the diagnostic
investigation of haematuria: how to follow up? J Clin Pathol, 2004. 57: 365.
https://www.ncbi.nlm.nih.gov/pubmed/15047737
65. Lokeshwar, V.B., et al. Bladder tumor markers beyond cytology: International Consensus Panel on
bladder tumor markers. Urology, 2005. 66: 35.
https://www.ncbi.nlm.nih.gov/pubmed/16399415
66. Glas, A.S., et al. Tumor markers in the diagnosis of primary bladder cancer. A systematic review.
J Urol, 2003. 169: 1975.
https://www.ncbi.nlm.nih.gov/pubmed/12771702
67. van Rhijn, B.W., et al. Urine markers for bladder cancer surveillance: a systematic review. Eur Urol,
2005. 47: 736.
https://www.ncbi.nlm.nih.gov/pubmed/15925067
68. Lotan, Y., et al. Considerations on implementing diagnostic markers into clinical decision making in
bladder cancer. Urol Oncol, 2010. 28: 441.
https://www.ncbi.nlm.nih.gov/pubmed/20610281
69. Yutkin, V., et al. Can urinary biomarkers replace cystoscopic examination in bladder cancer
surveillance? Expert Rev Anticancer Ther, 2010. 10: 787.
https://www.ncbi.nlm.nih.gov/pubmed/20553203
70. Hajdinjak, T. UroVysion FISH test for detecting urothelial cancers: meta-analysis of diagnostic
accuracy and comparison with urinary cytology testing. Urol Oncol, 2008. 26: 646.
https://www.ncbi.nlm.nih.gov/pubmed/18367109
71. Schlomer, B.J., et al. Prospective validation of the clinical usefulness of reflex fluorescence in situ
hybridization assay in patients with atypical cytology for the detection of urothelial carcinoma of the
bladder. J Urol, 2010. 183: 62.
https://www.ncbi.nlm.nih.gov/pubmed/19913822
72. Kamat, A.M., et al. Prospective trial to identify optimal bladder cancer surveillance protocol:
reducing costs while maximizing sensitivity. BJU Int, 2011. 108: 1119.
https://www.ncbi.nlm.nih.gov/pubmed/21426474
73. Vrooman, O.P., et al. Urinary markers in bladder cancer. Eur Urol, 2008. 53: 909.
https://www.ncbi.nlm.nih.gov/pubmed/18162285
74. Todenhofer, T., et al. Prognostic relevance of positive urine markers in patients with negative
cystoscopy during surveillance of bladder cancer. BMC Cancer, 2015. 15: 155.
https://www.ncbi.nlm.nih.gov/pubmed/25884545
75. van der Aa, M.N., et al. Microsatellite analysis of voided-urine samples for surveillance of low-grade
non-muscle-invasive urothelial carcinoma: feasibility and clinical utility in a prospective multicenter
study (Cost-Effectiveness of Follow-Up of Urinary Bladder Cancer trial [CEFUB]). Eur Urol, 2009. 55:
659.
https://www.ncbi.nlm.nih.gov/pubmed/25884545
NON-MUSCLE-INVASIVE BLADDER CANCER (TAT1 AND CIS) - LIMITED UPDATE MARCH 2017 35
76. Roupret, M., et al. A comparison of the performance of microsatellite and methylation urine analysis
for predicting the recurrence of urothelial cell carcinoma, and definition of a set of markers by
Bayesian network analysis. BJU Int, 2008. 101: 1448.
https://www.ncbi.nlm.nih.gov/pubmed/18325051
77. Grossman, H.B., et al. Detection of bladder cancer using a point-of-care proteomic assay. JAMA,
2005. 293: 810.
https://www.ncbi.nlm.nih.gov/pubmed/15713770
78. Kim, P.H., et al. Reflex fluorescence in situ hybridization assay for suspicious urinary cytology in
patients with bladder cancer with negative surveillance cystoscopy. BJU Int, 2014. 114: 354.
https://www.ncbi.nlm.nih.gov/pubmed/24128299
79. Roobol, M.J., et al. Feasibility study of screening for bladder cancer with urinary molecular markers
(the BLU-P project). Urol Oncol, 2010. 28: 686.
https://www.ncbi.nlm.nih.gov/pubmed/21062653
80. Lotan, Y., et al. Should we screen for bladder cancer in a high-risk population?: A cost per life-year
saved analysis. Cancer, 2006. 107: 982.
https://www.ncbi.nlm.nih.gov/pubmed/16862567
81. Grossman, H.B., et al. Surveillance for recurrent bladder cancer using a point-of-care proteomic
assay. JAMA, 2006. 295: 299.
https://www.ncbi.nlm.nih.gov/pubmed/16418465
82. Babjuk, M., et al. Urinary cytology and quantitative BTA and UBC tests in surveillance of patients
with pTapT1 bladder urothelial carcinoma. Urology, 2008. 71: 718.
https://www.ncbi.nlm.nih.gov/pubmed/18387400
83. van der Aa, M.N., et al. Cystoscopy revisited as the gold standard for detecting bladder cancer
recurrence: diagnostic review bias in the randomized, prospective CEFUB trial. J Urol, 2010. 183:
76.
https://www.ncbi.nlm.nih.gov/pubmed/19913254
84. Kurth, K.H., et al. Current methods of assessing and treating carcinoma in situ of the bladder with or
without involvement of the prostatic urethra. Int J Urol, 1995. 2 Suppl 2: 8.
https://www.ncbi.nlm.nih.gov/pubmed/7553309
85. Aaronson, D.S., et al. Meta-analysis: does lidocaine gel before flexible cystoscopy provide pain
relief? BJU Int, 2009. 104: 506.
https://www.ncbi.nlm.nih.gov/pubmed/19239453
86. Brausi, M., et al. Variability in the recurrence rate at first follow-up cystoscopy after TUR in stage
Ta T1 transitional cell carcinoma of the bladder: a combined analysis of seven EORTC studies. Eur
Urol, 2002. 41: 523.
https://www.ncbi.nlm.nih.gov/pubmed/12074794
87. Richterstetter, M., et al. The value of extended transurethral resection of bladder tumour (TURBT) in
the treatment of bladder cancer. BJU Int, 2012. 110: E76.
https://www.ncbi.nlm.nih.gov/pubmed/22313727
88. Kramer, M.W., et al. En bloc resection of urothelium carcinoma of the bladder (EBRUC): a European
multicenter study to compare safety, efficacy, and outcome of laser and electrical en bloc
transurethral resection of bladder tumor. World J Urol, 2015. 33: 1937.
https://www.ncbi.nlm.nih.gov/pubmed/25910478
89. Hurle, R., et al. “En Bloc” Resection of Nonmuscle Invasive Bladder Cancer: A Prospective Single-
center Study. Urology, 2016. 90: 126.
https://www.ncbi.nlm.nih.gov/pubmed/26776561
90. Migliari, R., et al. Thulium Laser Endoscopic En Bloc Enucleation of Nonmuscle-Invasive Bladder
Cancer. J Endourol, 2015. 29: 1258.
https://www.ncbi.nlm.nih.gov/pubmed/26102556
91. Zhang, X.R., et al. Two Micrometer Continuous-Wave Thulium Laser Treating Primary Non-Muscle-
Invasive Bladder Cancer: Is It Feasible? A Randomized Prospective Study. Photomed Laser Surg,
2015. 33: 517.
https://www.ncbi.nlm.nih.gov/pubmed/26397029
92. Mariappan, P., et al. Detrusor muscle in the first, apparently complete transurethral resection of
bladder tumour specimen is a surrogate marker of resection quality, predicts risk of early recurrence,
and is dependent on operator experience. Eur Urol, 2010. 57: 843.
https://www.ncbi.nlm.nih.gov/pubmed/19524354
36 NON-MUSCLE-INVASIVE BLADDER CANCER (TAT1 AND CIS) - LIMITED UPDATE MARCH 2017
93. Mariappan, P., et al. Good quality white-light transurethral resection of bladder tumours
(GQ-WLTURBT) with experienced surgeons performing complete resections and obtaining detrusor
muscle reduces early recurrence in new non-muscle-invasive bladder cancer: validation across time
and place and recommendation for benchmarking. BJU Int, 2012. 109: 1666.
https://www.ncbi.nlm.nih.gov/pubmed/22044434
94. Gupta, N.P., et al. Bipolar energy for transurethral resection of bladder tumours at low-power
settings: initial experience. BJU Int, 2011. 108: 553.
https://www.ncbi.nlm.nih.gov/pubmed/21176081
95. Venkatramani, V., et al. Monopolar versus bipolar transurethral resection of bladder tumors: a single
center, parallel arm, randomized, controlled trial. J Urol, 2014. 191: 1703.
https://www.ncbi.nlm.nih.gov/pubmed/24333244
96. Sugihara, T., et al. Comparison of Perioperative Outcomes including Severe Bladder Injury
between Monopolar and Bipolar Transurethral Resection of Bladder Tumors: A Population Based
Comparison. J Urol, 2014. 192: 1355.
https://www.ncbi.nlm.nih.gov/pubmed/24893311
97. Mashni, J., et al. Prospective evaluation of plasma kinetic bipolar resection of bladder cancer:
comparison to monopolar resection and pathologic findings. Int Urol Nephrol, 2014. 46: 1699.
https://www.ncbi.nlm.nih.gov/pubmed/24792236
98. Herr, H.W., et al. Management of low grade papillary bladder tumors. J Urol, 2007. 178: 1201.
https://www.ncbi.nlm.nih.gov/pubmed/17698090
99. Xu, Y., et al. Comparing the treatment outcomes of potassium-titanyl-phosphate laser vaporization
and transurethral electroresection for primary nonmuscle-invasive bladder cancer: A prospective,
randomized study. Lasers Surg Med, 2015. 47: 306.
https://www.ncbi.nlm.nih.gov/pubmed/25864416
100. Picozzi, S.C., et al. Is it oncologically safe performing simultaneous transurethral resection of the
bladder and prostate? A meta-analysis on 1,234 patients. Int Urol Nephrol, 2012. 44: 1325.
https://www.ncbi.nlm.nih.gov/pubmed/22710969
101. Tsivian, A., et al. Simultaneous transurethral resection of bladder tumor and benign prostatic
hyperplasia: hazardous or a safe timesaver? J Urol, 2003. 170: 2241.
https://www.ncbi.nlm.nih.gov/pubmed/14634388
102. van der Meijden, A., et al. Significance of bladder biopsies in Ta,T1 bladder tumors: a report from
the EORTC Genito-Urinary Tract Cancer Cooperative Group. EORTC-GU Group Superficial Bladder
Committee. Eur Urol, 1999. 35: 267.
https://www.ncbi.nlm.nih.gov/pubmed/10419345
103. Hara, T., et al. Risk of concomitant carcinoma in situ determining biopsy candidates among primary
non-muscle-invasive bladder cancer patients: retrospective analysis of 173 Japanese cases. Int J
Urol, 2009. 16: 293.
https://www.ncbi.nlm.nih.gov/pubmed/19207607
104. Palou, J., et al. Female gender and carcinoma in situ in the prostatic urethra are prognostic factors
for recurrence, progression, and disease-specific mortality in T1G3 bladder cancer patients treated
with bacillus Calmette-Guerin. Eur Urol, 2012. 62: 118.
https://www.ncbi.nlm.nih.gov/pubmed/22101115
105. Mungan, M.U., et al. Risk factors for mucosal prostatic urethral involvement in superficial transitional
cell carcinoma of the bladder. Eur Urol, 2005. 48: 760.
https://www.ncbi.nlm.nih.gov/pubmed/16005563
106. Huguet, J., et al. Cystectomy in patients with high risk superficial bladder tumors who fail
intravesical BCG therapy: pre-cystectomy prostate involvement as a prognostic factor. Eur Urol,
2005. 48: 53.
https://www.ncbi.nlm.nih.gov/pubmed/15967252
107. Kausch, I., et al. Photodynamic diagnosis in non-muscle-invasive bladder cancer: a systematic
review and cumulative analysis of prospective studies. Eur Urol, 2010. 57: 595.
https://www.ncbi.nlm.nih.gov/pubmed/20004052
108. Mowatt, G., et al. Photodynamic diagnosis of bladder cancer compared with white light cystoscopy:
Systematic review and meta-analysis. Int J Technol Assess Health Care, 2011. 27: 3.
https://www.ncbi.nlm.nih.gov/pubmed/21262078
109. Neuzillet, Y., et al. Assessment of diagnostic gain with hexaminolevulinate (HAL) in the setting of
newly diagnosed non-muscle-invasive bladder cancer with positive results on urine cytology. Urol
Oncol, 2014. 32: 1135.
https://www.ncbi.nlm.nih.gov/pubmed/25023786
NON-MUSCLE-INVASIVE BLADDER CANCER (TAT1 AND CIS) - LIMITED UPDATE MARCH 2017 37
110. Draga, R.O., et al. Photodynamic diagnosis (5-aminolevulinic acid) of transitional cell carcinoma
after bacillus Calmette-Guerin immunotherapy and mitomycin C intravesical therapy. Eur Urol, 2010.
57: 655.
https://www.ncbi.nlm.nih.gov/pubmed/19819064
111. Ray, E.R., et al. Hexylaminolaevulinate fluorescence cystoscopy in patients previously treated with
intravesical bacille Calmette-Guerin. BJU Int, 2010. 105: 789.
https://www.ncbi.nlm.nih.gov/pubmed/19832725
112. Schumacher, M.C., et al. Transurethral resection of non-muscle-invasive bladder transitional cell
cancers with or without 5-aminolevulinic Acid under visible and fluorescent light: results of a
prospective, randomised, multicentre study. Eur Urol, 2010. 57: 293.
https://www.ncbi.nlm.nih.gov/pubmed/19913351
113. Stenzl, A., et al. Detection and clinical outcome of urinary bladder cancer with 5-aminolevulinic acid-
induced fluorescence cystoscopy : A multicenter randomized, double-blind, placebo-controlled trial.
Cancer, 2011. 117: 938.
https://www.ncbi.nlm.nih.gov/pubmed/21351082
114. Burger, M., et al. Photodynamic diagnosis of non-muscle-invasive bladder cancer with
hexaminolevulinate cystoscopy: a meta-analysis of detection and recurrence based on raw data.
Eur Urol, 2013. 64: 846.
https://www.ncbi.nlm.nih.gov/pubmed/23602406
115. O’Brien, T., et al. Prospective randomized trial of hexylaminolevulinate photodynamic-assisted
transurethral resection of bladder tumour (TURBT) plus single-shot intravesical mitomycin C vs
conventional white-light TURBT plus mitomycin C in newly presenting non-muscle-invasive bladder
cancer. BJU Int, 2013. 112: 1096.
https://www.ncbi.nlm.nih.gov/pubmed/24053153
116. Gkritsios, P., et al. Hexaminolevulinate-guided transurethral resection of non-muscle-invasive
bladder cancer does not reduce the recurrence rates after a 2-year follow-up: a prospective
randomized trial. Int Urol Nephrol, 2014. 46: 927.
https://www.ncbi.nlm.nih.gov/pubmed/24249423
117. Mariappan, P., et al. Real-life Experience: Early Recurrence With Hexvix Photodynamic Diagnosis-
assisted Transurethral Resection of Bladder Tumour vs Good-quality White Light TURBT in New
Non-muscle-invasive Bladder Cancer. Urology, 2015. 86: 327.
https://www.ncbi.nlm.nih.gov/pubmed/26142924
118. Cauberg, E.C., et al. Narrow band imaging cystoscopy improves the detection of non-muscle-
invasive bladder cancer. Urology, 2010. 76: 658.
https://www.ncbi.nlm.nih.gov/pubmed/20223505
119. Zheng, C., et al. Narrow band imaging diagnosis of bladder cancer: systematic review and meta-
analysis. BJU Int, 2012. 110: E680.
https://www.ncbi.nlm.nih.gov/pubmed/22985502
120. Naito, S., et al. The Clinical Research Office of the Endourological Society (CROES) Multicentre
Randomised Trial of Narrow Band Imaging-Assisted Transurethral Resection of Bladder Tumour
(TURBT) Versus Conventional White Light Imaging-Assisted TURBT in Primary Non-Muscle-invasive
Bladder Cancer Patients: Trial Protocol and 1-year Results. Eur Urol, 2016. 70: 506.
https://www.ncbi.nlm.nih.gov/pubmed/27117749
121. Grimm, M.O., et al. Effect of routine repeat transurethral resection for superficial bladder cancer: a
long-term observational study. J Urol, 2003. 170: 433.
https://www.ncbi.nlm.nih.gov/pubmed/12853793
122. Divrik, R.T., et al. The effect of repeat transurethral resection on recurrence and progression rates
in patients with T1 tumors of the bladder who received intravesical mitomycin: a prospective,
randomized clinical trial. J Urol, 2006. 175: 1641.
https://www.ncbi.nlm.nih.gov/pubmed/16600720
123. Lazica, D.A., et al. Second transurethral resection after Ta high-grade bladder tumor: a 4.5-year
period at a single university center. Urol Int, 2014. 92: 131.
https://www.ncbi.nlm.nih.gov/pubmed/23988813
124. Vasdev, N., et al. The impact of early re-resection in patients with pT1 high-grade non-muscle
invasive bladder cancer. Ecancermedicalscience, 2012. 6: 269.
https://www.ncbi.nlm.nih.gov/pubmed/22988482
125. Angulo, J.C., et al. Second transurethral resection and prognosis of high-grade non-muscle invasive
bladder cancer in patients not receiving bacillus Calmette-Guerin. Actas Urol Esp, 2014. 38: 164.
https://www.ncbi.nlm.nih.gov/pubmed/24613147
38 NON-MUSCLE-INVASIVE BLADDER CANCER (TAT1 AND CIS) - LIMITED UPDATE MARCH 2017
126. Gendy, R., et al. Repeat transurethral resection for non-muscle-invasive bladder cancer: a
contemporary series. BJU Int, 2016. 117 Suppl 4: 54.
https://www.ncbi.nlm.nih.gov/pubmed/26486968
127. Hashine, K., et al. Results of second transurethral resection for high-grade T1 bladder cancer. Urol
Ann, 2016. 8: 10.
https://www.ncbi.nlm.nih.gov/pubmed/26834394
128. El-Barky, E., et al. The importance of second-look transurethral resection for superficial bladder
cancer. J Clin Urol, 2015. 8: 299.
http://journals.sagepub.com/doi/pdf/10.1177/2051415814560189
129. Dalbagni, G., et al. Clinical outcome in a contemporary series of restaged patients with clinical T1
bladder cancer. Eur Urol, 2009. 56: 903.
https://www.ncbi.nlm.nih.gov/pubmed/19632765
130. Fritsche, H.M., et al. Characteristics and outcomes of patients with clinical T1 grade 3 urothelial
carcinoma treated with radical cystectomy: results from an international cohort. Eur Urol, 2010. 57:
300.
https://www.ncbi.nlm.nih.gov/pubmed/19766384
131. Kulkarni, G.S., et al. An updated critical analysis of the treatment strategy for newly diagnosed high-
grade T1 (previously T1G3) bladder cancer. Eur Urol, 2010. 57: 60.
https://www.ncbi.nlm.nih.gov/pubmed/19740595
132. Sfakianos, J.P., et al. The effect of restaging transurethral resection on recurrence and progression
rates in patients with nonmuscle invasive bladder cancer treated with intravesical bacillus Calmette-
Guerin. J Urol, 2014. 191: 341.
https://www.ncbi.nlm.nih.gov/pubmed/23973518
133. Bishr, M., et al. Tumour stage on re-staging transurethral resection predicts recurrence and
progression-free survival of patients with high-risk non-muscle invasive bladder cancer. Can Urol
Assoc J, 2014. 8: E306.
https://www.ncbi.nlm.nih.gov/pubmed/24940455
134. Gontero, P., et al. The impact of re-transurethral resection on clinical outcomes in a large multicentre
cohort of patients with T1 high-grade/Grade 3 bladder cancer treated with bacille Calmette-Guerin.
BJU Int, 2016. 118: 44.
https://www.ncbi.nlm.nih.gov/pubmed/26469362
135. Baltaci, S., et al. Significance of the interval between first and second transurethral resection on
recurrence and progression rates in patients with high-risk non-muscle-invasive bladder cancer
treated with maintenance intravesical Bacillus Calmette-Guerin. BJU Int, 2015. 116: 721.
https://www.ncbi.nlm.nih.gov/pubmed/25715815
136. Lopez-Beltran, A., et al. Handling and pathology reporting of specimens with carcinoma of the
urinary bladder, ureter, and renal pelvis. Eur Urol, 2004. 45: 257.
https://www.ncbi.nlm.nih.gov/pubmed/15036668
137. Sylvester, R.J., et al. Predicting recurrence and progression in individual patients with stage Ta T1
bladder cancer using EORTC risk tables: a combined analysis of 2596 patients from seven EORTC
trials. Eur Urol, 2006. 49: 466.
https://www.ncbi.nlm.nih.gov/pubmed/16442208
138. Fernandez-Gomez, J., et al. Predicting nonmuscle invasive bladder cancer recurrence and
progression in patients treated with bacillus Calmette-Guerin: the CUETO scoring model. J Urol,
2009. 182: 2195.
https://www.ncbi.nlm.nih.gov/pubmed/19758621
139. van Rhijn, B.W., et al. Molecular grade (FGFR3/MIB-1) and EORTC risk scores are predictive in
primary non-muscle-invasive bladder cancer. Eur Urol, 2010. 58: 433.
https://www.ncbi.nlm.nih.gov/pubmed/20646825
140. Fernandez-Gomez, J., et al. The EORTC tables overestimate the risk of recurrence and progression
in patients with non-muscle-invasive bladder cancer treated with bacillus Calmette-Guerin: external
validation of the EORTC risk tables. Eur Urol, 2011. 60: 423.
https://www.ncbi.nlm.nih.gov/pubmed/21621906
141. Cambier, S., et al. EORTC Nomograms and Risk Groups for Predicting Recurrence, Progression,
and Disease-specific and Overall Survival in Non-Muscle-invasive Stage Ta-T1 Urothelial Bladder
Cancer Patients Treated with 1-3 Years of Maintenance Bacillus Calmette-Guerin. Eur Urol, 2016.
69: 60.
https://www.ncbi.nlm.nih.gov/pubmed/26210894
NON-MUSCLE-INVASIVE BLADDER CANCER (TAT1 AND CIS) - LIMITED UPDATE MARCH 2017 39
142. Gontero, P., et al. Prognostic factors and risk groups in T1G3 non-muscle-invasive bladder cancer
patients initially treated with Bacillus Calmette-Guerin: results of a retrospective multicenter study of
2451 patients. Eur Urol, 2015. 67: 74.
https://www.ncbi.nlm.nih.gov/pubmed/25043942
143. Golijanin, D., et al. Carcinoma in a bladder diverticulum: presentation and treatment outcome.
J Urol, 2003. 170: 1761.
https://www.ncbi.nlm.nih.gov/pubmed/14532771
144. Palou, J., et al. Recurrence at three months and high-grade recurrence as prognostic factor of
progression in multivariate analysis of T1G2 bladder tumors. Urology, 2009. 73: 1313.
https://www.ncbi.nlm.nih.gov/pubmed/19362341
145. Alkhateeb, S.S., et al. Long-term prognostic value of the combination of EORTC risk group
calculator and molecular markers in non-muscle-invasive bladder cancer patients treated with
intravesical Bacille Calmette-Guerin. Urol Ann, 2011. 3: 119.
https://www.ncbi.nlm.nih.gov/pubmed/21976923
146. Lamm, D.L. Carcinoma in situ. Urol Clin North Am, 1992. 19: 499.
https://www.ncbi.nlm.nih.gov/pubmed/1636234
147. Losa, A., et al. Low dose bacillus Calmette-Guerin for carcinoma in situ of the bladder: long-term
results. J Urol, 2000. 163: 68.
https://www.ncbi.nlm.nih.gov/pubmed/10604316
148. Griffiths, T.R., et al. Treatment of carcinoma in situ with intravesical bacillus Calmette-Guerin without
maintenance. J Urol, 2002. 167: 2408.
https://www.ncbi.nlm.nih.gov/pubmed/11992047
149. Takenaka, A., et al. Clinical outcomes of bacillus Calmette-Guerin instillation therapy for carcinoma
in situ of urinary bladder. Int J Urol, 2008. 15: 309.
https://www.ncbi.nlm.nih.gov/pubmed/18380817
150. Solsona, E., et al. The 3-month clinical response to intravesical therapy as a predictive factor for
progression in patients with high risk superficial bladder cancer. J Urol, 2000. 164: 685.
https://www.ncbi.nlm.nih.gov/pubmed/10953125
151. van Gils-Gielen, R.J., et al. Risk factors in carcinoma in situ of the urinary bladder. Dutch South East
Cooperative Urological Group. Urology, 1995. 45: 581.
https://www.ncbi.nlm.nih.gov/pubmed/7716838
152. Lammers, R.J., et al. Smoking status is a risk factor for recurrence after transurethral resection of
non-muscle-invasive bladder cancer. Eur Urol, 2011. 60: 713.
https://www.ncbi.nlm.nih.gov/pubmed/21794974
153. Rink, M., et al. Smoking reduces the efficacy of intravesical bacillus Calmette-Guerin
immunotherapy in non-muscle-invasive bladder cancer. Eur Urol, 2012. 62: 1204.
https://www.ncbi.nlm.nih.gov/pubmed/22980442
154. Rink, M., et al. Impact of smoking on outcomes of patients with a history of recurrent nonmuscle
invasive bladder cancer. J Urol, 2012. 188: 2120.
https://www.ncbi.nlm.nih.gov/pubmed/23083868
155. Crivelli, J.J., et al. Effect of smoking on outcomes of urothelial carcinoma: a systematic review of the
literature. Eur Urol, 2014. 65: 742.
https://www.ncbi.nlm.nih.gov/pubmed/23810104
156. Grotenhuis, A.J., et al. The effect of smoking and timing of smoking cessation on clinical outcome in
non-muscle-invasive bladder cancer. Urol Oncol, 2015. 33: 65 e9.
https://www.ncbi.nlm.nih.gov/pubmed/25023787
157. Muller, J., et al. Trends in the risk of second primary cancer among bladder cancer survivors: a
population-based cohort of 10 047 patients. BJU Int, 2016. 118: 53.
https://www.ncbi.nlm.nih.gov/pubmed/26469096
158. Soloway, M.S., et al. Urothelial susceptibility to tumor cell implantation: influence of cauterization.
Cancer, 1980. 46: 1158.
https://www.ncbi.nlm.nih.gov/pubmed/7214299
159. Pan, J.S., et al. Inhibition of implantation of murine bladder tumor by thiotepa in cauterized bladder.
J Urol, 1989. 142: 1589.
https://www.ncbi.nlm.nih.gov/pubmed/2511340
160. Brocks, C.P., et al. Inhibition of tumor implantation by intravesical gemcitabine in a murine model of
superficial bladder cancer. J Urol, 2005. 174: 1115.
https://www.ncbi.nlm.nih.gov/pubmed/16094076
40 NON-MUSCLE-INVASIVE BLADDER CANCER (TAT1 AND CIS) - LIMITED UPDATE MARCH 2017
161. Oosterlinck, W., et al. A prospective European Organization for Research and Treatment of Cancer
Genitourinary Group randomized trial comparing transurethral resection followed by a single
intravesical instillation of epirubicin or water in single stage Ta, T1 papillary carcinoma of the
bladder. J Urol, 1993. 149: 749.
https://www.ncbi.nlm.nih.gov/pubmed/8455236
162. Sylvester, R.J., et al. Systematic Review and Individual Patient Data Meta-analysis of Randomized
Trials Comparing a Single Immediate Instillation of Chemotherapy After Transurethral Resection with
Transurethral Resection Alone in Patients with Stage pTa-pT1 Urothelial Carcinoma of the Bladder:
Which Patients Benefit from the Instillation? Eur Urol, 2016. 69: 231.
https://www.ncbi.nlm.nih.gov/pubmed/26091833
163. Sylvester, R.J., et al. A single immediate postoperative instillation of chemotherapy decreases the
risk of recurrence in patients with stage Ta T1 bladder cancer: a meta-analysis of published results
of randomized clinical trials. J Urol, 2004. 171: 2186.
https://www.ncbi.nlm.nih.gov/pubmed/15126782
164. Abern, M.R., et al. Perioperative intravesical chemotherapy in non-muscle-invasive bladder cancer:
a systematic review and meta-analysis. J Natl Compr Canc Netw, 2013. 11: 477.
https://www.ncbi.nlm.nih.gov/pubmed/23584348
165. Perlis, N., et al. Immediate post-transurethral resection of bladder tumor intravesical chemotherapy
prevents non-muscle-invasive bladder cancer recurrences: an updated meta-analysis on 2548
patients and quality-of-evidence review. Eur Urol, 2013. 64: 421.
https://www.ncbi.nlm.nih.gov/pubmed/23830475
166. Pode, D., et al. The mechanism of human bladder tumor implantation in an in vitro model. J Urol,
1986. 136: 482.
https://www.ncbi.nlm.nih.gov/pubmed/3525861
167. Bohle, A., et al. Inhibition of bladder carcinoma cell adhesion by oligopeptide combinations in vitro
and in vivo. J Urol, 2002. 167: 357.
https://www.ncbi.nlm.nih.gov/pubmed/11743356
168. Oddens, J.R., et al. One immediate postoperative instillation of chemotherapy in low risk Ta, T1
bladder cancer patients. Is it always safe? Eur Urol, 2004. 46: 336.
https://www.ncbi.nlm.nih.gov/pubmed/15306104
169. Elmamoun, M.H., et al. Destruction of the bladder by single dose Mitomycin C for low-stage
transitional cell carcinoma (TCC)--avoidance, recognition, management and consent. BJU Int, 2014.
113: E34.
https://www.ncbi.nlm.nih.gov/pubmed/24053461
170. Bouffioux, C., et al. Intravesical adjuvant chemotherapy for superficial transitional cell bladder
carcinoma: results of 2 European Organization for Research and Treatment of Cancer randomized
trials with mitomycin C and doxorubicin comparing early versus delayed instillations and short-
term versus long-term treatment. European Organization for Research and Treatment of Cancer
Genitourinary Group. J Urol, 1995. 153: 934.
https://www.ncbi.nlm.nih.gov/pubmed/7853578
171. Kaasinen, E., et al. Factors explaining recurrence in patients undergoing chemoimmunotherapy
regimens for frequently recurring superficial bladder carcinoma. Eur Urol, 2002. 42: 167.
https://www.ncbi.nlm.nih.gov/pubmed/12160589
172. Sylvester, R.J., et al. The schedule and duration of intravesical chemotherapy in patients with non-
muscle-invasive bladder cancer: a systematic review of the published results of randomized clinical
trials. Eur Urol, 2008. 53: 709.
https://www.ncbi.nlm.nih.gov/pubmed/18207317
173. Tolley, D.A., et al. The effect of intravesical mitomycin C on recurrence of newly diagnosed
superficial bladder cancer: a further report with 7 years of follow up. J Urol, 1996. 155: 1233.
https://www.ncbi.nlm.nih.gov/pubmed/8632538
174. Huncharek, M., et al. Impact of intravesical chemotherapy on recurrence rate of recurrent superficial
transitional cell carcinoma of the bladder: results of a meta-analysis. Anticancer Res, 2001. 21: 765.
https://www.ncbi.nlm.nih.gov/pubmed/11299841
175. Bohle, A., et al. Intravesical bacille Calmette-Guerin versus mitomycin C in superficial bladder
cancer: formal meta-analysis of comparative studies on tumor progression. Urology, 2004. 63: 682.
https://www.ncbi.nlm.nih.gov/pubmed/15072879
176. Sylvester, R.J., et al. Intravesical bacillus Calmette-Guerin reduces the risk of progression in patients
with superficial bladder cancer: a meta-analysis of the published results of randomized clinical trials.
J Urol, 2002. 168: 1964.
https://www.ncbi.nlm.nih.gov/pubmed/12394686
NON-MUSCLE-INVASIVE BLADDER CANCER (TAT1 AND CIS) - LIMITED UPDATE MARCH 2017 41
177. Malmstrom, P.U., et al. An individual patient data meta-analysis of the long-term outcome of
randomised studies comparing intravesical mitomycin C versus bacillus Calmette-Guerin for non-
muscle-invasive bladder cancer. Eur Urol, 2009. 56: 247.
https://www.ncbi.nlm.nih.gov/pubmed/19409692
178. Sylvester, R.J., et al. Long-term efficacy results of EORTC genito-urinary group randomized phase 3
study 30911 comparing intravesical instillations of epirubicin, bacillus Calmette-Guerin, and bacillus
Calmette-Guerin plus isoniazid in patients with intermediate- and high-risk stage Ta T1 urothelial
carcinoma of the bladder. Eur Urol, 2010. 57: 766.
https://www.ncbi.nlm.nih.gov/pubmed/20034729
179. Shang, P.F., et al. Intravesical Bacillus Calmette-Guerin versus epirubicin for Ta and T1 bladder
cancer. Cochrane Database Syst Rev, 2011: CD006885.
https://www.ncbi.nlm.nih.gov/pubmed/21563157
180. Au, J.L., et al. Methods to improve efficacy of intravesical mitomycin C: results of a randomized
phase III trial. J Natl Cancer Inst, 2001. 93: 597.
https://www.ncbi.nlm.nih.gov/pubmed/11309436
181. Giesbers, A.A., et al. Recurrence of superficial bladder carcinoma after intravesical instillation of
mitomycin-C. Comparison of exposure times. Br J Urol, 1989. 63: 176.
https://www.ncbi.nlm.nih.gov/pubmed/2495144
182. Kuroda, M., et al. Effect of prophylactic treatment with intravesical epirubicin on recurrence of
superficial bladder cancer--The 6th Trial of the Japanese Urological Cancer Research Group
(JUCRG): a randomized trial of intravesical epirubicin at dose of 20mg/40ml, 30mg/40ml,
40mg/40ml. Eur Urol, 2004. 45: 600.
https://www.ncbi.nlm.nih.gov/pubmed/15082202
183. Arends, T.J., et al. Combined chemohyperthermia: 10-year single center experience in 160 patients
with nonmuscle invasive bladder cancer. J Urol, 2014. 192: 708.
https://www.ncbi.nlm.nih.gov/pubmed/24704017
184. Arends, T.J., et al. Results of a Randomised Controlled Trial Comparing Intravesical
Chemohyperthermia with Mitomycin C Versus Bacillus Calmette-Guerin for Adjuvant Treatment of
Patients with Intermediate- and High-risk Non-Muscle-invasive Bladder Cancer. Eur Urol, 2016. 69:
1046.
https://www.ncbi.nlm.nih.gov/pubmed/26803476
185. Di Stasi, S.M., et al. Sequential BCG and electromotive mitomycin versus BCG alone for high-risk
superficial bladder cancer: a randomised controlled trial. Lancet Oncol, 2006. 7: 43.
https://www.ncbi.nlm.nih.gov/pubmed/16389183
186. Shelley, M.D., et al. A systematic review of intravesical bacillus Calmette-Guerin plus transurethral
resection vs transurethral resection alone in Ta and T1 bladder cancer. BJU Int, 2001. 88: 209.
https://www.ncbi.nlm.nih.gov/pubmed/11488731
187. Han, R.F., et al. Can intravesical bacillus Calmette-Guerin reduce recurrence in patients with
superficial bladder cancer? A meta-analysis of randomized trials. Urology, 2006. 67: 1216.
https://www.ncbi.nlm.nih.gov/pubmed/16765182
188. Shelley, M.D., et al. Intravesical bacillus Calmette-Guerin is superior to mitomycin C in reducing
tumour recurrence in high-risk superficial bladder cancer: a meta-analysis of randomized trials.
BJU Int, 2004. 93: 485.
https://www.ncbi.nlm.nih.gov/pubmed/15008714
189. Bohle, A., et al. Intravesical bacillus Calmette-Guerin versus mitomycin C for superficial bladder
cancer: a formal meta-analysis of comparative studies on recurrence and toxicity. J Urol, 2003. 169:
90.
https://www.ncbi.nlm.nih.gov/pubmed/12478111
190. Duchek, M., et al. Bacillus Calmette-Guerin is superior to a combination of epirubicin and interferon-
alpha2b in the intravesical treatment of patients with stage T1 urinary bladder cancer. A prospective,
randomized, Nordic study. Eur Urol, 2010. 57: 25.
https://www.ncbi.nlm.nih.gov/pubmed/19819617
191. Jarvinen, R., et al. Long-term efficacy of maintenance bacillus Calmette-Guerin versus maintenance
mitomycin C instillation therapy in frequently recurrent TaT1 tumours without carcinoma in situ: a
subgroup analysis of the prospective, randomised FinnBladder I study with a 20-year follow-up. Eur
Urol, 2009. 56: 260.
https://www.ncbi.nlm.nih.gov/pubmed/19395154
42 NON-MUSCLE-INVASIVE BLADDER CANCER (TAT1 AND CIS) - LIMITED UPDATE MARCH 2017
192. Huncharek, M., et al. The influence of intravesical therapy on progression of superficial transitional
cell carcinoma of the bladder: a metaanalytic comparison of chemotherapy versus bacilli Calmette-
Guerin immunotherapy. Am J Clin Oncol, 2004. 27: 522.
https://www.ncbi.nlm.nih.gov/pubmed/15596924
193. Oddens, J.R., et al. The effect of age on the efficacy of maintenance bacillus calmette-guerin relative
to maintenance epirubicin in patients with stage ta t1 urothelial bladder cancer: results from EORTC
genito-urinary group study 30911. Eur Urol, 2014. 66: 694.
https://www.ncbi.nlm.nih.gov/pubmed/24948466
194. Rentsch, C.A., et al. Bacillus calmette-guerin strain differences have an impact on clinical outcome
in bladder cancer immunotherapy. Eur Urol, 2014. 66: 677.
https://www.ncbi.nlm.nih.gov/pubmed/24674149
195. Sengiku, A., et al. A prospective comparative study of intravesical bacillus Calmette-Guerin therapy
with the Tokyo or Connaught strain for nonmuscle invasive bladder cancer. J Urol, 2013. 190: 50.
https://www.ncbi.nlm.nih.gov/pubmed/23376145
196. van der Meijden, A.P., et al. Maintenance Bacillus Calmette-Guerin for Ta T1 bladder tumors is
not associated with increased toxicity: results from a European Organisation for Research and
Treatment of Cancer Genito-Urinary Group Phase III Trial. Eur Urol, 2003. 44: 429.
https://www.ncbi.nlm.nih.gov/pubmed/14499676
197. Brausi, M., et al. Side effects of Bacillus Calmette-Guerin (BCG) in the treatment of intermediate-
and high-risk Ta, T1 papillary carcinoma of the bladder: results of the EORTC genito-urinary cancers
group randomised phase 3 study comparing one-third dose with full dose and 1 year with 3 years of
maintenance BCG. Eur Urol, 2014. 65: 69.
https://www.ncbi.nlm.nih.gov/pubmed/23910233
198. Oddens, J.R., et al. Increasing age is not associated with toxicity leading to discontinuation of
treatment in patients with urothelial non-muscle-invasive bladder cancer randomised to receive 3
years of maintenance bacille Calmette-Guerin: results from European Organisation for Research and
Treatment of Cancer Genito-Urinary Group study 30911. BJU Int, 2016. 118: 423.
https://www.ncbi.nlm.nih.gov/pubmed/26945890
199. Herr, H.W. Intravesical bacillus Calmette-Guerin outcomes in patients with bladder cancer and
asymptomatic bacteriuria. J Urol, 2012. 187: 435.
https://www.ncbi.nlm.nih.gov/pubmed/22177154
200. Herr, H.W. Outpatient urological procedures in antibiotic-naive patients with bladder cancer with
asymptomatic bacteriuria. BJU Int, 2012. 110: E658.
https://www.ncbi.nlm.nih.gov/pubmed/22883017
201. Lamm, D.L., et al. Incidence and treatment of complications of bacillus Calmette-Guerin intravesical
therapy in superficial bladder cancer. J Urol, 1992. 147: 596.
https://www.ncbi.nlm.nih.gov/pubmed/1538436
202. Palou, J., et al. Intravesical bacillus Calmette-Guerin for the treatment of superficial bladder cancer
in renal transplant patients. Transplantation, 2003. 76: 1514.
https://www.ncbi.nlm.nih.gov/pubmed/14657696
203. Yossepowitch, O., et al. Safety and efficacy of intravesical bacillus Calmette-Guerin instillations in
steroid treated and immunocompromised patients. J Urol, 2006. 176: 482.
https://www.ncbi.nlm.nih.gov/pubmed/16813873
204. Roumeguere, T., et al. Bacillus Calmette-Guerin therapy in non-muscle-invasive bladder carcinoma
after renal transplantation for end-stage aristolochic acid nephropathy. Transpl Int, 2015. 28: 199.
https://www.ncbi.nlm.nih.gov/pubmed/25377421
205. Rodriguez, F., et al. [Practical guideline for the management of adverse events associated with BCG
installations]. Arch Esp Urol, 2008. 61: 591.
https://www.ncbi.nlm.nih.gov/pubmed/18709813
206. Witjes JA, P.J., Soloway M, et al. Clinical practice recommendations for the prevention and
management of intravesical therapy-associated adverse events. Eur Urol Suppl, 2008. 7: 667.
http://www.europeanurology.com/article/S1569-9056(08)00110-3/abstract
207. Palou, J., et al. Intravesical treatment of severe bacillus Calmette-Guerin cystitis. Int Urol Nephrol,
2001. 33: 485.
https://www.ncbi.nlm.nih.gov/pubmed/12230277
208. Falkensammer, C., et al. Late occurrence of bilateral tuberculous-like epididymo-orchitis after
intravesical bacille Calmette-Guerin therapy for superficial bladder carcinoma. Urology, 2005. 65:
175.
https://www.ncbi.nlm.nih.gov/pubmed/15667898
NON-MUSCLE-INVASIVE BLADDER CANCER (TAT1 AND CIS) - LIMITED UPDATE MARCH 2017 43
209. Tinazzi, E., et al. Reactive arthritis following BCG immunotherapy for urinary bladder carcinoma: a
systematic review. Rheumatol Int, 2006. 26: 481.
https://www.ncbi.nlm.nih.gov/pubmed/16220289
210. Morales, A., et al. Intracavitary Bacillus Calmette-Guerin in the treatment of superficial bladder
tumors. J Urol, 1976. 116: 180.
https://www.ncbi.nlm.nih.gov/pubmed/820877
211. Lamm, D.L., et al. Maintenance bacillus Calmette-Guerin immunotherapy for recurrent TA, T1 and
carcinoma in situ transitional cell carcinoma of the bladder: a randomized Southwest Oncology
Group Study. J Urol, 2000. 163: 1124.
https://www.ncbi.nlm.nih.gov/pubmed/10737480
212. Zlotta, A.R., et al. What is the optimal regimen for BCG intravesical therapy? Are six weekly
instillations necessary? Eur Urol, 2000. 37: 470.
https://www.ncbi.nlm.nih.gov/pubmed/10765079
213. Oddens, J., et al. Final results of an EORTC-GU cancers group randomized study of maintenance
bacillus Calmette-Guerin in intermediate- and high-risk Ta, T1 papillary carcinoma of the urinary
bladder: one-third dose versus full dose and 1 year versus 3 years of maintenance. Eur Urol, 2013.
63: 462.
https://www.ncbi.nlm.nih.gov/pubmed/23141049
214. Martinez-Pineiro, L., et al. Maintenance Therapy with 3-monthly Bacillus Calmette-Guerin for 3 Years
is Not Superior to Standard Induction Therapy in High-risk Non-muscle-invasive Urothelial Bladder
Carcinoma: Final Results of Randomised CUETO Study 98013. Eur Urol, 2015. 68: 256.
https://www.ncbi.nlm.nih.gov/pubmed/25794457
215. Martinez-Pineiro, J.A., et al. Long-term follow-up of a randomized prospective trial comparing
a standard 81 mg dose of intravesical bacille Calmette-Guerin with a reduced dose of 27 mg in
superficial bladder cancer. BJU Int, 2002. 89: 671.
https://www.ncbi.nlm.nih.gov/pubmed/11966623
216. Martinez-Pineiro, J.A., et al. Has a 3-fold decreased dose of bacillus Calmette-Guerin the same
efficacy against recurrences and progression of T1G3 and Tis bladder tumors than the standard
dose? Results of a prospective randomized trial. J Urol, 2005. 174: 1242.
https://www.ncbi.nlm.nih.gov/pubmed/16145378
217. Ojea, A., et al. A multicentre, randomised prospective trial comparing three intravesical adjuvant
therapies for intermediate-risk superficial bladder cancer: low-dose bacillus Calmette-Guerin (27
mg) versus very low-dose bacillus Calmette-Guerin (13.5 mg) versus mitomycin C. Eur Urol, 2007.
52: 1398.
https://www.ncbi.nlm.nih.gov/pubmed/17485161
218. Solsona, E., et al. Sequential combination of mitomycin C plus bacillus Calmette-Guerin (BCG) is
more effective but more toxic than BCG alone in patients with non-muscle-invasive bladder cancer
in intermediate- and high-risk patients: final outcome of CUETO 93009, a randomized prospective
trial. Eur Urol, 2015. 67: 508.
https://www.ncbi.nlm.nih.gov/pubmed/25301758
219. Jarvinen, R., et al. Long-term Outcome of Patients with Frequently Recurrent Non-muscle-invasive
Bladder Carcinoma Treated with One Perioperative Plus Four Weekly Instillations of Mitomycin C
Followed by Monthly Bacillus Calmette-Guerin (BCG) or Alternating BCG and Interferon-alpha2b
Instillations: Prospective Randomised FinnBladder-4 Study. Eur Urol, 2015. 68: 611.
https://www.ncbi.nlm.nih.gov/pubmed/25748117
220. Marttila, T., et al. Intravesical Bacillus Calmette-Guerin Versus Combination of Epirubicin and
Interferon-alpha2a in Reducing Recurrence of Non-Muscle-invasive Bladder Carcinoma:
FinnBladder-6 Study. Eur Urol, 2016. 70: 341.
https://www.ncbi.nlm.nih.gov/pubmed/27085624
221. Cui, J., et al. Combination of Intravesical Chemotherapy and Bacillus Calmette-Guerin Versus
Bacillus Calmette-Guerin Monotherapy in Intermediate- and High-risk Nonmuscle Invasive Bladder
Cancer: A Systematic Review and Meta-analysis. Medicine (Baltimore), 2016. 95: e2572.
https://www.ncbi.nlm.nih.gov/pubmed/26817914
222. Jakse, G., et al. Intravesical BCG in patients with carcinoma in situ of the urinary bladder: long-term
results of EORTC GU Group phase II protocol 30861. Eur Urol, 2001. 40: 144.
https://www.ncbi.nlm.nih.gov/pubmed/11528191
223. Gofrit, O.N., et al. The natural history of bladder carcinoma in situ after initial response to bacillus
Calmette-Guerin immunotherapy. Urol Oncol, 2009. 27: 258.
https://www.ncbi.nlm.nih.gov/pubmed/18440839
44 NON-MUSCLE-INVASIVE BLADDER CANCER (TAT1 AND CIS) - LIMITED UPDATE MARCH 2017
224. Sylvester, R.J., et al. Bacillus calmette-guerin versus chemotherapy for the intravesical treatment
of patients with carcinoma in situ of the bladder: a meta-analysis of the published results of
randomized clinical trials. J Urol, 2005. 174: 86.
https://www.ncbi.nlm.nih.gov/pubmed/15947584
225. Kaasinen, E., et al. Alternating mitomycin C and BCG instillations versus BCG alone in treatment of
carcinoma in situ of the urinary bladder: a nordic study. Eur Urol, 2003. 43: 637.
https://www.ncbi.nlm.nih.gov/pubmed/12767365
226. Solsona, E., et al. Extravesical involvement in patients with bladder carcinoma in situ: biological and
therapy implications. J Urol, 1996. 155: 895.
https://www.ncbi.nlm.nih.gov/pubmed/8583601
227. Palou, J., et al. Urothelial carcinoma of the prostate. Urology, 2007. 69: 50.
https://www.ncbi.nlm.nih.gov/pubmed/17280908
228. Palou Redorta, J., et al. Intravesical instillations with bacillus calmette-guerin for the treatment of
carcinoma in situ involving prostatic ducts. Eur Urol, 2006. 49: 834.
https://www.ncbi.nlm.nih.gov/pubmed/16426729
229. Herr, H.W., et al. Defining bacillus Calmette-Guerin refractory superficial bladder tumors. J Urol,
2003. 169: 1706.
https://www.ncbi.nlm.nih.gov/pubmed/12686813
230. Lerner, S.P., et al. Failure to achieve a complete response to induction BCG therapy is associated
with increased risk of disease worsening and death in patients with high risk non-muscle invasive
bladder cancer. Urol Oncol, 2009. 27: 155.
https://www.ncbi.nlm.nih.gov/pubmed/18367117
231. van den Bosch, S., et al. Long-term cancer-specific survival in patients with high-risk, non-muscle-
invasive bladder cancer and tumour progression: a systematic review. Eur Urol, 2011. 60: 493.
https://www.ncbi.nlm.nih.gov/pubmed/21664041
232. Gallagher, B.L., et al. Impact of previous bacille Calmette-Guerin failure pattern on subsequent
response to bacille Calmette-Guerin plus interferon intravesical therapy. Urology, 2008. 71: 297.
https://www.ncbi.nlm.nih.gov/pubmed/18308107
233. Rosevear, H.M., et al. Factors affecting response to bacillus Calmette-Guerin plus interferon for
urothelial carcinoma in situ. J Urol, 2011. 186: 817.
https://www.ncbi.nlm.nih.gov/pubmed/21788050
234. Morales, A., et al. Efficacy and safety of MCNA in patients with nonmuscle invasive bladder cancer
at high risk for recurrence and progression after failed treatment with bacillus Calmette-Guerin. J
Urol, 2015. 193: 1135.
https://www.ncbi.nlm.nih.gov/pubmed/25286009
235. Cockerill, P.A., et al. Intravesical gemcitabine in combination with mitomycin C as salvage treatment
in recurrent non-muscle-invasive bladder cancer. BJU Int, 2016. 117: 456.
https://www.ncbi.nlm.nih.gov/pubmed/25682834
236. Dalbagni, G., et al. Phase II trial of intravesical gemcitabine in bacille Calmette-Guerin-refractory
transitional cell carcinoma of the bladder. J Clin Oncol, 2006. 24: 2729.
https://www.ncbi.nlm.nih.gov/pubmed/16782913
237. Barlow, L., et al. A single-institution experience with induction and maintenance intravesical
docetaxel in the management of non-muscle-invasive bladder cancer refractory to bacille Calmette-
Guerin therapy. BJU Int, 2009. 104: 1098.
https://www.ncbi.nlm.nih.gov/pubmed/19389012
238. Steinberg, G., et al. Efficacy and safety of valrubicin for the treatment of Bacillus Calmette-Guerin
refractory carcinoma in situ of the bladder. The Valrubicin Study Group. J Urol, 2000. 163: 761.
https://www.ncbi.nlm.nih.gov/pubmed/10687972
239. Nativ, O., et al. Combined thermo-chemotherapy for recurrent bladder cancer after bacillus
Calmette-Guerin. J Urol, 2009. 182: 1313.
https://www.ncbi.nlm.nih.gov/pubmed/19683278
240. Joudi, F.N., et al. Final results from a national multicenter phase II trial of combination bacillus
Calmette-Guerin plus interferon alpha-2B for reducing recurrence of superficial bladder cancer. Urol
Oncol, 2006. 24: 344.
https://www.ncbi.nlm.nih.gov/pubmed/16818189
241. Di Lorenzo, G., et al. Gemcitabine versus bacille Calmette-Guerin after initial bacille Calmette-Guerin
failure in non-muscle-invasive bladder cancer: a multicenter prospective randomized trial. Cancer,
2010. 116: 1893.
https://www.ncbi.nlm.nih.gov/pubmed/20162706
NON-MUSCLE-INVASIVE BLADDER CANCER (TAT1 AND CIS) - LIMITED UPDATE MARCH 2017 45
242. Jones, G., et al. Intravesical gemcitabine for non-muscle invasive bladder cancer. Cochrane
Database Syst Rev, 2012. 1: CD009294.
https://www.ncbi.nlm.nih.gov/pubmed/22259002
243. Turker, P., et al. Upstaging of urothelial cancer at the time of radical cystectomy: factors associated
with upstaging and its effect on outcome. BJU Int, 2012. 110: 804.
https://www.ncbi.nlm.nih.gov/pubmed/22321341
244. May, M., et al. Pathological upstaging detected in radical cystectomy procedures is associated with
a significantly worse tumour-specific survival rate for patients with clinical T1 urothelial carcinoma of
the urinary bladder. Scand J Urol Nephrol, 2011. 45: 251.
https://www.ncbi.nlm.nih.gov/pubmed/21388337
245. Svatek, R.S., et al. Discrepancy between clinical and pathological stage: external validation of the
impact on prognosis in an international radical cystectomy cohort. BJU Int, 2011. 107: 898.
https://www.ncbi.nlm.nih.gov/pubmed/21244604
246. Shariat, S.F., et al. Discrepancy between clinical and pathologic stage: impact on prognosis after
radical cystectomy. Eur Urol, 2007. 51: 137.
https://www.ncbi.nlm.nih.gov/pubmed/16793197
247. Moschini, M., et al. Comparing long-term outcomes of primary and progressive carcinoma invading
bladder muscle after radical cystectomy. BJU Int, 2016. 117: 604.
https://www.ncbi.nlm.nih.gov/pubmed/25851271
248. Schrier, B.P., et al. Prognosis of muscle-invasive bladder cancer: difference between primary and
progressive tumours and implications for therapy. Eur Urol, 2004. 45: 292.
https://www.ncbi.nlm.nih.gov/pubmed/15036673
249. Kamat, A.M., et al. The case for early cystectomy in the treatment of nonmuscle invasive
micropapillary bladder carcinoma. J Urol, 2006. 175: 881.
https://www.ncbi.nlm.nih.gov/pubmed/16469571
250. Raj, G.V., et al. Treatment paradigm shift may improve survival of patients with high risk superficial
bladder cancer. J Urol, 2007. 177: 1283.
https://www.ncbi.nlm.nih.gov/pubmed/17382713
251. Stein, J.P., et al. Radical cystectomy in the treatment of invasive bladder cancer: long-term results in
1,054 patients. J Clin Oncol, 2001. 19: 666.
https://www.ncbi.nlm.nih.gov/pubmed/11157016
252. Hautmann, R.E., et al. Radical cystectomy for urothelial carcinoma of the bladder without
neoadjuvant or adjuvant therapy: long-term results in 1100 patients. Eur Urol, 2012. 61: 1039.
https://www.ncbi.nlm.nih.gov/pubmed/22381169
253. Shariat, S.F., et al. Outcomes of radical cystectomy for transitional cell carcinoma of the bladder: a
contemporary series from the Bladder Cancer Research Consortium. J Urol, 2006. 176: 2414.
https://www.ncbi.nlm.nih.gov/pubmed/17085118
254. Holmang, S., et al. Stage progression in Ta papillary urothelial tumors: relationship to grade,
immunohistochemical expression of tumor markers, mitotic frequency and DNA ploidy. J Urol, 2001.
165: 1124.
https://www.ncbi.nlm.nih.gov/pubmed/11257652
255. Gofrit, O.N., et al. Watchful waiting policy in recurrent Ta G1 bladder tumors. Eur Urol, 2006. 49:
303.
https://www.ncbi.nlm.nih.gov/pubmed/16413659
256. Pruthi, R.S., et al. Conservative management of low risk superficial bladder tumors. J Urol, 2008.
179: 87.
https://www.ncbi.nlm.nih.gov/pubmed/17997444
257. Hernandez, V., et al. Long-term oncological outcomes of an active surveillance program in recurrent
low grade Ta bladder cancer. Urol Oncol, 2016. 34: 165 e19.
https://www.ncbi.nlm.nih.gov/pubmed/26687318
258. Holmang, S., et al. Stage Ta-T1 bladder cancer: the relationship between findings at first followup
cystoscopy and subsequent recurrence and progression. J Urol, 2002. 167: 1634.
https://www.ncbi.nlm.nih.gov/pubmed/11912378
259. Mariappan, P., et al. A surveillance schedule for G1Ta bladder cancer allowing efficient use of check
cystoscopy and safe discharge at 5 years based on a 25-year prospective database. J Urol, 2005.
173: 1108.
https://www.ncbi.nlm.nih.gov/pubmed/15758711
260. Soukup, V., et al. Follow-up after surgical treatment of bladder cancer: a critical analysis of the
literature. Eur Urol, 2012. 62: 290.
https://www.ncbi.nlm.nih.gov/pubmed/22609313
46 NON-MUSCLE-INVASIVE BLADDER CANCER (TAT1 AND CIS) - LIMITED UPDATE MARCH 2017
261. Holmang, S., et al. Should follow-up cystoscopy in bacillus Calmette-Guerin-treated patients
continue after five tumour-free years? Eur Urol, 2012. 61: 503.
https://www.ncbi.nlm.nih.gov/pubmed/22119022
262. Niwa, N., et al. Comparison of outcomes between ultrasonography and cystoscopy in the
surveillance of patients with initially diagnosed TaG1-2 bladder cancers: A matched-pair analysis.
Urol Oncol, 2015. 33: 386 e15.
https://www.ncbi.nlm.nih.gov/pubmed/26027764
NON-MUSCLE-INVASIVE BLADDER CANCER (TAT1 AND CIS) - LIMITED UPDATE MARCH 2017 47
EAU Guidelines on
Urothelial
Carcinoma
of the Upper
Urinary Tract
M. Rouprêt, M. Babjuk, M. Burger, E. Compérat,
N. Cowan, P. Gontero, A.H. Mostafid, J. Palou,
B.W.G. van Rhijn, S.F. Shariat. R. Sylvester, R. Zigeuner,
Guidelines Associates: J.L. Dominguez-Escrig,
B. Peyronnet, T. Seisen
2. METHODS 5
2.1 Data identification 5
2.2 Review 5
2.3 Future goals 5
5. DIAGNOSIS 8
5.1 Symptoms 8
5.2 Diagnosis 8
5.2.1 Imaging 8
5.2.1.1 Computed tomography urography 8
5.2.1.2 Magnetic resonance imaging 9
5.2.2 Cystoscopy and urinary cytology 9
5.2.3 Diagnostic ureteroscopy 9
5.3 Summary of evidence and guidelines for the diagnosis of upper tract urothelial carcinoma 10
6. PROGNOSIS 10
6.1 Prognostic factors 10
6.1.1 Pre-operative factors 11
6.1.1.1 Age and sex 11
6.1.1.2 Ethnicity 11
6.1.1.3 Tobacco consumption 11
6.1.1.4 Tumour location 11
6.1.1.5 Surgical delay 11
6.1.1.6 Other 11
6.1.2 Post-operative factors 11
6.1.2.1 Tumour stage and grade 11
6.1.2.2 Lymph node involvement 11
6.1.2.3 Lymphovascular invasion 11
6.1.2.4 Surgical margins 11
6.1.2.5 Pathological factors 11
6.2 Molecular markers 12
6.3 Predictive tools 12
6.4 Bladder recurrence 12
6.5 Risk stratification 12
6.6 Summary of evidence and guidelines for prognosis 13
7. DISEASE MANAGEMENT 13
7.1 Localised disease 13
2 UROTHELIAL CARCINOMA OF THE UPPER URINARY TRACT - LIMITED UPDATE MARCH 2017
7.1.1 Kidney-sparing surgery 13
7.1.1.1 Ureteroscopy 13
7.1.1.2 Percutaneous access 13
7.1.1.3 Surgical open approach 13
7.1.1.4 Guidelines for kidney-sparing management of upper tract
urothelial carcinoma 14
7.1.1.5 Adjuvant topical agents 14
7.1.2 Radical nephroureterectomy 14
7.1.2.1 Laparoscopic radical nephroureterectomy 14
7.1.2.2 Lymph node dissection 14
7.1.2.3 Adjuvant bladder instillation 15
7.1.2.4 Summary of evidence and guidelines for radical nephroureterectomy 15
7.2 Advanced disease 17
7.2.1 Radical nephroureterectomy 17
7.2.2 Systemic chemotherapy 17
7.2.3 Radiotherapy 17
7.2.4 Summary of evidence and guideline for advanced disease 17
8. FOLLOW-UP 17
8.1 Summary of evidence and guidelines for follow-up of upper tract
urothelial carcinoma patients after initial treatment 18
9. REFERENCES 18
UROTHELIAL CARCINOMA OF THE UPPER URINARY TRACT - LIMITED UPDATE MARCH 2017 3
1. INTRODUCTION
1.1 Aim and objectives
The European Association of Urology (EAU) Non-muscle-invasive Bladder Cancer (NMIBC) Guidelines
Panel has compiled these clinical guidelines to provide urologists with evidence-based information and
recommendations for the management of urothelial carcinoma of the upper urinary tract (UTUC). Separate EAU
guidelines documents are available addressing non-muscle-invasive bladder cancer [1], muscle-invasive and
metastatic bladder cancer (MIBC) [2], and primary urethral carcinoma [3].
It must be emphasised that clinical guidelines present the best evidence available to the experts
but following guideline recommendations will not necessarily result in the best outcome. Guidelines can never
replace clinical expertise when making treatment decisions for individual patients, but rather help to focus
decisions - also taking personal values and preferences/individual circumstances of patients into account.
Guidelines are not mandates and do not purport to be a legal standard of care.
New section 3.3.1.1 - Summary of evidence for Chapter 3 (Epidemiology, aetiology and pathology) has been
added.
Summary of evidence LE
A small proportion of upper tract urothelial carcinoma belong to the tumour spectrum of the 3
hereditary non-polyposis colorectal cancer.
New section 5.3 - Summary of evidence section has been added to the Guidelines for the diagnosis of upper
tract urothelial carcinoma.
5.3 Summary of evidence and guidelines for the diagnosis of upper tract urothelial
carcinoma
Summary of evidence LE
The diagnosis of urothelial carcinoma of the upper urinary depends on computed tomography 2
urography.
Selective urinary cytology has high sensitivity in high-grade tumours including carcinoma in 3
situ.
4 UROTHELIAL CARCINOMA OF THE UPPER URINARY TRACT - LIMITED UPDATE MARCH 2017
New section 7.1.2.4 – Summary of evidence section has been added to the Guidelines for radical
nephroureterectomy.
Summary of evidence LE
Radical nephroureterectomy is the standard in high-risk upper tract urothelial carcinoma, 2
regardless of tumour location.
Open and laparoscopic approaches have equivalent efficacy and safety in T1–2/N0 upper 2
tract urothelial carcinoma.
2. METHODS
2.1 Data identification
Standard procedure for EAU Guidelines includes an annual assessment of newly published literature in the
field to guide future updates. For the 2017 UTUC Guidelines, new and relevant evidence has been identified,
collated and appraised through a structured assessment of the literature. A broad and comprehensive scoping
exercise covering all areas of the entire guideline was performed. Excluded from the search were basic
research studies, case series, reports and editorial comments. Only articles published in the English language,
addressing adults were included. The search was restricted to articles published between June 1st 2015
and April 22nd 2016. Databases searched included Pubmed, Ovid, EMBASE and both the Cochrane Central
Register of Controlled Trials and the Cochrane Database of Systematic Reviews. After deduplication, a total of
973 unique records were identified, retrieved and screened for relevance. A detailed search strategy is available
online: http://uroweb.org/guideline/upper-urinary-tract-urothelial-cell-carcinoma/?type=appendicespublicatio
ns.
References used in this text are assessed according to their level of evidence (LE) and Guidelines
are given a grade of recommendation (GR), according to a classification system modified from the Oxford
Centre for Evidence-Based Medicine Levels of Evidence [4]. Additional methodology information can be found
in the general Methodology section of this print, and online at the EAU website: http://uroweb.org/guidelines/.
A list of Associations endorsing the EAU Guidelines can also be viewed online at the above address.
2.2 Review
This document was peer-reviewed prior to publication in 2016.
UROTHELIAL CARCINOMA OF THE UPPER URINARY TRACT - LIMITED UPDATE MARCH 2017 5
In 17% of cases, concurrent bladder cancer is present [11]. Recurrence in the bladder occurs in 22-47% of
UTUC patients [12], compared with 2-6% in the contralateral upper tract [13, 14].
Approximately 60% of UTUC are invasive at diagnosis compared with 15-25% of bladder tumours
[8, 15]. Upper tract urothelial carcinomas have a peak incidence in people aged 70 to 90 years and are three
times more common in men [16, 17].
Familial/hereditary UTUC are linked to hereditary non-polyposis colorectal carcinoma (HNPCC) [18],
which can be screened for during an interview (Figure 3.1) [19]. Patients should undergo DNA sequencing to
identify hereditary cancers misclassified as sporadic if they fulfil the criteria for HNPCC [18, 20].
Figure 3.1: Selection of patients with UTUC for hereditary screening during the first medical interview
UTUC
Upper tract urothelial carcinoma often present after a bladder cancer. The average duration of exposure
needed to develop UTUC is ~7 years, with a latency of ~20 years following termination of exposure.
Several studies have revealed the carcinogenic potential of aristolochic acid contained in
Aristolochia fangchi and Aristolochia clematis. The aristolochic acid derivative dA-aristolactam causes a
specific mutation in the p53 gene at codon 139, which occurs mainly in patients with nephropathy due to
Chinese herbs or Balkan endemic nephropathy [22, 24, 25].
6 UROTHELIAL CARCINOMA OF THE UPPER URINARY TRACT - LIMITED UPDATE MARCH 2017
There is a high incidence of UTUC in Taiwan, especially on the South-west coast which represents 20-25%
of UCs in the region [22, 25]. There is a possible association of UTUC with blackfoot disease and arsenic
exposure in drinking water in this population [22, 25, 26].
Differences in the ability to counteract carcinogens may contribute to host susceptibility to UTUC. Some
genetic polymorphisms are associated with an increased risk of cancer or faster disease progression, which
introduces variability in the inter-individual susceptibility to the risk factors previously mentioned. Upper tract
urothelial carcinoma may share some risk factors or molecular disruption pathways with bladder UC. Two
UTUC-specific polymorphisms have been reported [27, 28].
Summary of evidence LE
A small proportion of upper tract urothelial carcinoma belong to the tumour spectrum of the hereditary 3
non-polyposis colorectal cancer.
UROTHELIAL CARCINOMA OF THE UPPER URINARY TRACT - LIMITED UPDATE MARCH 2017 7
Table 4.1: TNM classification 2017 for upper tract urothelial carcinoma [36]
T - Primary tumour
TX Primary tumour cannot be assessed
T0 No evidence of primary tumour
Ta Non-invasive papillary carcinoma
Tis Carcinoma in situ
T1 Tumour invades subepithelial connective tissue
T2 Tumour invades muscularis
T3 (Renal pelvis) Tumour invades beyond muscularis into peripelvic fat or renal parenchyma
(Ureter) Tumour invades beyond muscularis into periureteric fat
T4 Tumour invades adjacent organs or through the kidney into perinephric fat
N - Regional lymph nodes
NX Regional lymph nodes cannot be assessed
N0 No regional lymph node metastasis
N1 Metastasis in a single lymph node 2 cm or less in the greatest dimension
N2 Metastasis in a single lymph node more than 2 cm, or multiple lymph nodes
M - Distant metastasis
M0 No distant metastasis
M1 Distant metastasis
Recommendations LE GR
Classify the depths of invasion (staging) according to Tumour Node Metastasis classification, 3 A
8th edition.
Classify flat, high-grade tumours, confined to the mucosa, as carcinoma in situ (Tis). 3 A
Use the World Health Organization 1973 and 2004 grading systems for the histological 3 A
classification of upper tract urothelial carcinoma.
5. DIAGNOSIS
5.1 Symptoms
The most common symptom is visible- or non-visible haematuria (70-80%) [42, 43]. Flank pain occurs in
20-40% of cases, and a lumbar mass in 10-20% [44, 45]. Systemic symptoms (including anorexia, weight loss,
malaise, fatigue, fever, night sweats, or cough) are associated with UTUC and should prompt more rigorous
evaluation for metastatic disease [44, 45].
5.2 Diagnosis
5.2.1 Imaging
5.2.1.1 Computed tomography urography
Computed tomography (CT) urography has the highest diagnostic accuracy for UTUC of all the clinically
available imaging techniques [45]. The sensitivity of CT urography for UTUC is 0.67-1.0 and the specificity is
0.93-0.99 according to the technique used [21, 46-51]. Epithelial ‘flat lesions’ without mass effect or urothelial
thickening are not visible with CT [52].
8 UROTHELIAL CARCINOMA OF THE UPPER URINARY TRACT - LIMITED UPDATE MARCH 2017
Computed tomography urography is defined as CT examination of the kidneys, ureters and bladder following
the administration of intravenous contrast material [21, 53]. Rapid acquisition of thin sections provides
high-resolution isotropic images that can be viewed in multiple planes to assist with diagnosis without loss
of resolution. Computed-tomography urography usually includes several phases of acquisition following
administration of intravenous contrast media [21, 54].
The secondary sign of hydronephrosis is associated with advanced disease and poor oncological outcome
[21, 53, 55, 56]. The presence of enlarged lymph nodes is highly predictive of metastasis in UTUC [21].
Retrograde ureteropyelography is an option to evaluate UTUC [21, 49, 60, 61] but is now mostly used in
conjunction with ureteroscopy and not as a stand-alone diagnostic technique due to similar diagnostic
accuracy when compared with CT urography for UTUC [49]. Urinary cytology of the renal cavities and ureteral
lumina is preferable before application of contrast agent for retrograde ureteropyelography, because the latter
may cause deterioration of cytological specimens [59, 60].
The sensitivity of fluorescence in situ hybridisation (FISH) for molecular abnormalities characteristic of UTUC
parallels its performance in bladder cancer [62]. However, its use may be limited by the preponderance of
low-grade recurrent disease in the population undergoing surveillance and kidney-sparing therapy for UTUC
[63, 64]. FISH currently has limited value for the surveillance of UTUC [63, 64].
Flexible ureteroscopy is especially useful for diagnostic uncertainty, if kidney-sparing treatment is considered,
or in patients with a solitary kidney. Additional information can be provided by ureteroscopy with- or without
biopsy. Combining ureteroscopic biopsy grade, imaging findings such as hydronephrosis, and urinary cytology,
may help in the decision-making process between radical nephroureterectomy (RNU) and endoscopic
treatment [67, 69].
Technical developments in flexible ureteroscopes and the use of novel imaging techniques improve
visualisation and the diagnosis of flat lesions [70]. Narrow-band imaging is the most promising technique to
date but the results are preliminary [69, 71]. Table 5.3 lists the recommendations for diagnosis.
UROTHELIAL CARCINOMA OF THE UPPER URINARY TRACT - LIMITED UPDATE MARCH 2017 9
5.3 Summary of evidence and guidelines for the diagnosis of upper tract urothelial
carcinoma
Summary of evidence LE
The diagnosis of upper tract urothelial carcinoma depends on computed tomography urography. 2
Selective urinary cytology has high sensitivity in high-grade tumours including carcinoma in situ. 3
Recommendations GR
Perform urinary cytology as part of a standard diagnostic work-up. A
Perform a cystoscopy to rule out concomitant bladder tumour. A
Perform a computed tomography urography for the diagnostic work-up. A
Use diagnostic ureteroscopy and biopsy in cases where additional information will impact treatment C
decisions.
6. PROGNOSIS
6.1 Prognostic factors
Upper tract urothelial carcinomas that invade the muscle wall usually have a poor prognosis. The five-year
specific survival is < 50% for patients with pT2/pT3 tumours and < 10% for those with pT4 [71-73]. The main
prognostic factors are briefly listed below; Figure 6.1 presents a more exhaustive list.
UTUC
Prognostic factors
Pre-operative Post-operative
• Multifocality • Stage
• Grade (biopsy, cytology) • Grade
• Advanced age • Concomitant carcinoma in situ
• Tobacco consumption • Distal ureter management
• ECOG - PS ≥ 1 • Lymphovascular invasion
• Co-morbidity (ASA score) • Lymph node involvement
• Systemic revealing symptoms • Tumour architecture
• Hydronephrosis • Surgical margins status
• Delay surgery > 3 months • Tumour necrosis
• Tumour location • Molecular marker status
• BMI > 30 • Variant histology
• Neutrophil-to-lymphocyte ratio
• African race
10 UROTHELIAL CARCINOMA OF THE UPPER URINARY TRACT - LIMITED UPDATE MARCH 2017
6.1.1 Pre-operative factors
6.1.1.1 Age and sex
Gender is no longer considered an independent prognostic factor influencing UTUC mortality [16, 73, 74].
Older age at the time of RNU is independently associated with decreased cancer-specific survival [73, 75] (LE:
3). Many elderly patients can be cured with RNU [76], suggesting that age alone is an inadequate indicator
of outcome [75, 76]. Despite its association with survival, age alone should not prevent a potentially curable
approach.
6.1.1.2 Ethnicity
One multicentre study did not show any difference between races [77] but population-based studies have
indicated that African-American patients have worse outcomes compared to other ethnicities [76, 78] (LE: 3).
6.1.1.6 Other
The American Society of Anesthesiologists (ASA) score significantly correlates with cancer-specific survival
after RNU [91] (LE: 3). The Eastern Cooperative Oncology Group (ECOG) performance status correlates only
with overall survival [92]. Obesity and higher body mass index adversely affect cancer-specific outcomes
in UTUC [93, 94] (LE: 3). The pre-treatment derived neutrophil-lymphocyte ratio also correlates with higher
cancer-specific mortality [95, 96] (LE: 3).
UROTHELIAL CARCINOMA OF THE UPPER URINARY TRACT - LIMITED UPDATE MARCH 2017 11
6.2 Molecular markers
Several studies have investigated the prognostic impact of markers related to cell adhesion (E-cadherin
and CD24), cell differentiation (Snail and epidermal growth factor receptor), angiogenesis (hypoxia-inducible
factor-1α and metalloproteinases), cell proliferation (Ki67), epithelial-mesenchymal transition (Snail), mitosis
(Aurora-A), apoptosis (Bcl-2 and survivin), vascular invasion (RON), c-met protein (MET) and mTOR pathway
[21, 73, 113-117]. Microsatellite instability (MSI) is an independent molecular prognostic marker [118] and can
help detect germline mutations and hereditary cancers [18].
The rarity of UTUC means that the main limitations of the above studies were their retrospective nature and
small sample size. None of the markers have fulfilled the criteria necessary to support their introduction in daily
clinical decision-making.
UTUC
12 UROTHELIAL CARCINOMA OF THE UPPER URINARY TRACT - LIMITED UPDATE MARCH 2017
6.6 Summary of evidence and guidelines for prognosis
Summary of evidence LE
Age, sex and ethnicity are no longer considered as independent prognostic factors. 3
The primary recognised post-operative prognostic factors are tumour stage and grade, extranodal 3
extension and lymphovascular invasion.
Recommendations LE GR
Use microsatellite instability as an independent molecular prognostic marker to help detect 3 C
germline mutations and hereditary cancers.
Use the American Society of Anesthesiologists score to assess cancer-specific survival 3 C
following surgery.
7. DISEASE MANAGEMENT
7.1 Localised disease
7.1.1 Kidney-sparing surgery
Kidney-sparing surgery (KSS) for low-risk UTUC (Section 7.1.1.4) allows sparing the morbidity associated with
radical surgery, without compromising oncological outcomes and kidney function [128]. In low-risk cancers
it is the primary approach and survival is similar after KSS versus RNU [129]. This option should therefore be
discussed in all low-risk cases, irrespective of the status of the contralateral kidney [21, 130, 131]. In high-risk
tumours it can be considered in imperative cases (i.e. renal insufficiency or solitary functional kidney).
7.1.1.1 Ureteroscopy
Endoscopic ablation can be considered in patients with clinically low-risk cancer in the following situations
[132, 133]:
• laser generator [134] and pliers are available for biopsies [133, 135] (LE: 3);
• in case a flexible ureteroscope is available (rather than a rigid ureteroscope);
• the patient is informed of the need for closer, more stringent, surveillance;
• complete tumour resection can be achieved.
Nevertheless, a risk of under-staging and under-grading remains with endoscopic management.
Complete distal ureterectomy with neocystostomy are indicated for low-risk tumours in the distal ureter that
cannot be removed completely endoscopically, and for high-risk tumours when kidney-sparing surgery for renal
function preservation is necessary [21, 137, 138] (LE: 3).
Segmental resection of the iliac and lumbar ureter is associated with higher failure rates than for the distal
pelvic ureter [21, 137, 138] (LE: 3).
Partial pyelectomy or partial nephrectomy is almost never indicated. Open resection of tumours of the renal
pelvis or calices has almost disappeared.
UROTHELIAL CARCINOMA OF THE UPPER URINARY TRACT - LIMITED UPDATE MARCH 2017 13
7.1.1.4 Guidelines for kidney-sparing management of upper tract urothelial carcinoma
Recommendations GR
Offer kidney-sparing management as primary treatment option to patients with low-risk tumour and C
two functional kidneys.
Offer kidney-sparing management in patients with solitary kidney and/or impaired renal function, C
providing it will not compromise the oncological outcome. This decision will have to be made on a
case-by-case basis, engaging the patient in a shared decision-making process.
Offer a kidney-sparing approach in high-risk cancers for distal ureteral tumours and in imperative C
cases (solitary kidney and/or impaired renal function).
Use a laser for endoscopic treatment of upper tract urothelial carcinoma. C
Laparoscopic RNU is safe in experienced hands when adhering to strict oncologic principles. There is a
tendency towards equivalent oncological outcomes after laparoscopic or open RNU [21, 143-147] (LE: 3).
Only one prospective randomised study has shown that laparoscopic RNU is not inferior to open RNU for
non-invasive UTUC. In contrast, oncological outcomes were in favour of the open approach in pT3 and/or
high-grade tumours [148] (LE: 2). Oncological outcomes after RNU have not changed significantly over the past
three decades despite staging and refinements in staging and surgical technique [149] (LE: 3). A robot-assisted
laparoscopic approach can be considered, but solid data are still lacking [150].
14 UROTHELIAL CARCINOMA OF THE UPPER URINARY TRACT - LIMITED UPDATE MARCH 2017
or extent of LND [151, 152]. Lymph node dissection can be achieved following lymphatic drainage as follows:
LND on the side of the affected ureter, retroperitoneal LND for higher ureteral tumour and/or tumour of the renal
pelvis (i.e. right side: border vena cava or right side of the aorta; and left side: border aorta) [21, 98].
Summary of evidence LE
Radical nephroureterectomy is the standard in high-risk upper tract urothelial carcinoma, regardless of 2
tumour location.
Open and laparoscopic approaches have equivalent efficacy and safety in T1–2/N0 upper tract 2
urothelial carcinoma.
Recommendations GR
Perform radical nephroureterectomy in the following situations: B
• suspicion of infiltrating upper tract urothelial carcinoma on imaging;
• high-grade tumour (urinary cytology);
• multifocality (with two functional kidneys);
• non-invasive but large (> 1 cm) upper tract urothelial carcinoma.
Technical steps of radical nephroureterectomy:
Remove the bladder cuff. A
Perform a lymphadenectomy in invasive upper tract urothelial carcinoma. C
Offer a post-operative bladder instillation to lower the bladder recurrence rate. B
UROTHELIAL CARCINOMA OF THE UPPER URINARY TRACT - LIMITED UPDATE MARCH 2017 15
Figure 7.1: Proposed flowchart for the management of localised upper tract urothelial carcinoma
UTUC
Diagnostic evaluation:
CTU, urinary cytology, cystoscopy
Kidney-sparing surgery:
flexible ureteroscopy or segmental Open Laparoscopic
resection (prefer open in cT3, cN+)
or percutaneous approach
Recurrence
UTUC
Ureter Kidney
16 UROTHELIAL CARCINOMA OF THE UPPER URINARY TRACT - LIMITED UPDATE MARCH 2017
7.2 Advanced disease
7.2.1 Radical nephroureterectomy
There is no oncologic benefit for RNU in patients with metastatic UTUC except for palliative considerations
[15, 100] (LE: 3).
There were no adverse effects of neoadjuvant chemotherapy for UTUC in the only study published to date
[160], although survival data need to mature and longer follow-up is awaited. Adjuvant chemotherapy can
achieve a recurrence-free rate of < 50% [161, 162].
After a recent comprehensive search of studies examining the role of peri-operative chemotherapy for
UTUC, there appears to be an overall survival and disease-free survival benefit for cisplatin-based adjuvant
chemotherapy [163] (LE: 3). However, there are currently insufficient data to base recommendations on until
further evidence from an ongoing prospective trial is available [164].
7.2.3 Radiotherapy
The role of adjuvant radiotherapy is not well defined, neither alone, nor in combination with chemotherapy
[21, 165] (LE: 3). It may be of benefit in terms of loco-regional and bladder control in selected patients but data
are too scarce to give recommendations.
Summary of evidence LE
Peri-operative systemic cisplatin-based chemotherapy may provide a survival benefit. 3
Recommendation LE GR
In case chemotherapy is offered, a neoadjuvant approach is recommended, as the renal 3 C
function will decrease after radical nephroureterectomy.
8. FOLLOW-UP
The risk of disease recurrence and death evolves in the follow-up period after surgery and is less likely with
time [166, 167]. Stringent follow-up (Section 8.1) is mandatory to detect metachronous bladder tumours [13],
local recurrence, and distant metastases. When RNU is performed, local recurrence is rare and the risk of
distant metastases is directly related to the risk factors listed previously.
Surveillance regimens are based on cystoscopy and urinary cytology for > 5 years [11-13]. Bladder
recurrence is not a distant recurrence [12]. When kidney-sparing surgery is performed, the ipsilateral UUT
requires careful follow-up due to the high risk of disease recurrence [130, 135, 168]. Despite endourological
improvements, follow-up after kidney-sparing surgery is difficult; frequent and repeated endoscopic procedures
are mandatory. As done in bladder cancer, a second look has been proposed after KSS but is not yet routine
practice [169].
UROTHELIAL CARCINOMA OF THE UPPER URINARY TRACT - LIMITED UPDATE MARCH 2017 17
8.1 Summary of evidence and guidelines for follow-up of upper tract urothelial
carcinoma patients after initial treatment
Summary of evidence LE
Follow-up is more frequent and more strict in patients who have undergone kidney-sparing treatment 3
compared to radical nephroureterectomy.
Recommendations GR
After radical nephroureterectomy, > five years
Non-invasive tumour
Perform cystoscopy/urinary cytology at three months, and then annually. C
Perform computed tomography urography every year. C
Invasive tumour
Perform cystoscopy/urinary cytology at three months, and then annually. C
Perform computed tomography urography every six months for two years, and then annually. C
After kidney-sparing management, > five years
Perform urinary cytology and computed tomography urography at three and six months, and then C
annually.
Perform cystoscopy, ureteroscopy and cytology in situ at three and six months, and then every six C
months for two years, and then annually.
9. REFERENCES
1. Babjuk, M., et al., EAU Guidelines on Non-muscle-invasive Bladder Cancer (T1, T1 and CIS), in EAU
Guidelines, Edn. presented at the 32nd EAU Annual Congress, London. 2017, EAU Guidelines Office
Arnhem, The Netherlands.
2. Witjes, J.A., et al., EAU Guidelines on Muscle-invasive and Metastatic Bladder Cancer in EAU
Guidelines, Edn. presented at the 32nd EAU Annual Congress, London. 2017, EAU Guidelines Office
Arnhem, The Netherlands.
3. Gakis, G., et al., EAU Guidelines on Primary Urethral Carcinoma, in EAU Guidelines, Edn. presented
at the EAU Annual Congress, London. 2017, EAU Guidelines Office Arnhem, The Netherlands.
4. Bob Phillips, C.B., Dave Sackett, Doug Badenoch, Sharon Straus, Brian Haynes, Martin Dawes
since November 1998. Updated by Jeremy Howick March 2009. Oxford Centre for Evidence-based
Medicine Levels of Evidence (May 2009).
5. Peyronnet, B., et al. Oncological outcomes of laparoscopic/robotic nephroureterectomy versus open
nephroureterectomy for upper tract urothelial carcinoma: an EAU Guidelines systematic review. Eur
Urol Focus, 2017. Prior to print, 2017.
6. Bruins, M., et al. What are the benefits and harms of lymph node dissection (LND) during radical
nephroureterectomy for upper tract urothelial carcinoma (UTUC)?. PROSPERO International
prospective register of systematic reviews, 2015.
7. Siegel, R.L., et al. Cancer statistics, 2016. CA Cancer J Clin, 2016. 66: 7.
8. Babjuk, M., et al. EAU Guidelines on Non-Muscle-invasive Urothelial Carcinoma of the Bladder:
Update 2016. Eur Urol, 2016.
9. Siegel, R.L., et al. Cancer statistics, 2015. CA Cancer J Clin, 2015. 65: 5.
10. Munoz, J.J., et al. Upper tract urothelial neoplasms: incidence and survival during the last 2
decades. J Urol, 2000. 164: 1523.
11. Cosentino, M., et al. Upper urinary tract urothelial cell carcinoma: location as a predictive factor for
concomitant bladder carcinoma. World J Urol, 2013. 31: 141.
12. Seisen, T., et al. A Systematic Review and Meta-analysis of Clinicopathologic Factors Linked
to Intravesical Recurrence After Radical Nephroureterectomy to Treat Upper Tract Urothelial
Carcinoma. Eur Urol, 2015. 67: 1122.
13. Li, W.M., et al. Oncologic outcomes following three different approaches to the distal ureter and
bladder cuff in nephroureterectomy for primary upper urinary tract urothelial carcinoma. Eur Urol,
2010. 57: 963.
18 UROTHELIAL CARCINOMA OF THE UPPER URINARY TRACT - LIMITED UPDATE MARCH 2017
14. Novara, G., et al. Independent predictors of contralateral metachronous upper urinary tract
transitional cell carcinoma after nephroureterectomy: multi-institutional dataset from three European
centers. Int J Urol, 2009. 16: 187.
15. Margulis, V., et al. Outcomes of radical nephroureterectomy: a series from the Upper Tract Urothelial
Carcinoma Collaboration. Cancer, 2009. 115: 1224.
16. Shariat, S.F., et al. Gender differences in radical nephroureterectomy for upper tract urothelial
carcinoma. World J Urol, 2011. 29: 481.
17. Lughezzani, G., et al. Gender-related differences in patients with stage I to III upper tract urothelial
carcinoma: results from the Surveillance, Epidemiology, and End Results database. Urology, 2010.
75: 321.
18. Roupret, M., et al. Upper urinary tract urothelial cell carcinomas and other urological malignancies
involved in the hereditary nonpolyposis colorectal cancer (lynch syndrome) tumor spectrum.
Eur Urol, 2008. 54: 1226.
19. Audenet, F., et al. A proportion of hereditary upper urinary tract urothelial carcinomas are
misclassified as sporadic according to a multi-institutional database analysis: proposal of patient-
specific risk identification tool. BJU Int, 2012. 110: E583.
20. Acher, P., et al. Towards a rational strategy for the surveillance of patients with Lynch syndrome
(hereditary non-polyposis colon cancer) for upper tract transitional cell carcinoma. BJU Int, 2010.
106: 300.
21. Roupret, M., et al. European Association of Urology Guidelines on Upper Urinary Tract Urothelial
Cell Carcinoma: 2015 Update. Eur Urol, 2015. 68: 868.
22. Colin, P., et al. Environmental factors involved in carcinogenesis of urothelial cell carcinomas of the
upper urinary tract. BJU Int, 2009. 104: 1436.
23. Crivelli, J.J., et al. Effect of smoking on outcomes of urothelial carcinoma: a systematic review of the
literature. Eur Urol, 2014. 65: 742.
24. Grollman, A.P., et al. Aristolochic acid and the etiology of endemic (Balkan) nephropathy.
Proc Natl Acad Sci U S A, 2007. 104: 12129.
25. Chen, C.H., et al. Aristolochic acid-associated urothelial cancer in Taiwan. Proc Natl Acad Sci U S A,
2012. 109: 8241.
26. Chiou, H.Y., et al. Incidence of transitional cell carcinoma and arsenic in drinking water: a follow-up
study of 8,102 residents in an arseniasis-endemic area in northeastern Taiwan. Am J Epidemiol,
2001. 153: 411.
27. Roupret, M., et al. Genetic variability in 8q24 confers susceptibility to urothelial carcinoma of the
upper urinary tract and is linked with patterns of disease aggressiveness at diagnosis. J Urol, 2012.
187: 424.
28. Roupret, M., et al. Phenol sulfotransferase SULT1A1*2 allele and enhanced risk of upper urinary
tract urothelial cell carcinoma. Cancer Epidemiol Biomarkers Prev, 2007. 16: 2500.
29. Sakano, S., et al. Impact of variant histology on disease aggressiveness and outcome after
nephroureterectomy in Japanese patients with upper tract urothelial carcinoma. Int J Clin Oncol,
2015. 20: 362.
30. Ouzzane, A., et al. Small cell carcinoma of the upper urinary tract (UUT-SCC): report of a rare entity
and systematic review of the literature. Cancer Treat Rev, 2011. 37: 366.
31. Rink, M., et al. Impact of histological variants on clinical outcomes of patients with upper urinary
tract urothelial carcinoma. J Urol, 2012. 188: 398.
32. Masson-Lecomte, A., et al. Impact of micropapillary histological variant on survival after radical
nephroureterectomy for upper tract urothelial carcinoma. World J Urol, 2014. 32: 531.
33. Olgac, S., et al. Urothelial carcinoma of the renal pelvis: a clinicopathologic study of 130 cases.
Am J Surg Pathol, 2004. 28: 1545.
34. Perez-Montiel, D., et al. High-grade urothelial carcinoma of the renal pelvis: clinicopathologic study
of 108 cases with emphasis on unusual morphologic variants. Mod Pathol, 2006. 19: 494.
35. Tang, Q., et al. The prognostic impact of squamous and glandular differentiation for upper tract
urothelial carcinoma patients after radical nephroureterectomy. World J Urol, 2016. 34: 871.
36. Brierley JD., et al. TNM classification of malignant tumors. UICC International Union Against Cancer.
8th edn. 2017, Oxford.
37. Roscigno, M., et al. International validation of the prognostic value of subclassification for AJCC
stage pT3 upper tract urothelial carcinoma of the renal pelvis. BJU Int, 2012. 110: 674.
38. Park, J., et al. Reassessment of prognostic heterogeneity of pT3 renal pelvic urothelial carcinoma:
analysis in terms of proposed pT3 subclassification systems. J Urol, 2014. 192: 1064.
UROTHELIAL CARCINOMA OF THE UPPER URINARY TRACT - LIMITED UPDATE MARCH 2017 19
39. Sauter G, A.F., Amin M, et al., Tumours of the urinary system: non-invasive urothelial neoplasias.
In: WHO classification of classification of tumours of the urinary system and male genital organs.,
in Tumours of the urinary system: non-invasive urothelial neoplasias. In: WHO classification of
classification of tumours of the urinary system and male genital organs. A.F. Sauter G, Amin M, et al.,
Editor. 2004, IARCC Press: Lyon.
40. Epstein, J.I., et al. The World Health Organization/International Society of Urological Pathology
consensus classification of urothelial (transitional cell) neoplasms of the urinary bladder. Bladder
Consensus Conference Committee. Am J Surg Pathol, 1998. 22: 1435.
41. Moch, H., et al., WHO Classification of Tumours of the Urinary System and Male Genital Organs.
4th ed. ed, ed. O. H. 2016, Lyon, France.
42. Inman, B.A., et al. Carcinoma of the upper urinary tract: predictors of survival and competing causes
of mortality. Cancer, 2009. 115: 2853.
43. Cowan, N.C. CT urography for hematuria. Nat Rev Urol, 2012. 9: 218.
44. Raman, J.D., et al. Does preoperative symptom classification impact prognosis in patients with
clinically localized upper-tract urothelial carcinoma managed by radical nephroureterectomy?
Urol Oncol, 2011. 29: 716.
45. Ito, Y., et al. Preoperative hydronephrosis grade independently predicts worse pathological
outcomes in patients undergoing nephroureterectomy for upper tract urothelial carcinoma.
J Urol, 2011. 185: 1621.
46. Chow, L.C., et al. Split-bolus MDCT urography with synchronous nephrographic and excretory
phase enhancement. AJR Am J Roentgenol, 2007. 189: 314.
47. Maheshwari, E., et al. Split-bolus MDCT urography: Upper tract opacification and performance for
upper tract tumors in patients with hematuria. AJR Am J Roentgenol, 2010. 194: 453.
48. Sudakoff, G.S., et al. Multidetector computerized tomography urography as the primary imaging
modality for detecting urinary tract neoplasms in patients with asymptomatic hematuria.
J Urol, 2008. 179: 862.
49. Wang, L.J., et al. Diagnostic accuracy of transitional cell carcinoma on multidetector computerized
tomography urography in patients with gross hematuria. J Urol, 2009. 181: 524.
50. Wang, L.J., et al. Multidetector computerized tomography urography is more accurate than
excretory urography for diagnosing transitional cell carcinoma of the upper urinary tract in adults
with hematuria. J Urol, 2010. 183: 48.
51. Jinzaki, M., et al. Comparison of CT urography and excretory urography in the detection and
localization of urothelial carcinoma of the upper urinary tract. AJR Am J Roentgenol, 2011. 196:
1102.
52. Xu, A.D., et al. Significance of upper urinary tract urothelial thickening and filling defect seen on
MDCT urography in patients with a history of urothelial neoplasms. AJR Am J Roentgenol, 2010.
195: 959.
53. Van Der Molen, A.J., et al. CT urography: definition, indications and techniques. A guideline for
clinical practice. Eur Radiol, 2008. 18: 4.
54. Vrtiska, T.J., et al. Spatial resolution and radiation dose of a 64-MDCT scanner compared with
published CT urography protocols. AJR Am J Roentgenol, 2009. 192: 941.
55. Messer, J.C., et al. Multi-institutional validation of the ability of preoperative hydronephrosis to
predict advanced pathologic tumor stage in upper-tract urothelial carcinoma. Urologic oncology,
2013. 31: 904.
56. Hurel, S., et al. Influence of preoperative factors on the oncologic outcome for upper urinary tract
urothelial carcinoma after radical nephroureterectomy. World J Urol, 2015. 33: 335.
57. Takahashi, N., et al. Gadolinium enhanced magnetic resonance urography for upper urinary tract
malignancy. J Urol, 2010. 183: 1330.
58. Witjes, J.A., et al. Hexaminolevulinate-guided fluorescence cystoscopy in the diagnosis and
follow-up of patients with non-muscle-invasive bladder cancer: review of the evidence and
recommendations. Eur Urol, 2010. 57: 607.
59. Messer, J., et al. Urinary cytology has a poor performance for predicting invasive or high-grade
upper-tract urothelial carcinoma. BJU Int, 2011. 108: 701.
60. Lee, K.S., et al. MR urography versus retrograde pyelography/ureteroscopy for the exclusion of
upper urinary tract malignancy. Clin Radiol, 2010. 65: 185.
61. Cowan, N.C., et al. Multidetector computed tomography urography for diagnosing upper urinary
tract urothelial tumour. BJU Int, 2007. 99: 1363.
62. Reynolds, J.P., et al. Comparison of urine cytology and fluorescence in situ hybridization in upper
urothelial tract samples. Cancer Cytopathol, 2014. 122: 459.
20 UROTHELIAL CARCINOMA OF THE UPPER URINARY TRACT - LIMITED UPDATE MARCH 2017
63. Johannes, J.R., et al. Voided urine fluorescence in situ hybridization testing for upper tract urothelial
carcinoma surveillance. J Urol, 2010. 184: 879.
64. Chen, A.A., et al. Is there a role for FISH in the management and surveillance of patients with upper
tract transitional-cell carcinoma? J Endourol, 2008. 22: 1371.
65. Rojas, C.P., et al. Low biopsy volume in ureteroscopy does not affect tumor biopsy grading in upper
tract urothelial carcinoma. Urologic oncology, 2013. 31: 1696.
66. Smith, A.K., et al. Inadequacy of biopsy for diagnosis of upper tract urothelial carcinoma:
implications for conservative management. Urology, 2011. 78: 82.
67. Clements, T., et al. High-grade ureteroscopic biopsy is associated with advanced pathology of
upper-tract urothelial carcinoma tumors at definitive surgical resection. J Endourol, 2012. 26: 398.
68. Ishikawa, S., et al. Impact of diagnostic ureteroscopy on intravesical recurrence and survival in
patients with urothelial carcinoma of the upper urinary tract. J Urol, 2010. 184: 883.
69. Brien, J.C., et al. Preoperative hydronephrosis, ureteroscopic biopsy grade and urinary cytology can
improve prediction of advanced upper tract urothelial carcinoma. J Urol, 2010. 184: 69.
70. Bus, M.T., et al. Optical diagnostics for upper urinary tract urothelial cancer: technology, thresholds,
and clinical applications. J Endourol, 2015. 29: 113.
71. Abouassaly, R., et al. Troubling outcomes from population-level analysis of surgery for upper tract
urothelial carcinoma. Urology, 2010. 76: 895.
72. Jeldres, C., et al. A population-based assessment of perioperative mortality after
nephroureterectomy for upper-tract urothelial carcinoma. Urology, 2010. 75: 315.
73. Lughezzani, G., et al. Prognostic factors in upper urinary tract urothelial carcinomas: a
comprehensive review of the current literature. Eur Urol, 2012. 62: 100.
74. Fernandez, M.I., et al. Evidence-based sex-related outcomes after radical nephroureterectomy for
upper tract urothelial carcinoma: results of large multicenter study. Urology, 2009. 73: 142.
75. Shariat, S.F., et al. Advanced patient age is associated with inferior cancer-specific survival after
radical nephroureterectomy. BJU Int, 2010. 105: 1672.
76. Chromecki, T.F., et al. Chronological age is not an independent predictor of clinical outcomes after
radical nephroureterectomy. World J Urol, 2011. 29: 473.
77. Matsumoto, K., et al. Racial differences in the outcome of patients with urothelial carcinoma of the
upper urinary tract: an international study. BJU Int, 2011. 108: E304.
78. Hosain, G.M., et al. Racial/ethnic differences in upper-tract urothelial cancer. Ethn Dis, 2012. 22:
295.
79. Rink, M., et al. Impact of smoking on oncologic outcomes of upper tract urothelial carcinoma after
radical nephroureterectomy. Eur Urol, 2013. 63: 1082.
80. Simsir, A., et al. Prognostic factors for upper urinary tract urothelial carcinomas: stage, grade, and
smoking status. Int Urol Nephrol, 2011. 43: 1039.
81. Xylinas, E., et al. Impact of smoking status and cumulative exposure on intravesical recurrence of
upper tract urothelial carcinoma after radical nephroureterectomy. BJU Int, 2014. 114: 56.
82. Isbarn, H., et al. Location of the primary tumor is not an independent predictor of cancer specific
mortality in patients with upper urinary tract urothelial carcinoma. J Urol, 2009. 182: 2177.
83. Yafi, F.A., et al. Impact of tumour location versus multifocality in patients with upper tract urothelial
carcinoma treated with nephroureterectomy and bladder cuff excision: a homogeneous series
without perioperative chemotherapy. BJU Int, 2012. 110: E7.
84. Ouzzane, A., et al. Ureteral and multifocal tumours have worse prognosis than renal pelvic tumours
in urothelial carcinoma of the upper urinary tract treated by nephroureterectomy. Eur Urol, 2011. 60:
1258.
85. Chromecki, T.F., et al. The impact of tumor multifocality on outcomes in patients treated with radical
nephroureterectomy. Eur Urol, 2012. 61: 245.
86. Williams, A.K., et al. Multifocality rather than tumor location is a prognostic factor in upper tract
urothelial carcinoma. Urol Oncol, 2013. 31: 1161.
87. Sundi, D., et al. Upper tract urothelial carcinoma: impact of time to surgery. Urol Oncol, 2012. 30:
266.
88. Gadzinski, A.J., et al. Long-term outcomes of immediate versus delayed nephroureterectomy for
upper tract urothelial carcinoma. J Endourol, 2012. 26: 566.
89. Waldert, M., et al. A delay in radical nephroureterectomy can lead to upstaging. BJU Int, 2010. 105:
812.
90. Lee, J.N., et al. Impact of surgical wait time on oncologic outcomes in upper urinary tract urothelial
carcinoma. J Surg Oncol, 2014. 110: 468.
UROTHELIAL CARCINOMA OF THE UPPER URINARY TRACT - LIMITED UPDATE MARCH 2017 21
91. Berod, A.A., et al. The role of American Society of Anesthesiologists scores in predicting urothelial
carcinoma of the upper urinary tract outcome after radical nephroureterectomy: results from a
national multi-institutional collaborative study. BJU Int, 2012. 110: E1035.
92. Martinez-Salamanca, J.I., et al. Prognostic role of ECOG performance status in patients with
urothelial carcinoma of the upper urinary tract: an international study. BJU Int, 2012. 109: 1155.
93. Liu, J.Y., et al. Influence of body mass index on oncological outcomes in patients with upper urinary
tract urothelial carcinoma treated with radical nephroureterectomy. Int J Urol, 2014. 21: 136.
94. Ehdaie, B., et al. Obesity adversely impacts disease specific outcomes in patients with upper tract
urothelial carcinoma. J Urol, 2011. 186: 66.
95. Dalpiaz, O., et al. Validation of the pretreatment derived neutrophil-lymphocyte ratio as a prognostic
factor in a European cohort of patients with upper tract urothelial carcinoma. Br J Cancer, 2014.
110: 2531.
96. Tanaka, N., et al. A multi-institutional validation of the prognostic value of the neutrophil-to-
lymphocyte ratio for upper tract urothelial carcinoma treated with radical nephroureterectomy. Ann
Surg Oncol, 2014. 21: 4041.
97. Mbeutcha, A., et al. Prognostic factors and predictive tools for upper tract urothelial carcinoma: a
systematic review. World J Urol, 2016.
98. Fajkovic, H., et al. Prognostic value of extranodal extension and other lymph node parameters in
patients with upper tract urothelial carcinoma. J Urol, 2012. 187: 845.
99. Roscigno, M., et al. Lymphadenectomy at the time of nephroureterectomy for upper tract urothelial
cancer. Eur Urol, 2011. 60: 776.
100. Lughezzani, G., et al. A critical appraisal of the value of lymph node dissection at
nephroureterectomy for upper tract urothelial carcinoma. Urology, 2010. 75: 118.
101. Kikuchi, E., et al. Lymphovascular invasion predicts clinical outcomes in patients with node-negative
upper tract urothelial carcinoma. J Clin Oncol, 2009. 27: 612.
102. Novara, G., et al. Prognostic role of lymphovascular invasion in patients with urothelial carcinoma of
the upper urinary tract: an international validation study. Eur Urol, 2010. 57: 1064.
103. Godfrey, M.S., et al. Prognostic indicators for upper tract urothelial carcinoma after radical
nephroureterectomy: the impact of lymphovascular invasion. BJU Int, 2012. 110: 798.
104. Colin, P., et al. Influence of positive surgical margin status after radical nephroureterectomy on upper
urinary tract urothelial carcinoma survival. Ann Surg Oncol, 2012. 19: 3613.
105. Zigeuner, R., et al. Tumour necrosis is an indicator of aggressive biology in patients with urothelial
carcinoma of the upper urinary tract. Eur Urol, 2010. 57: 575.
106. Seitz, C., et al. Association of tumor necrosis with pathological features and clinical outcome
in 754 patients undergoing radical nephroureterectomy for upper tract urothelial carcinoma: an
international validation study. J Urol, 2010. 184: 1895.
107. Remzi, M., et al. Tumour architecture is an independent predictor of outcomes after
nephroureterectomy: a multi-institutional analysis of 1363 patients. BJU Int, 2009. 103: 307.
108. Fritsche, H.M., et al. Macroscopic sessile tumor architecture is a pathologic feature of biologically
aggressive upper tract urothelial carcinoma. Urol Oncol, 2012. 30: 666.
109. Otto, W., et al. Concomitant carcinoma in situ as an independent prognostic parameter for
recurrence and survival in upper tract urothelial carcinoma: a multicenter analysis of 772 patients.
World J Urol, 2011. 29: 487.
110. Wheat, J.C., et al. Concomitant carcinoma in situ is a feature of aggressive disease in patients with
organ confined urothelial carcinoma following radical nephroureterectomy. Urol Oncol, 2012. 30:
252.
111. Youssef, R.F., et al. Prognostic effect of urinary bladder carcinoma in situ on clinical outcome of
subsequent upper tract urothelial carcinoma. Urology, 2011. 77: 861.
112. Pieras, E., et al. Concomitant carcinoma in situ and tumour size are prognostic factors for bladder
recurrence after nephroureterectomy for upper tract transitional cell carcinoma. BJU Int, 2010. 106:
1319.
113. Comperat, E., et al. Prognostic value of MET, RON and histoprognostic factors for urothelial
carcinoma in the upper urinary tract. J Urol, 2008. 179: 868.
114. Scarpini, S., et al. Impact of the expression of Aurora-A, p53, and MIB-1 on the prognosis of
urothelial carcinomas of the upper urinary tract. Urol Oncol, 2012. 30: 182.
115. Kosaka, T., et al. Expression of snail in upper urinary tract urothelial carcinoma: prognostic
significance and implications for tumor invasion. Clin Cancer Res, 2010. 16: 5814.
116. Feng, C., et al. Predictive value of clinicopathological markers for the metachronous bladder cancer
and prognosis of upper tract urothelial carcinoma. Sci Rep, 2014. 4: 4015.
22 UROTHELIAL CARCINOMA OF THE UPPER URINARY TRACT - LIMITED UPDATE MARCH 2017
117. Bagrodia, A., et al. Evaluation of the prognostic significance of altered mammalian target of
rapamycin pathway biomarkers in upper tract urothelial carcinoma. Urology, 2014. 84: 1134.
118. Roupret, M., et al. Microsatellite instability as predictor of survival in patients with invasive upper
urinary tract transitional cell carcinoma. Urology, 2005. 65: 1233.
119. Margulis, V., et al. Preoperative multivariable prognostic model for prediction of nonorgan confined
urothelial carcinoma of the upper urinary tract. J Urol, 2010. 184: 453.
120. Favaretto, R.L., et al. Combining imaging and ureteroscopy variables in a preoperative multivariable
model for prediction of muscle-invasive and non-organ confined disease in patients with upper tract
urothelial carcinoma. BJU Int, 2012. 109: 77.
121. Cha, E.K., et al. Predicting clinical outcomes after radical nephroureterectomy for upper tract
urothelial carcinoma. Eur Urol, 2012. 61: 818.
122. Yates, D.R., et al. Cancer-specific survival after radical nephroureterectomy for upper urinary tract
urothelial carcinoma: proposal and multi-institutional validation of a post-operative nomogram.
Br J Cancer, 2012. 106: 1083.
123. Seisen, T., et al. Postoperative nomogram to predict cancer-specific survival after radical
nephroureterectomy in patients with localised and/or locally advanced upper tract urothelial
carcinoma without metastasis. BJU Int, 2014. 114: 733.
124. Roupret, M., et al. Prediction of cancer specific survival after radical nephroureterectomy for upper
tract urothelial carcinoma: development of an optimized postoperative nomogram using decision
curve analysis. J Urol, 2013. 189: 1662.
125. Ku, J.H., et al. External validation of an online nomogram in patients undergoing radical
nephroureterectomy for upper urinary tract urothelial carcinoma. Br J Cancer, 2013. 109: 1130.
126. Roupret, M., et al. A new proposal to risk stratify urothelial carcinomas of the upper urinary tract
(UTUCs) in a predefinitive treatment setting: low-risk versus high-risk UTUCs. Eur Urol, 2014. 66:
181.
127. Seisen, T., et al. Risk-adapted strategy for the kidney-sparing management of upper tract tumours.
Nat Rev Urol, 2015. 12: 155.
128. Yakoubi, R., et al. Radical nephroureterectomy versus endoscopic procedures for the treatment
of localised upper tract urothelial carcinoma: a meta-analysis and a systematic review of current
evidence from comparative studies. Eur J Surg Oncol, 2014. 40: 1629.
129. Seisen, T., et al. Oncologic Outcomes of Kidney-sparing Surgery Versus Radical
Nephroureterectomy for Upper Tract Urothelial Carcinoma: A Systematic Review by the EAU Non-
muscle Invasive Bladder Cancer Guidelines Panel. Eur Urol, 2016. 70: 1052.
130. Mandalapu, R.S., et al. Update of the ICUD-SIU consultation on upper tract urothelial carcinoma
2016: treatment of low-risk upper tract urothelial carcinoma. World J Urol, 2016.
131. Gadzinski, A.J., et al. Long-term outcomes of nephroureterectomy versus endoscopic management
for upper tract urothelial carcinoma. J Urol, 2010. 183: 2148.
132. Cutress, M.L., et al. Long-term endoscopic management of upper tract urothelial carcinoma:
20-year single-centre experience. BJU Int, 2012. 110: 1608.
133. Cutress, M.L., et al. Ureteroscopic and percutaneous management of upper tract urothelial
carcinoma (UTUC): systematic review. BJU Int, 2012. 110: 614.
134. Kondo, T., et al. Template-based lymphadenectomy in urothelial carcinoma of the upper urinary
tract: impact on patient survival. Int J Urol, 2010. 17: 848.
135. Cornu, J.N., et al. Oncologic control obtained after exclusive flexible ureteroscopic management of
upper urinary tract urothelial cell carcinoma. World J Urol, 2010. 28: 151.
136. Roupret, M., et al. Upper urinary tract transitional cell carcinoma: recurrence rate after percutaneous
endoscopic resection. Eur Urol, 2007. 51: 709.
137. Jeldres, C., et al. Segmental ureterectomy can safely be performed in patients with transitional cell
carcinoma of the ureter. J Urol, 2010. 183: 1324.
138. Colin, P., et al. Comparison of oncological outcomes after segmental ureterectomy or radical
nephroureterectomy in urothelial carcinomas of the upper urinary tract: results from a large French
multicentre study. BJU Int, 2012. 110: 1134.
139. Giannarini, G., et al. Antegrade perfusion with bacillus Calmette-Guerin in patients with non-muscle-
invasive urothelial carcinoma of the upper urinary tract: who may benefit? Eur Urol, 2011. 60: 955.
140. Irie, A., et al. Intravesical instillation of bacille Calmette-Guerin for carcinoma in situ of the urothelium
involving the upper urinary tract using vesicoureteral reflux created by a double-pigtail catheter.
Urology, 2002. 59: 53.
141. Phe, V., et al. Does the surgical technique for management of the distal ureter influence the outcome
after nephroureterectomy? BJU Int, 2011. 108: 130.
UROTHELIAL CARCINOMA OF THE UPPER URINARY TRACT - LIMITED UPDATE MARCH 2017 23
142. Roupret, M., et al. Oncological risk of laparoscopic surgery in urothelial carcinomas. World J Urol,
2009. 27: 81.
143. Ong, A.M., et al. Trocar site recurrence after laparoscopic nephroureterectomy. J Urol, 2003. 170:
1301.
144. Favaretto, R.L., et al. Comparison between laparoscopic and open radical nephroureterectomy in
a contemporary group of patients: are recurrence and disease-specific survival associated with
surgical technique? Eur Urol, 2010. 58: 645.
145. Ni, S., et al. Laparoscopic versus open nephroureterectomy for the treatment of upper urinary tract
urothelial carcinoma: a systematic review and cumulative analysis of comparative studies. Eur Urol,
2012. 61: 1142.
146. Walton, T.J., et al. Oncological outcomes after laparoscopic and open radical nephroureterectomy:
results from an international cohort. BJU Int, 2011. 108: 406.
147. Ariane, M.M., et al. Assessment of oncologic control obtained after open versus laparoscopic
nephroureterectomy for upper urinary tract urothelial carcinomas (UUT-UCs): results from a large
French multicenter collaborative study. Ann Surg Oncol, 2012. 19: 301.
148. Simone, G., et al. Laparoscopic versus open nephroureterectomy: perioperative and oncologic
outcomes from a randomised prospective study. Eur Urol, 2009. 56: 520.
149. Adibi, M., et al. Oncological outcomes after radical nephroureterectomy for upper tract urothelial
carcinoma: comparison over the three decades. Int J Urol, 2012. 19: 1060.
150. Aboumohamed, A.A., et al. Oncologic Outcomes Following Robot-Assisted Laparoscopic
Nephroureterectomy with Bladder Cuff Excision for Upper Tract Urothelial Carcinoma. J Urol, 2015.
194: 1561.
151. Abe, T., et al. Outcome of regional lymphadenectomy in accordance with primary tumor location on
laparoscopic nephroureterectomy for urothelial carcinoma of the upper urinary tract: a prospective
study. J Endourol, 2015. 29: 304.
152. Kondo, T., et al. Possible role of template-based lymphadenectomy in reducing the risk of regional
node recurrence after nephroureterectomy in patients with renal pelvic cancer. Jpn J Clin Oncol,
2014. 44: 1233.
153. Fradet, V., et al. Risk factors for bladder cancer recurrence after nephroureterectomy for upper tract
urothelial tumors: results from the Canadian Upper Tract Collaboration. Urol Oncol, 2014. 32: 839.
154. O’Brien, T., et al. Prevention of bladder tumours after nephroureterectomy for primary upper
urinary tract urothelial carcinoma: a prospective, multicentre, randomised clinical trial of a single
postoperative intravesical dose of mitomycin C (the ODMIT-C Trial). Eur Urol, 2011. 60: 703.
155. Ito, A., et al. Prospective randomized phase II trial of a single early intravesical instillation of
pirarubicin (THP) in the prevention of bladder recurrence after nephroureterectomy for upper urinary
tract urothelial carcinoma: the THP Monotherapy Study Group Trial. J Clin Oncol, 2013. 31: 1422.
156. Fang, D., et al. Prophylactic intravesical chemotherapy to prevent bladder tumors after
nephroureterectomy for primary upper urinary tract urothelial carcinomas: a systematic review and
meta-analysis. Urol Int, 2013. 91: 291.
157. Audenet, F., et al. The role of chemotherapy in the treatment of urothelial cell carcinoma of the upper
urinary tract (UUT-UCC). Urol Oncol, 2013. 31: 407.
158. Kaag, M.G., et al. Changes in renal function following nephroureterectomy may affect the use of
perioperative chemotherapy. Eur Urol, 2010. 58: 581.
159. Lane, B.R., et al. Chronic kidney disease after nephroureterectomy for upper tract urothelial
carcinoma and implications for the administration of perioperative chemotherapy. Cancer, 2010.
116: 2967.
160. Matin, S.F., et al. Incidence of downstaging and complete remission after neoadjuvant
chemotherapy for high-risk upper tract transitional cell carcinoma. Cancer, 2010. 116: 3127.
161. Hellenthal, N.J., et al. Adjuvant chemotherapy for high risk upper tract urothelial carcinoma: results
from the Upper Tract Urothelial Carcinoma Collaboration. J Urol, 2009. 182: 900.
162. Vassilakopoulou, M., et al. Outcomes after adjuvant chemotherapy in the treatment of high-
risk urothelial carcinoma of the upper urinary tract (UUT-UC): results from a large multicenter
collaborative study. Cancer, 2011. 117: 5500.
163. Leow, J.J., et al. A Systematic Review and Meta-analysis of Adjuvant and Neoadjuvant
Chemotherapy for Upper Tract Urothelial Carcinoma. Eur Urol, 2014. 66: 529.
164. Birtle, A.J., et al. Time to define an international standard of postoperative care for resected upper
urinary tract transitional cell carcinoma (TCC) - opening of the peri-operative chemotherapy versus
surveillance in upper tract urothelial cancer (POUT) Trial. BJU Int, 2012. 110: 919.
165. Jwa, E., et al. Adjuvant radiotherapy for stage III/IV urothelial carcinoma of the upper tract.
Anticancer Res, 2014. 34: 333.
24 UROTHELIAL CARCINOMA OF THE UPPER URINARY TRACT - LIMITED UPDATE MARCH 2017
166. Ploussard, G., et al. Conditional survival after radical nephroureterectomy for upper tract carcinoma.
Eur Urol, 2015. 67: 803.
167. Colin, P., et al. Risk stratification of metastatic recurrence in invasive upper urinary tract carcinoma
after radical nephroureterectomy without lymphadenectomy. World J Urol, 2014. 32: 507.
168. Bagley, D.H., et al. Ureteroscopic laser treatment of upper urinary tract neoplasms. World J Urol,
2010. 28: 143.
169. Villa, L., et al. Early repeated ureteroscopy within 6-8 weeks after a primary endoscopic treatment
in patients with upper tract urothelial cell carcinoma: preliminary findings. World J Urol, 2016. 34:
1201.
UROTHELIAL CARCINOMA OF THE UPPER URINARY TRACT - LIMITED UPDATE MARCH 2017 25
26 UROTHELIAL CARCINOMA OF THE UPPER URINARY TRACT - LIMITED UPDATE MARCH 2017
EAU Guidelines on
Muscle-invasive
and Metastatic
Bladder Cancer
J.A. Witjes (Chair), E. Compérat, N.C. Cowan,
G. Gakis, V. Hernández, T. Lebret, A. Lorch,
A.G. van der Heijden, M.J. Ribal
Guidelines Associates: M. Bruins, E. Linares Espinós,
M. Rouanne, Y. Neuzillet, E. Veskimäe
2. METHODS 6
2.1 Data identification 6
2.2 Review 6
2.3 Future goals 6
5. DIAGNOSTIC EVALUATION 10
5.1 Primary diagnosis 10
5.1.1 Symptoms 10
5.1.2 Physical examination 10
5.1.3 Bladder imaging 10
5.1.4 Urinary cytology and urinary markers 10
5.1.5 Cystoscopy 11
5.1.6 Transurethral resection of invasive bladder tumours 11
5.1.7 Second resection 11
5.1.8 Concomitant prostate cancer 11
5.1.9 Summary of evidence and specific recommendations
for the primary assessment of presumably invasive bladder tumours 12
5.2 Imaging for staging of MIBC 12
5.2.1 Local staging of MIBC 12
5.2.1.1 MRI for local staging of invasive bladder cancer 12
5.2.1.2 CT imaging for local staging of MIBC 12
5.2.2 Imaging of lymph nodes in MIBC 13
5.2.3 Upper urinary tract urothelial carcinoma 13
5.2.4 Distant metastases at sites other than lymph nodes 13
5.2.5 Future developments 13
5.2.6 Summary of evidence and recommendations for staging in
muscle-invasive bladder cancer 13
7. DISEASE MANAGEMENT 16
7.1 Treatment failure of non-muscle invasive bladder cancer 16
7.1.1 High-risk non-muscle-invasive urothelial carcinoma 16
7.1.2 Recommendations for treatment failure of non-muscle-invasive bladder cancer 17
7.2 Neoadjuvant chemotherapy 17
7.2.1 Introduction 17
7.2.2 The role of imaging and biomarkers to identify responders 18
7.2.3 Summary of available data 18
7.2.4 Summary of evidence and recommendations for neoadjuvant chemotherapy 19
7.3 Pre- and post-operative radiotherapy in muscle-invasive bladder cancer 19
7.3.1 Post-operative radiotherapy 19
7.3.2 Pre-operative radiotherapy 19
7.3.2.1 Retrospective studies 19
7.3.2.2 Randomised studies 19
7.3.3 Summary of evidence and recommendations for
pre- and post-operative radiotherapy 20
7.4 Radical surgery and urinary diversion 20
7.4.1 Removal of the tumour-bearing bladder 20
7.4.1.1 Introduction 20
7.4.2 Timing and delay of cystectomy 20
7.4.2.1 Indications 20
7.4.3 Radical cystectomy: technique and extent 21
7.4.3.1 Pelvic organ preservation techniques in men:
oncological and functional outcomes 21
7.4.3.1.1 Summary of evidence and recommendations
for sexual-preserving techniques in men 22
7.4.3.2 Pelvic organ preservation techniques in women:
oncological and functional outcomes 23
7.4.3.2.1 Summary of evidence and recommendations
for sexual-preserving techniques in women 23
7.4.3.3 Laparoscopic/robotic-assisted laparoscopic cystectomy 23
7.4.3.3.1 Summary of evidence and recommendations for
laparoscopic/robotic-assisted laparoscopic cystectomy 25
7.4.4 Urinary diversion after radical cystectomy 25
7.4.4.1 Preparations for surgery 25
7.4.4.2 Patient selection for orthotopic diversion 26
7.4.4.2.1 Ureterocutaneostomy 26
7.4.4.2.2 Ileal conduit 27
7.4.4.2.3 Continent cutaneous urinary diversion 27
7.4.4.2.4 Ureterocolonic diversion 27
7.4.4.2.5 Orthotopic neobladder 27
7.4.5 Morbidity and mortality 28
7.4.6 Survival 30
7.4.7 Summary of evidence and recommendations for radical
cystectomy and urinary diversion 31
7.5 Unresectable tumours 32
7.5.1 Palliative cystectomy for muscle-invasive bladder carcinoma 32
7.5.1.1 Recommendations for unresectable tumours 33
7.5.2 Supportive care 33
7.5.2.1 Obstruction of the UUT 33
8. FOLLOW-UP 43
8.1 Introduction 43
8.2 Site of recurrence 43
8.2.1 Local recurrence 43
8.2.2 Distant recurrence 43
8.2.3 Summary of evidence and recommendations for specific recurrence sites 44
8.3 Follow-up of functional outcomes and complications 44
9. REFERENCES 45
References used in this text are assessed according to their level of evidence (LE) and Guidelines are given
a grade of recommendation (GR), according to a classification system modified from the Oxford Centre for
Evidence-Based Medicine Levels of Evidence [5]. Additional methodology information can be found in the
general Methodology section of this print, and online at the EAU website: http://uroweb.org/guidelines/.
A list of Associations endorsing the EAU Guidelines can also be viewed online at the above address.
2.2 Review
No separate peer-review was done for the 2017 print of the MIBC Guidelines.
3.2 Aetiology
3.2.1 Tobacco smoking
Tobacco smoking is the most well-established risk factor for BC, causing 50-65% of male cases and 20-30%
of female cases [13]. A causal relationship has been established between exposure to tobacco and cancer in
studies in which chance, bias and confounding can be discounted with reasonable confidence [14].
The incidence of BC is directly related to the duration of smoking and the number of cigarettes smoked per day
[15]. A meta-analysis looked at 216 observational studies on cigarette smoking and cancer published between
1961 and 2003, and the pooled risk estimates for BC demonstrated a significant association for both current
3.2.3 Radiotherapy
Increased rates of secondary bladder malignancies have been reported after external-beam radiotherapy
(EBRT) for gynaecological malignancies, with relative risks of 2-4 [21]. In a population-based cohort study, the
standardised incidence ratios for BC developing after radical prostatectomy (RP), EBRT, brachytherapy (BT),
and EBRT-BT were 0.99, 1.42, 1.10, and 1.39, respectively, in comparison with the general U.S. population [22].
It has recently been proposed that patients who have received radiotherapy (RT) for prostate
cancer with modern modalities such as intensity-modulated radiotherapy (IMRT) may have lower rates of
in-field bladder- and rectal secondary malignancies [23]. Nevertheless, since longer follow-up data are not
yet available, and as BC requires a long period to develop, patients treated with radiation and with a long life-
expectancy are at a higher risk of developing BC [23].
3.2.6 Gender
Although men are more likely to develop BC than women, women present with more advanced disease and
have worse survival rates. A meta-analysis including nearly 28,000 patients shows that female gender was
associated with a worse survival outcome (HR: 1.20; 95% CI: 1.09-1.32) compared to male gender after radical
cystectomy (RC) [29]. This finding had already been presented in a descriptive Nation-Wide Analysis based on
27,773 Austrian patients. After their analysis the authors found that cancer-specific-survival (CSS) was identical
for pT1-tumours in both sexes, while women had a worse CSS in both age cohorts (< 70 years and > 70 years)
with higher tumour stages [30]. However this higher mortality is questioned once both genders receive the
same therapy. In the population-based study from the Ontario Cancer Registry analysing all patients with BC
treated with cystectomy or radical RT between 1994 and 2008, no differences in overall survival (OS), mortality
and outcomes were found between males and females following radical therapy [31].
A population-based study from the MarketScan databases suggests that a possible reason for
worse survival in the female population may be that women experienced longer delays in diagnosis than men,
as the differential diagnosis in women includes diseases that are more prevalent than BC [32].
Furthermore, differences in the gender prevalence of BC may be due to other factors besides
tobacco and chemical exposure. In a large prospective cohort study, post-menopausal status was associated
3.2.8 Summary of evidence and recommendations for epidemiology and risk factors
Summary of evidence LE
Worldwide, bladder cancer is the 11th most commonly diagnosed cancer. 2a
Several risk factors connected with the risk of bladder cancer diagnosis have been identified. 3
Active and passive tobacco smoking continues to be the main risk factor, while the exposure-related 2a
incidence is decreasing.
The increased risk of developing bladder cancer in patients undergoing external-beam radiotherapy 3
(EBRT), brachytherapy (BT), or a combination of EBRT and BT, must be taken into account during
patient follow-up. As bladder cancer requires time to develop, patients treated with radiation at a
young age are at the greatest risk and should be followed up closely.
Recommendations GR
The principal preventable risk factor for MIBC is active and passive smoking. B
Notwithstanding stricter regulations, workers should be informed about the potential carcinogenic A
effects of a number of recognised substances, duration of exposure, and latency periods. Protective
measures should be recommended.
3.3 Pathology
3.3.1 Handling of transurethral resection and cystectomy specimens
In transurethral resection (TUR), a snap frozen specimen from the tumour and normal looking bladder wall
should be taken, if possible. Separate specimens should be taken from the superficial and deep areas of
the tumour and sent to the pathology laboratory separately, in case the outcome will impact on treatment
decisions. If random biopsies of the flat mucosa are taken, each biopsy specimen of the flat mucosa should
also be sent separately.
In RC, bladder fixation must be carried out as soon as possible. The pathologist must open the
specimen from the urethra to the bladder dome and fix the specimen. In some circumstances this procedure
can also be performed by the urologist. In a female cystectomy specimen, the length of the urethral segment
removed en bloc with the specimen should be checked, preferably by the urological surgeon [40].
Specimen handling should follow the general rules as published by a collaborative group of pathologists and
urologists [41, 42]. It must be stressed that it may be very difficult to confirm the presence of a neoplastic lesion
using gross examination of the cystectomy specimen after TUR or chemotherapy, so the entire retracted or
ulcerated area should be included.
It is compulsory to study the urethra, the ureters, the prostate in men and the radial margins [43]. In
urethra-sparing cystectomy; the level of urethral dissection, completeness of the prostate, specifically at the
apex (in men), and the inclusion of the entire bladder neck and amount of adjacent urethra, uterus and vaginal
top (in women) should be inked and documented.
All lymph node (LN) specimens should be provided in their totality, in clearly labelled containers. In case of
doubt, or adipose differentiation of the LN, the entire specimen is to be included. LNs should be counted and
measured on slides, capsular extension and percentage of LN invasion should be reported as well as vascular
embols [44, 45]. In the case of metastatic spread in the perivesical fat without real LN structures (capsule,
subcapsular sinus), this localisation should nevertheless be considered as N+.
Recommendations GR
Record the depth of invasion (categories pT2a and pT2b, pT3a and pT3b or pT4). A*
Record margins with special attention paid to the radial margin, prostate, ureter, urethra and peritoneal
fat and uterus and vaginal top.
Record the number of lymph nodes (LNs) and number of positive LNs.
Record lymphatic or blood vessel invasion and extranodal extension.
Record the presence of carcinoma in situ.
*Upgraded following panel consensus.
T - Primary Tumour
Tx Primary tumour cannot be assessed
T0 No evidence of primary tumour
Ta Non-invasive papillary carcinoma
Tis Carcinoma in situ: “flat tumour”
T1 Tumour invades subepithelial connective tissue
T2 Tumour invades muscle
T2a Tumour invades superficial muscle (inner half)
T2b Tumour invades deep muscle (outer half)
T3 Tumour invades perivesical tissue:
T3a microscopically
T3b macroscopically (extravesical mass)
T4 Tumour invades any of the following: prostate stroma, seminal vesicles, uterus, vagina, pelvic wall,
abdominal wall
T4a Tumour invades prostate stroma, seminal vesicles, uterus, or vagina
T4b Tumour invades pelvic wall or abdominal wall
N - Regional Lymph Nodes
Nx Regional lymph nodes cannot be assessed
N0 No regional lymph node metastasis
N1 Metastasis in a single lymph node in the true pelvis (hypogastric, obturator, external iliac, or presacral)
N2 Metastasis in multiple regional lymph nodes in the true pelvis (hypogastric, obturator, external iliac, or
presacral)
N3 Metastasis in a common iliac lymph node(s)
M - Distant Metastasis
M0 No distant metastasis
M1a Non-regional lymph nodes
M1b Other distant metastasis
5. DIAGNOSTIC EVALUATION
5.1 Primary diagnosis
5.1.1 Symptoms
Painless haematuria is the most common presenting complaint. Other clinical signs include urgency, dysuria,
increased frequency, and in more advanced tumours, pelvic pain and symptoms related to urinary tract
obstruction.
A standardised reporting system redefining urinary cytology diagnostic categories was published in 2016 by
the Paris Working Group [67]:
• Adequacy of urine specimens (Adequacy);
• Negative for high-grade urothelial carcinoma (Negative);
• Atypical urothelial cells (AUC);
• Suspicious for high-grade urothelial carcinoma (Suspicious);
• High-grade urothelial carcinoma (HGUC);
• Low-grade urothelial neoplasia (LGUN).
5.1.5 Cystoscopy
Ultimately, the diagnosis of BC is made by cystoscopy and histological evaluation of resected tissue. In
general, cystoscopy is initially performed in the office using a flexible instrument. If a bladder tumour has been
visualised unequivocally in earlier imaging studies, such as computed tomography (CT), magnetic resonance
imaging (MRI), or ultrasound (US), diagnostic cystoscopy may be omitted and the patient can proceed directly
to TURB for histological diagnosis. Currently, there is no evidence for the role of photodynamic diagnosis (PDD)
in the standard diagnosis of invasive BC.
A careful description of the cystoscopic findings is necessary. This should include documentation
of the site, size, number, and appearance (papillary or solid) of the tumours, as well as a description of any
mucosal abnormalities. The use of a bladder diagram is recommended.
The use of PDD could be considered if a T1 high-grade tumour is present, to identify associated
CIS. Presence of CIS may lead to a modified treatment plan (see Section 7.1). Photodynamic diagnosis is
highly sensitive for the detection of CIS, but in experienced hands, the rate of false-positive results may be
similar to that with regular white-light cystoscopy [68].
The involvement of the prostatic urethra and ducts in men with bladder tumours has been reported. The exact
risk is not known, but it seems to be higher if the tumour is located on the trigone or bladder neck, in the
presence of bladder CIS, and in multiple tumours [70, 71] (LE: 3). Involvement of the prostatic urethra can be
determined either at the time of primary TURB or by frozen section during the cystoprostatectomy procedure.
A frozen section has a higher negative-predictive value and is more accurate [72-74].
Summary of evidence LE
Currently, treatment decisions cannot be based on molecular markers. 3
Recommendations GR
During cystoscopy, describe all macroscopic features of the tumour (site, size, number and C
appearance) and mucosal abnormalities. A bladder diagram is recommended.
Take a biopsy of the prostatic urethra for cases of bladder neck tumour, when bladder carcinoma in C
situ is present or suspected, when there is positive cytology without evidence of tumour in the bladder,
or when abnormalities of the prostatic urethra are visible.
Take a biopsy at the time of the second resection, if no biopsy was taken during the initial procedure. C
In women undergoing subsequent orthotopic neobladder construction, obtain procedural information C
(including histological evaluation) of the bladder neck and urethral margin, either prior to or at the time
of cystoscopy.
Specify the grade, depth of tumour invasion, and whether the lamina propria and muscle tissue are C
present in the specimen in the pathological report.
In 2006, a link was established between the use of gadolinium-based contrast agents and nephrogenic
systemic fibrosis (NSF), which may result in fatal or severely debilitating systemic fibrosis. Patients with
impaired renal function are at risk of developing NSF and the non-ionic linear gadolinium-based contrast
agents should be avoided (gadodiamide, gadopentetate dimeglumine and gadoversetamide). A stable
macrocyclic contrast agent should be used (gadobutrol, gadoterate meglumine or gadoteridol). Contrast-
enhanced CT using iodinated contrast media should be considered as an alternative [91] (LE: 4).
5.2.6 Summary of evidence and recommendations for staging in muscle-invasive bladder cancer
Summary of evidence LE
Imaging as part of staging in muscle-invasive bladder cancer (MIBC) provides information about 2b
prognosis and assists in selection of the most appropriate treatment.
There are currently insufficient data on the use of diffusion-weighted imaging (DWI) and
fluorodeoxyglucose- positron emission tomography/computed tomography (FDG-PET/CT) in MIBC to
allow a recommendation to be made.
6. PROGNOSIS
6.1 Introduction
The treatment and prognosis for MIBC is mainly determined by tumour and nodal stage [85].The pathological
report will inform on histological type, lymphovascular invasion, presence of CIS, positive margins and
extranodal extension. In clinical practice, CT and MRI are the imaging techniques used.
Interpretation
Health assessment of oncology patients must be supplemented by measuring their activity level. Extermann
et al. have shown that there is no correlation between morbidity and competitive activity level [155]. The
Eastern Cooperative Oncology Group (ECOG) PS scores and Karnofsky index have been validated to measure
patient activity [156] (LE: 3). Performance score is correlated with patient OS after RC [151] and palliative
chemotherapy [157-159].
1. Calculate Charlson Comorbidity Score or Index = i
a. Add comorbidity score to age score
b. Total denoted as ‘i’ in the Charlson Probability calculation (see below). i = sum of
comorbidity score to age score
2. Calculate Charlson Probability (10-year mortality = Y)
a. Calculate Y = 10(i x 0.9)
b. Calculate Z _ = 0.983Y (where Z
_ is the 10-year survival)
According to a consensus conference of the National Institutes of Health, the aim of the Standardized Geriatric
Assessment (SGA) is to discover, describe and explain the many problems of elderly people, to catalogue
their resources and strengths, to assess individual service needs, and to develop a co-ordinated plan of care.
The SGA can be carried out by means of several protocols. These protocols differ in the completeness of
diagnostic research. The most complete protocol is the Comprehensive Geriatric Assessment (CGA) [160]
which is tailored to the care of cancer patients [161]. In BC, the CGA has been used to adapt gemcitabine
chemotherapy in previously untreated elderly patients with advanced BC [162].
Summary of evidence LE
Chronological age is of limited relevance. 3
A comorbidity score developed in particular for the assessment of patients diagnosed with bladder 3
cancer would be helpful.
In 2014, the Cancer Genome Atlas (TCGA) project in BC reported on the integrated genomic analysis of the first
131 MIBC patients, identifying genes that are mutated in a significant proportion of BCs, several of which were
not previously reported [166]. Profiling studies have also reported on validated biomarker panels that predict
prognosis and can be used to identify patients who may benefit from more aggressive therapy [167]. In the
coming years, expanding knowledge of BC carcinogenesis may change our management of the disease.
7. DISEASE MANAGEMENT
7.1 Treatment failure of non-muscle invasive bladder cancer
7.1.1 High-risk non-muscle-invasive urothelial carcinoma
The recurrence and progression rate of non-muscle invasive BC (NMIBC) strongly correlates with the factors
as described in the European Organisation for Research and Treatment of Cancer (EORTC) risk calculator
[168]. According to this calculator, the risk of progression after five years is 45% for high-risk tumours. In
2015, however, the EORTC group presented new nomograms based on two large phase III trials with a median
follow up of 7.4 years. With one to three years of maintenance bacillus Calmette-Guérin (BCG), the risk for
progression at five years was much lower: 19.3% for T1G3 tumours [169].
Meta-analyses have demonstrated that BCG-therapy prevents the risk of tumour recurrence [170] and the
risk of tumour progression [171, 172] but so far, no significant overall- or disease-specific survival advantages
have been shown, as compared to no intravesical therapy [171-173]. The EAU NMIBC Guidelines present data
supporting cystectomy in selected patients with NMIBC.
Large cystectomy series show a risk of an understaging error in TaT1 tumours of 35-62%. This may
be caused by the presence of persisting or recurrent tumours due to omission of a second TURB or re-TURB,
and the absence of neoadjuvant therapy [174-176]. Second TURB identifies upstaging to > T2 tumours in
10-20% of patients [177, 178].
Progression to MIBC significantly decreases CSS. In a review of nineteen trials including 3,088
patients, CSS after progression from NMIBC to MIBC was 35%, which is significantly worse compared to
patients with MIBC without a history of NMIBC. This underlines the need to recommend early radical treatment,
such as RC, in case of intravesical therapy failure [2, 179, 180].
According to the EAU NMIBC Guidelines, it is reasonable to propose immediate RC to patients with non-
muscle-invasive tumour who are at highest risk of progression [168, 181-183]. Risk factors are any of the
following:
Although the percentage of patients with primary TaT1 tumours and the indication for cystectomy in TaT1
tumours is not specified in large cystectomy series, the ten-year recurrence-free survival rate is 80% and
similar to that of TURB and BCG maintenance therapy [2, 175, 184, 185] (LE: 3).
Radical cystectomy is also strongly recommended in patients with BCG-refractory tumours, defined in the
NMIBC guideline as:
• whenever muscle-invasive tumour is detected during follow-up;
• if high-grade, non-muscle-invasive papillary tumour is present at three months;
• if CIS (without concomitant papillary tumour) is present at both three and six months;
• if high-grade tumour appears during BCG therapy [186];
• high-grade recurrence after BCG (recurrence of high-grade/grade 3 [WHO 1973/2004] tumour after
completion of BCG maintenance, despite an initial response).
Patients with disease recurrence within two years of initial TURB plus BCG therapy have a better outcome than
patients who already have muscle-invasive disease, indicating that cystectomy should be performed at first
recurrence, even in non-muscle-invasive disease [187] (LE: 3; GR: C).
There are now several bladder-preservation strategies available; immunotherapy, chemotherapy, device-
assisted therapy, and combination therapy [188]. However, experience is limited and treatments other than RC
must be considered oncologically inferior at the present time [188].
Recommendations GR
Consider immediate radical treatment in all T1 tumours at high risk of progression (i.e., high grade, C
multifocality, carcinoma in situ, and tumour size, as outlined in the EAU Guidelines for Non-muscle-
invasive Bladder Cancer).
Offer radical treatment to all T1 patients failing intravesical therapy. B
There are many advantages and disadvantages of administering chemotherapy before planned definitive
surgery to patients with resectable muscle-invasive urothelial carcinoma of the bladder and cN0M0 disease:
• Chemotherapy is delivered at the earliest time-point, when the burden of micrometastatic disease is
expected to be low.
• Potential reflection of in-vivo chemosensitivity.
• Tolerability of chemotherapy and patient compliance are expected to be better pre-cystectomy.
• Patients might respond to NAC and reveal a favourable pathological status, determined mainly by
achieving pT0, pN0 and negative surgical margins.
• Delayed cystectomy might compromise the outcome in patients not sensitive to chemotherapy [195,
196], although published studies on the negative effect of delayed cystectomy only include chemo-
naive patients. There are no trials indicating that delayed surgery, due to NAC, has a negative impact on
survival.
Three meta-analyses were undertaken to establish if NAC prolongs survival [211-213]. In the most recent meta-
analysis, published in 2005 [213], with updated patient data from 11 randomised trials (n = 3,005), a significant
survival benefit was shown in favour of NAC. The results of this analysis confirmed the previously published
data and showed a 5% absolute improvement in survival at five years.
The Nordic combined trial showed an absolute benefit of 8% survival at five years and 11% in
the clinical T3 subgroup, translating into nine patients needed to treat [198]. Only cisplatin combination
chemotherapy with at least one additional chemotherapeutic agent resulted in a meaningful therapeutic
benefit [211, 213]; the regimens tested were methotrexate, vinblastine, adriamycin plus cisplatin (MVA(E)
C), cisplatin, methotrexate plus vinblastine (CMV), cisplatin and methotrexate (CM), cisplatin/adriamycin,
cisplatin/5-fluorouracil (5-FU), and carboplatin, methotrexate, vinblastine (CarboMV).
More modern chemotherapeutic regimens such as gemcitabine/cisplatin have shown similar pT0/
pT1 rates as methotrexate, vinblastine, adriamycin plus cisplatin (MVAC) in the most recent retrospective
series and pooled data analyses, but have not been used in randomised controlled trials (RCTs) [227-230].
The updated analysis of the largest randomised phase III trial [201] with a median follow-up of eight years
confirmed previous results and provided some additional interesting findings:
• 16% reduction in mortality risk;
• improvement in ten-year survival from 30% to 36% with neoadjuvant CMV;
• benefit with regard to distant metastases;
• no benefit for locoregional control and locoregional disease-free survival, with the addition of neoadjuvant
CMV independent of the definitive treatment.
The presence of micrometastases is postulated to be lower in smaller tumours (T2) compared to more
extensive tumours (T3b-T4b). T4 stage tumours are prone to a higher degree of clinical understaging because
macrometastatic nodal deposits are detected more often in post-cystectomy specimens [198]. Data support
the use of NAC in the T2b-T3b tumour subgroup (former classification T3), and has shown a modest, but
substantial, improvement in long-term survival as well as significant downstaging [218].
Conclusions LE
Neoadjuvant chemotherapy has its limitations regarding patient selection, current development of 3
surgical techniques, and current chemotherapy combinations.
Neoadjuvant cisplatin-containing combination chemotherapy improves overall survival (OS) (5-8% at 1a
five years).
Neoadjuvant treatment of responders and especially patients who show complete response (pT0 N0) 2
has a major impact on OS.
Currently, no tools are available to select patients who have a higher probability of benefitting from
neoadjuvant chemotherapy (NAC). In the future, genetic markers, in a personalised medicine setting,
might facilitate the selection of patients for NAC and differentiate responders from non-responders.
Recommendations GR
Offer neoadjuvant chemotherapy (NAC) for T2-T4a, cN0M0 bladder cancer. A
In this case, always use cisplatin-based combination therapy.
Do not offer NAC to patients who are ineligible for cisplatin-based combination chemotherapy. A
Summary of evidence LE
No data exist to support that pre-operative radiotherapy (RT) for operable muscle-invasive bladder 2a
cancer (MIBC) increases survival.
Pre-operative RT for operable MIBC, using a dose of 45-50 Gy in fractions of 1.8-2 Gy, results in 2
downstaging after four-six weeks.
Limited high-quality evidence supports the use of pre-operative RT to decrease the local recurrence of 3
MIBC after radical cystectomy.
Recommendations GR
Do not offer pre-operative radiotherapy (RT) to improve survival. A
Offer pre-operative RT for operable MIBC since it can result in tumour downstaging after four to six C
weeks.
It is particularly important to evaluate functioning and QoL of elderly patients using a standardised geriatric
assessment, as well as carrying out a standard medical evaluation (see Section 6.2) [245].
7.4.2.1 Indications
Traditionally, RC was recommended for patients with MIBC T2-T4a, N0-Nx, M0 [243]. Other indications include
high risk and recurrent superficial tumours, BCG-resistant Tis, T1G3 (see Section 7.1), as well as extensive
papillary disease that cannot be controlled with TURB and intravesical therapy alone.
Two important autopsy studies for RC have been performed so far. The first study showed that in 215 patients
with MIBC and nodal dissemination, the frequency of metastasis was 92% in regional (perivesical or pelvic),
72% in retroperitoneal, and 35% in abdominal LNs. There was also a significant correlation between nodal
metastases and concomitant distant metastases (p < 0.0001).
Approximately 47% of the patients had both nodal metastases and distant dissemination and only
12% of the patients had nodal dissemination as the sole metastatic manifestation [252]. The second autopsy
study focused on the nodal yield when super-extended pelvic LN dissection (LND) was performed. Substantial
inter-individual differences were found with counts ranging from 10 to 53 nodes [253]. These findings
demonstrate the limited utility of node count as a surrogate for extent of dissection.
Regional LNs have been shown to consist of all pelvic LNs below the bifurcation of the aorta [254-258].
Mapping studies have also found that skipping lesions at locations above the bifurcation of the aorta, without
more distally located LN metastases, is rare [258, 259].
The extent of LND has not been established to date. Standard lymphadenectomy in BC patients involves
removal of nodal tissue cranially up to the common iliac bifurcation, with the ureter being the medial
border, and including the internal iliac, presacral, obturator fossa and external iliac nodes [260]. Extended
lymphadenectomy includes all LNs in the region of the aortic bifurcation, and presacral and common
iliac vessels medial to the crossing ureters. The lateral borders are the genitofemoral nerves, caudally the
circumflex iliac vein, the lacunar ligament and the LN of Cloquet, as well as the area described for standard
lymphadenectomy [260-264]. A super-extended lymphadenectomy extends cranially to the level of the inferior
mesenteric artery [265, 266].
In order to assess how and if cancer outcome is influenced by the extent of lymphadenectomy in patients
with clinical N0M0 MIBC, a SR of the literature was undertaken [267]. Out of 1,692 abstracts retrieved and
assessed, nineteen studies fulfilled the review criteria [260-264, 266, 268-280]. All five studies comparing LND
vs. no LND reported a better oncological outcome for the LND group. Seven out of twelve studies comparing
(super-)extended with limited or standard LND reported a beneficial outcome for (super)extended in at least a
subset of patients which is in concordance with several other recently performed meta-analyses [281, 282]. No
difference in outcome was reported between extended and super-extended LND in the two high-volume-centre
studies identified [266, 278]. Further data from on-going randomised trials on the therapeutic impact of the
extent of lymphadenectomy are awaited.
It has been suggested that PFS as well as OS might be correlated with the number of LNs removed during
surgery, although there are no data from RCTs on the minimum number of LNs that should be removed.
Nevertheless, survival rates increase with the number of dissected LNs [283]. Removal of at least ten LNs has
been postulated as sufficient for evaluation of LN status, as well as being beneficial for OS in retrospective
studies [284-286]. In conclusion, extended LND might have a therapeutic benefit compared to less-extensive
LND, but due to study bias, no firm conclusions can be drawn [267].
7.4.3.1 Pelvic organ preservation techniques in men: oncological and functional outcomes
Different approaches have been described to improve voiding and sexual function in patients undergoing RC
for BC. No consensus exists regarding which approach preserves function best. Concern remains regarding
the impact of “sparing-techniques” on oncological outcomes.
To determine the effect of sexual function-preserving cystectomy (SPC) on functional and
oncological outcomes a SR was undertaken [287].
Out of 8,517 screened abstracts twelve studies recruiting a total of 1,098 patients (823 in the intervention
group vs. 275 in the control group) were identified, including nine comparative studies (one RCT and two
retrospective non-RCTs with matched pair design [250, 288-297] and three single-arm case series [298-300].
Sexual function-preserving cystectomy described included prostate-, capsule-, seminal vesicle- and nerve-
sparing techniques. In the majority of cases, the open surgical approach was used and the urinary diversion of
choice was an orthotopic neobladder. Median follow-up was longer than three years in nine studies, with three
studies presenting results at a median follow-up longer than five years.
The majority of the studies included patients who were potent pre-operatively with organ-confined disease
without tumour in the bladder neck and/or prostatic urethra. Prostate cancer was ruled out in all of the SPC
techniques, except in those performing nerve-sparing cystectomy.
Oncological outcomes did not differ between groups in any of the comparative studies that
measured local recurrence, metastatic recurrence, DSS and OS, at a median follow-up of three to five years.
Local recurrence after SPC was commonly defined as any urothelial cancer (UC) recurrence below the iliac
bifurcation within the pelvic soft tissue and ranged from 1.2-61.1% vs. 16-55% in the control group. Metastatic
recurrence ranged from 0-33.3%.
For those techniques preserving prostatic tissue (prostate or capsule sparing) rates of incidental
prostate cancer in the intervention group ranged from 0 to 15%. In no case, incidental prostate cancer with
Gleason score > 8 was reported.
Sexual outcomes were evaluated using validated-questionnaires (International Index of Erectile
Function [IIEF], Erection Hardness Scale [EHS], Bladder Cancer Index [BCI]) in eight studies. Post-operative
potency was significantly better in patients who underwent any type of sexual-preserving technique compared
to conventional RC (p < 0.05), ranging 80-90%, 50-100% and 29-78% for prostate-, capsule- or nerve-sparing
techniques, respectively. Data did not show superiority of any sexual-preserving technique.
Urinary continence, defined as the use of no pads in the majority of studies, ranged from 88 to
100% (day-time continence) and from 31-96% (night-time continence) in the prostate-sparing cystectomy
patients. No major impact was shown with regard to continence rates for any of the three approaches.
The evidence base suggests that these procedures may yield better sexual outcomes than standard
cystectomy without compromising oncological outcomes. However, the overall quality of the evidence
was moderate, and hence if a sexual-preserving technique is offered, patients must be carefully selected,
counselled and closely monitored.
Summary of evidence LE
The majority of patients motivated to preserve their sexual function will benefit from sexual-preserving 2
techniques.
None of the sexual-preserving techniques (prostate/capsule/seminal/nerve sparing) have shown to be
superior and no particular technique can be recommended.
Recommendations LE GR
Offer sexual-preserving techniques to men motivated to preserve their sexual function since 2 B
the majority will benefit.
Select patients based on: 2 A
• organ-confined disease;
• absence of any kind of tumour at the level of the prostate, prostatic urethra or bladder
neck.
Do not offer sexual-preserving cystectomy as standard therapy for muscle-invasive bladder C
cancer.
Summary of evidence LE
Data regarding pelvic organ-preserving radical cystectomy for female patients remain immature. 3
Recommendations LE GR
Offer sexual-preserving techniques to female patients motivated to preserve their sexual 3 C
function since the majority will benefit.
Select patients based on: C
• organ-confined disease;
• absence of tumour in bladder neck or urethra.
Do not offer pelvic organ-preserving radical cystectomy for female patients as standard C
therapy for muscle-invasive bladder cancer.
A number of new publications have become available (cut-off date for the literature search was Oct 1st, 2015),
in particular on RARC; a SR [302], a consensus panel report [303], an RCT from the Memorial Sloan Kettering
Cancer Center (MSKCC) group [304] a SR on oncologic and functional outcomes after RARC [305] and a
retrospective review on the recurrence patterns after open radical cystectomy (ORC) and RARC [306]. Since
there is a continuous flow of reports on RARC, this text section and the recommendations will be be subject to
significant updates in the coming years.
For the methodology of the SR we refer to the manuscript [302]. In short, out of 1,071 abstracts
assessed, 105 studies were selected as meeting the inclusion criteria. Of the 105 papers 102 had a level of
evidence of 4, and only three publications had a level of evidence of 2b.
The Pasadena Consensus Panel (a group of experts on RC, lymphadenectomy and urinary reconstruction)
reached similar conclusions as the Novara review based on the same methodology and literature [303]. They
presented similar outcomes comparing RARC and ORC for operative endpoints, pathological and intermediate
oncological endpoints (positive surgical margins and LN yield), functional endpoints and complication
outcomes. Additionally, RARC was associated with increased costs, although there are ergonomic advantages
for the surgeon, as compared to laparoscopic radical cystectomy (LRC). For both techniques surgeons’
experience and institutional volume strongly predicted outcome. According to the literature, proficiency
is reached after 20-250 cases. However, the Pasadena Consensus Panel performed statistical modelling
and came to the conclusion that 30 cases should be enough to achieve proficiency in RARC, but they also
concluded that challenging cases (high BMI, post chemo- or RT, pelvic surgery, T4 or bulky tumours or positive
nodes) should be performed by experienced robotic surgeons only. Experience is defined as a high volume
centre, > 30 RARCs/year and experience in ORC.
In the only sufficiently powered RCT, comparing ORC (n = 58) vs. RARC (n = 60) and open diversion,
the primary endpoint was an advantage in 90 days grade 2-5 complications for RARC [304]. Since the
complication rates were similar (62% for RARC vs. 66% for ORC), the trial was closed after a planned interim
analysis. Robotic-assisted radical cystectomy resulted in less blood loss but had a longer operative time and
higher costs. Length of hospital stay, pathology, and QoL were similar. Limitations of this study are lack of
long-term outcomes and limited experience in RARC as compared to ORC in this group of patients. A similar
health-related QoL (HRQoL) was also found in an initial report of a prospective RCT comparing ORC and RARC
[307]. Similar functional and oncological outcomes with five years follow up were also reported by Yuh et al.
[305]. Ngyuyen et al. also reported that RARC was not an independent predictor of recurrence after surgery in a
retrospective review of 383 consecutive patients [306].
Most reviewed series used extracorporeal reconstruction which leaves room for improvement.
Although an intracorporeal neobladder is a very complex robotic procedure [308] the choice for neobladder or
cutaneous diversion, must not depend on the surgical approach.
For LRC, a recent review came to similar conclusions as described for RARC [308]. The review included sixteen
eligible studies on LRC. As compared to ORC, LRC had a significantly longer operative time, fewer overall
complications, blood transfusions and analgesic use, less blood loss and a shorter length of hospital stay.
However, the review was limited by the inherent limitations of the included studies. Although this review also
showed better oncological outcomes, these appeared comparable to ORC series in the largest LRC multicentre
study to date [308].
Summary of evidence LE
Robot-assisted radical cystectomy (RARC) provides longer operative time (1-1.5 hours), major 1
costs, but shorter length of hospital stay (1-1.5 days) and less blood loss compared to open radical
cystectomy (ORC).
RARC series suffer from a significant stage selection bias as compared to ORC. 1
Grade 3, 90-day complication rate is lower with RARC. 2
Most endpoints, if reported, including intermediate term oncological endpoint and quality of life are 2
not different between RARC and ORC.
Surgeons experience and institutional volume are considered the key factor for outcome of both 2
RARC and ORC, not the technique.
Recommendations on how to define challenging patients and an experienced RARC surgeon are still 3
under discussion.
The use of neobladder after RARC still seems under-utilised, and functional results of intracorporeally 4
constructed neobladders should be studied.
Recommendations GR
Inform the patient of the advantages and disadvantages of open radical cystectomy (ORC) and robot- C
assisted radical cystectomy (RARC) to allow selection of the proper procedure.
Select experienced centres, not specific techniques, both for RARC and ORC. B
Beware of neobladder under-utilisation and outcome after RARC. C
Different types of segments of the intestinal tract have been used to reconstruct the urinary tract, including the
stomach, ileum, colon and appendix [309]. Several studies have compared certain aspects of HRQoL, such as
sexual function, urinary continence and body image, in patient cohorts with different types of urinary diversion.
However, further research is needed on pre-operative tumour stage and functional situation, socio-economic
status, and time interval to primary surgery.
ASA
1 No organic pathology, or patients in whom the pathological process is localised and does not cause
any systemic disturbance or abnormality.
2 A moderate but definite systemic disturbance caused either by the condition that is to be treated or
surgical intervention, or which is caused by other existing pathological processes.
3 Severe systemic disturbance from any cause or causes. It is not possible to state an absolute measure
of severity, as this is a matter of clinical judgment.
4 Extreme systemic disorders that have already become an imminent threat to life, regardless of the
type of treatment. Because of their duration or nature, there has already been damage to the organism
that is irreversible.
5 Moribund patients not expected to survive 24 hours, with or without surgery.
For cystectomy, general preparations are necessary as for any other major pelvic and abdominal surgery. If the
urinary diversion is constructed from gastrointestinal segments, the length or size of the respective segments
and their pathophysiology when storing urine must be considered [315]. Despite the necessary interruption and
re-anastomosis of bowel, a formal bowel preparation may not be necessary [316]. Bowel recovery time can be
reduced by the use of early mobilisation and early oralisation, gastrointestinal stimulation with metoclopramide
and chewing gum [317]. Patients treated according to the “fast tract”/ERAS (Early Recovery After Surgery)
protocol have shown to score better on the emotional and physical functioning scores and suffer less from
wound healing disorders, fever and thrombosis [318].
A cornerstone of the ERAS protocol is post-operative pain management which involves significantly
reducing the use of opioids; offering opioids mainly as breakthrough pain medication. Instead of patient-
controlled analgesia (PCA) and epidural opioids, most patients receive high-dose acetaminophen and/or
ketorolac, starting intra-operatively. Patients on ERAS experience more pain as compared to patients on
a traditional protocol (VAS 3.1 vs. 1.1, p < 0.001), but post-operative ileus decreased from 22% to 7.3%
(p = 0.003) [319].
A multicentre randomised placebo-controlled trial showed that patients receiving alvimopan, a
peripherally acting μ-opioid receptor antagonist, experienced quicker bowel recovery compared to patients
receiving placebo [320]. However, this drug is, as yet, not approved in Europe.
Patients undergoing continent urinary diversion must be motivated to learn about their diversion and to be
manually skilful in manipulating their diversion. Contraindications to more complex forms of urinary diversion
include:
• debilitating neurological and psychiatric illnesses;
• limited life expectancy;
• impaired liver or renal function;
• transitional cell carcinoma of the urethral margin or other surgical margins.
Relative contraindications specific for an orthotopic neobladder are high-dose pre-operative RT, complex
urethral stricture disease, and severe urethral sphincter-related incontinence [321].
7.4.4.2.1 Ureterocutaneostomy
Ureteral diversion to the abdominal wall is the simplest form of cutaneous diversion. Operating time,
complication rate, stay at intensive care and length of hospital stay are lower in patients treated with
In a retrospective multicentre study peri-operative morbidity was evaluated for urinary diversion using bowel as
compared to ureterocutaneostomy. Patients selected for a ureterocutaneostomy were older and had a higher
ASA score, while their mean Charlson score was lower (4.2 vs. 5.6, p < 0.001) [332].
Despite the limited comparative data available, it must be taken into consideration that older
data and clinical experience suggest ureter stenosis at the skin level and ascending UTI are more frequent
complications in ureterocutaneostomy compared to an ileal conduit diversion. In a retrospective study
comparing various forms of intestinal diversion, ileal conduits had fewer late complications than continent
abdominal pouches or orthotopic neobladders [333].
In conclusion, standard RC in male patients with bladder neoplasms includes removal of the entire bladder,
prostate, seminal vesicles, distal ureters (segment length undefined), and corresponding LNs (extent undefined)
(LE: 2b). In female patients, standard RC includes removal of the entire bladder, urethra and adjacent vagina,
uterus, distal ureters, and corresponding LNs.
A detailed investigation of the bladder neck prior to RC is important for women who are scheduled
for an orthotopic bladder substitute [358]. In women undergoing RC the rate of concomitant urethral
malignancy has been reported to range from 12-16% [359]. Localisation of the primary tumour at the bladder
neck correlated strongly with concomitant urethral malignancy. Additionally, the tumours were at higher risk of
advanced stage and nodal involvement [360].
Currently, it is not possible to recommend a particular type of urinary diversion. However, most institutions
prefer ileal orthotopic neobladders and ileal conduits, based on clinical experience [361, 362]. In selected
patients, such as patients with a single kidney, ureterocutaneostomy is surgically the least burdensome type of
diversion (LE: 3). Recommendations related to RC and urinary diversions are listed in section 7.5.
2 Intraoperative tranexamin acid infusion reduces peri-operative blood transfusion rates from 57.7% to 31.1%.
There was no increase seen in peri-operative venous thromboembolism [374].
3 ammond and co-workers reviewed 20,762 cases of venous thromboembolism (VTE) after major surgery and
H
found cystectomy patients to have the second highest rate of VTE among all cancers studied [375]. These
patients benefit from 30 days low-molecular-weight heparin prophylaxis. Subsequently, it was demonstrated
that BMI > 30 and non-urothelial BCs are independently associated with VTE after cystectyomy. In these
patients extended (90 days) heparin prophylaxis should be considered [376].
7.4.6 Survival
According to a multi-institutional database of 888 consecutive patients undergoing RC for BC, the five-year
recurrence-free survival was 58% and the CSS was 66% [377]. Recent external validation of post-operative
nomograms for BC-specific mortality showed similar results, with bladder-CSS of 62% [378].
Recurrence-free survival and OS in a large single-centre study of 1,054 patients was 68% and 66%
at five years and 60% and 43%, at ten years, respectively [176]. However, the five-year recurrence-free survival
in node-positive patients who underwent cystectomy was considerably less at 34-43% [175, 176, 379]. In a
surgery-only study, the five-year recurrence-free survival was 76% in patients with pT1 tumours, 74% for pT2,
52% for pT3, and 36% for pT4 [176].
A trend analysis according to the five-year survival and mortality rates of BC in the U.S.A., between 1973 and
2009 with a total of 148,315 BC patients, revealed an increased stage-specific five-year survival rate for all
stages, except for metastatic disease [380].
Summary of evidence LE
For muscle-invasive bladder cancer, offer radical cystectomy as the curative treatment of choice. 3
A higher case load reduces morbidity and mortality of cystectomy. 3
Radical cystectomy includes removal of regional lymph nodes. 3
There are data to support that extended lymph node dissection (LND) (vs. standard or limited LND) 3
improves survival after radical cystectomy.
Radical cystectomy in both sexes must not include removal of the entire urethra in all cases, which 3
may then serve as the outlet for an orthotopic bladder substitution. The terminal ileum and colon are
the intestinal segments of choice for urinary diversion.
The type of urinary diversion does not affect oncological outcome. 3
Laparoscopic cystectomy and robotic-assisted laparoscopic cystectomy are feasible but still 3
investigational. Current best practice is open radical cystectomy.
In patients aged > 80 years with MIBC, cystectomy is an option. 3
Surgical outcome is influenced by comorbidity, age, previous treatment for bladder cancer or other 2
pelvic diseases, surgeon and hospital volumes of cystectomy, and type of urinary diversion.
Surgical complications of cystectomy and urinary diversion should be reported using a uniform 2
grading system. Currently, the best-adapted, graded system for cystectomy is the Clavien grading
system.
No conclusive evidence exists as to the optimal extent of LND. 2a
Recommendations GR
Do not delay cystectomy for > 3 months as it increases the risk of progression and cancer-specific B
mortality.
Before cystectomy, fully inform the patient about the benefits and potential risks of all possible B
alternatives. The final decision should be based on a balanced discussion between the patient and the
surgeon.
Offer an orthotopic bladder substitute or ileal conduit diversion to male and female patients lacking B
any contraindications and who have no tumour in the urethra or at the level of urethral dissection.
Do not offer pre-operative radiotherapy when subsequent cystectomy with urinary diversion is A
planned.
Pre-operative bowel preparation is not mandatory. “Fast track” measurements may reduce the time of C
bowel recovery.
Offer radical cystectomy in T2-T4a, N0M0, and high-risk non-MIBC (as outlined above). A*
Perform a lymph node dissection as an integral part of cystectomy. A
Preserve the urethra if margins are negative. B
Check the urethra regularly if no bladder substitution is attached. B
*Upgraded following EAU Working Panel consensus.
Diagnosis
1
- Males: biopsy apical prostatic urethra
• Cystoscopy and tumour resection or frozen section during surgery
• Evaluation of urethra1
• CT imaging of abdomen, chest, UUT 1 - Females: biopsy of proximal urethra or
• MRI can be used for local staging frozen section during surgery
Neoadjuvant chemotherapy2
• Should be considered in selected 2
- Neoadjuvant radiotherapy is not
patients recommended
• 5-7% five year survival benefit
Radical cystectomy
• Know general aspects of surgery
o Preparation
o Surgical technique
o Integrated node dissection
o Urinary diversion
o Timing of surgery
• A higher case load improves outcome
CT = computed tomography; MRI = magnetic resonance imaging; UUT = upper urinary tract.
Locally advanced MIBC can be associated with ureteral obstruction due to a combination of mechanical
blockage by the tumour and invasion of ureteral orifices by tumour cells. In a series of 61 patients with
obstructive uraemia, RC was not an option in 23 patients, and obstruction was relieved using permanent
nephrostomy tubes [384]. Another ten patients underwent palliative cystectomy, but local pelvic recurrence
occurred in all ten patients within the first year of follow-up. Another small study (n = 20) showed that primary
cystectomy for T4 BC was technically feasible and associated with a very tolerable therapy-related morbidity
and mortality [385].
Recommendations GR
Offer radical cystectomy as a palliative treatment to patients with inoperable locally advanced tumours B
(T4b).
Offer palliative cystectomy in patients with symptoms. B
Radiation therapy is another common strategy for control of bleeding, and is also used to control pain. An
older study reported control of haematuria in 59% of patients and pain control in 73% [387]. Irritative bladder
and bowel complaints due to irradiation are possible, but are usually mild. Non-conservative options are
embolisation of specific arteries in the small pelvis, with success rates as high as 90% [386]. Radical surgery is
a last resort and includes cystectomy and diversion (see above Section 7.5.1).
In conclusion, TURB alone should only be considered as a therapeutic option for muscle-invasive disease
after radical TURB, when the patient is unfit for cystectomy or a multimodality bladder-preserving approach, or
refuses open surgery [392].
Recommendation LE GR
Do not offer transurethral resection of bladder tumour alone as a curative treatment option as 2a B
most patients will not benefit.
In 2007 long-term results were reported by Chung et al. [396]. A total of 340 patients with MIBC were treated
with EBRT alone, EBRT with concurrent chemotherapy, or NAC followed by EBRT. The overall CR was 55%
and the ten-year DSS and OS were 35% and 19%, respectively. Complete response was 64% after EBRT
alone, 79% after concurrent chemotherapy (n = 36), and 52% after NAC (n = 57). Younger age, lower tumour
stage and absence of CIS were associated with a significant improvement in survival.
A 2002 Cochrane analysis demonstrated that RC has an OS benefit compared to RT [397], although this was
not the case in a 2014 retrospective review using a propensity score analysis [398].
In conclusion, EBRT can be an alternative treatment in patients unfit for radical surgery.
Summary of evidence LE
External beam radiotherapy alone should only be considered as a therapeutic option when the patient 3
is unfit for cystectomy or a multimodality bladder-preserving approach.
Radiotherapy can also be used to stop bleeding from the tumour when local control cannot be 3
achieved by transurethral manipulation because of extensive local tumour growth.
Recommendation GR
Do not offer radiotherapy alone as primary therapy for localised bladder cancer. B
7.6.3 Chemotherapy
Chemotherapy alone rarely produces durable complete remissions. In general, a clinical CR rate of up to 56%,
as reported in some series, which must be weighed against a staging error of > 60% [399, 400]. Response
to chemotherapy is a prognostic factor for treatment outcome and eventual survival [199], though it may be
confounded by patient selection.
Several groups have reported the effect of chemotherapy on resectable tumours (neoadjuvant approach), as
well as unresectable primary tumours [197, 226, 401, 402]. Neoadjuvant chemotherapy with 2-3 cycles of
MVAC or CMV has led to a downstaging of the primary tumour in different prospective series [197, 226, 401].
Pathological complete responses of primary bladder tumours were reached in 12-50% of patients after MVAC
and in 12-22% of patients after gemcitabine/cisplatin (GC) in phase II and phase III trials [197, 226, 401, 403-
410].
Contemporary series with GC followed by RC reported inferior pT0 rates, which may have been
related to a lack of dose density and inappropriate delay of surgery [230].
For highly selected patients, a bladder-conserving strategy with TURB and systemic cisplatin-based
chemotherapy, preferably with MVAC, may allow long-term survival with intact bladder [199]. However, this
approach cannot be recommended for routine use.
7.6.3.1 Summary of evidence and recommendation for chemotherapy for muscle-invasive bladder tumours
Summary of evidence LE
With cisplatin-based chemotherapy as primary therapy for locally advanced tumours in highly selected 2b
patients, complete and partial local responses have been reported.
Recommendation GR
Do not offer chemotherapy alone as primary therapy for localised bladder cancer. A
There are no completed RCTs to compare the outcome of MMT with the gold standard, RC, but this
approach has been shown to be superior to RT alone [412, 413]. Many of the reported series have differing
characteristics as compared to the large surgical series which typically have median ages in the mid-late 60s
compared to mid-70s for some large RT series (reviewed in [412]). In the case of MMT, two distinct patterns of
care may be distinguished: treatment aimed at patients fit for cystectomy and treatment aimed at older, less fit
patients. For the former category MMT presents selective bladder preservation. In that case, the initial step is a
radical TURB, where as much tumour as possible should be resected. This implies that proper patient selection
(T2 tumours, no CIS) is critical [414]. For patients who are not candidates for cystectomy, less stringent
criteria can be applied, though extensive CIS and poor bladder function should both be regarded as strong
contraindications.
Following TURB and staging, treatment comprises EBRT with concurrent radiosensitising drugs.
Two schedules are in common use worldwide: a split dose format with interim cystoscopy is used in North
America [414] whilst single-phase treatment is more commonly used elsewhere [412]. For radiosensitising
chemotherapy, cisplatin [415] or mitomycin C plus 5-fluorouracil (5-FU) can be used [412], but also other
schedules have been used. In particular, hypoxic cell sensitisation with nicotinamide and carbogen has been
evaluated in a large phase III trial [416]. In a recent phase I trial gemcitabine was used [417]. The regimen was
well tolerated with promising results.
With MMT, five-year CSS and OS rates are achieved from 50-82% and from 36-74% respectively
[393, 412, 415, 416, 418-420]. Salvage cystectomy rates are 10-30% [412, 415, 420]. There are data that major
complication rates are similar for salvage and primary cystectomy [421]. The majority of recurrences post-MMT
are non invasive and can be managed conservatively [412]. The collaborative review comes to the conclusion
that there are accumulating data suggesting that bladder preservation with MMT leads to acceptable outcomes
and therefore may be considered a reasonable treatment option in well-selected patients as compared to RC
[422]. It should also be considered in all patients where surgery is contraindicated, either relatively or absolutely
as the factors that determine fitness for surgery and chemoradiotherapy differ.
A bladder-preserving multimodality strategy requires very close multidisciplinary co-operation and
a high level of patient compliance. Even if a patient has shown a CR to a multimodality bladder-preserving
strategy, the bladder remains a potential source of recurrence, hence long-term bladder monitoring is essential
and patients should be counselled that this will be required. A recent subanalysis from two RTOG trials looked
at CR (T0) and near CR (Ta or Tis) after MMT [423]. After a median follow up of 5.9 years 41/119 (35%) of
these patients experienced a bladder recurrence, and fourteen required a salvage cystectomy. There was no
difference between complete and near-complete responders.
7.6.4.1 Summary of evidence and recommendations for multimodality treatment in muscle-invasive bladder
cancer
Summary of evidence LE
In a highly selected patient population, long-term survival rates of multimodality treatment are 2b
comparable to those of early cystectomy.
Recommendations GR
Offer surgical intervention or multimodality treatments as primary curative therapeutic approaches B
since they are more effective than radiotherapy alone.
Offer multimodality treatment as an alternative in selected, well-informed and compliant patients, B
especially for whom cystectomy is not an option.
There is limited evidence from adequately conducted and accrued randomised phase III trials in favour of the
routine use of adjuvant chemotherapy [424, 426-431]. Individual patient data from six randomised trials [420,
432-435] of adjuvant chemotherapy were included in one meta-analysis [426] with 491 patients for survival
analysis (unpublished data from Otto et al., were included in the analysis). All these trials were suboptimal with
serious deficiencies, including small sample size (underpowered), early cessation of patient entry, and flaws
in design and statistical analysis, including irrelevant endpoints or a lack of recommendations concerning
salvage chemotherapy for relapse or metastases [424]. In these trials, three or four cycles of CMV, cisplatin,
cyclophosphamide, and adriamycin (CISCA), methotrexate, vinblastine, adriamycin or epirubicin, and cisplatin
(MVA(E)C) and cisplatin and methotrexate (CM) were used [436], and one trial used cisplatin monotherapy
[434]. These data were not convincing enough to give an unequivocal recommendation for the use of adjuvant
chemotherapy.
In a 2014 meta-analysis [427], an additional three studies were included [428-430]. However, only 945 patients
were included in this meta-analysis of nine trials, and none of the trials were fully accrued and no individual
patient data were used [427]. For one trial, only an abstract was available at the time of the meta-analysis
[429], and none of the included trials by themselves were significantly positive for OS in favour of adjuvant
chemotherapy. In two of the trials, more modern chemotherapy regimens were used (gemcitabine/ cisplatin
and paclitaxel/gemcitabine and cisplatin) [428, 429]. The HR for OS was 0.77 and there was a trend towards
an OS benefit when including all nine trials. The effect was stronger for DFS (HR: 0.66; 95% CI: 0.48-0.92)
and when stratified for the ratio of nodal positivity (HR: 0.64; 95% CI: 0.45- 0.91). The background of this
finding was heterogeneity in outcomes observed between the included studies. After stratification of the
studies by the ratio of node positivity, no further heterogeneity was identified. The HR for DFS associated with
adjuvant cisplatin-based chemotherapy in studies with higher nodal involvement was 0.39 (95% CI: 0.28-0.54),
compared with 0.89 (95% CI: 0.69-1.15) in studies with less nodal involvement.
Furthermore, a retrospective cohort analysis that included 3,974 patients after cystectomy and
LND showed an OS benefit in high-risk subgroups (extravesical extension and nodal involvement) [HR: 0.75;
CI: 0.62-0.90] [437]. The most recent publication of the so far largest RCT (EORTC 30994), although not fully
accrued, showed a significant improvement of PFS for immediate compared with deferred treatment (HR: 0.54;
95% CI: 0.4-0.73, p < 0.0001), there was, however, no significant OS benefit [438].
From the currently available evidence, it is still unclear whether immediate adjuvant chemotherapy or
chemotherapy at the time of relapse is superior, or if the two approaches are equivalent with respect to the
endpoint of OS. Cisplatin-based combination chemotherapy results in long-term DFS, even in metastatic
disease, mainly in patients with LN metastases only, and with a good PS [407, 439, 440]. In the most recent
meta-analysis, the positive role of adjuvant chemotherapy for BC has been strengthened, however, still with
a poor level of evidence [427]. Patients should be informed about potential chemotherapy options before RC,
including neoadjuvant and adjuvant chemotherapy, and the limited evidence for adjuvant chemotherapy.
Recommendation GR
Offer adjuvant cisplatin-based combination chemotherapy to patients with pT3/4 and/or pN+ disease B
if no neoadjuvant chemotherapy has been given.
More than 50% of patients with UC are not eligible for cisplatin-based chemotherapy [456-459].
Renal function assessment in UC is of utmost importance for treatment selection. Calculation of
creatinine clearance (CrCl) (24-h urine collection) with current formulae tend to underestimate clearance in
patients aged > 65 years compared to measured CrCl [456, 460].
High-dose intensity MVAC (HD-MVAC) combined with G-CSF is less toxic and more efficacious than standard
MVAC in terms of dose density, complete response, and two-year survival rate. However, there is no significant
difference in median survival between the two regimens [466, 467]. In general, all disease sites have been
shown to respond to cisplatin-based combination chemotherapy. A response rate of 66% and 77% with MVAC
and HD-MVAC, respectively, has been reported in retroperitoneal LNs vs. 29% and 33% at extranodal sites
[466]. The disease sites also have an impact on long-term survival. In lymph-node-only disease, 20.9% of
patients were alive at five years compared to only 6.8% of patients with visceral metastases [439].
Further intensification of treatment using the new paclitaxel, cisplatin and gemcitabine (PCG) triple regimen did
not result in a significant improvement in OS in the intent-to-treat (ITT) population of a large randomised phase
III trial, comparing PCG triple regimen to GC [468]. However, the overall response rate (ORR) was higher with
the triple regimen (56% vs. 44%; p = 0.0031), and the trend for OS improvement in the ITT population (15.8 vs.
12.7 months; HR = 0.85, p = 0.075) became significant in the eligible population. Adding paclitaxel to GC did
not induce major additional side effects. Grade 4 neutropenia was more common (35.8% vs. 20% for GC), as
Vinflunine, a novel third-generation vinca alkaloid, provided promising results in phase II trials [482]. A
randomised phase III trial compared vinflunine plus best supportive care (BSC) against BSC alone in patients
progressing after first-line treatment with platinum-containing combination chemotherapy for metastatic
disease [483]. The results showed a modest ORR (8.6%), a clinical benefit with a favourable safety profile
and, most importantly, a survival benefit in favour of vinflunine, which was statistically significant in the eligible
patient population (not in the ITT population). For second-line treatment of advanced or metastatic UC, this
trial reached the highest level of evidence ever reported. Currently, in Europe, vinflunine is the only approved
second-line treatment. Vinflunine has not been approved for this indication in the United States.
Patients treated with ZA or denosumab should be informed about possible side effects and receive
prophylactic treatment for jaw osteonecrosis and hypocalcaemia, which is more common with denosumab.
Aggressive calcium and vitamin D supplementation is recommended. Dosing regimens of ZA should follow
regulatory recommendations and should be adjusted according to pre-existing medical conditions [507]. For
denosumab, no dose adjustments are required for variations in renal function.
Summary of evidence LE
In a first-line setting, performance status (PS) and the presence or absence of visceral metastases are 1b
independent prognostic factors for survival.
In a second-line setting, negative prognostic factors are: liver metastasis, PS > 1 and low haemoglobin 1b
(< 10 g/dL)
Cisplatin-containing combination chemotherapy can achieve median survival of up to 14 months, with 1b
long-term disease-free survival reported in ~15% of patients with nodal disease and good PS.
Single-agent chemotherapy provides low response rates of usually short duration. 2a
Carboplatin combination chemotherapy is less effective than cisplatin-based chemotherapy in terms 2a
of complete response and survival.
Non-platinum combination chemotherapy produces substantial responses in first- and second-line 2a
settings.
Non-platinum combination chemotherapy has not been tested against standard chemotherapy 4
inpatients who are fit or unfit for cisplatin combination chemotherapy.
There is no defined standard chemotherapy for unfit patients with advanced or metastatic urothelial 2b
cancer (UC).
Vinflunine reaches the highest level of evidence ever reported for second-line use. 1b
Post-chemotherapy surgery after partial or complete response may contribute to long-term disease- 3
free survival in selected patients.
Zoledronic acid and denosumab have been approved for all cancer types including UC, because they 1b
reduce and delay skeletal related events in metastatic bone disease.
PD-L1 inhibitor atezolizumab has been FDA approved for patients that have progressed during or after 2a
previous platinum-based chemotherapy based on the results of a phase-II trial.
7.8.12 Biomarkers
Modest disease control rates, with sporadic marked responses, in some patients with UC have led to the
investigation of biomarkers for assessment of post-operative prognosis and the potential value of peri-
operative chemotherapy, and as predictors of response to chemotherapy or its monitoring. Most of the
biomarkers are associated with tumour angiogenesis. Small studies, usually retrospective, have investigated
microvessel density, altered p53 tumour expression [510], serum vascular endothelial growth factor [511],
urinary and tissue basic fibroblast growth factor [512], urinary (wild-type and mutant) and tissue fibroblast
growth factor receptor-3 [513], and more recently, thrombospondin-1 [514], circulating tumour cells [515, 516],
and multidrug resistance gene expression [517]. Although a few biomarkers have shown potential, as yet, there
is insufficient evidence to support their routine clinical use (LE: 3).
Recommendation GR
Do not use biomarkers in daily clinical practice since they have no impact on predicting outcome, A*
treatment decisions, or monitoring therapy in muscle-invasive bladder cancer.
*Upgraded following panel consensus.
Patient characteristics
PS 0-1/ 2/ >2
GFR ≥/< 60 mL/min
Comorbidities
CISPLATIN?
YES NO NO
Second-line treatment
PS 0-1 PS ≥ 2
BSC = best supportive care; GC = gemcitabine plus cisplatin; GFR = glomular filtration rate; MVAC =
methotrexate, vinblastine, adriamycin plus cisplatin; HD MVAC = high-dose methotrexate, vinblastine,
adriamycin plus cisplatin; PS = performance status; PCG = paclitaxel, cisplatin, gemcitabine.
Several questionnaires have been validated for assessing HRQoL in patients with BC, including FACT
(Functional Assessment of Cancer Therapy)-G [518], EORTC QLQ-C30 [519], EORTC QLQ-BLM (muscle-
invasive BC module) [520], and SF (Short Form)-36 [521, 522] and recently the BCI questionnaire specifically
designed and validated for BC patients [523].
A psychometric test, such as the FACT-BL, should be used for recording BC morbidity. New
intensive interviewing techniques have added valuable information to our knowledge of HRQoL, which greatly
depends on patients’ individual preferences [524].
Due to improved surgical techniques in orthotopic bladder substitution, some recent studies are supportive of
continent bladder substitutes [362, 520, 527]. Patients with an orthotopic substitution had significantly better
physical function and a more active lifestyle compared to patients with an ileal conduit. It is important to note
that HRQoL parameters are independent prognostic factors for OS [528]. Patients with a continent bladder-
substitute generally scored more favourably than those with an incontinent diversion, as judged by body image,
social activity and physical function [527, 529]. Note that all studies investigated mostly male patients. Also
of interest is the urinary bother in female neobladder. Bartsch and co-workers found in 56 female patients
day-time and night-time incontinence rates of respectively 29.6% and 35.2%. Thirty-five patients (62.5%)
performed clean intermittent catheterisation, which is much worse compared to male neobladder patients.
Moreover, patients with non-organ-confined disease (p = 0.04) and patients with a college degree (p = 0.001)
showed worse outcome on HRQoL scores [530].
Nevertheless, the HRQoL outcome is most likely a result of good patient selection. An older more isolated
patient is probably better served with an ileal conduit whereas a younger patient with more interest in body
image and sexuality is better off with an orthotopic diversion.
Alternative definitive treatments of MIBC, e.g. trimodality bladder-sparing procedures, have shown similar
survival times compared to cystectomy. However, the impact on HRQoL has been controversial [136, 393, 535-
538].
Summary of evidence LE
No randomised, prospective health-related quality of life (HRQoL) study has evaluated the different 2b
forms of definitive treatment for MIBC.
In most patient groups studied, the overall HRQoL after cystectomy remains good, irrespective of the
type of urinary diversion used. The suggestion that continent diversions are associated with a better
HRQoL has not been sufficiently substantiated.
Important determinants of (subjective) quality of life are a patient’s personality, coping style and social
support.
Recommendations GR
Use validated questionnaires to assess HRQoL in patients with MIBC. B
Offer a continent urinary diversion unless a patient’s comorbidities, tumour variables and coping C
abilities present clear contraindications.
Pre-operative patient information, patient selection, surgical techniques, and careful post-operative C
follow-up are the cornerstones for achieving good long-term results.
Encourage patients to actively participate in the decision-making process.
Provide clear and exhaustive information on all potential benefits and side-effects, allowing patients to A
make informed decisions.
Nomograms on CSS following RC have been developed and externally validated. However, their wider use
cannot be recommended until further data becomes available [540, 541].
Surveillance protocols are commonly based on patterns of recurrence observed from retrospective series.
Diagnosis of asymptomatic recurrence based on routine oncological follow-up and results from retrospective
studies are controversial [542, 543]. Importantly, these retrospective studies use different follow-up regimens
and imaging techniques that make final analysis and conclusive recommendations difficult. Prospective trials
demonstrating the effectiveness of follow up after RC and its impact on OS are lacking [544].
Contemporary cystectomy has a 5-15% probability of pelvic recurrence. Most recurrence manifests during
the first 24 months, often within six to eighteen months after surgery. However, late recurrence can occur up
to five years after cystectomy. Pathological stage and LN status are predictive for pelvic recurrence, as well as
positive margins, extent of LND, and peri-operative chemotherapy [545].
Patients have poor prognosis after pelvic recurrence. Even with treatment, the median survival ranges from four
to eight months following diagnosis. Definitive therapy can prolong survival, but mostly provides significant
palliation of symptoms. Treatment comprises systemic chemotherapy, local surgery, or RT [544].
The value of monitoring in diagnosis of asymptomatic metastases and its impact on survival is questionable.
Some studies have demonstrated no impact on survival despite using routine monitoring, although others
have suggested that diagnosis of asymptomatic metastases, especially in the lungs, improves survival [542,
543]. Consideration must also be given to the possibility of longer survival in patients with minimal metastatic
disease undergoing multimodal treatment, including metastasectomy. There are reports of survival rates of
28-33% at five years in patients undergoing resection of metastases after objective response to chemotherapy
[495, 502].
The incidence of new urethral tumours after RC is 1.5-6.0% in men, with a mean recurrence-free interval of
13.5-39.0 months and median survival of 28-38 months, of which > 50% die from systemic disease.
Secondary urethral tumours are likely to occur at one to three years after surgery. Prophylactic
urethrectomy at cystectomy is no longer justified in most patients. Independent predictors for urethral
recurrence are: cystectomy for NMIBC, prostate involvement, and history of recurrent NMIBC [544].
In women, the main risk factor is bladder neck disease. Many studies have demonstrated that the risk of
urethral recurrence after orthotopic diversion (0.9-4.0%) [551-554] is significantly less than after non-orthotopic
diversion (6.4-11.1%) [545, 551, 553].
Upper urinary urothelial carcinomas occur in 1.8-6.0% of cases and represent the most common sites of
late recurrence (three years DFS following RC). Median OS is 10-55 months, and 60-67% of patients die of
metastatic disease [544].
A meta-analysis found that 38% of UTUC recurrence was diagnosed by follow-up investigation,
whereas in the remaining 62%, diagnosis was based on symptoms. When urine cytology was used in
surveillance, the rate of primary detection was 7% and 29.6% with UUT imaging [559]. This meta-analysis
concluded that patients with non-invasive cancer are twice as likely to have UTUC as patients with invasive
disease. Multifocality increases the risk of recurrence by three-fold, while positive ureteral or urethral margins
increase the risk by seven-fold. Radical nephroureterectomy can prolong survival [560].
Although general recommendations are not advised based on high level of evidence, closer follow-up could
be considered in patients with locally advanced disease or LN involvement. The suggested follow-up includes
four-monthly CT scans during the first year, six-monthly until the third year, and annual imaging thereafter.
Patients with multifocal disease, NMIBC with CIS or positive ureteral margins are at higher risk of
developing UTUC which can develop late (> 3 years). In those cases, monitoring of the UUT is mandatory
during follow-up. Computed tomography is to be used to assess the UUT [559].
This rate increases over time, and exceeds 54% after fifteen years of follow up. Therefore, long-term follow up
of functional outcomes is desirable [544] (LE: 3), and may stop after fifteen years.
The functional complications are diverse and include: vitamin B12 deficiency, metabolic acidosis, worsening of
9. REFERENCES
1. Rouprêt, M., et al. Guidelines on Upper Urinary Tract Urothelial Cell Carcinoma. EAU Guidelines
2017. Edn presented at the 32nd EAU Annual Congress London 2017.
2. Babjuk, M., et al. Guidelines on Non-muscle-invasive bladder cancer (TaT1 and CIS). 2017. Edn
presented at the 32nd EAU Annual Congress London 2017.
3. Gakis, G., et al. Guidelines on Primary Urethral Carcinoma EAU Guidelines 2017. Edn presented at
the 32nd EAU Annual Congress London 2017.
4. Witjes, A.J., et al. Updated 2016 EAU Guidelines on Muscle-invasive and Metastatic Bladder
Cancer. Eur Urol, 2017. 71: 462.
https://www.ncbi.nlm.nih.gov/pubmed/27375033
5. Phillips, B., et al. Oxford Centre for Evidence-based Medicine Levels of Evidence. Updated by
Jeremy Howick March 2009.
http://www.cebm.net/oxford-centre-evidence-based-medicine-levels-evidence-march-2009/
6. Ferlay, J., et al. Cancer incidence and mortality patterns in Europe: estimates for 40 countries in
2012. Eur J Cancer, 2013. 49: 1374.
https://www.ncbi.nlm.nih.gov/pubmed/23485231
7. GLOBOCAN 2012 v1.0: Estimated cancer incidence, mortality and prevalence worldwide in 2012.
2016.
http://globocan.iarc.fr/Default.aspx
8. Burger, M., et al. Epidemiology and risk factors of urothelial bladder cancer. Eur Urol, 2013. 63: 234.
https://www.ncbi.nlm.nih.gov/pubmed/22877502
9. Bosetti, C., et al. Trends in mortality from urologic cancers in Europe, 1970-2008. Eur Urol, 2011. 60:
1.
https://www.ncbi.nlm.nih.gov/pubmed/21497988
10. Chavan, S., et al. International variations in bladder cancer incidence and mortality. Eur Urol, 2014.
66: 59.
https://www.ncbi.nlm.nih.gov/pubmed/24451595
11. Comperat, E., et al. Clinicopathological characteristics of urothelial bladder cancer in patients less
than 40 years old. Virchows Arch, 2015. 466: 589.
https://www.ncbi.nlm.nih.gov/pubmed/25697540
12. Steinmaus, C., et al. Increased lung and bladder cancer incidence in adults after in utero and early-
life arsenic exposure. Cancer Epidemiol Biomarkers Prev, 2014. 23: 1529.
https://www.ncbi.nlm.nih.gov/pubmed/24859871
13. Freedman, N.D., et al. Association between smoking and risk of bladder cancer among men and
women. JAMA, 2011. 306: 737.
https://www.ncbi.nlm.nih.gov/pubmed/21846855
14. Tobacco smoke and involuntary smoking. IARC Monogr Eval Carcinog Risks Hum, 2004. 83: 1.
https://www.ncbi.nlm.nih.gov/pubmed/15285078
15. Brennan, P., et al. Cigarette smoking and bladder cancer in men: a pooled analysis of 11 case-
control studies. Int J Cancer, 2000. 86: 289.
https://www.ncbi.nlm.nih.gov/pubmed/10738259
16. Gandini, S., et al. Tobacco smoking and cancer: a meta-analysis. Int J Cancer, 2008. 122: 155.
https://www.ncbi.nlm.nih.gov/pubmed/17893872
17. Pashos, C.L., et al. Bladder cancer: epidemiology, diagnosis, and management. Cancer Pract, 2002.
10: 311.
https://www.ncbi.nlm.nih.gov/pubmed/12406054
18. Harling, M., et al. Bladder cancer among hairdressers: a meta-analysis. Occup Environ Med, 2010.
67: 351.
https://www.ncbi.nlm.nih.gov/pubmed/20447989
2. METHODS 3
2.1 Data identification 3
2.2 Review 3
2.3 Future goals 4
6. PROGNOSIS 7
6.1 Long-term survival after primary urethral carcinoma 7
6.2 Predictors of survival in primary urethral carcinoma 7
7. DISEASE MANAGEMENT 8
7.1 Treatment of localised primary urethral carcinoma in males 8
7.2 Treatment of localised urethral carcinoma in females 8
7.2.1 Urethrectomy and urethra-sparing surgery 8
7.2.2 Radiotherapy 8
7.3 Multimodal treatment in advanced urethral carcinoma in both genders 9
7.3.1 Preoperative platinum-based chemotherapy 9
7.3.2 Preoperative chemoradiotherapy in locally advanced squamous cell carcinoma
of the urethra 9
7.4 Treatment of urothelial carcinoma of the prostate 9
8. FOLLOW-UP 10
9. REFERENCES 10
2. METHODS
2.1 Data identification
For the 2017 Primary urethral Carcinoma Guidelines, new and relevant evidence has been identified, collated
and appraised through a structured assessment of the literature. An updated systematic literature search was
performed to identify studies reporting data on urethral malignancies since the prior search, covering a time
frame between January 1st 2014 and September 20th, 2016. Databases searched included Ovid (Medline),
EMBASE and the Cochrane Central Register of Controlled Trials and Cochrane Database of Systematic
Reviews. A total of 309 records were identified, retrieved and screened for relevance. A detailed search
strategy is available online:
https://uroweb.org/guideline/primary-urethral-carcinoma/?type=appendices-publications.
Recommendations in this text are assessed according to their level of evidence (LE) and Guidelines are given
a grade of recommendation (GR), according to a classification system modified from the Oxford Centre for
Evidence-Based Medicine Levels of Evidence [4]. Additional methodology information can be found in the
general Methodology section of this print, and online at the EAU website: http://uroweb.org/guidelines/.
A list of Associations endorsing the EAU Guidelines can also be viewed on line at the above
address.
2.2 Review
This document was peer-reviewed prior to publication in 2015.
3.2 Aetiology
For male primary UC, various predisposing factors have been reported, including urethral strictures [9, 10],
chronic irritation after intermittent catheterisation/urethroplasty [11-13], external beam irradiation therapy [14],
radioactive seed implantation [15], and chronic urethral inflammation/urethritis following sexually transmitted
diseases (i.e. condylomata associated with human papilloma virus 16) [16, 17]. In female UC, urethral
diverticula [18-20] and recurrent urinary tract infections [21] have been associated with primary UC. Clear cell
adenocarcinoma (AC) may also have a congenital origin [22, 23].
3.3 Histopathology
Both the Surveillance of Rare Cancers in Europe (RARECARE) project and SEER database have reported that
urothelial carcinoma of the urethra is the predominant histological type of primary urethral cancer (54-65%),
followed by squamous cell carcinoma (SCC) (16-22%) and AC (10-16%) [7, 8]. A recent SEER analysis of 2,065
men with primary UC (mean age: 73 years) found that UC was most common (78%), and SCC (12%) and AC
(5%) were significantly less frequent [24]. In women, a recent report of the Dutch National Cancer Registry on
primary urethral cancer reported that UC occurred in 45% of cases, followed by AC in 29%, SCC in 19%, and
other histological entities in 6% [25].
T - Primary Tumour
TX Primary tumour cannot be assessed
T0 No evidence of primary tumour
Urethra (male and female)
Ta Non-invasive papillary, polypoid, or verrucous carcinoma
Tis Carcinoma in situ
T1 Tumour invades subepithelial connective tissue
T2 Tumour invades any of the following structures: corpus spongiosum, prostate, periurethral muscle
T3 Tumour invades any of the following structures: corpus cavernosum, beyond prostatic capsule,
anterior vagina, bladder neck (extraprostatic extension)
T4 Tumour invades other adjacent organs (invasion of the bladder)
Urothelial (transitional cell) carcinoma of the prostate
Tis pu Carcinoma in situ, involvement of prostatic urethra
Tis pd Carcinoma in situ, involvement of prostatic ducts
T1 Tumour invades subepithelial connective tissue (for tumours involving prostatic urethra only)
T2 Tumour invades any of the following: prostatic stroma, corpus spongiosum, periurethral muscle
T3 Tumour invades any of the following: corpus cavernosum, beyond prostatic capsule, bladder neck
(extraprostatic extension)
T4 Tumour invades other adjacent organs (invasion of the bladder or rectum)
N - Regional Lymph Nodes
NX Regional lymph nodes cannot be assessed
N0 No regional lymph node metastasis
N1 Metastasis in a single lymph node
N2 Metastasis in multiple lymph nodes
M - Distant Metastasis
M0 No distant metastasis
M1 Distant metastasis
Recommendation LE GR
Use the 2017 TNM classification and 2004/2016 WHO grading systems for pathological 3 B
staging and grading of primary urethral carcinoma.
Summary of evidence LE
Patients with clinically enlarged inguinal or pelvic lymph nodes often exhibit pathological lymph node 3
metastasis.
Recommendations LE GR
Use urethrocystoscopy with biopsy and urinary cytology to diagnose urethral carcinoma. 3 B
Assess the presence of distant metastases by computed tomography of the thorax and 3 B
abdomen.
Use pelvic magnetic resonance imaging to assess the local extent of urethral tumour (mapping 3 B
tumour extension).
6. PROGNOSIS
6.1 Long-term survival after primary urethral carcinoma
According to the RARECARE project, the mean one- and five-year overall survival (OS) in patients with UC
in Europe is 71% and 54%, respectively [7]. With longer follow-up, a SEER analysis of 1,615 cases reported
median five- and ten-year OS rates of 46% and 29%, respectively. Cancer-specific survival (CSS) at five and
ten years was 68% and 60%, respectively [8].
Some limitations have to be taken into account in the interpretation of these results. In the Dutch study, the
numbers were low (n = 91) [26]. In the large SEER database (n = 2,046), therapy is not well specified in relation
to survival [25]. Finally, in contrast to the RARECARE project [7], the opposite findings were reported in the
SEER database in relation to the role of histology on survival in male patients [47].
7. DISEASE MANAGEMENT
7.1 Treatment of localised primary urethral carcinoma in males
Previously, treatment of male anterior UC has followed the procedure for penile cancer, with aggressive surgical
excision of the primary lesion with a wide safety margin [30]. Distal urethral tumours exhibit significantly
improved survival rates compared with proximal tumours [49]. Therefore, optimising treatment of distal UC has
become the focus of clinicians to improve functional outcome and quality of life, while preserving oncological
safety. A retrospective series found no evidence of local recurrence, even with < 5 mm resection margins
(median follow-up: 17-37 months), in men with pT1-3N0-2 anterior UC treated with well-defined penis-
preserving surgery and additional iliac/inguinal lymphadenectomy for clinically suspected LN disease [50].
This suggests that prognosis is mainly determined by nodal stage. Similar results for the feasibility of penile-
preserving surgery have also been reported in recent series [51, 52].
Summary of evidence LE
In distal urethral tumours performing a partial urethrectomy with a minimal safety margin does not 3
increase the risk of local recurrence.
Recommendation LE GR
Offer distal urethrectomy as an alternative to penile amputation in localised anterior urethral 3 B
tumours, if surgical margins are negative.
7.2.2 Radiotherapy
In women, radiotherapy was investigated in several older long-term series with a medium follow up of 91-105
months [46, 50]. With a median cumulative dose of 65 Gy (range: 40-106 Gy), the five year local control rate
was 64% and seven year CSS was 49% [46]. Most local failures (95%) occurred within the first two years
after primary treatment [50]. The extent of urethral tumour involvement was found to be the only parameter
independently associated with local tumour control but the type of radiotherapy (external beam radiotherapy
[EBRT] vs. interstitial brachytherapy) was not [46]. In one study, the addition of brachytherapy to EBRT reduced
the risk of local recurrence by a factor of 4.2 [56]. Of note, pelvic toxicity in those achieving local control was
considerable (49%), including urethral stenosis, fistula, necrosis, and cystitis and/or haemorrhage, with 30% of
the reported complications graded as severe [46].
Recommendations LE GR
Offer urethra-sparing surgery as an alternative to primary urethrectomy to women with anterior 3 B
urethral tumours, if negative surgical margins can be achieved intra-operatively.
Offer local radiotherapy as an alternative to urethral surgery to women with localised urethral 3 C
tumours, but discuss local toxicity.
7.3.2 Preoperative chemoradiotherapy in locally advanced squamous cell carcinoma of the urethra
The clinical feasibility of preoperative local radiotherapy with concurrent radiosensitising chemotherapy as
an alternative to surgery in locally advanced SCC has been reported in several recent series. This approach
offers a potential for genital preservation [57-62]. The largest and recently updated series reported outcomes
in 25 patients with primary locally advanced SCC of the urethra treated with two cycles of 5-fluorouracil and
mitomycin C with concurrent EBRT. A complete response to primary chemoradiotherapy was observed in
~80%. The five-year OS and DSS survival was 52% and 68%, respectively. In this updated series, salvage
surgery initiated only in non-responders or in case of local failure was not reported to be associated with
improved survival [58].
Summary of evidence LE
In locally advanced urethral carcinoma, cisplatin-based chemotherapy with curative intent prior to 4
surgery improves survival compared to chemotherapy alone, or surgery followed by chemotherapy.
In locally advanced squamous cell carcinoma (SCC) of the urethra, the prognostic role and timing of 4
surgery after completion of chemoradiotherapy is unclear.
Recommendations LE GR
Discuss treatment of patients with locally advanced urethral carcinoma within a 4 A
multidisciplinary team of urologists, radio-oncologists and oncologists.
Use cisplatinum-based chemotherapeutic regimens with curative intent prior to surgery. 4 C
In locally advanced SCC of the urethra, offer the combination of curative radiotherapy with 4 C
radiosensitising chemotherapy for genital preservation.
Recommendations LE GR
Offer a urethra-sparing approach with transurethral resection (TUR) and BCG to patients with 3 C
non-invasive urethral carcinoma or carcinoma in situ of the prostatic urethra and prostatic
ducts.
In patients with non-invasive UC or carcinoma in situ, perform a prior TUR of the prostate to 3 C
improve response to BCG.
In patients not responding to BCG, or in patients with extensive ductal or stromal involvement, 3 C
perform a cystoprostatectomy with extended pelvic lymphadenectomy.
8. FOLLOW-UP
Given the low incidence of primary urethral cancer, follow-up has not been investigated systematically so far.
Therefore, it seems reasonable to tailor surveillance regimens according to patients’ individual risk factors (see
Chapter 6.2). In patients undergoing urethra-sparing surgery, it seems prudent to advocate a more extensive
follow-up with urinary cytology, urethrocystoscopy and cross-sectional imaging despite the lack of specific
data.
9. REFERENCES
1. Boorjian, S.A., et al. Risk factors and outcomes of urethral recurrence following radical cystectomy.
Eur Urol, 2011. 60: 1266.
https://www.ncbi.nlm.nih.gov/pubmed/21871713
2. Witjes, J.A., et al., EAU Guidelines on Muscle-invasive and Metastatic Bladder Cancer. Edn.
presented at the 32nd EAU Annual Congress London in EAU Guidelines 2017: Arnhem. The
Netherlands.
https://uroweb.org/guideline/primary-urethral-carcinoma/
3. Gakis, G., et al. EAU guidelines on primary urethral carcinoma. Eur Urol, 2013. 64: 823.
https://www.ncbi.nlm.nih.gov/pubmed/23582479
4. Phillips, B., et al. Oxford Centre for Evidence-based Medicine Levels of Evidence. Updated by
Jeremy Howick March 2009.
http://www.cebm.net/oxford-centre-evidence-based-medicine-levels-evidence-march-2009/
5. Gatta, G., et al. Rare cancers are not so rare: the rare cancer burden in Europe. Eur J Cancer, 2011.
47: 2493.
https://www.ncbi.nlm.nih.gov/pubmed/22033323
6. Brierley, J.D., et al., TNM classification of malignant tumors. UICC International Union Against
Cancer. 2017, Wiley/Blackwell. p. 208.
http://www.uicc.org/resources/tnm
7. Visser, O., et al. Incidence and survival of rare urogenital cancers in Europe. Eur J Cancer, 2012. 48:
456.
https://www.ncbi.nlm.nih.gov/pubmed/22119351
8. Swartz, M.A., et al. Incidence of primary urethral carcinoma in the United States. Urology, 2006. 68:
1164.
https://www.ncbi.nlm.nih.gov/pubmed/17141838
9. Medina Perez, M., et al. [Squamous carcinoma of the male urethra, its presentation as a scrotal
abscess]. Arch Esp Urol, 1999. 52: 792.
https://www.ncbi.nlm.nih.gov/pubmed/10540772
2. METHODS 11
2.1 Data identification 11
2.2 Review 12
2.3 Future goals 12
5. DIAGNOSTIC EVALUATION 16
5.1 Screening and early detection 16
5.1.1 Guidelines for screening and early detection 18
5.2 Clinical diagnosis 18
5.2.1 Digital rectal examination 18
5.2.2 Prostate-specific antigen 18
5.2.2.1 PSA density 19
5.2.2.2 PSA velocity and doubling time 19
5.2.2.3 Free/total PSA ratio 19
5.2.2.4 Additional serum testing 19
5.2.2.5 PCA3 marker 19
5.2.2.6 Guidelines for risk-assessment of asymptomatic men 20
5.2.3 Prostate biopsy 20
5.2.3.1 Baseline biopsy 20
5.2.3.2 Repeat biopsy after previously negative biopsy 20
5.2.3.3 Saturation biopsy 21
5.2.3.4 Sampling sites and number of cores 21
5.2.3.5 Diagnostic transurethral resection of the prostate 21
5.2.3.6 Seminal vesicle biopsy 21
5.2.3.7 Transition zone biopsy 21
5.2.3.8 Antibiotics prior to biopsy 21
5.2.3.9 Local anaesthesia prior to biopsy 21
5.2.3.10 Fine-needle aspiration biopsy 21
6. DISEASE MANAGEMENT 29
6.1 Treatment: Deferred treatment (active surveillance/watchful waiting) 29
6.1.1 Introduction 29
6.1.1.1 Definition 29
6.1.1.1.1 Active surveillance 29
6.1.1.1.2 Watchful waiting 30
6.1.2 Deferred treatment of localised PCa (stage T1/T2, Nx/N0, M0) 30
6.1.2.1 Active surveillance 30
6.1.2.2 Watchful waiting 32
6.1.2.2.1 Patient selection for watchful waiting 32
6.1.2.2.2 Outcome of watchful waiting compared
to active treatment 32
6.1.2.3 The ProtecT study 33
6.1.3 Deferred treatment for locally advanced PCa (stage T3-T4, Nx-N0, M0) 33
6.1.4 Deferred treatment for metastatic PCa (stage M1) 33
6.1.5 Guidelines for active surveillance and watchful waiting 34
6.2 Treatment: Radical prostatectomy 34
6.2.1 Introduction 34
6.2.2 Low-risk PCa 34
6.2.3 Intermediate-risk, localised PCa 35
6.2.4 High-risk and locally advanced PCa 35
6.2.4.1 High-risk PCa 35
6.2.4.1.1 Gleason score 8-10 35
6.2.4.1.2 Prostate-specific antigen > 20 ng/mL 35
6.2.4.2 Locally advanced PCa 36
6.2.5 Indication and extent of pelvic lymph node dissection 36
6.2.5.1 Technique of lymph node dissection 36
7. FOLLOW-UP 83
7.1 Follow-up: After local treatment 83
7.1.1 Definition 83
7.1.2 Why follow-up? 83
7.1.3 How to follow-up? 83
7.1.3.1 Prostate-specific antigen monitoring 83
7.1.3.2 Definition of prostate-specific antigen progression 84
7.1.3.3 Prostate-specific antigen monitoring after radical prostatectomy 84
7.1.3.4 PSA monitoring after radiotherapy 84
7.1.3.5 Digital rectal examination 84
7.1.3.6 Transrectal ultrasound, bone scintigraphy, computed tomography,
magnetic resonance imaging, and 11C-choline positron
emission tomography computed tomography 84
7.1.3.6.1 Transrectal ultrasonography/magnetic resonance
imaging guided biopsy. Biopsy of the prostate bed
and urethrovesical anastomosis or of the remaining
prostate after radiotherapy, are only indicated if local
recurrence affects treatment decisions. 84
7.1.4 When to follow-up? 84
7.1.5 Summary of evidence and guidelines for follow-up after treatment
with curative intent 85
7.2 Follow-up: During hormonal treatment 85
7.2.1 Introduction 85
7.2.2 Purpose of follow-up 85
7.2.3 Methods of follow-up 85
7.2.3.1 Clinical follow-up 85
7.2.3.1.1 Prostate-specific antigen monitoring 85
7.2.3.1.2 Creatinine, haemoglobin and liver function monitoring 85
7.2.3.1.3 Bone scan, ultrasound and chest X-ray 86
7.2.3.1.4 Testosterone monitoring 86
7.2.3.1.5 Monitoring of metabolic complications 86
7.2.4 When to follow-up 86
7.2.4.1 Stage M0 - M1 patients 86
7.2.4.2 Castration-refractory PCa 86
7.2.5 Guidelines for follow-up during hormonal treatment 87
9. REFERENCES 95
All imaging sections in the text have been developed, jointly with the European Society of Urogenital Radiology
(ESUR). Representatives of ESUR in the PCa Guidelines Panel are (in alphabetical order): Prof.Dr. O Rouvière
and Dr. I.G. Schoots.
Section 6.3: Treatment - Definitive Radiotherapy, has been developed jointly with the European
Society for Radiotherapy & Oncology (ESTRO). Representatives of ESTRO in the PCa Guidelines Panel are (in
alphabetical order): Prof.Dr. M. Bolla, Prof.Dr. A.M. Henry, Prof.Dr. M.D. Mason and Prof.Dr. T. Wiegel.
All experts involved in the production of this document have submitted potential conflict
of interest statements which can be viewed on the EAU website Uroweb: http://uroweb.org/guideline/
prostatecancer/?type=panel.
1.2.1 Acknowledgement
The PCa Guidelines Panel are most grateful for the support and considerable expertise provided by
Prof.Dr. J-P. Droz, Emeritus Professor of Medical Oncology (Lyon, France) on the topic of ‘Management of
PCa in senior adults’. As a leading expert in this field, and prominent member of the International Society of
Geriatric Oncology, his contribution has been invaluable.
Summary of evidence
Prostate cancer is a major health issue in men, the incidence mainly dependent on age.
Genetic factors are associated with risk of (aggressive) PCa but ongoing trials will need to define the
clinical applicability of screening for genetic susceptibility of PCa.
A variety of exogenous/environmental factors may have an impact on the risk of progression.
5-ARIs are not EMA-approved for PCa prevention.
Selenium or vitamin-E supplements have no beneficial effect in preventing PCa.
In hypogonadal men, testosterone supplementation does not increase the risk of PCa.
Recommendation
No definitive recommendation can be provided for specific preventive or dietary measures to reduce
the risk of developing prostate cancer.
Table 4.2.2: E
AU risk groups for biochemical recurrence of localised and locally advanced prostate
cancer
Definition
Low-risk Intermediate-risk High-risk
PSA < 10 ng/mL PSA 10-20 ng/mL PSA > 20 ng/mL any PSA
and GS < 7 (ISUP Grade 1) or GS 7 (ISUP Grade 2/3) or GS > 7 (ISUP Grade 4/5) any GS cT3-4
and cT1-2a or cT2b or cN+
or cT2c Any ISUP Grade
Localised Locally advanced
GS = Gleason score; ISUP = International Society for Urologcal Pathology; PSA = prostate-specific antigen.
Recommendation LE GR
Do not perform a frozen section of nodes during radical prostatectomy to decide 2a A
whether to proceed with, or abandon, the procedure.
Recommendations LE GR
Offer both radical prostatectomy and radiotherapy in patients with low- and 1b A
intermediate-risk disease and a life expectancy > 10 years.
Offer active surveillance as an alternative to surgery in patients with low-risk disease 1b A
and a life expectancy of > 10 years.
Summary of evidence LE
The optimum duration of androgen deprivation therapy (ADT) with external beam radiation 1b
therapy (EBRT) is well established in the literature. There is no evidence that these durations
should change when using brachytherapy boost with EBRT.
Limited data, from experienced centres only, are available for the use of fractionated high- 2a
dose-rate brachytherapy as monotherapy in patients with low and intermediate-risk PCa.
Recommendations LE GR
Moderate hypofractionation (HFX) with IMRT including image-guided radiation therapy 1a A
(IGRT) to the prostate only can be offered to carefully selected patients with localised
disease (as discussed in the text).
Moderate HFX should adhere to radiotherapy-protocols from trials with equivalent 1a A
outcome and toxicity, i.e. 60 Gy/20 fractions in four weeks or 70 Gy/28 fractions in six
weeks.
8.3.1.1 Guidelines for long term quality of life in men with localised disease
Recommendations LE GR
Advise eligible patients for active surveillance, that global quality of life is equivalent 1b A
for up to five years compared to radical prostatectomy or radiotherapy.
Discuss the negative impact of surgery on urinary and sexual function, as well as the 1b A
negative impact of radiotherapy on bowel function with patients.
Advise patients treated with brachytherapy of the negative impact on irritative urinary 1b C
symptomatology at one year but not after five years.
8.3.2.1 Guidelines on improving quality of life in men who have been diagnosed with prostate cancer
Recommendations LE GR
Offer men on androgen deprivation therapy, twelve weeks of supervised (by trained 1a A
exercise specialists) combined aerobic and resistance exercise.
Offer men with T1-T3 disease specialist nurse led, multi-disciplinary rehabilitation 1b A
based on the patients’ personal goals addressing incontinence, sexuality, depression
and fear of recurrence, social support and positive lifestyle changes after any radical
treatment.
2. METHODS
2.1 Data identification
For the 2017 PCa Guidelines, new and relevant evidence has been identified, collated and appraised through a
structured assessment of the literature.
A broad and comprehensive literature search, covering all sections of the PCa Guidelines was
performed. The search was limited to studies representing only high levels of evidence (i.e. SRs with meta-
analysis, randomised controlled trials (RCTs), and prospective comparative studies) published in the English
language. Databases searched included Medline, EMBASE and the Cochrane Libraries, covering a time
Specific sections of the text have been updated based on a SR questions prioritised by the Guidelines Panel.
These reviews were performed using standard Cochrane systematic review methodology;
http://www.cochranelibrary.com/about/about-cochrane-systematic-reviews.html:
• What is the negative predictive value of multiparametric MRI in excluding prostate cancer at biopsy?
A systematic review and meta-analysis from the EAU Prostate Cancer Guidelines Panel [prior to print] [3].
• The Benefits and Harms of Different Extents of Lymph Node Dissection During Radical Prostatectomy for
Prostate Cancer: A systematic review [4].
• Systematic review of quality of life outcomes as assessed by PROMS following primary treatment of
clinically localised prostate cancer.
Recommendations in this text are assessed according to their level of evidence (LE) and Guidelines are given
a grade of recommendation (GR), according to a classification system modified from the Oxford Centre for
Evidence-Based Medicine Levels of Evidence [5]. Additional methodology information can be found in the
general Methodology section of this print, and online at the EAU website: http://uroweb.org/guidelines/.
A list of Associations endorsing the EAU Guidelines can also be viewed online at the above address.
In addition, the International Society of Geriatric Oncology (SIOG), the European Society for Radiotherapy
& Oncology (ESTRO) and the European Society for Urogenital Radiology (ESUR) have endorsed the PCa
Guidelines.
2.2 Review
Publications ensuing from the systematic reviews have all been peer-reviewed. The following sections were
subjected to peer review prior to publication:
All Imaging sections:
• Section 5.2.3 - The role of imaging in PCa diagnosis;
• Section 5.3 - The role of imaging in clinical staging;
• Section 6.1.2.1 - The role of multiparametric magnetic resonance imaging in active surveillance
• Section 6.6.8 (new section) - Imaging as a marker of response in metastatic PCa,
• Sections 6.10.4 and 6.10.5 - The role of imaging in PSA-only recurrence after treatment with curative
intent.
• Section 6.10 – Treatment - Management of PSA-only recurrence after treatment with curative intent.
• Section 6.10 – Treatment – Castration-resistant PCa
3.2 Aetiology
3.2.1 Family history/genetics
Family history and racial/ethnic background are associated with an increased PCa incidence suggesting
a genetic predisposition [10, 11]. However, only a small subpopulation of men with PCa (~9%) have true
hereditary disease. This is defined as three or more affected relatives, or at least two relatives who have
developed early-onset PCa (< 55 years) [11]. Patients with hereditary PCa usually have a disease onset six-
seven years earlier than average, but their clinical course does not seem to differ in other ways, e.g. for disease
aggressiveness [11, 12]. Men with African ethnicity origin show a higher incidence of PCa and generally have a
more lethal course of disease [13].
Of the underlying determinants of genomic diversity and mechanisms between genetic and
environmental factors, much remains unknown. Genome-wide association studies have identified 100 common
susceptibility loci contributing to the risk for PCa, explaining ~38.9% of the familial risk for this disease [14,
15]. Furthermore, an incidence was found of 11.8% of germline mutations in genes mediating DNA-repair
processes among men with metastatic PCa [16]. Germline mutations in genes such as HOXB13 and BRCA1/2
have been associated with an increased risk of PCa, targeted genomic analysis of these genes could offer
options to identify families at high risk [17, 18]. Trials of screening for PCa-targeting BRCA mutation carriers are
ongoing [19].
3.2.2.1.1 Diabetes/metformin
On a population level, metformin users (but not other oral hypoglycaemics) were found to be at a decreased
risk of PCa diagnosis, compared with never-users (adjusted OR: 0.84; 95% CI: 0.74-0.96) [24]. In 540 diabetic
participants of the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) study, metformin use was
not significantly associated with PCa (OR: 1.19; p = 0.50) [25].
3.2.2.1.2 Cholesterol/statins
A meta-analysis of fourteen large prospective studies did not show an association between blood total
cholesterol (TC), high-density lipoprotein cholesterol (HDL), low-density lipoprotein cholesterol (LDL) levels
and the risk of either overall PCa or high-grade PCa [26]. Results of the REDUCE study also did not show a
preventive effect of statins on PCa risk [25].
3.2.2.1.3 Obesity
Within the REDUCE study, obesity was associated with lower risk of low-grade PCa in multivariable analyses
(OR: 0.79; p = 0.01), but increased risk of high-grade PCa (OR, 1.28; p = 0.042) [27]. This effect seems mainly
explained by environmental determinants of height/BMI rather than genetically elevated height or BMI [28].
Alcohol High alcohol intake, but also total abstention from alcohol have been associated with
a higher risk of PCa and PCa-specific mortality [29].
Dairy A weak correlation between insulin-like growth factor-I (IGF-1) levels and high intake
of protein from dairy products and the risk of PCa was found [30].
Fat No association between intake of long-chain omega-3 poly-unsaturated fatty acids
and PCa was found [31]. A relation between intake of fried foods and risk of PCa may
exist [32].
Lycopene A trend towards a favourable effect of lycopene on PCa incidence has been identified
(carotenes) in meta-analyses [33], RCTs comparing lycopene with placebo did not identify a
significant decrease in the incidence of PCa [34].
Meat A meta-analysis did not show an association between red meat or processed meat
consumption and PCa [35].
Vitamin D (25(OH)D) An U-shaped association has been observed, with both low- and high vitamin-D
concentrations being associated with an increased risk of PCa, and more strongly for
high-grade disease [36, 37].
Selenium/Vitamin E Selenium and Vitamin E were found not to affect PCa incidence [38].
3.2.2.3.2 Testosterone
Hypogonadal men receiving testosterone supplementation did not have an increased risk of PCa [42].
Summary of evidence
Prostate cancer is a major health issue in men, the incidence mainly dependent on age.
Genetic factors are associated with risk of (aggressive) PCa but ongoing trials will need to define the clinical
applicability of screening for genetic susceptibility of PCa.
A variety of exogenous/environmental factors may have an impact on the risk of progression.
5-ARIs are not EMA-approved for PCa prevention.
Selenium or vitamin-E supplements have no beneficial effect in preventing PCa.
In hypogonadal men, testosterone supplementation does not increase the risk of PCa.
Recommendation
No definitive recommendation can be provided for specific preventive or dietary measures to reduce the risk
of developing prostate cancer.
T - Primary Tumour
TX Primary tumour cannot be assessed
T0 No evidence of primary tumour
T1 Clinically inapparent tumour that is not palpable
T1a Tumour incidental histological finding in 5% or less of tissue resected
T1b Tumour incidental histological finding in more than 5% of tissue resected
T1c Tumour identified by needle biopsy (e.g. because of elevated prostate-specific antigen (PSA) level)
T2 Tumour that is palpable and confined within the prostate
T2a Tumour involves one half of one lobe or less
T2b Tumour involves more than half of one lobe, but not both lobes
T2c Tumour involves both lobes
T3 Tumour extends through the prostatic capsule1
T3a Extracapsular extension (unilateral or bilateral) including microscopic bladder neck involvement
T3b Tumour invades seminal vesicle(s)
T4 Tumour is fixed or invades adjacent structures other than seminal vesicles: external sphincter, rectum,
levator muscles, and/or pelvic wall
N - Regional Lymph Nodes2
NX Regional lymph nodes cannot be assessed
N0 No regional lymph node metastasis
N1 Regional lymph node metastasis
M - Distant Metastasis3
M0 No distant metastasis
M1 Distant metastasis
M1a Non-regional lymph node(s)
M1b Bone(s)
M1c Other site(s)
1Invasion into the prostate apex or into (but not beyond) the prostate capsule is not classified as T3, but as T2.
2Metastasis no larger than 0.2 cm can be designated pNmi.
2T2a to c only exist for clinical T2 (cT2). For pathological T2 they are no longer present in the 2017 TNM. Only
pT2 exists.
3When more than one site of metastasis is present, the most advanced category is used. (p)M1c is the most
advanced category.
4.2 Gleason score and International Society of Urological Pathology 2014 grade groups
The 2005 International Society of Urological Pathology (ISUP) modified Gleason score of biopsy-detected PCa
comprises the Gleason grade or the most extensive (primary pattern) pattern, plus the second most common
pattern (secondary pattern), if two are present. If one pattern is present, it needs to be doubled to yield the
Gleason score. For three grades, the Gleason score comprises the most common grade plus the highest
grade, irrespective of its extent. When a carcinoma is largely grade 4/5, identification of < 5% of Gleason
grade 2 or 3 glands should not be incorporated in the Gleason score. A Gleason score < 4 should not be given
based on prostate biopsies [57]. In addition to reporting of the carcinoma features for each biopsy, an overall
(or global) Gleason score based on the carcinoma-positive biopsies can be provided. The 2014 ISUP Gleason
grading conference of prostatic carcinoma [58, 59] limits the number of PCa grades, ranging them from 1 to 5
(see table 4.2.1), in order to:
1. align the PCa grading with the grading of other carcinomas;
The ISUP 2014 Gleason grading represents a compression of Gleason scores < 6 to ISUP grade 1, and
Gleason scores 9-10 to ISUP grade 5, whereas Gleason score 7 is expanded to ISUP grade 2, i.e. 7 (3 + 4) and
ISUP grade 3, i.e. 7 (4 + 3).
Table 4.2.2: E
AU risk groups for biochemical recurrence of localised and locally advanced prostate
cancer
Definition
Low-risk Intermediate-risk High-risk
PSA < 10 ng/mL PSA 10-20 ng/mL PSA > 20 ng/mL any PSA
and GS < 7 (ISUP grade 1) or GS 7 (ISUP grade 2/3) or GS > 7 (ISUP grade 4/5) any GS cT3-4 or cN+
and cT1-2a Any ISUP grade
or cT2b or cT2c
Localised Locally advanced
GS = Gleason score; ISUP = International Society for Urologcal Pathology; PSA = prostate-specific antigen.
5. DIAGNOSTIC EVALUATION
5.1 Screening and early detection
Population or mass screening is defined as the ‘systematic examination of asymptomatic men (at risk)’ and
is usually initiated by health authorities. In contrast, early detection or opportunistic (ad-hoc) testing consists
of individual case findings, which are initiated by the man being tested (patient) and/or his physician. The
co-primary objectives of both strategies are:
• reduction in mortality due to PCa;
• at least, a maintained quality of life (QoL) as expressed by QoL-adjusted gain in life years (QUALYs).
Prostate cancer mortality trends range widely from country to country in the industrialised world [61]. Mortality
due to PCa has decreased in most Western countries but the magnitude of the reduction varies between
countries. The reduced mortality rate seen recently in the USA is considered to be partly due to a widely
adopted aggressive PCa screening policy [62]. However, there is still no level 1 evidence that PSA mass
screening is cost-effective in reducing PCa mortality [63].
Currently, screening for PCa is one of the most controversial topics in the urological literature [64]. Three large
A Cochrane review published in 2013 [63], which has been updated since [73] presents the main overview of
the date. The findings of the updated publication (based on a literature search until April 3, 2013) are almost
identical to the 2013 review:
• Screening is associated with an increased diagnosis of PCa (RR: 1.3; 95% CI: 1.02-1.65).
• Screening is associated with detection of more localised disease (RR: 1.79; 95% CI: 1.19-2.70) and less
advanced PCa (T3-4, N1, M1) (RR: 0.80; 95% CI: 0.73-0.87).
• From the results of five RCTs, randomising more than 341,000 men, no PCa-specific survival benefit was
observed (RR: 1.00; 95% CI: 0.86-1.17). This was the main endpoint in all trials.
• From the results of four available RCTs, no overall survival (OS) benefit was observed (RR: 1.00; 95% CI:
0.96-1.03).
Moreover, screening was associated with minor and major harms such as over-diagnosis and over-treatment.
Surprisingly, the diagnostic tool (i.e. biopsy) was not associated with any mortality in the selected papers,
which is in contrast with other known data [40, 41].
The impact on the patient’s overall QoL is still unclear [74-76], but screening has never been
shown to be detrimental at population level. All these findings have led to strong advice against systematic
population-based screening in all countries, including Europe.
Since 2013, the European Randomized Study of Screening for Prostate Cancer (ERSPC) data have been
updated with 13 years of follow up (see Table 5.1.1) [77]. The key message is that with extended follow up,
the mortality reduction remains unchanged (21%, and 29% after non-compliance adjustment). However the
number needed to screen and to treat is decreasing, and is now below the number needed to screen observed
in breast cancer trials [78].
An individualised risk-adapted strategy for early detection might be offered to a well-informed man with at
least ten-fifteen years of life expectancy. However, this approach may still be associated with a substantial risk
of over-diagnosis. It is therefore important to carefully identify the patient cohorts likely to benefit most from
individual early diagnosis, taking into account the potential balances and harms involved.
Men at elevated risk of having PCa are those > 50 years, or at age > 45 years with a family history
of PCa (both paternal or maternal [79]), or African-Americans [80]. In addition, men with a PSA > 1 ng/mL at
40 years and > 2 ng/mL at 60 years [81, 82] are also at increased risk of PCa metastasis or death from PCa
several decades later. The long-term survival and QoL benefits of such an approach remains to be proven
at a population level. In 2014, as for breast cancer, a genetic abnormality associated with an increased risk
has been shown prospectively i.e. BRCA2 [19, 83]. Several new biological markers such as TMPRSS2-Erg
fusion, PCA3 [84, 85] or kallikreines as incorporated in the Phi or 4Kscore tests [86, 87] have been shown to
add sensitivity and specificity on top of PSA, potentially avoiding unnecessary biopsies and lowering over-
diagnosis. At this time there is too limited data to base a recommendation on.
Risk calculators may be useful in helping to determine (on an individual basis) what the potential risk of cancer
may be, thereby reducing the number of unnecessary biopsies. Several tools developed from cohort studies
are available:
Informed men requesting an early diagnosis should be given a PSA test and undergo a digital rectal
examination (DRE) [89]. The optimal intervals for PSA testing and DRE follow-up are unknown, as they varied
between several prospective trials. A risk-adapted strategy might be considered based on the initial PSA level.
This could be every two years for those initially at risk, or postponed up to eight to ten years in those not at risk
[90].
The age at which early diagnosis should be stopped remains controversial, but an individual’s
life expectancy must definitely be taken into account. Men who have less than a fifteen-year life expectancy
are unlikely to benefit based on data from the Prostate Cancer Intervention Versus Observation Trial (PIVOT)
and the ERSPC trials. Furthermore, although there is no simple tool to evaluate individual life expectancy,
co-morbidity is at least as important as age. A detailed review can be found in Section 6.7 on senior adults and
in the recently updated SIOG Guidelines [91].
Based on the tools currently available, an individualised strategy will diagnose many insignificant lesions (over
50% in some trials), most of which will not require any form of active treatment (see Section 6.1 - Deferred
treatment). It is important to realise that breaking the link between diagnosis and active treatment is the only
way to decrease over-treatment, while still maintaining the potential benefit of individual early diagnosis for men
requesting it.
Recommendations LE GR
Do not subject men to prostate-specific antigen (PSA) testing without counselling them on the 3 B
potential risks and benefits.
Offer an individualised risk-adapted strategy for early detection to a well-informed man with a 3 B
good performance status and a life-expectancy of at least ten to fifteen years.
Offer early PSA testing in well-informed men at elevated risk of having PCa: 2b A
• men > 50 years of age;
• men > 45 years of age and a family history of PCa;
• African-Americans > 45 years of age;
• men with a PSA level of > 1 ng/mL at 40 years of age;
• men with a PSA level of > 2 ng/mL at 60 years of age.
Offer a risk-adapted strategy (based on initial PSA level), with follow-up intervals of two years 3 C
for those initially at risk:
• men with a PSA level of > 1 ng/mL at 40 years of age;
• men with a PSA level of > 2 ng/mL at 60 years of age;
Postpone follow-up to eight years in those not at risk.
Decide on the age at which early diagnosis of PCa should be stopped based on life 3 A
expectancy and performance status; men who have a life-expectancy of < 15-years are
unlikely to benefit.
There are no agreed standards defined for measuring PSA [98]. PSA is a continuous parameter, with higher
levels indicating greater likelihood of PCa. Many men may harbour PCa despite having low serum PSA [99].
Table 5.2.1 demonstrates the occurrence of Gleason > 7 (or ISUP grade 2) PCa at low PSA levels, precluding
an optimal PSA threshold for detecting non-palpable but clinically significant PCa. The use of nomograms may
help in predicting indolent PCa [100].
PSA level (ng/mL) Risk of PCa (%) Risk of Gleason > 7 PCa (%)
0.0-0.5 6.6 0.8
0.6-1.0 10.1 1.0
1.1-2.0 17.0 2.0
2.1-3.0 23.9 4.6
3.1-4.0 26.9 6.7
Prostate specific antigen velocity and PSA-DT may have a prognostic role in treating PCa [103], but limited
diagnostic use because of background noise (total prostate volume, and BPH), different intervals between PSA
determinations, and acceleration/deceleration of PSAV and PSA-DT over time. These measurements do not
provide additional information compared with PSA alone [104-107].
Recommendations LE GR
In order to avoid unnecessary biopsies, offer further risk-assessment to asymptomatic men 3 C
with a prostate specific antigen level between 2-10 ng/mL prior to performing a prostate
biopsy. Use one of the following tools:
• risk-calculator;
• an additional serum or urine-based test (e.g. Prostate Health Index test [PHI], four
kallikrein [4K]score or Prostate cancer gene 3 [PCA3]) or imaging.
Additional information may be gained by the Progensa DRE urine test for PCA3, the serum 4Kscore and PHI
tests or a tissue-based epigenetic test (ConfirmMDx). The role of PHI and Progensa PCA3 in deciding whether
to take a repeat biopsy in men who had a previous negative biopsy is uncertain and probably not cost-effective
[118]. The ConfirmMDx test is based on the concept that benign prostatic tissue in the vicinity of a PCa focus
shows distinct epigenetic alterations. If, due to sampling bias, the PCa is missed at biopsy, demonstration of
epigenetic changes in the adjacent benign tissue would indicate the presence of carcinoma. The ConfirmMDX
test quantifies the methylation level of promoter regions of three genes (RASSF1, GSTP1 and APC) in benign
prostatic tissue. A multicentre study found a negative predictive value of 88% when methylation was absent in
all three markers, implying that a repeat biopsy could be avoided in these men [129]. Given the limited available
data, no recommendation can be made regarding its routine application.
Table 5.2.2: Description of additional investigational tests after a negative prostate biopsy*
5.2.3.11 Complications
Biopsy complications are listed in Table 5.2.3 [144]. Severe post-procedural infections were initially reported
in < 1% of cases, but have increased as a consequence of antibiotic resistance [145]. Low-dose aspirin is no
longer an absolute contraindication [146]. A SR found favourable infections rates for transperineal compared to
transrectal biopsies with similar rates of haematuria, haematospermia and urinary retention [147].
Table 5.2.3: Percentage of complications per biopsy session, irrespective of the number of cores
Table 5.2.4: P
Ca detection rates (%) by mpMRI for tumour volume and Gleason score in radical
prostatectomy specimen [151]
Multiparametric magnetic resonance imaging can reliably detect aggressive tumours in candidates for prostate
biopsy with a negative (NPV) and positive predictive value (PPV) ranging from 63 to 98% and from 34 to 68%,
respectively [153]. As a result, mpMRI is increasingly performed before prostate biopsy.
Theoretically, pre-biopsy mpMRI could be used in two different ways. The first strategy uses
mpMRI to improve the detection of clinically significant prostate cancer (csPCa). In this diagnostic pathway,
MRI-targeted biopsy (TBx) would be added to systematic biopsies in case of positive mpMRI, and systematic
biopsies would be performed in all patients with negative mpMRI. The second strategy uses mpMRI as a triage
test before biopsy. In this diagnostic pathway, only MRI-TBx would be performed in case of a positive mpMRI.
Patients with negative mpMRI results would not undergo a prostate biopsy at all.
A large body of evidence suggests that MRI-TBx has a higher detection rate of detecting csPCa
as compared to systematic biopsy [154-158]. However, sub-groups analysis showed that the impact of
mpMRI was most marked in the repeat-biopsy setting, but not in biopsy-naïve men [154, 155]. Single centre
RCTs performed in biopsy-naïve men provided contradictory findings as to whether or not the combination
of systematic biopsies and MRI-TBx had a higher detection rate for PCa and csPCa than systematic biopsies
alone [159-161]. Two large multicentre studies (MRI-FIRST and PRECISION) are currently ongoing to define the
added value of pre-biopsy MRI in biopsy-naïve patients. It is therefore too early to make recommendations on
the routine use of pre-biopsy mpMRI in biopsy-naïve patients.
Magnetic resonance imaging-targeted biopsies can be obtained through cognitive guidance, Ultrasound/
mpMRI fusion software or direct in-bore guidance. Controlled studies and a SR did not show a clear superiority
of one technique over the others [158, 162-164].
Whether systematic biopsies can be omitted in patients (or prostate lobes) with negative mpMRI
depends on the NPV of mpMRI. A SR performed under the auspices of the EAU-ESTRO-ESUR-SIOG PCa
Guidelines Panel showed a highly variable prevalence of overall PCa (13.0-74.7%) and csPCa (13.7-50.9%)
in patients undergoing pre-biopsy mpMRI (unpublished results). Due to the fact that the NPV decreases when
prevalence increases, it is necessary to risk-stratify patients before defining the patients that could safely omit
biopsy in case of a negative mpMRI. Prostate-specific antigen density [165] or risk calculators [88] can be used
to identify groups of patients with low risk of PCa in whom mpMRI would have a high NPV. The impact of these
risk-stratification tools on the NPV of pre-biopsy mpMRI needs to be carefully evaluated, both in the biopsy-
naïve and in the repeat-biopsy setting.
Despite the use of the new PIRADS v2 scoring system [166], mpMRI has a low specificity, with high rates
of false positives, especially among lesions scored 3/5 and 4/5 [167]. Multiparametric magnetic resonance
imaging inter-reader reproducibility is also moderate [168-171], which currently limits its broad use outside
expert centres. At this moment it is too soon to define if quantitative approaches and computer-aided
diagnosis systems will improve the characterisation of lesions seen at mpMRI in the future [172-174].
Recommendations LE GR
Before repeat biopsy, perform multiparametric magnetic resonance imaging (mpMRI) when 1a A
clinical suspicion of PCa persists in spite of negative biopsies.
During repeat biopsy, include systematic biopsies and targeting of any mpMRI lesions seen. 2a B
Each biopsy site should be reported individually, including its location (in accordance with the sampling site)
and histopathological findings, which include the histological type and the ISUP 2014 Gleason grading system)
[181]. A global Gleason score comprising all biopsies is also reported according to the ISUP 2014 grade
(see Section 4.2). Intraductal carcinoma, lymphovascular invasion (LVI) and extra-prostatic extension (EPE)
must each be reported, if identified. More recently, expansile cribriform pattern of PCa as well as intraductal
carcinoma in biopsies were identified as independent prognosticators of metastatic disease [182].
The proportion of carcinoma-positive cores as well as the extent of tumour involvement per biopsy core
correlate with the Gleason score, tumour volume, surgical margins and pathologic stage in RP specimens and
predicts BCR, post-prostatectomy progression and RT failure. These parameters are included in nomograms
created to predict pathologic stage and seminal vesicle invasion after RP and RT failure [183-185]. A pathology
report should therefore provide both the proportion of carcinoma-positive cores and the extent of cancer
involvement for each core. The length in mm and percentage of carcinoma in the biopsy have equal prognostic
impact [186]. An extent of > 50% of adenocarcinoma in a single core is used in some AS protocols as a cut off
[187] triggering immediate treatment vs. AS in patients with Gleason score 6.
A prostate biopsy that does not contain glandular tissue should be reported as diagnostically
inadequate. Mandatory elements to be reported for a carcinoma-positive prostate biopsy are:
• type of carcinoma;
• primary and secondary/worst Gleason grade (per biopsy site and global);
• percentage high-grade carcinoma (global);
• extent of carcinoma (in mm or percentage) (at least per biopsy site);
• if present: EPE, seminal vesicle invasion, LVI, intraductal carcinoma/cribriform pattern, peri-neural
invasion;
• ISUP 2014 grade (global).
Ink the entire RP specimen upon receipt in the laboratory, to demonstrate the surgical margins. Specimens
are fixed by immersion in buffered formalin for at least 24 hours, preferably before slicing. Fixation can be
enhanced by injecting formalin, which provides more homogeneous fixation and sectioning after 24 hours
[190]. After fixation, the apex and the base (bladder neck) are removed and cut into (para)sagittal or radial
sections; the shave method is not recommended [57]. The remainder of the specimen is cut in transverse,
3-4 mm sections, perpendicular to the long axis of the urethra. The resultant tissue slices can be embedded
and processed as whole-mounts or after quadrant sectioning. Whole-mounts provide better topographic
visualisation, faster histopathological examination and better correlation with pre-operative imaging, although
they are more time-consuming and require specialist handling. For routine sectioning, the advantages of whole
mounts do not outweigh their disadvantages.
Recommendations LE GR
Ensure total embedding, by conventional (quadrant) or whole-mount sectioning. 3 C
Ink the entire surface before cutting, to evaluate the surgical margin. 3 A
Examine the apex and base separately, using the cone method with sagittal or radial 3 A
sectioning.
Histopathological type
Type of carcinoma, e.g. conventional acinar, or ductal
Histological grade
Primary (predominant) Gleason grade
Secondary Gleason grade
Tertiary Gleason grade (if applicable)
Global Gleason score/ISUP 2014 grade
Approximate percentage of Gleason grade 4 or 5
Tumour quantitation (optional)
Percentage of prostate involved
Size/volume of dominant tumour nodule
Pathological staging (pTNM)
If extraprostatic extension is present:
indicate whether it is focal or extensive;
specify sites;
indicate whether there is seminal vesicle invasion.
If applicable, regional lymph nodes:
location;
number of nodes retrieved;
number of nodes involved.
Surgical margins
If carcinoma is present at the margin:
specify sites.
Other
Presence of lymphovascular/angio-invasion
Location of dominant tumour
Presence of intraductal carcinoma/cribriform architecture
The Gleason score is the sum of the most and second-most dominant (in terms of volume) Gleason grade. If
only one grade is present, the primary grade is doubled. If a grade comprises < 5% of the cancer volume, it is
not incorporated in the Gleason score (5% rule). The primary and secondary grades are reported in addition to
the Gleason score. A global Gleason score is given for multiple tumours, but a separate tumour focus with a
higher Gleason score should also be mentioned. Tertiary Gleason grade 4 or 5, particularly if > 5% of the PCa
volume, is an unfavourable prognostic indicator for BCR. The tertiary grade and its approximate proportion of
the cancer volume should also be reported [193] in addition to the global Gleason score as well as the ISUP
2014 grade group (see Section 4.2).
Recommendations LE GR
Do not use transurethral resection of the prostate as a tool for cancer detection. 2a A
Use the International Society of Urological Pathology (ISUP) 2014 Gleason grading system for 2a A
grading of PCa.
In symptomatic men, base the initial decision to perform a biopsy on prostate-specific antigen 2b A
(PSA) testing and digital rectal examination (DRE).
Use the additional diagnostic options in asymptomatic men with a normal DRE and a PSA 3 C
between 2.0 and 10 ng/mL (risk calculator, or an additional serum or urine-based test [e.g.
Prostate Health Index, 4Kscore or prostate cancer gene 3] or imaging).
Do not initially offer transition zone biopsies due to low detection rates. 2b B
For initial diagnosis, perform a core biopsy of ten to twelve systematic transrectal or 2a B
transperineal peripheral zone biopsies under ultrasound guidance.
Perform transrectal prostate needle biopsies under antibiotic protection. 1b A
Use a local anaesthetic by periprostatic infiltration for transrectal prostate needle biopsies. 1a A
Ensure that prostate core biopsies from different sites are submitted separately for processing 3 A
and pathology reporting.
Adhere to the 2010 ISUP consensus meeting Guidelines for processing and reporting of 3 A
prostatectomy specimens.
Perform one set of repeat biopsies for persistent indications for PCa (abnormal DRE, elevated 2a B
PSA or histopathological findings suggestive of malignancy at initial biopsy).
5.3.1 T-staging
5.3.1.1 Definitions
Extraprostatic extension is defined as carcinoma mixed with periprostatic adipose tissue, or tissue that extends
beyond the prostate gland (e.g., neurovascular bundle, anterior prostate, or bladder neck) and corresponds to
stage T3a. It is to be distinguished from seminal vesicle invasion (SVI) which corresponds to stage T3b (see
Section 5.2 for details).
Serum PSA levels increase with tumour stage, although they are limited for accurate prediction of final
The use of high field (3T) or functional imaging in addition to T2-weighted imaging improves sensitivity for
EPE or SVI detection [222], but the experience of the reader remains of paramount importance [225] and the
inter-reader agreement remains moderate with kappa values ranging from 0.41 to 0.68 [226]. Multiparametric
magnetic resonance imaging, although not perfect for local staging, may improve prediction of the pathological
stage when combined with clinical data [227, 228]. Other MRI-derived parameters such as the tumour volume
or the contact length of the tumour with the capsule [229-231], or the Gleason score obtained through MRI-TBx
[232] could further improve the local staging.
Given its low sensitivity for focal (microscopic) EPE, mpMRI is not recommended for local staging in low-risk
patients [227, 233, 234]. However, mpMRI can still be useful for treatment planning in selected low-risk patients
(e.g. candidates for brachytherapy) [235].
5.3.2 N-staging
N-staging should be performed only when it might directly influence treatment decisions. High PSA values,
T2b-T3 stage, poor tumour differentiation and perineural invasion are associated with high risk of nodal
metastases [236, 237]. Measurement of PSA alone is unhelpful in predicting LN metastases. Nomograms
can define patients at low risk (< 10%) of nodal metastasis, although nomograms may be more accurate in
establishing the extent of nodal involvement [213, 238]. The simple Roach formula can also be used [239].
Patients with low- and intermediate-risk PCa may be spared N-staging before potentially curative treatment.
Gleason 4 pattern in sextant biopsies can define the risk of N1 disease. Risk of nodal metastases
was 20-45% if any core had a predominant Gleason 4 pattern, or > 3 cores had any Gleason 4 pattern. For the
remaining patients, the risk was 2.5%, suggesting that nodal staging is unnecessary in selected patients [240].
Because of their low sensitivity, CT or MRI should not be used for nodal staging in low-risk patients and be
reserved for high-risk cancer patients.
5.3.3 M-staging
5.3.3.1 Bone scan
99mTc-Bone scan (BS) has been the most widely used method for evaluating bone metastases of PCa. A
2014 meta-analysis showed a combined sensitivity and specificity of 79% (95% CI: 73-83%) and 82% (95%
CI: 78-85%) at patient level and 59% (95% CI: 55-63%) and 75% (95% CI: 71-79%) at lesion level [257].
Adding single-photon emission computed tomography (SPECT) to plain BS has been shown to reduce the
number of equivocal lesions [258]. Bone scan diagnostic yield is significantly influenced by the PSA level, the
clinical stage and the tumour Gleason score and these three factors were the only independent predictors
of BS positivity in a study of 853 patients [259]. The mean BS positivity rate in 23 different series was 2.3%
in patients with PSA levels < 10 ng/mL, 5.3% in patients with PSA level between 10.1 and 19.9 ng/mL, and
16.2% in patients with PSA levels of 20.0-49.9 ng/mL. It was 6.4% in men with organ-confined cancer and
49.5% in men with locally advanced cancers. Detection rates were 5.6% and 29.9% for Gleason scores of 7
and > 8 respectively [241]. In two studies, a major Gleason pattern of 4 was found to be a significant predictor
of positive BS [260, 261].
Bone scanning should be performed in symptomatic patients, independent of PSA level, Gleason
score or clinical stage [241].
Table 5.3.1: Sensitivity and specificity for detecting bone metastases on a per-patient basis [257]
Although evidence shows that choline PET/CT and mpMRI are more accurate than BS, the clinical benefit of
detecting bone metastases at an earlier time-point using more sensitive techniques remains unclear in the
initial staging setting [268]. Bone scan is therefore usually preferred in most centres.
Intermediate-risk PCa LE GR
In predominantly Gleason pattern 4 (ISUP grade 3), include at least cross-sectional 2a A*
abdominopelvic imaging and a bone-scan for metastatic screening.
In predominantly Gleason pattern 4 (ISUP grade 3), use prostate multiparametric magnetic 2b A
resonance imaging (mpMRI) for local staging.
*Upgraded following panel consensus.
6. DISEASE MANAGEMENT
6.1 Treatment: Deferred treatment (active surveillance/watchful waiting)
6.1.1 Introduction
Many men with screening-detected localised PCa will not benefit from definitive treatment [269] and 45% of
them are candidates for deferred management. There are two distinct strategies for conservative management
that aim to reduce over-treatment: active surveillance (AS) and watchful waiting (WW) (Table 6.1.1).
6.1.1.1 Definition
6.1.1.1.1 Active surveillance
Active surveillance aims to achieve correct timing for curative treatment in patients with clinically localised
PCa, rather than delay palliative treatment [270]. Patients remain under close surveillance, and treatment is
prompted by predefined thresholds indicative of potentially life-threatening disease, still potentially curable,
while considering individual life expectancy.
Several cohorts have investigated AS in organ-confined disease, the findings of which were summarised
in a SR including > 3,900 patients [274]. There is considerable variation between studies regarding patient
selection, follow-up policies and when active treatment should be instigated.
Selection criteria for AS are limited by a lack of prospective RCTs, or findings from a formal consensus
meeting. The criteria most often published include: Gleason 6, when specified < 2-3 positive cores with
< 50% cancer involvement in every positive core, a clinical T1c or T2a, a PSA < 10 ng/mL and a PSA density
< 0.15 ng/mL/cc [274, 275]. The latter threshold remains controversial [275, 276]. A pathology consensus
group suggested excluding men from AS when any of the following features were present: predominant ductal
carcinoma (including pure intraductal carcinoma), sarcomatoid carcinoma, small cell carcinoma, EPE or LVI in
needle biopsy [277] and perineal invasion [278]. A Canadian consensus group pose that AS is the treatment of
choice for low-risk disease, without stratifying for biopsy results, although they clearly recommend that men
< 55 years should be closely scrutinised for high-volume Gleason 6 cancer. The same authors pose that low
volume Gleason 7 (3 + 4) (< 10% pattern 4) may also be considered for AS. However, recent findings suggest
that any grade 4 pattern is associated with a three-fold increased risk of metastases compared to Gleason 6,
while a PSA up to 20 ng/mL might be an acceptable threshold [279-281].
In this setting, re-biopsy within six to twelve months to exclude sampling error is mandatory [275,
281] even if this could be modified in the future [282].
Biological markers, including urine PCA3, transmembrane protease, serine 2-TMPRSS2-ERG fusion, or PSA
isoforms appear promising, as does genomics on the tissue sample itself [283-285]. However, further data will
be needed before such markers can be used in standard clinical practice.
The added value may differ at different time points in an AS setting. At confirmatory biopsy in men who did
not have an mpMRI before, the reclassification rate due to targeted biopsies can be estimated to be 2-22%
(absolute numbers) [287-291]. The added value of mpMRI for surveillance/repeat biopsies (hence more than
one year following the confirmatory biopsy assessment) has not been evaluated yet. However, combined
data of confirmatory and surveillance repeat biopsies show a reclassification rate due to targeted biopsies of
2-14% (absolute numbers) [292-294]. These numbers are directly related to the eligibility criteria for AS, and the
reclassification criteria used within these populations.
The concordance of systematic and targeted biopsies at confirmatory biopsies is approximately
80%. However omitting systematic biopsies may induce a misclassification rate of 3-13% [287-290, 292-294],
therefore systematic biopsy should be systematically performed, even facing a normal mpMRI.
Targeted biopsies of suspicious lesions on mpMRI are mainly performed for Likert/PIRADS (Prostate
Image Reporting and Data System) > 3 lesions. Although increased rates of reclassification occur in PIRADS 4
and 5 lesions, a substantial proportion of PIRADS 3 lesions show reclassification following targeted biopsies
[288, 289], thereby confirming the significance to biopsy Likert/PIRADS > 3 lesions within AS management.
The follow up strategy is based on serial DRE (at least once/yearl), PSA (at least once, every six months) and
repeated biopsy (at a minimum interval of three to five years). Based on two small single centre studies [295,
296], not all patients with progression/reclassification at biopsy had radiological progression and vice versa.
Therefore, mpMRI cannot be used as a stand-alone tool to trigger follow-up biopsies, but efforts are being
made to define and standardise radiological progression during AS [297].
Risk prediction in men on AS is under investigation to further reduce unnecessary biopsies and
misclassification [298]. In an AS cohort of 259 men with Gleason 6 and Gleason 7 (3 + 4) cancers detected by
MRI-targeted and systematic biopsies, independent predictors of upgrading at 3 years were Gleason 7 (3 + 4),
PSA density > 0.15 ng/mL/cm3 and a score 5 lesion on MRI [299]. Thus, the role of mpMRI in risk prediction
should be further investigated.
Gleason 6-10 tumours carry a continuously increasing mortality risk up to fifteen years follow-up after WW
[319]. Others have shown that the mortality risk of PCa was high in Gleason 7-10 tumours, intermediate in
Gleason 6 tumours, but low in Gleason 2-5 tumours (Table 6.1.3) [320, 321].
In an analysis at ten years follow up in 19,639 patients aged > 65 years who were not given curative treatment,
most men with a Charlson comorbidity index (CCI) score > 2 died from competing causes at ten years
whatever their initial age. Tumour aggressiveness had little impact on OS suggesting that patients could have
been spared biopsy and diagnosis of cancer. Men with a CCI score < 1 had a low risk of death at ten years,
especially for well- or moderately-differentiated lesions [322]. This highlights the importance of checking the
CCI before considering a biopsy.
Table 6.1.3: F
ifteen-year mortality risk for localised PCa in relation to Gleason score in patients aged
55-74 years [320, 321, 323]
The data on deferred and conservative management of low-risk disease contrasts with the recent increase
in the incidence of local treatment from 25 to 34% in the USA in men with a life expectancy < 10 years [326].
Swedish data show a higher prevalence of deferred treatment in low-risk disease of 46% [327].
6.1.3 Deferred treatment for locally advanced PCa (stage T3-T4, Nx-N0, M0)
The final analysis of the largest RCT focusing on this specific question was published in 2013 [328]. Nine
hundred and eighty-five patients with T0-4 N0-2 M0 PCa were treated with androgen-deprivation therapy
(ADT), either immediately or after symptomatic progression or occurrence of serious complications. After a
median follow-up of 12.8 years, the OS HR was 1.21 (95% CI: 1.05-1.39), favouring immediate treatment but
showing no significant difference in PCa mortality or symptom-free survival which raises the question of its
clinical value. Patients with a baseline PSA > 50 ng/mL had a > 3.5-fold higher mortality risk than those with a
PSA baseline of < 8 ng/mL. If baseline PSA was 8-50 ng/mL, the mortality risk was ~7.5-fold higher in patients
with a PSA-DT of < 12 months compared with > 12 months. The median time to start deferred treatment was
seven years. In the deferred arm, 25.6% died without needing treatment (44%).
The decision to offer RP in cases of low-risk cancer should be based on the probability of clinical progression,
side-effects and potential benefit to survival [339]. The results of the ProtecT trial suggest that AM and surgery
are alternatives to EBRT in patients whose tumours are most likely to be clinically insignificant (this is covered
in more detail in Sections 6.1 and 6.3). Apart from disease characteristics, age and comorbidities also impact
When managed with non-curative intent, intermediate-risk PCa is associated with ten- and fifteen-year PCa-
specific mortality (PCSM) rates of 13% and 19.6%, respectively [341].
The risk of having positive LNs in intermediate-risk PCa is between 3.7% and 20.1% [340]. An eLND should
be performed in intermediate-risk PCa if the estimated risk for pN+ exceeds 5% [340]. In all other cases, eLND
can be omitted, which means accepting a low risk of missing positive nodes. Table 6.2.1 presents data from
three RCTs.
There is no consensus regarding the optimal treatment of men with high-risk PCa. Provided that the tumour is
not fixed to the pelvic wall, or that there is no invasion of the urethral sphincter, RP is a reasonable first step in
selected patients with a low tumour volume. Extended LND should be performed in all high-risk PCa cases, as
the estimated risk for positive LNs is 15-40% [340].
The indication for RP in all previously described stages assumes the absence of clinically detectable nodal
involvement. Only limited evidence exists supporting RP of cN+ patients. In a recent study, the outcomes of 50
patients with cN+ were compared with those of 252 patients with pN1, but cN0 at pre-operative staging, and
cN+ was not a significant predictor of CSS [363].
6.2.6 Radical prostatectomy in cN0 patients who are found to have pathologically confirmed lymph
node invasion (pN1)
At fifteen years of follow up, cN0 patients who were treated with RP but were found to have pN1 at the time of
surgery, were reported to have a CSS and OS of 45% and 42%, respectively [369-375].
In terms of performing frozen section of nodes during RP, two retrospective observational studies have shown
a better CSS and OS in favour of a completed RP vs. an abandoned RP in patients who were found to be pN+
at the time of surgery [372, 373, 376]. This highlights the fact that frozen section should no longer be performed
and supports the role of RP as an important component of multimodal strategies of pN+ PCa.
6.2.7.5 Guidelines for extended lymph node dissection in prostate cancer and pN+ patients
Recommendations LE GR
Do not perform a lymph node dissection (LND) in low-risk PCa. 2b A
Perform an extended(e)LND in intermediate-risk PCa if the estimated risk for positive lymph 2b B
nodes exceeds 5%.
Perform an eLND in high-risk PCa. 2a A
Do not perform a frozen section of nodes during radical prostatectomy (RP) to decide whether 2a A
to proceed with, or abandon, the procedure.
Do not perform a limited LND. 2a A
Upon detection of nodal involvement during RP:
• offer adjuvant androgen deprivation therapy (ADT); 1b A
• discuss adjuvant ADT with additional radiotherapy (see Section 6.2.6.3); 2b A
• offer observation (expectant management) to a patient after eLND with < 2 nodes with 2b B
microscopic involvement, and a PSA < 0.1 ng/mL and absence of extranodal extension.
Recommendations LE GR
Offer both radical prostatectomy (RP) and RT in patients with low- and intermediate-risk 1b A
disease and a life expectancy > 10 years.
Offer AS as an alternative to surgery or RT in patients with low-risk disease and a life 1b A
expectancy of > 10 years.
Offer nerve-sparing surgery in patients with a low risk of extracapsular disease (refer to Partin 2b B
tables/nomograms).
Offer RP in patients with high-risk localised PCa and a life expectancy of > 10 years only as 2a A
part of multi-modal therapy.
Offer RP in selected patients with locally advanced (cT3a) disease and a life expectancy > 10 2b B
years only as part of multi-modal therapy.
Offer RP in highly selected patients with locally advanced disease (cT3b-T4 N0 or any T N1) 3 C
only as part of multi-modal therapy.
Do not offer neoadjuvant hormonal therapy before RP. 1a A
Do not offer adjuvant hormonal therapy after RP for pN0 disease. 1a A
If IMRT and IGRT are used for dose escalation, severe late side effects > Grade 3 for the rectum is about 2-3%
and for the genito-urinary tract is 2-5% [412, 419, 421-434] (see also Chapter 8).
Radiotherapy with > 3.4 Gy has been suggested to define extreme HFX [448]. Respective studies largely
include low- to intermediate-risk patients and obtain very favourable results. Table 6.3.3 gives an overview on
selected studies. It seems prudent to restrict extreme HFX to prospective clinical trials and to inform patients
on the uncertainties of the long-term outcome.
Whether these results should be applied to patients with intermediate- or high-risk localised PCa is unclear.
The Boston trial has shown an improved eight-year OS rate for patients without moderate or severe
comorbidity assigned to six months of complete ADT (p = 0.01) [454], and the RTOG 94-08 study showed an
increased ten-year OS rate for intermediate risk only with four months of complete ADT (p = 0.003) [415].
The EORTC trial 22961, an equivalence trial with 970 patients (78% T3-4, 92% N0) combined RT
(70 Gy) with either six months or with three years of LHRH analogue treatment. With a median follow-up of 6.4
years, both CSS and overall mortality were significantly lower with long-term androgen suppression [416].
In the RTOG 9910 trial, 1,579 intermediate-risk PCa patients were randomised to LHRH antagonist
therapy for eight weeks before RT (70.2 Gy in 2-D or 3-D techniques) followed by either another eight or 28
weeks of anti-hormonal treatment. Extended androgen suppression did not significantly improve ten-year rates
of distant (both arms 6%), loco-regional (6% vs. 4%) or biochemical progression (both arms 27%), or DSS
(96% vs. 95%) or OS (66% vs. 67%). The 8 + 8 week scheme was confirmed as a standard procedure [457].
Table 6.3.3: S
tudies of use and duration of androgen deprivation therapy in combination with
radiotherapy for prostate cancer
6.3.3.6 Recommended external beam radiation therapy treatment policy for localised PCa
6.3.3.6.1 Low-risk PCa
Intensity-modulated RT with escalated dose without ADT is an alternative to brachytherapy (see below).
6.3.3.6.5 M
RC PR3/PR07 study - The National Cancer Institute of Canada (NCIC)/UK Medical Research
Council (MRC)/Southwest Oncology Group (SWOG) intergroup PR3/PR07 study
This study comprised 1,205 patients, consisting of T3-4 (n = 1,057), or T2, PSA > 40 ng/mL (n = 119), or
T2, PSA > 20 ng/mL and Gleason score > 8 (n = 25), who were randomly assigned to lifelong ADT (bilateral
orchidectomy or LHRH agonist), with or without RT (65-70 Gy to the prostate, with or without 45 Gy to the
pelvic LNs). With a median follow-up of eight years, OS was significantly improved in the patients allocated
to ADT + RT (HR:, 0.70; 95% CI: 0.57-0.85; p < 0.001). Deaths from PCa were significantly reduced by
the addition of RT to ADT (HR: 46; 95% CI: 0.34-0.61; p < 0.001). Patients on ADT + RT reported a higher
frequency of adverse events related to bowel toxicity, but only two of 589 patients had Grade 3 or greater
diarrhoea at 24 months after RT [462].
A total of 273 patients with locally advanced PCa T3-4 or pT3 N0 M0 were randomly assigned to three years
Another study compared hormonal treatment alone (i.e. three months of continuous androgen blockade
followed by continuous flutamide treatment (n = 439) with the same treatment combined with RT (n = 436)
[460]. The ten (fifteen) year cumulative PCSM was 18.9% (30.7%) and 8.3% (12.4%) (HR: 0.35; [p < 4.1E-10
for fifteen year results]), and overall mortality was 35.3% (56.7%) and 26.4% (43.4%) (HR: 0.70; p = 0.0006 for
fifteen-year results), respectively.
Low-dose rate brachytherapy uses radioactive seeds permanently implanted into the prostate. Patients
with low- and favourable intermediate-risk PCa are the most suitable candidates for LDR brachytherapy as
monotherapy. The use of guidelines is strongly recommended [479-481]. There have been no RCTs comparing
brachytherapy as monotherapy with other curative treatment modalities. Outcome data are available from a
number of large population cohorts with mature follow-up [482-489]. The BDFS for Gleason 6 patients after five
and ten years has been reported to range from 71% to 93% and 65% to 85%, respectively [482-489].
A significant correlation has been shown between the implanted dose and recurrence rates [490].
Patients receiving a D90 (dose covering 90% of the prostate volume) of > 140 Gy had a significantly higher
biochemical control rate (PSA < 1.0 ng/mL) after four years than patients who received less than 140 Gy (92 vs.
68%).
In men with intermediate- or high-risk PCa, LDR brachytherapy boost with supplemental EBRT and hormonal
treatment [491] may be considered. Dose-escalated EBRT has been compared with EBRT and LDR
brachytherapy boost in intermediate-risk and high-risk patients in a RCT [492]. The ASCENDE-RT (Androgen
Suppression Combined with Elective Nodal and Dose Escalated Radiation Therapy) multi-centre Canadian
trial compared EBRT (total dose of 78 Gy) to EBRT (total dose 46 Gy) followed by LDR brachytherapy boost
(prescribed dose 115 Gy). The use of LDR boost resulted in five- and seven-year PSA PFS rates of 89% and
86%, respectively compared to 84% and 75% in those treated with EBRT alone. This improvement in PSA
control came with an increase in late urinary toxicity with 18% experiencing G3+ toxicity in the LDR boost arm
as compared to 8% in the EBRT alone arm. Toxicity was mainly due to urethral strictures and incontinence and
great care should be taken during treatment planning.
6.3.6 Immediate (adjuvant) post-operative external irradiation after RP (cN0 or pN0) (Table 6.3.5)
Extracapsular invasion (pT3), Gleason score > 7 and positive surgical margins (R1) are associated with a risk of
local recurrence, which can be as high as 50% after five years [500]. Three prospective RCTs have assessed
the role of immediate post-operative RT (adjuvant RT [ART]), as follows:
6.3.6.4 Conclusion
Thus, for patients classified as pT3 pN0 with a high risk of local failure after RP due to positive margins (highest
impact), capsule rupture, and/or invasion of the seminal vesicles, who present with a PSA level of < 0.1 ng/mL,
two options can be offered in the framework of informed consent. These are:
• immediate ART to the surgical bed [501, 502, 504] after recovery of urinary function.
or
• clinical and biological monitoring followed by salvage radiotherapy (SRT) before the PSA exceeds
0.5 ng/mL [505, 506] (see Section 6.10.5.1).
Summary of evidence LE
The highest effect of adjuvant radiotherapy is seen in patients with pT3R1 PCa. 1a
The optimum duration of androgen deprivation therapy (ADT) with external beam radiation therapy 1b
(EBRT) is well established in the literature. There is no evidence that these durations should change
when using brachytherapy boost with EBRT.
Limited data, from experienced centres only, are available for the use of fractionated high-dose-rate 2a
brachytherapy as monotherapy in patients with low and intermediate-risk PCa.
Recommendations LE GR
Offer external beam radiation therapy (EBRT) to all risk groups of non-metastatic PCa 1b A
In low-risk PCa, use a total dose of 74 to 78 Gy. 1a A
In patients with low-risk PCa, and selected intermediate-risk PCa, without a 2a A
previous transurethral resection of the prostate (TURP) and with a good International
Prostate Symptom Score and a prostate volume < 50 mL, offer low-dose rate (LDR)
brachytherapy.
In patients with intermediate-risk PCa use a total dose of 76-78 Gy, in combination with 1b A
short-term ADT (four to six months).
In patients with high-risk localised PCa and locally advanced cN0 PCa, use EBRT to a 1a A
dose of 76-78 Gy, or combined EBRT with brachytherapy boost (either high-dose rate EBRT
[HDR] or LDR). Radiotherapy should be given in combination with long-term androgen 1b
deprivation therapy (two to three years). brachytherapy
Offer intensity-modulated radiotherapy (IMRT) for definitive treatment of PCa by EBRT. 2a A
Moderate hypofractionation (HFX) with IMRT including image-guided radiation therapy 1a A
(IGRT) to the prostate only can be offered to carefully selected patients with localised
disease (as discussed in the text).
Moderate HFX should adhere to radiotherapy-protocols from trials with equivalent 1a A
outcome and toxicity, i.e. 60 Gy/20 fractions in four weeks or 70 Gy/28 fractions in six
weeks.
6.4 Treatment: Options other than surgery and radiotherapy for the primary treatment of
localised prostate cancer
6.4.1 Background
Besides RP, EBRT and brachytherapy, other modalities have emerged as therapeutic options in patients with
clinically localised PCa [507-510]. In this section, both whole gland and focal treatment will be considered,
looking particularly at high-intensity focused US (HIFU) and cryosurgical ablation of the prostate (CSAP)
as sufficient data are available to form the basis of some initial judgements on these latest additions to
the management of PCa. Other options - such as photodynamic therapy, radiofrequency ablation and
electroporation, among others - are considered to be in the early phases of evaluation and will therefore not be
discussed in this edition of the Guidelines. Both HIFU and CSAP have been developed as minimally invasive
procedures with the aim of providing equivalent oncological safety, reduced toxicity and improved functional
outcomes. In addition, a relatively newer development is focal ablative therapy, whereby lesion-targeted
ablation is undertaken in a precise, organ-sparing manner.
6.4.2 Cryosurgery
Cryosurgery uses freezing techniques to induce cell death by:
• dehydration resulting in protein denaturation;
• direct rupture of cellular membranes by ice crystals;
• vascular stasis and microthrombi, resulting in stagnation of the microcirculation with consecutive
ischaemic apoptosis [507-510].
Freezing of the prostate is ensured by the placement of 12-15 x 17 gauge cryoneedles under TRUS guidance,
placement of thermosensors at the level of the external sphincter and bladder neck, and insertion of a urethral
warmer. Two freeze-thaw cycles are used under TRUS guidance, resulting in a temperature of -40°C in the mid-
gland and at the neurovascular bundle. Currently, third and fourth generation cryosurgery devices are mainly
used.
Potential candidates for CSAP are those who have organ-confined PCa and those identified as having minimal
tumour extension beyond the prostate [507-509], The PSA should be < 20 ng/mL, and the Gleason score
should be < 7:
• patients with low-risk PCa, or intermediate-risk PCa whose condition prohibits RT or surgery;
• at the time of therapy, the size of the prostate should be < 40 mL; volume reduction may be achieved by
androgen ablation to avoid any technical difficulty in placing cryoprobes under the pubic arch.
It is important that patients with a life expectancy > 10 years should be fully informed that there are limited data
on the long-term outcome for cancer control > 10 years and that this treatment modality is still considered as
experimental.
In an earlier SR and meta-analysis [514], 150 papers related to HIFU were identified and evaluated with regard
to various oncological and functional outcome parameters [514]. No RCT was available for analysis, and no
survival data were presented. No validated biochemical surrogate end-point was available for HIFU therapy.
The review found HIFU to be associated with a PFS (based on PSA ± biopsy data) of 63-87% (projected three-
to five-year data), but median follow up in the studies ranged from 12-24 months only.
Ramsay et al.’s [502] SR and network meta-analysis of ablative therapy in men with localised PCa performed
a sub-group analysis of focal therapy vs. RP and EBRT. Nine case series reporting on focal therapy were
identified (five studies reporting on focal CSAP, three studies on focal HIFU, and one study reporting on both).
For focal CSAP vs. RP or EBRT, no statistically significant differences were found for BCR at three years.
For focal HIFU vs. RP or EBRT, there were no comparable data on oncological, continence nor potency
outcomes at one year or more. More recently, Valerio et al. [521] performed a SR to summarise the evidence
regarding the effectiveness of focal therapy in localised PCa. Data from 3,230 patients across 37 studies were
included, covering different energy sources including HIFU, CSAP, photodynamic therapy, laser interstitial
thermotherapy, focal brachytherapy, irreversible electroporation and radiofrequency ablation. The overall
quality of the evidence was low, due to the majority of studies being single-centre, non-comparative and
retrospective in design, heterogeneity of definitions, approaches, follow-up strategies, outcomes, and duration
of follow-up. Although the review suggests that focal therapy has a favourable toxicity profile in the short to
medium-term, its oncological effectiveness remains unproven due to lack of reliable comparative data against
standard interventions such as RP and EBRT. Robust prospective trials reporting standardised outcomes [522]
are needed before recommendations in support of focal therapy for routine clinical practice can be made.
Summary of evidence LE
The available short-term data regarding cryosurgery and high-intensity focused ultrasound (HIFU) 2b
does not prove equivalence to standard interventions.
There is no reliable long-term comparative data to indicate that cryosurgery or HIFU leads to 3
equivalent oncological outcomes compared with radical prostatectomy or external beam radiation
therapy.
Prostate specific antigen nadir values after ablative therapies may have prognostic value. 3
Focal therapy of any sort appears promising but remains investigational, with uncertainties 3
surrounding outcome definitions, follow-up and re-treatment criteria.
Recommendations LE GR
Only offer cryotherapy and high-intensity focused ultrasound within a clinical trial setting. 3 A
Only offer focal therapy within a clinical trial setting. 3 A
6.5.3 Oestrogens
Treatment with oestrogens results in testosterone suppression and is not associated with bone loss [529].
Early studies tested oral diethylstilboestrol (DES) at several doses. Due to severe side effects, especially
thromboembolic complications, even at lower doses [530, 531] these drugs are not considered as standard
first-line treatment.
Degarelix
Degarelix is an LHRH antagonist. The standard dosage is 240 mg in the first month, followed by monthly
injections of 80 mg. Most patients achieve a castrate level at day three [536]. An extended follow-up has been
published, suggesting a better PFS compared to monthly leuprorelin [536]. Its definitive superiority over the
LHRH analogues remains to be proven.
6.5.6 Anti-androgens
These oral compounds are classified according to their chemical structure as:
• steroidal, e.g. cyproterone acetate (CPA), megestrol acetate and medroxyprogesterone acetate;
• non-steroidal or pure, e.g. nilutamide, flutamide and bicalutamide.
Both classes compete with androgens at the receptor level. This is the sole action of non-steroidal anti-
androgens and leads to an unchanged or slightly elevated testosterone level. Conversely, steroidal anti-
androgens have progestational properties leading to central inhibition by crossing the blood-brain barrier.
6.5.6.2.1 Nilutamide
Nilutamide monotherapy has not been compared to castration and is not licensed for monotherapy. Non-
androgen pharmacological side effects are visual disturbances (i.e. delayed adaptation to darkness), alcohol
intolerance, nausea, and specifically severe interstitial pneumonitis (potentially life-threatening).
6.5.6.2.2 Flutamide
Flutamide has been studied as monotherapy. Flutamide is a pro-drug, and the half-life of the active metabolite
is five-six hours, allowing for a three times daily dose. The recommended total daily dosage is 750 mg. The
6.5.6.2.3 Bicalutamide
The dosage licensed for use in CAB is 50 mg/day, and 150 mg for monotherapy. The androgen
pharmacological side-effects are mainly gynaecomastia (70%) and breast pain (68%). However, bicalutamide
monotherapy offers clear bone protection compared with LHRH analogues and probably LHRH antagonists
[539, 541].
6.5.7.2 Enzalutamide
Enzalutamide is a novel anti-androgen with a higher affinity than bicalutamide for the AR receptor. While non-
steroidal anti-androgens still allow transfer of ARs to the nucleus, enzalutamide also blocks AR transfer and
therefore suppresses any possible agonist-like activity.
So far, the SWOG 9346 [561] is the largest trial conducted in M1b patients. Out of 3,040 selected patients,
only 1,535 were randomised based on the inclusion criteria set. This highlights that, at best, only 50% of M1b
patients might be candidates for IAD, i.e. the best PSA responders. This was a non-inferiority trial leading to
inconclusive results: (HR: 1.1; CI: 0.99-1.23), with the upper limit being above the pre-specified 90% upper
limit of 1.2. The pre-specified non-inferiority limit was not achieved, and the results did not show a significant
inferiority for any treatment arm. However, inferior survival with IAD cannot be completely ruled out based on
this study.
Other trials did not show any survival difference with a HR for OS of 1.04 (0.91-1.19). These reviews
and the meta-analyses came to the conclusion that there was no difference in OS or CSS between IAD and
continuous androgen deprivation. A recent review of the available phase III trials highlighted the limitations
of most trials and suggests a cautious interpretation of the non-inferiority results [562]. None of the trials
addressing M1 patients only showed a survival benefit, but there was a trend favouring continuous treatment
for OS and PFS. Most of these trials, however, were non-inferiority trials. There is a trend favouring IAD in terms
of QoL, especially regarding treatment-related side effects, such as hot flushes. In some cohorts the negative
impact on sexual function was less pronounced with IAD. Two prospective trials came to the same conclusions
[563, 564].
Other possible long-term benefits of IAD include bone protection [565] and a protective effect against
metabolic syndrome. This possible protective effect has been challenged recently [566] with an increased risk
for thrombotic and ischaemic events, while no benefit was observed for the endocrine, psychiatric, sexual and
neurological side effects based on a detailed analysis from the SWOG 9346 trial. Testosterone recovery was
observed in most studies [567] leading to intermittent castration. This, as well as the lack of any survival benefit
in M1 patients, suggests that this modality must only be considered as an option in a well-informed patient
bothered by significant side effects and willing to avoid them.
The PSA threshold at which ADT must be stopped or resumed still needs to be defined in prospective studies
[557, 567]. Nevertheless, there is consensus amongst authors on some statements:
• Intermittent androgen deprivation is based on intermittent castration; therefore, only drugs leading to
castration are suitable.
• Luteinising-hormone releasing hormone antagonist might be a valid alternative to an agonist.
• The induction cycle cannot be longer than nine months, otherwise testosterone recovery is unlikely.
• Androgen deprivation therapy should be stopped only if patients have fulfilled all of the following criteria:
In the GETUG 15 trial [569], all patients had newly diagnosed M1 PCa, either primary or after a primary
treatment. They were stratified based on previous treatment, and Glass risk factors [545]. In the
Chemohormonal Therapy versus Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer
(CHAARTED) trial, the same inclusion criteria applied and patients were stratified according to disease volume;
high volume being defined as either presence of visceral metastases or four, or more, bone metastases, with at
least one outside the spine and pelvis [547].
STAMPEDE is a multi-arm multi-stage trial in which the reference arm (ADT monotherapy) included
1,184 patients. One of the experimental arms was docetaxel combined with ADT (n = 593 patients), another
was docetaxel combined with zoledronic acid (n = 593). Patients were included with either M1, or N1 or having
two criteria out of three: T3/4, PSA > 40 ng/mL, Gleason 8-10. Also relapsed patients after local treatment were
included if they met one of the following criteria: PSA > 4 ng/mL with a PSA-DT < 6 months, a PSA > 20 ng/mL,
N1 or M1. No stratification was used regarding metastatic disease volume (high/low volume) [473].
In the three trials toxicity was mainly haematological with around 12-15% Grade 3-4 neutropenia,
and 6-12% Grade 3-4 febrile neutropenia. Determination of granulocyte colony-stimulating factor receptor
(GCSF) was shown to be helpful and its use should be based on available guidelines [571, 572].
In practice, imaging to assess progression leading to treatment change must be limited to a clear progression:
RECIST criteria for non-bone lesions; for bone lesions, only BS progression (occurrence of two new hot spots,
later confirmed) should be considered. The practical impact of mpMRI in assessing bone progression remains
unclear.
Recommendations LE GR
Offer castration combined with chemotherapy (docetaxel) to all patients whose first 1a A
presentation is M1 disease and who are fit enough for chemotherapy.
Offer castration alone, with or without an anti-androgen, to patients unfit for, or unwilling to 1b A
consider, castration combined with chemotherapy.
Do not prescribe abiraterone acetate or enzalutamide outside of a clinical trial. 3 A
Use castration combined with any local treatment (radiotherapy/surgery) in an investigational 3 A
setting only.
Recommendations LE GR
In M1 symptomatic patients, offer immediate castration to palliate symptoms and reduce 1b A
the risk for potentially catastrophic sequelae of advanced disease (spinal cord compression,
pathological fractures, ureteral obstruction, extra-skeletal metastasis).
In M1 asymptomatic patients, offer immediate castration to defer progression to a 1b A
symptomatic stage and prevent serious disease progression-related complications.
In newly diagnosed M1 patients, offer castration combined with docetaxel, provided patients 1a A
are fit enough to receive chemotherapy.
In M1 asymptomatic patients, discuss deferred castration with a well-informed patient since it 2b B
lowers the treatment side effects, provided the patient is closely monitored.
Anti-androgens
In M1 patients treated with a luteinising-hormone releasing hormone (LHRH) agonist, offer 2a A
short-term administration of anti-androgens to reduce the risk of the ‘flare-up’ phenomenon.
Start anti-androgens used for ‘flare-up’ prevention on the same day as an LHRH analogue 3 A
is started or for up to seven days before the first LHRH analogue injection if the patient has
symptoms. Treat for four weeks.
Do not offer anti-androgen monotherapy. 1a A
Intermittent treatment
In asymptomatic M1 patients, offer intermittent treatment to highly motivated men, with a 1b B
major prostate-specific antigen (PSA) response after the induction period.
• In M1 patients, follow the schedules used in published clinical trials on timing of 4 C
intermittent treatment.
• Stop treatment when the PSA level is < 4 ng/mL after six to seven months of treatment.
• Resume treatment when the PSA level is > 10-20 ng/mL (or returned to the initial level of
< 20 ng/mL).
In M1 patients, offer combined treatment with LHRH agonists and a non-steroidal anti- 1b A
androgen.
Offer LHRH antagonists, especially in patients with an impending spinal cord compression or 2 B
bladder outlet obstruction.
Despite the high incidence and mortality rates in senior adults, they may be under-treated [587, 588]. In the
USA, only 41% of patients aged > 75 years with intermediate- and high-risk disease receive curative treatment
compared to 88% aged 65-74 [589].
6.7.1.2.1 Comorbidity
Comorbidity is a major predictor of non-cancer-specific death in localised PCa treated with RP [590]. This can
be explained by the observations from a study in which patients did not receive active local treatment for their
PCa [322]. At ten years, most men with a CCI score > 2 had died from competing causes, irrespective of age or
tumour aggressiveness.
Currently, the Cumulative Illness Score Rating-Geriatrics (CISR-G; Table 6.7.1) [591] is the best tool
for assessing mortality risk unrelated to PCa [592].
6.7.1.2.3 Malnutrition
Malnutrition is associated with increased mortality in senior patients [596]. Nutritional status can be estimated
from body weight during the previous three months:
• Good nutritional status < 5% weight loss;
• Risk of malnutrition: 5-10% weight loss;
• Severe malnutrition: > 10% weight loss.
Reversible = Nonreversible =
- Abnormal ADL: 1 or 2 - Abnormal ADL: > 2
- Weight loss 5–10% - Weight loss > 10%
- Comorbidities CISR-G - Comorbidities CISR-G
grades 1-2 grades 3-4
CGA then
geriatric
intervention
Disabled/severe
Fit Frail
comorbidities
*Reproduced with permission of Elsevier, from Droz J-P, et al. Eur Urol 2017 (prior to press) [599].
Mini-COGTM = mini-COGTM cognitive test; ADL = activities of daily living; CIRS-G = cumulative illness rating
score-geriatrics; CGA = comprehensive geriatric assessment.
A G8 score > 14 shows that patients should receive the same treatment as younger patients. Patients with
score G8 < 14 should undergo a full geriatric evaluation, assessing comorbidity, nutritional status, and cognitive
and physical functions, to determine if the impairment is reversible [602]. Patients with reversible impairment
(frail patients) should be treated according to the EAU-ESTRO-ESUR-SIOG Prostate Cancer Guidelines.
Patients with irreversible impairment (disabled patients) should receive adapted treatment [599].
6.7.1.2.6 Conclusions
Systematic assessment, using the G8 tool, is recommended by the SIOG PCWG [599]. Patients with G8 score
< 14 should undergo complete geriatric assessment to evaluate reversibility of any impairments [599].
Senior adults can be classified into one of four groups regarding health status based on G8 score > 14 (patient
considered fit), or score < 14 (patient considered frail or disabled). The treatment policy is then:
• fit or healthy older men should receive standard treatment;
• frail patients may receive standard treatment after resolution of any geriatric problems;
• disabled patients (i.e. non-reversible problems) should receive adapted treatment;
• patients who are too sick with terminal illness should receive only palliative treatment [599].
After resolution of reversible impairments, a similar urological approach should be carried out in fit or frail
patients [1, 2]. Older men with PCa should be managed according to their individual health status, which is
directed by the presence of any associated comorbidity and not age.
*Reproduced with permission of Elsevier, from Droz J-P, et al. Eur Urol 2017 (prior to press) [599].
Mini-COGTM = mini-COGTM cognitive test; ADL = activities of daily living; CIRS-G = cumulative illness rating
score-geriatrics; CGA = comprehensive geriatric assessment.
6.7.3 Guidelines for the treatment of senior adults (> 70 years of age)
Table 6.8.1: E
AU risk groups for biochemical recurrence of localised and locally advanced prostate
cancer
Definition
Low-risk Intermediate-risk High-risk
PSA < 10 ng/mL PSA 10-20 ng/mL PSA > 20 ng/mL any PSA
and GS < 7 or GS 7 (ISUP grade 2/3) or GS > 7 (ISUP grade 4/5) any GS cT3-4 or cN+
(ISUP grade 1) any ISUP grade
and cT1-2a or cT2b or cT2c
Localised Locally advanced
PSA = prostate-specific antigen.
Recommendations GR
Low-risk PCa
Active surveillance Offer active surveillance (AS) to patients with the lowest risk of cancer A
progression: > 10 years life expectancy, cT1/2, prostate-specific antigen
(PSA) ≤ 10 ng/mL, biopsy Gleason score ≤ 6 , ≤ 2 positive biopsies,
minimal biopsy core involvement (≤ 50% cancer per biopsy).
Base follow up on digital rectal examination (DRE), PSA and repeated A
biopsies.
Counsel patients about the possibility of needing further treatment in the A
future.
Radical prostatectomy Offer both radical prostatectomy (RP) and radiotherapy (RT) in patients A
with low- and intermediate-risk PCa and a life expectancy > 10 years.
Do not perform a lymph node dissection (LND) in low-risk PCa. A
6.9 Treatment - Management of PSA-only recurrence after treatment with curative intent
6.9.1 Background
Between 27% and 53% of all patients undergoing RP or RT develop PSA-recurrence (see Sections 6.2
and 6.3). Whilst a rising PSA level universally precedes metastatic progression, physicians must inform the
patient that the natural history of PSA-only recurrence may be prolonged and that a measurable PSA may
not necessarily lead to clinically apparent metastatic disease. Physicians treating patients with PSA-only
recurrence face a difficult set of decisions in attempting to delay the onset of metastatic disease and death
while avoiding over-treating patients whose disease may never affect their OS or QoL. It should be emphasised
that the treatment recommendations for these patients should be given after discussion in a multidisciplinary
team.
After primary RT, with or without short-term hormonal manipulation, the RTOG-ASTRO Phoenix Consensus
Conference definition of PSA failure (with an accuracy of > 80%) is any PSA increase > 2 ng/mL higher than the
PSA nadir value, regardless of the serum concentration of the nadir [621].
Importantly, patients with PSA-recurrence after RP or primary RT have different risks of subsequent
symptomatic metastatic disease. Therefore, physicians should carefully interpret BCR endpoints when
comparing treatments.
Several studies have attempted to identify risk factors for metastases and PCSM in patients experiencing PSA-
only recurrence following RP. A PSA-DT < 3 months, SVI (pT3b), specimen Gleason score 8-10, or time to PSA-
recurrence < 3 years indicate a high risk of metastases and PCSM. Conversely, a PSA-recurrence > 3 years
following surgery, specimen Gleason score < 7, pathologic organ-confined disease or limited extracapsular
extension (pT3a), and PSA-DT > 12 months indicate a low risk of metastases and PCSM [623-626]. Patients
in the low-risk subgroup typically respond very well to SRT with a high probability of PSA being undetectable
[627]. However, it must be stressed that most patients within the low-risk subgroup have an excellent outcome
even without any salvage treatment. Patients within the high-risk subgroup need early and aggressive salvage
treatment [628]. Trock et al. demonstrated that SRT was associated with a significant three-fold increase in
PCa-specific survival relative to those who received no salvage treatment. The increase in PCa-specific survival
associated with SRT was limited to men with a PSA-DT of < 6 months and remained after adjustment for
pathological stage and other established prognostic factors. Salvage RT initiated > 2 years after recurrence
provided no significant increase in PCa-specific survival [628].
Choline PET/CT sensitivity is strongly dependent on the PSA level and kinetics [249, 639-641]. In patients with
BCR after RP, PET/CT detection rates are only 5-24% when the PSA level is < 1 ng/mL, but rises to 67-100%
when the PSA level is > 5 ng/mL. In a meta-analysis, choline PET/CT detection rates were 65% (95% CI: 58%-
71%) when the PSA-DT was < 6 months, and were 71% (95% CI: 66%-76%) and 77% (95% CI: 71%-82%)
when the PSA velocity was > 1 and > 2 ng/mL/year, respectively [639].
Despite these limitations, choline PET/CT may change medical management in 18-48% of patients with BCR
after primary treatment [642-644]. In a retrospective bi-centric study of 150 patients, 14 of the 55 (25.5%)
patients scheduled for palliative treatment were switched to salvage therapy based on choline PET/CT results.
Salvage therapy induced a complete biochemical response in 35.7% of these patients at the end of a median
follow-up of 18.3 months (range, 10-48 months) [644] suggesting it continues to miss small volume metastasis.
In patients not considered fit enough for curative salvage treatments choline PET/CT should be avoided.
After RP, the optimal PSA cut-off level for choline PET/CT analysis seems to be between 1 and 2
ng/mL. Choline PET/CT detection rate was 26% in patients showing PSA < 1 ng/mL but raised up to 44% in
the population with PSA values between 1 and 2 (moreover 37% of them were oligo-metastatic) [645]. It has
been suggested that a PSA-DT < 6 months and a PSA velocity > 2 ng/mL/year might also select men in whom
choline PET/CT could be recommended [646].
After RT, the PSA cut-off level is unclear due to the lack of sufficient data and because the PSA
level is more difficult to interpret due to the “physiological” amount of measurable PSA produced by the non-
tumoural prostate [640]. In a study of 46 patients with PSA relapse after RT or brachytherapy, the choline
PET/CT detection rate was 54.5%, 81%, 89% and 100% when the PSA level was 1-2 ng/mL, 2-4 ng/mL, 4-6
ng/mL and > 6 ng/mL, respectively [647]. In another study of 140 patients the choline PET/CT detection rate
was not influenced by the PSA level, but only by PSA kinetics [648].
68Ga-PSMA PET/CT has shown promising potential in patients with BCR. Detection rates of 58% and 76%
have been reported for PSA ranges of 0.2-1 and 1-2 ng/mL, respectively [256]. This suggests that 68Ga-PSMA
is substantially more sensitive at low PSA levels than choline PET/CT. Two head-to-head comparisons
confirmed this finding [651, 652]. However, studies incorporated varying proportions of initial therapy (RP or
RT) and a majority of studies included patients on current ADT. Further prospective studies on homogeneous
populations are needed to better define the role of 68Ga-PSMA PET/CT in patients with BCR. Therefore it
cannot yet be considered as a standard evaluation tool. However, in case local salvage treatment is planned
and 68Ga-PSMA PET/CT is available, it should be considered as a valuable assessment option.
Several studies have reported promising results in the detection of local recurrences using MRI, particularly
dynamic contrast-enhanced MRI which showed sensitivities and specificities of 76-90% and 82-100%,
respectively [656-659]. However, the mean PSA level in these studies was 0.7-1.9 ng/mL, which is higher than
the 0.5 ng/mL threshold usually used for salvage therapy. Two studies evaluated mpMRI in patients with a PSA
level < 0.5 ng/mL. One found a sensitivity of only 13% in men with PSA level < 0.3 ng/mL [660], while the other
reported a sensitivity of 86% in patients with a PSA level < 0.4 ng/mL [661]. It remains to be seen whether MRI
can correctly detect local recurrences in patients with a PSA level < 0.5 ng/mL in order to allow a stereotaxic
boost to the recurrence site during SRT. Therefore, SRT is usually decided on the basis of BCR, without
histological proof of the local recurrence. The dose delivered to the prostatic bed also tends to be uniform as it
has not been demonstrated that a focal dose escalation at the site of recurrence improves the outcome. Thus,
most patients undergo SRT without local imaging.
Transrectal US is not reliable in depicting local recurrences after RT. In contrast, mpMRI has yielded excellent
results [631, 662-664] and can be used for biopsy targeting and guiding local salvage treatment. Detection of
recurrent cancer is also feasible with choline PET/CT [648], and a nomogram able to predict the probability of
extra pelvic disease has been proposed [665]. It is also too soon to know if 68Ga-PSMA PET/CT could play a
role in the detection of local recurrences after RT [256].
Table 6.9.1: S
elected studies on post-prostatectomy salvage radiotherapy, sorted by pre-salvage
radiotherapy PSA level*
Addition of androgen deprivation to SRT improves outcomes. The Radiation Therapy Oncology Group RTOG
96-01 comparing RT + placebo vs. a combination of RT + bicalutamide (150 mg daily) for 24 months in the
post-operative setting reported improved overall all survival (82% vs 78% at ten years) [677]. The investigators
concluded that 24 months of HT also, significantly reduces metastatic disease, reduces death from CaP
(from 7.5% to 2.3%, NNT = 17), reduced overall death (from 22% to 18%) and reduced tumour progression.
They found that toxicity was similar in both arms, and that gynaecomastia was extremely common in the
bicalutamide group. The GETUG-AFU 16 study [678] confirmed improved bPFS and clinical progression at five
years when combining six months of goserelin with SRT, but survival remained unchanged.
Decision-making on whether to proceed with adjuvant RT for high-risk PCa - pT3-4 pN0 M0 with undetectable
PSA after RP, or to postpone RT as an early salvage procedure in the case of biochemical relapse, remains
difficult. In everyday practice, the urologist should explain to the patient before RP that adjuvant RT may be
administered if the patient has negative prognostic risk factors.
No data were found on the effectiveness of different types of HT, although it is unlikely that this will have a
significant impact on survival outcomes in this setting. Non-steroidal anti-androgens have been claimed to
be inferior compared to castration, but this difference was not seen in M0 patients [628]. One of the included
RCTs suggested that intermittent HT is not inferior to continuous HT in terms of OS and CSS [688]. A small
advantage was found in some QoL domains but not overall QoL outcomes. An important limitation of this RCT
is the lack of any stratifying criteria such as PSA-DT or initial risk factors.
Based on the lack of definitive efficacy and the undoubtedly associated significant side effects, not all patients
with recurrence after primary curative therapy should receive standard HT. Only a minority of them will progress
to metastases or PCa-caused death. The objective of HT should be to improve OS, postpone DM, and improve
QoL. Biochemical response to only HT holds no clinical benefit for a patient. For older patients and those
with comorbidities, the side effects of HT may even decrease life expectancy; in particular, cardiovascular
risk factors need to be considered [689, 690]. Early HT should be reserved for those at highest risk of disease
progression, defined mainly by a short PSA-DT at relapse (< 6-12 months) or a high initial Gleason score
(> 7), and a long life expectancy. In all other situations, the potential benefits of salvage HT should be
judiciously considered and balanced against its potential harms.
Table 6.9.2: O
ncological results of selected salvage radical prostatectomy case series, including at least
30 patients
6.9.6.1.2 Morbidity
Compared to primary open RP, SRP is associated with a higher risk of later anastomotic stricture (47 vs.
5.8%), urinary retention (25.3% vs 3.5%), urinary fistula (4.1% vs 0.06%), abscess (3.2% vs 0.7%) and rectal
injury (9.2 vs. 0.6%) [705]. In more recent series, these complications appear to be less common [698, 701].
Functional outcomes are also worse compared to primary surgery, with urinary incontinence ranging from 21%
to 90% and ED in nearly all patients [701].
Reference n Rectal injury Anastomotic Clavien 3-5 (%) Blood loss, mL,
(%) stricture (%) mean, range
Stephenson, et al. 2004 100 15 vs. 2* 30 33 vs. 13* -
[698]
Ward, et al. 2005 [706] 138 5 22 - -
Sanderson, et al. 2006 [702] 51 2 41 6 -
Gotto, et al. 2010 [705] 98 9 41 25 -
Heidenreich, et al. 2010 55 2 11 3.6 360 (150-1450)
[699]
* SRP performed before vs. after 1993.
n = number of patients.
Table 6.9.4: O
ncological results of selected salvage cryoablation of the prostate case series, including at
least 50 patients
6.9.7.2 Morbidity
According to Cespedes, et al. [714], the risks of urinary incontinence and ED at least twelve months after SCAP
were as high as 28% and 90%, respectively. In addition, 8-40% of patients reported persistent rectal pain,
and an additional 4% of patients underwent surgical procedures for the management of treatment-associated
complications. In a recent study by Pisters, et al., the urinary incontinence rate was 4.4%. The rectal fistulae
rate was 1.2% and 3.2% of patients required a TURP for removal of sloughed tissue [709]. With the use
of third-generation technology, complications such as urinary incontinence and obstruction/retention have
significantly decreased during the last decade (see Table 6.9.5) [715].
Table 6.9.6: O
ncological results of selected salvage high-intensity focused ultrasound case series,
including at least 20 patients
6.9.10 Observation
Patients who have signs of only local recurrence (i.e., low-risk patients with late recurrence and a slow PSA
rise) who do not wish to undergo second-line curative options are best managed by observation alone. A
retrospective cohort analysis of HT vs. WW in 248 men with PSA failure after RT showed no advantage for HT
in the subgroup of men with a PSA-DT of > 12 months after RT. The five-year metastasis-free survival rate was
88% with HT vs. 92% with WW (p = 0.74) [729].
Recommendation GR
Discuss salvage lymph node dissection (LND) with men experiencing nodal recurrence after local C
treatment but it should be considered experimental and biochemical recurrence after salvage LND
occurs in the majority of cases.
6.9.12 Guidelines for second-line therapy after treatment with curative intent
Table 6.10.2: R
andomised phase III controlled trials - first-line treatment of metastatic castration-
resistant PCa*
TAX 327 2008 [609, docetaxel, every mitoxantrone, OS: 19.2 for 3 weekly
743] 3 weeks, 75 mg/ every 3 weeks, vs.17.8 mo. for
m2 prednisone 12 mg/m2, weekly and 16.3 in
5 mg BID Or Prednisone 5 the control group.
docetaxel, mg BID (p = 0.004, HR: 0.79
weekly, 30 mg/ 95% CI: 0.67-0.93)
m2 prednisone 5
mg BID
6.10.3.2 Enzalutamide
A randomised phase III trial (PREVAIL) [747] included a similar patient population and compared enzalutamide
and placebo. Men with visceral metastases were accepted although the numbers were small. Corticosteroids
were allowed but not mandatory. PREVAIL was conducted in a chemo-naïve mCRPC population of 1,717
men and showed a significant improvement in both co-primary endpoints, rPFS (HR: 0.186; CI: 0.15-0.23,
p < 0.0001), and OS (HR: 0.706; CI: 0.6-0.84, p < 0.001). A > 50% decrease in PSA was seen in 78% of
patients. The most common clinically relevant AEs were fatigue and hypertension and again it was equally
well tolerated in men > 75 years [751] as well as in those with or without visceral metastases [752]. For the
subgroup of visceral metastases, there seems to be limited benefit concerning OS [752]. Enzalutamide has also
been compared with bicalutamide in a phase II study [753] revealing a significant improvement in PFS (15.7
months vs. 5.8 months, HR 0.44, p < 0.0001).
6.10.3.4 Sipuleucel-T
In 2010, a phase III trial of sipuleucel-T showed a survival benefit in 512 asymptomatic or minimally
symptomatic mCRPC patients [738]. After a median follow-up of 34 months, the median survival was 25.8
months in the sipuleucel-T group compared to 21.7 months in the placebo group, leading to a significant HR of
0.78 (p = 0.03). No PSA decline was observed and PFS was equivalent in both arms. The overall tolerance was
very good, with more cytokine-related AEs Grade 1-2 in the sipuleucel-T group, but the same Grade 3-4 AEs in
both arms. In Europe, sipuleucel-T is not available.
Table 6.10.3: Randomised controlled phase III - second-line trials in metastatic castration-resistant PCa*
6.10.4.1 Cabazitaxel
Cabazitaxel is a novel taxane with activity in docetaxel-resistant cancers. It was studied in a large prospective,
randomised, phase III trial (TROPIC trial) comparing cabazitaxel + prednisone vs. mitoxantrone + prednisone in
755 patients with mCRPC, who had progressed after or during docetaxel-based chemotherapy [613]. Patients
received a maximum of ten cycles of cabazitaxel (25 mg/m2) or mitoxantrone (12 mg/m2) + prednisone (10 mg/
day), respectively. Overall survival was the primary end-point, which was significantly longer with cabazitaxel
(median: 15.1 vs. 12.7 months p < 0.0001). There was also a significant improvement in PFS (median: 2.8 vs.
1.4 months, p < 0.0001), objective RECIST response (14.4% vs. 4.4%, p < 0.005), and PSA response rate
(39.2% vs. 17.8%, p < 0.0002). Treatment-associated WHO Grade 3-4 AEs developed significantly more often
in the cabazitaxel arm, particularly haematological (68.2% vs. 47.3%, p < 0.0002) but also non-haematological
(57.4 vs. 39.8%, p < 0.0002) toxicity [759]. In two post marketing randomised phase 3 trials, firstly, cabazitaxel
was shown not to be superior to docetaxel in the first line setting and, secondly, it was seen that in the second
line setting, 20 mg/m² cabazitaxel is not inferior to 25 mg/m² in terms of OS, but less toxic. Therefore, the
lower dose should be preferred [760, 761]. In any case, cabazitaxel should be administered by physicians with
expertise in handling neutropenia and sepsis, preferably with prophylactic granulocyte colony-stimulating factor
at least in the high-risk patient population [762].
6.10.4.4 Radium-223
The only bone-specific drug that is associated with a survival benefit is radium-223, an α-emitter. In a large
6.10.5 Treatment after docetaxel and one line of hormonal treatment for mCRPC
The choice of further treatment after docetaxel and one line of hormonal treatment for mCRPC is open. Either
further HT (enzalutamide or abiraterone) or second-line chemotherapy (cabazitaxel) are reasonable options
albeit with low levels of evidence. PARP inhibitors have shown high rates of response in men with somatic
homologous recombination deficiency (HRD) in initial studies. Men previously treated with both docetaxel and
at least one novel hormonal agent and whose tumours demonstrated homozygous deletions or deleterious
mutations in DNA-repair genes showed an 88% response rate [764]. Patients without HRD did not clearly
benefit from olaparib. Although not yet available they offer an exciting opportunity to tailor therapy based on
the mutation profile contained within a tumour.
In general however, and in unselected patients, subsequent treatments can be expected to have a
smaller response [765, 766] with evidence of cross-resistance between enzalutamide and abiraterone [767].
The potential toxicity (e.g., osteonecrosis of the jaw) of these drugs, must always be kept in mind [773, 779].
Patients should have a dental examination before starting therapy as the risk of jaw necrosis is increased by a
history of trauma, dental surgery or dental infection [783].
6.10.10 Summary of evidence and guidelines for life-prolonging treatments of castrate-resistant PCa
Summary of evidence LE
No definitive strategy regarding first treatment choice (which drug/drug family first) can be devised. 4
No clear-cut recommendation can be made for the most effective drug for secondary treatment (i.e. 3
hormone therapy, chemotherapy or radium-223) as no clear predictive factors exist.
Recommendations LE GR
Ensure that testosterone levels are confirmed to be < 50 ng/mL, before diagnosing castration- 4 A
resistant PCa (CRPC).
Do not treat patients for non-metastatic CRPC outside of a clinical trial. 3 A
Counsel, manage and treat patients with metastatic (m)CRPC in a multidisciplinary team. 3 A
Treat patients with mCRPC with life prolonging agents. 1b A
Base the choice of first line treatment on the performance status, symptoms, comorbidities,
location and extent of disease (alphabetical order: abiraterone, docetaxel, enzalutamide,
radium-223, sipuleucel-T).
Recommendations LE GR
Counsel, manage and treat patients with metastatic castration-resistant PCa (mCRPC) in a 3 A
multidisciplinary team.
Offer patients with mCRPC who are candidates for cytotoxic therapy docetaxel with 75 mg/m2 1a A
every three weeks.
In patients with mCRPC and progression following docetaxel chemotherapy offer further 1a A
life-prolonging treatment options, which include cabazitaxel, abiraterone, enzalutamide and
radium-223.
Base second-line treatment decisions of mCRPC on pre-treatment performance status, B
comorbidities and extent of disease.
Recommendations LE GR
Offer bone protective agents to patients with metastatic castration-resistant PCa (mCRPC) and 1a B
skeletal metastases to prevent osseous complications.
Offer calcium and vitamin D supplementation when prescribing either denosumab or 1b A
bisphosphonates.
Treat painful bone metastases early on with palliative measures such as external beam 1a B
radiotherapy, and adequate use of analgesics.
In patients with spinal cord compression start immediate high-dose corticosteroids and 1b A
assess for spinal surgery followed by irradiation. Offer radiation therapy alone if surgery is not
appropriate.
7. FOLLOW-UP
7.1 Follow-up: After local treatment
7.1.1 Definition
Local treatment is defined as RP or RT, either by EBRT or low- or high-dose brachytherapy, or any combination
of these. Unestablished alternative treatments, such as HIFU and cryosurgery do not have a well-defined,
validated PSA cut-off to define BCF, but do follow the general principles as presented in this section.
7.1.3.6 Transrectal ultrasound, bone scintigraphy, computed tomography, magnetic resonance imaging, and
11C-choline positron emission tomography computed tomography
Imaging techniques have no place in routine follow-up of localised PCa. They are only justified in patients with
BCF or in patients with symptoms for whom the findings affect treatment decisions. (See Section 6.9.4.5 for a
more detailed discussion).
7.1.5 Summary of evidence and guidelines for follow-up after treatment with curative intent
Summary of evidence LE
After radical prostatectomy serum prostate-specific antigen (PSA) level > 0.2 ng/mL is associated with 2a
residual or recurrent disease.
After radiotherapy, an increase in PSA > 2 ng/mL above the nadir, rather than a specific threshold 2a
value, is the most reliable sign of recurrence.
Palpable nodules and increasing serum PSA are signs of local recurrence. 2a
Recommendations GR
Routinely follow-up asymptomatic patients, by obtaining a disease-specific history and serum B
prostate-specific antigen (PSA) measurement supplemented by digital rectal examination (DRE). These
should be performed at three, six and twelve months after treatment, then every six months until three
years, and then annually.
Imaging to detect local recurrence is only recommended if it affects treatment planning. Biopsy is B
usually not necessary before second-line therapy.
Do not routinely offer bone scans and other imaging modalities to asymptomatic patients if there are B
no signs of biochemical relapse. In case patients have bone pain or other symptoms of progression,
re-staging should be considered irrespective of serum PSA level.
Recommendations GR
Evaluate patients at three to six months after the initiation of treatment. A
As a minimum, tests should include serum prostate-specific antigen (PSA) measurement, digital rectal A
examination (DRE), serum testosterone, and careful evaluation of symptoms in order to assess the
treatment response and side effects.
In patients undergoing intermittent androgen deprivation, monitor PSA and testosterone at fixed A
intervals during the treatment pause (monthly or at three-month intervals).
Adapt follow-up to the individual patient, according to stage of disease, prior symptoms, prognostic A
factors and the treatment given.
In patients with stage M0 disease with a good treatment response, schedule follow-up every A
six months. As a minimum requirement, include a disease-specific history, DRE and serum PSA
determination in the diagnostic work-up.
In patients with stage M1 disease with a good treatment response, schedule follow-up every three A
to six months. As a minimum requirement, include a disease-specific history, DRE, serum PSA,
haemoglobin, serum creatinine and alkaline phosphatase measurements in the diagnostic work-up.
The testosterone level should be checked, especially during the first year.
Counsel patients (especially with M1b status) about the clinical signs suggestive of spinal cord A
compression.
When disease progression occurs, or if the patient does not respond to treatment, adapt/individualise A
follow up.
In patients with suspected progression, assess the testosterone level. By definition, castration- B
resistant PCa (CRPC) requires a testosterone level < 50 ng/mL (< 1 mL/L).
Do not offer routine imaging to otherwise stable patients. B
8.1 Introduction
Quality of life and personalised care go hand in hand. Treating prostate cancer can affect an individual both
physically and mentally, as well as his close relations and his work or vocation. These multifaceted issues
all have a bearing on his perception of ‘quality of life’ [803]. Approaching care from a holistic point of view
requires the intervention of a multi-disciplinary team ranging from urologist, medical oncologist, radiation
oncologist, oncology nurse to psychologists and many others. Attention to the psychosocial concerns of men
with prostate cancer is integral to quality clinical care, and this includes the needs of carers and partners [762].
Prostate cancer care should not be reduced to focusing on the organ in isolation: side effects or late adverse
effects of treatment can manifest systemically and have a major influence on the patient’s QoL. Taking QoL into
consideration relies on understanding the patient’s wishes and preferences so that optimal treatment proposals
can be formulated and discussed.
Table 8.2.1: Intra-and peri-operative complications of retropubic RP and RALP (Adapted from [388])
8.2.2 Radiotherapy
8.2.2.1 Side effects of external beam radiotherapy
Retrospective studies suggest that RT affects erectile function to a lesser degree than surgery of patients
[808], and this has been borne out by the recent ProtecT study results (see below). A meta-analysis has
shown that the one-year probability rates for maintaining erectile function were 0.76 after brachytherapy, 0.60
after brachytherapy + EBRT, 0.55 after EBRT, 0.34 after nerve-sparing RP, and 0.25 after standard RP. When
studies with more than two years of follow-up were selected (i.e. excluding brachytherapy), the rates became
0.60, 0.52, 0.25, and 0.25, respectively, with a greater spread between the radiation techniques and surgical
approaches [809].
Studies have demonstrated a significantly increased risk of developing secondary malignancies of the
rectum and bladder following EBRT [810, 811]. In a retrospective evaluation of 30,552 and 55,263 men, who
had undergone either EBRT or RP, the risk of being diagnosed with rectal cancer increased by 1.7-fold in
comparison with the surgery group [810]. Another analysis [811] showed that the relative risk of developing
bladder cancer increased by 2.34-fold in comparison with a healthy control population. On the other hand,
a re-analysis of SEER data including more than 100,000 patients, demonstrated a risk of about 0.16% (i.e.
160 cases per 100,000 patients) of radiation-induced malignant tumours [812]. The Memorial Sloan-Kettering
Cancer Center group have also reported corresponding data on late toxicity from their experience in 1,571
patients with T1-T3 disease treated with either 3D-CRT or IMRT at doses of between 66 Gy and 81 Gy, with
a median follow-up of ten years [813]. Both acute gastrointestinal and GU toxicity appeared to be predictive
for corresponding late toxicity. The overall rate of NCIC/Common Toxicity Criteria (CTC) Grade 2 or more
Table 8.2.2: A
cute gastrointestinal and genitourinary complications according to the Radiation Therapy
Oncology Group (RTOG)/European Organisation for Research and Treatment of Cancer
morbidity scale (adaptations with regard to the original RTOG scale in italics) according to
Huang et al. [817]*.
*Reproduced with permission of Elsevier, from Budäus L et al. Eur Urol 2012 Jan;61(2):112-7.
GI = gastrointestinal; GU = genito-urinary; TURP = transurethral resection of the prostate.
Serotonin re-uptake inhibitors (e.g. venlafaxine or sertraline) appear to be effective in men, but less than HT
based on a prospective randomised trial comparing venlafaxine, 75 mg daily, with medroxyprogesterone, 20
mg daily, or CPA, 100 mg daily [827]. After six months of LHRH (n = 919), 311 men had significant hot flushes
and were randomised to one of the treatments. Venlafaxine was clearly inferior compared to the hormonal
agents, which showed similar efficacy to each other.
With a placebo effect influencing up to 30% of patients [828], the efficacy of clonidine, veralipride,
gabapentine [829] and acupuncture [830] must be compared in prospective RCTs.
8.2.4.4.3 Bisphosphonates
Bisphosphonates increase BMD in the hip and spine by up to 7% in 1 year. The optimal regimen for zoledronic
acid remains unclear: quarterly [836] or yearly [837] injections. The question is relevant as the risk of jaw
necrosis is both dose- and time-related [838]. A quarterly regimen could be considered for a BMD < 2.5 as a
yearly injection is unlikely to provide sufficient protection [839].
In contrast to breast cancer, a significant benefit in OS has only been demonstrated in PCa in a
post-hoc analysis for the oral first-generation clodronate with an absolute 8% OS increase after eight years of
follow-up [840]. This benefit has never been observed with more recent bisphosphonates.
enosumab (a fully human monoclonal antibody against receptor activator of NF-κB ligand [RANKL])
D
In M0 patients, denosumab has been shown to increase the lumbar BMD by 5.6% compared to a 1% decrease
in the placebo arm after two years, using a 60 mg subcutaneous regimen every six months [841]. This was
associated with a significant decrease in vertebral fracture risk (1.5% vs. 3.9%, p = 0.006). The benefits were
similar whatever the age (< or > 70 years), the duration or type of ADT, the initial BMD, the patient’s weight or
the initial BMI. This benefit was not associated with any significant toxicity, e.g. jaw osteonecrosis or delayed
healing in vertebral fractures. In M0 patients, with the use of a higher dosage (120 mg every four weeks), a
delay in bone metastases of 4.2 months has been shown [782] without any impact on OS, but with an increase
in side effects. Therefore, this later regimen cannot be recommended.
Metabolic syndrome is an association of independent cardiovascular disease risk factors, often associated with
insulin resistance. The definition requires at least three of the following criteria [843]:
• waist circumference > 102 cm;
• serum triglyceride > 1.7 mmol/L;
• blood pressure > 130/80 mmHg or use of medication for hypertension;
• high-density lipoprotein (HDL) cholesterol < 1 mmol/L;
• glycaemia > 5.6 mmol/L or the use of medication for hyperglycaemia.
The prevalence of a metabolic-like syndrome is higher during ADT compared with men not receiving ADT [844].
It has been suggested that LHRH antagonists might be associated with less cardiovascular morbidity
compared to agonists [851]. However, the methodology used in these studies does not provide convincing
evidence to show a clear superiority of these compounds.
These data resulted in an FDA warning and consensus paper from the American Heart, Cancer
Society and Urological Associations [689]. Preventive advice includes non-specific measures such as loss of
8.2.4.7 Fatigue
Fatigue often develops as a side-effect of ADT. Regular exercise appears to be the best protective measure
[852, 853], with prolonged efficacy [854] and improved specific survival [855].
Anaemia may be a cause of fatigue. Anaemia requires an etiological diagnosis (medullar invasion,
mainly inflammatory, renal insufficiency, iron deficiency, chronic bleeding) and individualised treatment. Iron
supplementation (using injectable formulations only) must be systematic if deficiency is observed. Regular
blood transfusions are required if severe anaemia is present. Erythropoiesis-stimulating agents might be
considered in dedicated cases, taking into account the possible increased risk of thrombovascular events
[856].
The concept of ‘quality of life’ is subjective and can mean different things to different men, but there are some
generally common features across virtually all patients. Drawing from these common features, specific tools
or ‘patient reported outcome measures’ (PROMs) have been developed and validated for men with prostate
cancer. These questionnaires assess common issues that affect men after prostate cancer diagnosis and
treatment and generate scores which reflect the impact on perceptions of HRQoL. During the process of
undertaking two dedicated SRs around cancer-specific QoL outcomes in men with PCa as the foundation for
our guideline recommendations, the following validated PROMs were found in our searches (see Table 8.3.1).
8.3.1 Long-term (> 12 months) quality of life outcomes in men with localised disease.
Men undergoing local treatments
Recently the results of the Prostate Testing for Cancer and Treatment (ProtecT) trial (n = 1,643 men) were
published [875]. The study reported no difference in EORTC QLQ-C30 assessed global QoL, up to five years
of follow-up in men aged 50-69 years with T1-T2 disease randomised for treatment with AM, RP or RT [875].
However, EPIC urinary summary scores (at 6 years) were worse in men treated with RP compared to AM or
RT (88.7 vs. 89.0 vs. 91.4, respectively) as were urinary incontinence (80.9 vs. 85.8 vs. 89.4, respectively) and
sexual summary, function and bother scores (32.3 vs. 40.6 vs. 41.3 for sexual summary, 23.7 vs. 32.5 vs. 32.7
for sexual function and 51.4 vs. 57.9 vs. 60.1 for sexual bother, respectively) at six years of follow-up. Minimal
clinically important differences for the 50 item EPIC questionnaire are not to our knowledge available. For
men receiving RT, EPIC bowel scores were poorer compared to AM and RP in all domains: function (90.8 vs.
92.3 vs. 92.3, respectively), bother (91.7 vs. 94.2 vs. 93.7, respectively) and summary (91.2 vs. 93.2 vs. 93.0,
respectively) at six years of follow-up in the ProtecT trial.
The findings regarding RP and RT are supported by other observational studies, the most important being
The Prostate Cancer Outcomes Study (PCOS) [876] that studied a cohort of 1,655 men, of whom 1,164 had
undergone RP and 491 RT. The study reported that at five years of follow-up, men who underwent RP had a
higher prevalence of urinary incontinence and ED, while men treated with RT had a higher prevalence of bowel
dysfunction. However, despite these differences detected at five years, there were no significant differences in
the adjusted odds of urinary incontinence, bowel dysfunction or ED between RP and RT at fifteen years.
With respect to brachytherapy cancer-specific QoL outcomes, the best available evidence come from one
small RCT (n = 200) evaluating bilateral nerve sparing RP and brachytherapy in men with localised disease (up
to T2a), which reported worsening of physical functioning as well as irritative urinary symptomatology in 20%
of brachytherapy patients at one year of follow-up. However, there were no significant differences in EORTC-
QLQ-C30/PR-25 scores at five years of follow-up when comparing to pre-treatment values [877]. It should be
noted of this trial within group tests only were reported.
Recommendations LE GR
Advise eligible patients for active surveillance, that global quality of life is equivalent for up to 1b A
five years compared to radical prostatectomy or radiotherapy.
Discuss the negative impact of surgery on urinary and sexual function, as well as the negative 1b A
impact of radiotherapy on bowel function with patients.
Advise patients treated with brachytherapy of the negative impact on irritative urinary 1b C
symptomatology at one year but not after five years.
8.3.2 Improving quality of life in men who have been diagnosed with prostate cancer
Men undergoing local treatments
In men with localised disease, nurse led multi-disciplinary rehabilitation (addressing sexual functioning, cancer
worry, dyadic adjustment, depression, managing bowel and urinary function problems) provided positive short-
term effects (four months) on sexual function (effect size 0.45) and long-term (twelve months) positive effects
on sexual limitation (effect size 0.5) and cancer worry (effect size 0.51) [878].
The use of PDE5 inhibitors in penile rehabilitation has been subject to some debate. A single centre,
double blind RCT of 100 men undergoing nerve-sparing surgery reported no benefit of nightly sildenafil (50
mg) compared to on-demand use [405]. However, a multi-centre double blind RCT (n = 423) in men aged <
68 years, with normal pre-treatment erectile function undergoing either open, conventional or robot assisted
laparoscopic nerve-sparing RP, Tadalafil (5 mg) once per day improved participants EPIC sexual domain-scores
(least squares mean difference +9.6: 95% CI: 3.1-16.0) when compared to 20 mg ‘on demand’ or placebo at
nine months of follow-up [406]. Therefore, based on discordant results, no clear recommendation is possible,
even if a trend exists for early use of PDE5 inhibitors after RP for penile rehabilitation. A detailed discussion can
be found in the EAU Male Sexual Dysfunction Guidelines [879].
Recommendations LE GR
Offer men on androgen deprivation therapy, twelve weeks of supervised (by trained exercise 1a A
specialists) combined aerobic and resistance exercise.
Offer men with T1-T3 disease specialist nurse led, multi-disciplinary rehabilitation based on the 1b A
patients’ personal goals addressing incontinence, sexuality, depression and fear of recurrence,
social support and positive lifestyle changes after any radical treatment.
9. REFERENCES
1. Mottet, N., et al. EAU-ESTRO-SIOG Guidelines on Prostate Cancer. Part 1: Screening, Diagnosis,
and Local Treatment with Curative Intent. Eur Urol, 2016.
https://www.ncbi.nlm.nih.gov/pubmed/27568654
2. Cornford, P., et al. EAU-ESTRO-SIOG Guidelines on Prostate Cancer. Part II: Treatment of
Relapsing, Metastatic, and Castration-Resistant Prostate Cancer. Eur Urol, 2016.
https://www.ncbi.nlm.nih.gov/pubmed/27591931
3. Moldovan P., et al. What is the performance of prostate pre-biopsy multi parametric MRI in
predicting prostate biopsy results?. PROSPERO International prospective register of systematic
reviews, 2015.
http://www.crd.york.ac.uk/PROSPERO/display_record.asp?ID=CRD42015021929
4. Fossati, N., et al. The Benefits and Harms of Different Extents of Lymph Node Dissection During
Radical Prostatectomy for Prostate Cancer: A Systematic Review. Eur Urol, 2017.
https://www.ncbi.nlm.nih.gov/pubmed/28126351
5. Phillips, B., et al. Oxford Centre for Evidence-based Medicine Levels of Evidence. Updated by
Jeremy Howick March 2009.
http://www.cebm.net/oxford-centre-evidence-based-medicine-levels-evidence-march-2009/
6. Van den Broeck T., et al. How does biochemical recurrence following curative treatment for prostate
cancer impact on overall survival, cancer-specific survival and development of metastatic disease?.
PROSPERO International prospective register of systematic reviews, 2015.
http://www.crd.york.ac.uk/PROSPERO/display_record.asp?ID=CRD42015026807
7. Ferlay, J., et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in
GLOBOCAN 2012. Int J Cancer, 2015. 136: E359.
https://www.ncbi.nlm.nih.gov/pubmed/25220842
8. Haas, G.P., et al. The worldwide epidemiology of prostate cancer: perspectives from autopsy
studies. Can J Urol, 2008. 15: 3866.
https://www.ncbi.nlm.nih.gov/pubmed/18304396
9. Bell, K.J., et al. Prevalence of incidental prostate cancer: A systematic review of autopsy studies. Int
J Cancer, 2015. 137: 1749.
https://www.ncbi.nlm.nih.gov/pubmed/25821151
10. Jansson, K.F., et al. Concordance of tumor differentiation among brothers with prostate cancer. Eur
Urol, 2012. 62: 656.
https://www.ncbi.nlm.nih.gov/pubmed/22386193
11. Hemminki, K. Familial risk and familial survival in prostate cancer. World J Urol, 2012. 30: 143.
https://www.ncbi.nlm.nih.gov/pubmed/16455635
259. Briganti, A., et al. When to perform bone scan in patients with newly diagnosed prostate cancer:
external validation of the currently available guidelines and proposal of a novel risk stratification tool.
Eur Urol, 2010. 57: 551.
https://www.ncbi.nlm.nih.gov/pubmed/20034730
260. O’Sullivan, J.M., et al. Broadening the criteria for avoiding staging bone scans in prostate cancer: a
retrospective study of patients at the Royal Marsden Hospital. BJU Int, 2003. 92: 685.
https://www.ncbi.nlm.nih.gov/pubmed/14616446
261. Ayyathurai, R., et al. A study on staging bone scans in newly diagnosed prostate cancer. Urol Int,
2006. 76: 209.
https://www.ncbi.nlm.nih.gov/pubmed/16601380
262. Tateishi, U., et al. A meta-analysis of (18)F-Fluoride positron emission tomography for assessment of
metastatic bone tumor. Ann Nucl Med, 2010. 24: 523.
https://www.ncbi.nlm.nih.gov/pubmed/20559896
263. Evangelista, L., et al. Diagnostic imaging to detect and evaluate response to therapy in bone
metastases from prostate cancer: current modalities and new horizons. Eur J Nucl Med Mol
Imaging, 2016. 43: 1546.
https://www.ncbi.nlm.nih.gov/pubmed/26956538
264. Picchio, M., et al. [11C]Choline PET/CT detection of bone metastases in patients with PSA
progression after primary treatment for prostate cancer: comparison with bone scintigraphy. Eur J
Nucl Med Mol Imaging, 2012. 39: 13.
https://www.ncbi.nlm.nih.gov/pubmed/21932120
55: 223.
https://www.ncbi.nlm.nih.gov/pubmed/24434294
655. van Leeuwen, P.J., et al. (68) Ga-PSMA has a high detection rate of prostate cancer recurrence
outside the prostatic fossa in patients being considered for salvage radiation treatment. BJU Int,
2016. 117: 732.
https://www.ncbi.nlm.nih.gov/pubmed/26683282
https://www.ncbi.nlm.nih.gov/pubmed/25150640
731. Suardi, N., et al. Long-term outcomes of salvage lymph node dissection for clinically recurrent
prostate cancer: results of a single-institution series with a minimum follow-up of 5 years. Eur Urol,
2015. 67: 299.
https://www.ncbi.nlm.nih.gov/pubmed/24571959
732. Tilki, D., et al. Salvage lymph node dissection for nodal recurrence of prostate cancer after radical
prostatectomy. J Urol, 2015. 193: 484.
https://www.ncbi.nlm.nih.gov/pubmed/25180792
733. Rigatti, P., et al. Pelvic/retroperitoneal salvage lymph node dissection for patients treated with
radical prostatectomy with biochemical recurrence and nodal recurrence detected by [11C]choline
positron emission tomography/computed tomography. Eur Urol, 2011. 60: 935.
https://www.ncbi.nlm.nih.gov/pubmed/21840116
734. Rischke, H.C., et al. Adjuvant radiotherapy after salvage lymph node dissection because of nodal
relapse of prostate cancer versus salvage lymph node dissection only. Strahlenther Onkol, 2015.
191: 310.
https://www.ncbi.nlm.nih.gov/pubmed/25326142
735. Ploussard, G., et al. Management of Node Only Recurrence after Primary Local Treatment for
Prostate Cancer: A Systematic Review of the Literature. J Urol, 2015. 194: 983.
https://www.ncbi.nlm.nih.gov/pubmed/25963190
736. Eisenhauer, E.A., et al. New response evaluation criteria in solid tumours: revised RECIST guideline
(version 1.1). Eur J Cancer, 2009. 45: 228.
https://www.ncbi.nlm.nih.gov/pubmed/19097774
737. Smith, M.R., et al. Natural history of rising serum prostate-specific antigen in men with castrate
nonmetastatic prostate cancer. J Clin Oncol, 2005. 23: 2918.
https://www.ncbi.nlm.nih.gov/pubmed/15860850
738. Smith, M.R., et al. Disease and host characteristics as predictors of time to first bone metastasis
and death in men with progressive castration-resistant nonmetastatic prostate cancer. Cancer,
2011. 117: 2077.
https://www.ncbi.nlm.nih.gov/pubmed/21523719
739. Crawford, E.D., et al. Challenges and recommendations for early identification of metastatic disease
in prostate cancer. Urology, 2014. 83: 664.
https://www.ncbi.nlm.nih.gov/pubmed/24411213
740. Hussain, M., et al. Effects of continued androgen-deprivation therapy and other prognostic factors
on response and survival in phase II chemotherapy trials for hormone-refractory prostate cancer: a
Southwest Oncology Group report. J Clin Oncol, 1994. 12: 1868.
https://www.ncbi.nlm.nih.gov/pubmed/8083710
741. Taylor, C.D., et al. Importance of continued testicular suppression in hormone-refractory prostate
cancer. J Clin Oncol, 1993. 11: 2167.
https://www.ncbi.nlm.nih.gov/pubmed/8229130
742. Scher, H.I., et al. Design and end points of clinical trials for patients with progressive prostate cancer
and castrate levels of testosterone: recommendations of the Prostate Cancer Clinical Trials Working
Group. J Clin Oncol, 2008. 26: 1148.
https://www.ncbi.nlm.nih.gov/pubmed/18309951
743. Tannock, I.F., et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced
prostate cancer. N Engl J Med, 2004. 351: 1502.
https://www.ncbi.nlm.nih.gov/pubmed/15470213
2. METHODS 7
2.1 Data identification 7
2.2 Review 8
2.3 Future goals 8
5. DIAGNOSTIC EVALUATION 15
5.1 Symptoms 15
5.1.1 Physical examination 15
5.1.2 Laboratory findings 15
5.2 Imaging investigations 15
5.2.1 Presence of enhancement 15
5.2.2 Computed tomography or magnetic resonance imaging 15
5.2.3 Other investigations 16
5.2.4 Radiographic investigations to evaluate RCC metastases 16
5.2.5 Bosniak classification of renal cystic masses 16
5.3 Renal tumour biopsy 16
5.4 Summary of evidence and recommendations for the
diagnostic assessment of renal cell cancer 17
6. PROGNOSTIC FACTORS 18
6.1 Classification 18
6.2 Anatomical factors 18
6.3 Histological factors 18
6.4 Clinical factors 19
6.5 Molecular factors 19
6.6 Prognostic systems and nomograms 20
6.7 Summary of evidence and recommendations for prognostic factors 20
8. FOLLOW-UP IN RCC 41
8.1 Introduction 41
8.2 Which investigations for which patients, and when? 41
8.3 Summary of evidence and recommendations for surveillance
following RN or PN or ablative therapies in RCC 42
8.4 Research priorities 42
9. REFERENCES 43
Acknowledgement
The RCC Guidelines Panel is most grateful for the methodological and scientific support provided by Prof.
Dr. O. Hes (pathologist, Pilzen, Czech Republic) for two sections of this document: Histological diagnosis and
Other renal tumours.
New data and recommendations have been included in the following sections:
5.4 S
ummary of evidence and recommendations for the diagnostic assessment of renal cell
cancer
Summary of evidence LE
Contrast enhanced multi-phasic CT has a high sensitivity and specificity for characterisation 2
and detection of RCC, invasion, tumour thrombus and metastatic RCC.
MRI has a slightly higher sensitivity and specificity for small renal masses and tumour 2
thrombus as compared to CT.
CEUS has a high sensitivity and specificity for characterisation of renal masses. 2
US, Power-Doppler US and PET-CT have a low sensitivity and specificity for detection and 2
characterisation of RCC.
Summary of evidence LE
Adjuvant cytokines do not improve survival after nephrectomy. 1b
Adjuvant sunitinib improved disease-free survival in one of the two available studies, but not 1b
overall survival, after nephrectomy in selected high-risk patients.
Recommendations grade
Do not offer adjuvant therapy with sorafenib. strong ↓↓
Do not offer adjuvant sunitinib following surgically resected high-risk clear-cell renal weak ↓
cell cancer.
Recommendation grade
Consider local therapy for metastatic disease (including metastasectomy) in patients weak ↑
with a favourable risk profile in whom complete resection is achievable or when
local symptoms need to be controlled.
7.4.1.1 Summary of evidence and recommendation for systemic therapy for advanced/metastatic renal cell cancer
Summary of evidence LE
In metastatic RCC, 5-FU combined with immunotherapy has equivalent efficacy to INF-α. 1b
In metastatic RCC, chemotherapy is otherwise not effective with the exception of gemcitabine 3
and doxorubicine in sarcomatoid and rapidly progressive disease.
Recommendations grade
Do not offer chemotherapy as first-line therapy in patients with metastatic clear-cell strong ↓↓
renal cell cancer (RCC).
Consider offering a combination of gemcitabine and doxorubicin to patients with weak ↑
sarcomatoid or rapidly progressive RCC.
7.4.6.3 Summary of evidence and recommendations for systemic therapy in metastatic renal cell cancer
Summary of evidence LE
First line pazopanib is not inferior to sunitinib in clear-cell mRCC patients. 1b
Cabozantinib is superior to everolimus in terms of PFS and OS in patients failing one or more 1b
lines of VEGF-targeted therapy.
Everolimus prolongs PFS in patients who have previously failed or are intolerant of VEGF- 1b
targeted therapy when compared to placebo.
No combination has proven to be better than single-agent therapy, with the exception of the 1a
combination of lenvatinib plus everolimus.
2. METHODS
2.1 Data identification
For the 2017 Guidelines, new and relevant evidence has been identified, collated and appraised through a
structured assessment of the literature for the chapters as listed in Table 2.1.
A broad and comprehensive scoping exercise was performed. The search was limited to studies
representing high levels of evidence (i.e. systematic reviews [SRs] with meta-analysis [MA], randomised
controlled trials (RCTs), and prospective non-randomised comparative studies only) published in the English
language. The search was restricted to articles published between July 30th 2015 and June 30th 2016.
Databases covered included Medline, EMBASE, and the Cochrane Library. A total of 1,602 unique records
were identified, retrieved and screened for relevance. A search strategy is published online: https://uroweb.org/
guideline/renal-cell-carcinoma/?type=appendices-publications.
Specific chapters were updated by way of SRs, commissioned and undertaken by the panel in conjunction
with the EAU Guidelines Office, based on topics or questions prioritised by the Guidelines Panel. These reviews
were performed using standard Cochrane SR methodology http://www.cochranelibrary.com/about/about-
cochranesystematic-reviews.html.
A list of Associations endorsing the EAU Guidelines can also be viewed online at the above address.
The EAU Guidelines Office are in the process of introducing modified GRADE methodology accross all 20
guidelines [3, 4]. This will be a phased introduction, with the RCC Guidelines Panel already incorporating these
changes in their 2017 Guidelines print.
The Summary of Evidence (SOE) tables provided for each recommendation within the guidelines address a
number of key elements:
1. the overall quality of the evidence which exists for the recommendation;
2. the magnitude of the effect (individual or combined effects);
3. the certainty of the results (precision, consistency, heterogeneity and other statistical or
study related factors);
4. the balance between desirable and undesirable outcomes;
5. the impact of patient values and preferences on the intervention;
6. the certainty of those patient values and preferences.
These key elements are the basis which panels use to define the strength of each recommendation. The
strength of each recommendation is represented by the words ‘strong’ or ‘weak’ and is directional, either ‘do
it’ (as represented by arrows pointing upwards) or ‘do not do it’ (arrows pointing downwards) [5]. The strength
of each recommendation is determined by the balance between desirable and undesirable consequences of
alternative management strategies, the quality of the evidence (including certainty of estimates), and nature
and variability of patient values and preferences. The SOE tables will be posted online for consultation.
The findings of a number of SR topics have been incorporated in this 2017 update:
• Imaging in Suspected Renal Cell Carcinoma: A Systematic Review [6]
• What is the best surgical treatment option for clinical > T2, N0M0 tumours? What is the best way of
performing this procedure? [7];
• A Systematic Review and Meta-analysis Comparing the Effectiveness and Adverse Effects of Different
Systemic Treatments for Non-clear Cell Renal Cell Carcinoma [8].
2.2 Review
Chapter 7 ‘Disease management’ was peer reviewed prior to publication. Publications ensuing from SRs have
all been peer reviewed. The other sections of the RCC Guidelines were peer reviewed prior to publication in
2015.
The use of clinical quality indicators is an area of interest for the RCC Panel. A number of key quality indicators
for this patient group have been selected:
• thorax computed tomography (CT) for staging of pulmonary metastasis;
• proportion of patients with T1aN0M0 tumours undergoing nephron-sparing surgery as first treatment;
• the proportion of patients treated within six weeks after diagnosis;
• the proportion of patients with metastatic RCC offered treatment with targeting agents;
• proportion of patients who undergo minimally invasive or operative treatment as first treatment who die
within 30 days;
Panel members have set up a database to capture current practice of follow-up of RCC patients in a number of
European Centres. Assessing patterns of recurrence and use of imaging techniques are primary outcomes for
this project.
The results of ongoing and new SRs will be included in the 2018 update of the RCC Guidelines.
Summary of evidence LE
Several verified risk factors have been identified including smoking, obesity and hypertension. These 2a
are considered definite risk factors for RCC.
Recommendation grade
For the most important primary prevention of RCC, eliminate cigarette smoking and reduce strong ↑↑
weight.
Histological diagnosis includes, besides RCC type; evaluation of nuclear grade, sarcomatoid features, vascular
invasion, tumour necrosis, and invasion of the collecting system and peri-renal fat, pT or even pN categories.
The four-tiered WHO/ISUP (International Society of Urological Pathology) grading system has replaced the
Fuhrman grading system [32, 33].
3.3.1 Carcinoma associated with end-stage renal disease; acquired cystic disease-associated RCC
Cystic degenerative changes (acquired cystic kidney disease [ACKD]) and a higher incidence of RCC are
typical features of ESKD (end-stage kidney disease). Renal cell cancers of native end-stage kidneys are
found in about 4% of patients. Their lifetime risk of developing RCCs is at least ten times higher than in the
general population. Compared with sporadic RCCs, RCCs associated with ESKD are generally multicentric
and bilateral, found in younger patients (mostly male), and are less aggressive [44, 45]. The relatively indolent
outcome of tumours in ESKD is due to the mode of diagnosis and a specific ACKD-related molecular pathway
which has still to be determined [45]. Although the histological spectrum of ESKD tumours is similar to that of
sporadic RCC, the predominant form is pRCC. The remaining tumours are mostly ccRCC [44-46]. A specific
subtype of RCC occurring only in end-stage kidneys has been described as Acquired Cystic Disease-
associated RCC (ACD-RCC) [47] with indolent clinical behaviour, likely due to early detection in patients with
ESKD on periodic follow-up [33].
Patients with hereditary kidney cancer syndromes may require repeated surgical interventions [52, 53].
Appropriately timed nephron-sparing approaches are recommended with the exception of Hereditary
Leiomyomatosis and RCC (HLRCC) and succinate dehydrogenase (SDH) syndromes, for which surveillance
is recommended until the largest solid tumour reaches 3 cm in diameter, to reduce interventions [54]. Active
3.3.4 Angiomyolipoma
Angiomyolipoma (AML) is a benign mesenchymal tumour, which can occur sporadically, and is four times more
common in females [57]. Angiomyolipoma also occurs in tuberous sclerosis and accounts for approximately
1% of surgically removed tumours. Ultrasound, CT, and magnetic resonance imaging (MRI) often lead to
diagnosis due to the presence of adipose tissue. Biopsy is rarely useful. Pre-operatively, it may be difficult
to differentiate between smooth muscle cell tumours and epithelial tumours. Angiomyolipoma can be
found in tuberous sclerosis in lymph nodes (LNs), but it is not metastasis, and has a multicentric genesis.
Angiomyolipoma can be due to angiotrophic-type growth extending into the renal vein or the inferior vena cava.
Angiomyolipoma with LN involvement and tumorous thrombus is benign. Only epithelioid AML is potentially
malignant [48, 58]. Angiomyolipoma has a slow and consistent growth rate, and minimal morbidity [59]. The
main complications of renal AML are retroperitoneal bleeding or bleeding into the urinary collection system,
which can be life-threatening [60]. The bleeding tendency is related to the angiogenic component of the tumour
that includes irregular and aneurysmatic blood vessels [60]. The major risk factors for bleeding are tumour
size, grade of the angiogenic component, and the presence of tuberous sclerosis [60, 61]. Indications for
intervention are pain, bleeding, or suspected malignancy.
3.3.4.1 Treatment
Active surveillance (AS) is the most appropriate option for most AMLs [57, 59, 62] (LE: 3). Risk factors
for delayed intervention include tumour size > 4 cm and symptoms at diagnosis [62]. Selective arterial
embolisation (SAE) seems to be the first-line option used for active treatment after AS is discontinued [62]
(LE: 3). Selective arterial embolisation is an efficient treatment for AML devascularisation, but only for volume
reduction [63].
Although SAE controls haemorrhage in the acute setting, it has limited value long-term [64, 65].
If surgery is selected, most cases of AML can be managed by conservative nephron-sparing surgery (NSS),
although some patients may require complete nephrectomy [61] (LE: 3). Radiofrequency ablation (RFA) can
be an option as well [59, 60, 66]. The volume of AML can be reduced by the mammalian target of rapamycin
(mTOR) inhibitor everolimus [67]. A clinical phase II trial and its open-label extension of medical management
with everolimus in AMLs not requiring surgical intervention, showed a response rate of 81.6 (64.5%) (> 50% or
30% tumour volume reduction) by week 96, confirming the long-term safety profile of everolimus [67]. Sirolimus
can be combined with deferred surgery [68].
3.3.4.2 Summary
A variety of renal tumours exist, and about 15% are benign. All kidney lesions require examination for malignant
behaviour.
3.4 Summary of evidence and recommendations for the management of other renal
tumours
Recommendations grade
Treat Bosniak type III or IV cysts the same as RCC. strong ↑↑
Treat angiomyolipoma (AML) with selective arterial embolisation or nephron-sparing surgery, weak ↑
in:
• large tumours (a recommended threshold of intervention does not exist, the formerly
recommended size of > 4 cm wide is disputed);
• females of childbearing age;
• patients in whom follow-up or access to emergency care may be inadequate.
Treat AMLs that are not candidates for active treatment with active surveillance. weak ↑
In AML > 3 cm not requiring surgical intervention, medical treatment with everolimus can be weak ↑
considered.
Offer active surveillance to patients with biopsy-proven oncocytomas. weak ↑
For advanced uncommon renal tumours, develop individualised oncological treatment plans strong ↑↑
for each patient.
T - Primary Tumour
TX Primary tumour cannot be assessed
T0 No evidence of primary tumour
T1 Tumour < 7 cm or less in greatest dimension, limited to the kidney
T1a Tumour < 4 cm or less
T1b Tumour > 4 cm but < 7 cm
T2 Tumour > 7 cm in greatest dimension, limited to the kidney
T2a Tumour > 7 cm but < 10 cm
T2b Tumours > 10 cm, limited to the kidney
T3 Tumour extends into major veins or perinephric tissues but not into the ipsilateral adrenal gland and
not beyond Gerota fascia
T3a Tumour grossly extends into the renal vein or its segmental (muscle-containing) branches,
or tumour invades perirenal and/or renal sinus fat (peripelvic fat), but not beyond Gerota
fascia
T3b Tumour grossly extends into the vena cava below diaphragm
T3c Tumour grossly extends into vena cava above the diaphragm or invades the wall of the vena
cava
T4 Tumour invades beyond Gerota fascia (including contiguous extension into the ipsilateral adrenal
gland)
N - Regional Lymph Nodes
NX Regional lymph nodes cannot be assessed
N0 No regional lymph node metastasis
N1 Metastasis in regional lymph node(s)
M - Distant Metastasis
M0 No distant metastasis
M1 Distant metastasis
TNM stage grouping
Stage I T1 N0 M0
Stage II T2 N0 M0
Stage III T3 N0 M0
T1, T2, T3 N1 M0
Stage IV T4 Any N M0
Any T Any N M1
A help desk for specific questions about TNM classification is available at http://www.uicc.org/tnm.
Split renal function should be estimated using renal scintigraphy in the following situations [97, 98] (LE: 2b):
• when renal function is compromised, as indicated by increased serum creatinine or significantly
decreased GFR;
• when renal function is clinically important - e.g., in patients with a solitary kidney or multiple or bilateral
tumours.
Renal scintigraphy is an additional diagnostic option in patients at risk of future renal impairment due to
comorbid disorders.
Abdominal contrast-enhanced CT angiography is useful in selected cases for detailed information on renal
vascular supply [109, 110].
If the results of CT are indeterminate, contrast enhanced ultrasound (CEUS) is a valuable alternative
to further characterise renal lesions [6] (LE: 1b).
Renal biopsy is not indicated for comorbid and frail patients who can be considered only for conservative
management (watchful waiting) regardless of biopsy results. Due to the high diagnostic accuracy of abdominal
imaging, renal tumour biopsy is not necessary in patients with a contrast-enhancing renal mass for whom
surgery is planned (LE: 4).
Percutaneous sampling can be performed under local anaesthesia with needle core biopsy and/or fine needle
5.4 Summary of evidence and recommendations for the diagnostic assessment of renal
cell cancer
Summary of evidence LE
Contrast enhanced multi-phasic CT has a high sensitivity and specificity for characterisation and 2
detection of RCC, invasion, tumour thrombus and metastatic RCC.
MRI has a slightly higher sensitivity and specificity for small renal masses and tumour thrombus as 2
compared to CT.
CEUS has a high sensitivity and specificity for characterisation of renal masses. 2
US, Power-Doppler US and PET-CT have a low sensitivity and specificity for detection and 2
characterisation of RCC.
6. PROGNOSTIC FACTORS
6.1 Classification
Prognostic factors can be classified into: anatomical, histological, clinical, and molecular.
Table 6.1: Basic characteristics of three main types of RCC [35, 36, 154]
In all RCC types, prognosis worsens with stage and histopathological grade (Tables 6.2 and 6.3). The five-year
overall survival (OS) for all types of RCC is 49%, which has improved since 2006 probably due to an increase
in incidentally detected RCCs and the introduction of tyrosine kinase inhibitors (TKIs) [156, 157]. Sarcomatoid
changes can be found in all RCC types and are equivalent to high grade and very aggressive tumours.
T1N0M0 Referent
T2N0M0 2.71 (2.17-3.39)
T3N0M0 5.20 (4.36-6.21)
T4N0M0 16.88 (12.40-22.98)
N+M0 16.33 (12.89-20.73)
M+ 33.23 (28.18-39.18)
Grade 1 Referent
Grade 2 1.16 (0.94-1.42)
Grade 3 1.97 (1.60-2.43)
Grade 4 2.82 (2.08-3.31)
CI = confidential interval. HR = hazard ratio.
Long-term survival in RCC patients treated by RN or PN between 1970 and 2003; for unilateral, sporadic
ccRCC, pRCC or chRCC in a cohort study [154] (Table 6.3).
Table 6.3: C
ancer-specific survival of surgically treated patients by RCC type (estimated survival rate in
percentage [95% CI])
Survival time 5 years (%) 10 years (%) 15 years (%) 20 years (%)
clear-cell RCC 71 (69-73) 62 (60-64) 56 (53-58) 52 (49-55)
papillary RCC 91 (88-94) 86 (82-89) 85 (81-89) 83 (78-88)
chromophobe RCC 88 (83-94) 86 (80-92) 84 (77-91) 81 (72-90)
Two subgroups of pRCC with different outcomes have been identified [158]. Type 1 have a favourable
prognosis. Type 2 are mostly high-grade tumours with a propensity for metastases (LE: 3). For more details,
see Section 3.2 Histological diagnosis. Renal cell cancer with Xp 11.2 translocation has a poor prognosis
[159]. Its incidence is low, but it should be systematically addressed in young patients. Renal cell cancer type
classification has been confirmed by cytogenetic and genetic analyses [155, 160, 161] (LE: 2b).
The recognition of the potential relevance of immunotherapy as an approach to RCC management is growing.
Prognostic information of cytokines and blockade of immune-inhibitory molecules such as PD-L1 have
shown promising therapeutic results. Emerging evidence of chromosomal alterations, through Genome-Wide
Association Studies (GWAS), miRNA, SNPs and gene methylations all contribute to improving diagnostic
and prognostic information. A number of studies have confirmed prognostic information based on gain
of chromosomal regions 7q, 8q and 20q, and chromosomal losses of regions 9p, 9q and 14q, which are
associated with poor survival. CpG-methylation-based assays also independently predict survival in ccRCC
[177, 178]. An international collaboration is currently investigating GWAS loci for prognostic information.
Summary of evidence LE
In RCC patients, TNM stage, tumour nuclear grade, and RCC subtype provide important prognostic 2
information [22].
Recommendations grade
Use the current Tumour, Node, Metastasis classification system. strong ↑↑
Use grading systems and classify RCC subtype. strong ↑↑
Use prognostic systems in the metastatic setting. strong ↑↑
In localised disease do not routinely use integrated prognostic systems or nomograms for weak ↓
patient selection. Prognostic systems or nomograms can provide a rational for enrolling
patients into clinical trials.
Do not use molecular prognostic markers in routine clinical practice. weak ↓
In patients receiving targeted treatments, use molecular prognostic markers to predict weak ↑
response.
Prognostic Variables
Models
TNM ECOG Karnofsky RCC Fuhrman Tumour Tumour Delay LDH Corrected Haemoglobin Neutrophil Platelet
Stage PS PS related grade necrosis size between calcium count count
symptoms diagnosis
and
treatment
Localised UISS x x x
RCC SSIGN x x x x
Post- x x x x
operative
Karakiewicz’s
nomogram
21
7. DISEASE MANAGEMENT
7.1 Treatment of localised RCC
7.1.1 Introduction
A SR underpins the findings of sections 7.1.2 to 7.2.4.2. The review included all relevant published literature
comparing surgical management of localised RCC (T1-2N0M0) [189, 190]. Randomised or quasi-RCTs were
included. However, due to the very limited number of RCTs, non-randomised studies (NRS), prospective
observational studies with controls, retrospective matched-pair studies, and comparative studies from the
databases of well-defined registries were also included.
When compared with a radical surgical approach, for NSS, several retrospective analyses of large databases
have suggested a decreased cardiac-specific mortality [196, 197] as well as improved OS as compared to
RN. However, in some series this held true only for a younger patient population and/or patients without
significant comorbidity at the time of the surgical intervention [198, 199]. An analysis of the Medicare database
[200] could not demonstrate an OS benefit for patients > 75 years of age when RN or PN were compared with
non-surgical management. Another series that addressed this question and also included Medicare patients
suggested an OS benefit in an older RCC patient population (75-80 years) when subjected to surgery rather
than non-surgical management. Shuch et al. compared patients subjected to PN for RCC with a non-cancer,
healthy control group via a retrospective database analysis, showing an OS benefit for the cancer cohort, [201].
These conflicting results indicate that unknown statistical confounders hamper the retrospective analysis of
population-based tumour registries.
In contrast, the only prospectively randomised but prematurely closed and heavily underpowered,
trial available so far did not demonstrate an inferiority of RN vs. PN in terms of OS. Taken together, the OS
advantage suggested for PN vs. RN remains an unresolved issue.
It has been suggested that the more pronounced deterioration of renal function after RN negatively affects
patients´ OS [98, 202]. Patients with a normal pre-operative renal function and a decreased GFR due to surgical
treatment, generally present with a stable renal function longer term [203]. In contrast, adverse OS in patients
with a pre-existing GFR reduction does not seem to result from further renal function impairment following
surgery, but rather from other medical comorbidities causing pre-surgical CKD. However, in particular in
patients with pre-existing CKD, PN is the treatment of choice to limit the risk of development of ESKD which
requires haemodialysis.
Only a limited number of studies are available addressing quality of life (QoL) following PN vs. RN irrespective
of the surgical approach used (open- vs. minimally invasive). Quality of life was ranked higher following PN as
compared to RN, but in general, patients’ health status deteriorated following both approaches [191, 192, 194,
204-208].
In terms of the intra- and peri-operative morbidity/complications associated with PN vs. RN, there was no
difference in the length of hospital stay [192, 193, 207], the number of red blood cell (RBC) units applied [192,
207, 208], or the mean intra-operative blood loss [192, 207]. Complication rates were inconsistently reported
and one intervention was not favoured over another [209]. One study indicated a longer operation time for open
PN [209], but this was not confirmed by others [210].
In view of the above and since oncological safety (CSS and FS) of PN has been proven to be similar for RN,
PN is the treatment of choice for T1b RCC since it preserves kidney function better and in the long term limits
development of metabolic as well as cardiovascular disorders. Whether decreased mortality from any cause
can be attributed to PN is still unresolved, but in patients with pre-existing CKD, PN is the preferred surgical
treatment option as it avoids further deterioration of kidney function, the latter being associated with a higher
risk of development of ESKD and the need for haemodialysis.
In these situations the curative therapy is RN including removal of the tumour-bearing kidney. Complete
resection of the primary tumour by open- or laparoscopic surgery offers a reasonable chance of cure.
7.1.2.2.2 Lymph node dissection for clinically negative lymph nodes (cN0)
The indication for lymph node dissection (LND) together with PN or RN is still controversial [212]. The clinical
assessment of LN status is based on the detection of an enlargement of LNs; either by CT/MRI or the intra-
operative palpability of enlarged nodes. Less than 20% of suspected metastatic nodes (cN+) are positive for
metastatic disease at histopathological examination (pN+) [213]. Both CT and MRI are unsuitable for detecting
malignant disease in nodes of normal shape and size [214]. For clinically positive LNs (cN+) see Section 7.2.2.
For patients with clinically negative LNs (cN0) six clinical trials have evaluated the clinical value of
LND [212], the latter including one RCT [213] and five comparative studies [215-219].
Smaller retrospective studies have suggested a clinical benefit associated with a more or less extensive
lymphadenectomy preferably in patients at high risk for lymphogenic spread. The number of LN metastases
(< / > 4) as well as the intra– and extracapsular extension of intranodal metastasis correlated with the patients´
clinical prognosis in some studies [214, 220-222]. Better survival outcomes were seen in patients with a low
number of positive LNs (< 4) and no extranodal extension. On the basis of a retrospective SEER database
analysis of > 9,000 patients no effects of an extended LND on the disease-specific survival (DSS) of patients
with pathologically confined negative nodes was demonstrated [223]. However, in patients with pathologically
proven lymphogenic spread (pN+), an increase of ten for the number of nodes dissected resulted in a 10%
absolute increase in DSS. In addition, in a larger cohort of 1,983 patients Capitano et al. demonstrated that
extended LND results in a significant prolongation of CSS in patients with unfavourable prognostic features
(e.g., sarcomatoid differentiation, large tumour size) [224].
Only one prospective RCT evaluating the clinical value of LND combined with surgical treatment of primary
RCC has been published so far. With an incidence of only 4%, lymphatic spread appears to be very low.
Recognising the latter, only a staging effect was attributed to a (super)extended LND [213]. This trial included
a very high percentage of patients with pT2 tumours, which are not at increased risk for LN metastases.
Additionally, only 25% of patients with pT3 tumours were subjected to a complete LND. The LN template used
by the authors was also not clearly stated.
The most optimal surgical approach remains controversial. Retrospective studies suggest that an extended
LND should involve the LNs surrounding the ipsilateral great vessel and the inter-aortocaval region from the
crus of the diaphragm to the common iliac artery. Involvement of inter-aortocaval LNs without regional hilar
involvement is reported in up to 35-45% of cases [214, 215, 225]. At least fifteen LNs should be removed [224,
226]. Sentinel LND is an investigational technique [227, 228].
7.1.2.2.3 Embolisation
Before routine nephrectomy, tumour embolisation has no benefit [229, 230]. In patients unfit for surgery, or
with non-resectable disease, embolisation can control symptoms, including visible haematuria or flank pain
[231-233]. These indications will be repeated in Sections 7.2 and 7.3 with cross reference to the summary of
evidence and recommendations below.
Summary of evidence LE
The oncological outcome in terms of DSS following PN equals that of a radical approach in patients 1b
with c/p T1 RCC.
Ipsilateral adrenalectomy, in the absence of clinical evident adrenal involvement during RN or PN, has 3
no survival advantage.
In patients with localised disease without evidence of lymph node metastases, a survival advantage of 1b
LND in conjunction with RN is not demonstrated in randomised trials.
In patients unfit for surgery with massive haematuria or flank pain, embolisation can be a beneficial 3
palliative approach.
Recommendations grade
Offer surgery to achieve cure in localised renal cell cancer. strong ↑↑
Offer partial nephrectomy to patients with T1 tumours. strong ↑↑
Do not perform ipsilateral adrenalectomy if there is no clinical evidence of invasion of the strong ↓↓
adrenal gland.
Consider an extended lymph node dissection in patients with adverse clinical features weak ↑
including a large diameter of the primary tumour or sarcomatoid histological features.
Hand-assisted laparoscopic PN (HALPN) is rarely performed. A recent comparative study of open vs. HALPN
showed no difference in OS or RFS at intermediate-term follow-up. The authors observed a lower rate of intra-
operative and all-grade post-operative 30-day complications in HALPN than in open PN patients, but there
was no significant difference in high Clavien Grade complications. Glomerular filtration rate three months after
operation was lower in the HALPN than in the open PN group [258].
The feasibility of off-clamp laparoscopic PN and laparo-endoscopic single-site PN has been shown in selected
patients but larger studies are needed to confirm their safety and clinical role [259, 260].
At present, the oncological outcomes of robot-assisted vs. laparoscopic or open PN have been compared only
in studies with short-term follow-up. One recent study prospectively compared the peri-operative outcomes of
a series of robot-assisted and open PN performed by the same experienced surgeon. Robot-assisted PN was
superior to open PN in terms of lower estimated blood loss and shorter hospital stay. Warm ischaemia time,
operative time, immediate- early- and short-term complications, variation of creatinine levels, and pathologic
margins were similar among the groups [261].
A recent meta-analysis, including a series of NSS, with variable methodological quality compared the peri-
operative outcomes of robot-assisted and laparoscopic PN. The robotic group had a significantly lower rate of
conversion to open surgery and to radical surgery, shorter warm ischaemia time, smaller change in estimated
GFR after surgery and shorter length of stay. No significant difference was observed between the two groups
regarding complications, change of serum creatinine after surgery, operative time, estimated blood loss and
positive surgical margins (PSMs) [262].
Summary of evidence LE
Laparoscopic radical nephrectomy has lower morbidity than open surgery. 1b
Oncological outcomes for T1-T2a tumours are equivalent between laparoscopic and open radical 2a
nephrectomy.
Partial nephrectomy can be performed, either with an open, pure laparoscopic or robot-assisted 2b
approach, based on surgeon’s expertise and skills.
Partial nephrectomy is associated with a higher percentage of positive surgical margins compared 3
with radical nephrectomy.
Recommendations grade
Offer laparoscopic radical nephrectomy to patients with T2 tumours and localised masses not strong ↑↑
treatable by partial nephrectomy.
Do not perform radical nephrectomy in patients with T1 tumours for whom partial strong ↓↓
nephrectomy is indicated.
7.1.4.2 Surveillance
Elderly and comorbid patients with incidental small renal masses have a low RCC-specific mortality and
significant competing-cause mortality [276, 277]. Active surveillance is defined as the initial monitoring of
tumour size by serial abdominal imaging (US, CT, or MRI) with delayed intervention reserved for tumours
showing clinical progression during follow-up [278]. The concept of AS differs from the concept of watchful
waiting. Watchful waiting is reserved for patients whose comorbidities contraindicate any subsequent active
treatment and do not require follow-up imaging, unless clinically indicated.
In the largest reported series of AS, the growth of renal tumours was low and progression to
metastatic disease was reported in only a limited number of patients [279, 280].
A single-institutional comparative study evaluating patients aged > 75 years showed decreased
OS for those who underwent surveillance and nephrectomy relative to NSS for clinically T1 renal tumours.
However, patients selected for surveillance were older with greater comorbidity. At multi-variate analysis,
management type was not associated with OS after adjusting for age, comorbidity, and other variables [276].
No statistically significant difference in OS and CSS were observed in another study of RN vs. PN vs. AS for
T1a renal masses with a follow-up of 34 months [281].
The initial results of the multi-institutional Delayed Intervention and Surveillance for Small Renal
Masses (DISSRM) registry were recently published. This prospective, NRS enrolled 497 patients with solid
renal masses < 4 cm in size who chose AS or primary active intervention. Patients who selected AS were older,
had worse ECOG scores, more comorbidities, smaller tumours, and more often multiple and bilateral lesions.
Overall survival for primary intervention and AS was 98% and 96% at two years, and 92% and 75% at five
years, respectively (p = 0.06). At five years, CSS was 99% and 100%, respectively (p = 0.3). Active surveillance
was not predictive of OS or CSS in regression modelling with relatively short follow up [282].
Overall, both short- and intermediate-term oncological outcomes indicate that in selected patients
with advanced age and/or comorbidities, AS is appropriate to initially monitor small renal masses, followed, if
required, by treatment for progression [278-280, 283-286].
A multicentre study assessed QoL of patients undergoing immediate intervention vs. AS. Patients
undergoing immediate intervention had higher QoL scores at baseline, specifically for physical health. The
perceived benefit in physical health persisted for at least one year following intervention. Mental health, which
includes domains of depression and anxiety, was not adversely affected while on AS [287].
A recent study compared 1,057 patients treated by PN to 180 treated by RFA and 187 treated by cryoablation
for a cT1 tumour and found no difference regarding RFS between the three techniques. Metastasis-free survival
was superior after PN and cryoablation compared to RFA for cT1a patients. However, follow-up of patients
treated by thermal ablations was shorter [198].
7.1.4.3.7 Summary of evidence and recommendation for therapeutic approaches as alternative to surgery
Summary of evidence LE
Most population-based analyses show a significantly lower cancer-specific mortality for patients 3
treated with surgery compared to non-surgical management.
In active surveillance cohorts, the growth of small renal masses is low in most cases and progression 3
to metastatic disease is rare (1-2%).
Quality of the available data does not allow definitive conclusions regarding morbidity and oncological 3
outcomes of cryoablation and radiofrequency ablation.
Low quality studies suggest a higher local recurrence rate for thermal ablation therapies compared to 3
partial nephrectomy.
7.2.4.1 The evidence base for surgery in patients with venous tumour thrombus
The data on whether patients with venous tumour thrombus should undergo surgery is derived from case
series. In one of the largest published studies [313] a higher level of thrombus was not associated with
increased tumour dissemination to LNs, perinephric fat or distant metastasis. Thus, all patients with non-
metastatic disease and venous tumour thrombus, and an acceptable PS, should be considered for surgical
intervention, irrespective of the extent of tumour thrombus at presentation (LE: 3). The surgical technique and
approach for each case should be selected based on the extent of tumour thrombus (LE: 3).
7.2.4.3 Summary of evidence and recommendations for the management of RCC with venous tumour
thrombus
Summary of evidence LE
In patients with locally advanced disease due to clinically enlarged lymph nodes, the survival benefit of 3
lymph node dissection is unclear but lymph node dissection can add staging information.
Low quality data suggest that tumour thrombus excision in non-metastatic disease may be beneficial. 3
Tumour embolisation or inferior vena cava filter do not appear to offer any benefits. 3
Summary of evidence LE
Adjuvant cytokines do not improve survival after nephrectomy. 1b
Adjuvant sunitinib improved disease-free survival in one of the two available studies, but not overall 1b
survival, after nephrectomy in selected high-risk patients.
Recommendations grade
Do not offer adjuvant therapy with sorafenib. strong ↓↓
Do not offer adjuvant sunitinib following surgically resected high-risk clear-cell renal cell weak ↓
cancer.
Summary of evidence LE
Cytoreductive nephrectomy combined with interferon-alpha improves survival in patients with 1a
metastatic RCC and good performance status.
Cytoreductive nephrectomy for patients with simultaneous complete resection of a single metastasis 3
or oligometastases may improve survival and delay systemic therapy.
Recommendation grade
Offer cytoreductive nephrectomy to favourable- and intermediate-risk patients with weak ↑
metastatic RCC.
Eight studies reported on local therapies of RCC-metastases in various organs [335-342]. This included
metastases to any single organ or multiple organs. Three studies reported on local therapies of RCC
metastases in bone, including the spine [343-345], two in the brain [346, 347] and one each in the liver [348]
lung [349] and pancreas [350]. Three studies [339, 341, 349] were abstracts. Data were too heterogeneous for
meta-analysis. There was considerable variation in the type and distribution of systemic therapies (cytokines
and VEGF-inhibitors) and in reporting the results.
7.3.2.5 Summary of evidence and recommendations for local therapy of metastases in metastatic RCC
Summary of evidence LE
All included studies were retrospective non-randomised comparative studies, resulting in a high risk of 3
bias associated with non-randomisation, attrition, and selective reporting.
With the exception of brain and possibly bone metastases, metastasectomy remains by default the 3
only local treatment for most sites.
Retrospective comparative studies consistently point towards a benefit of complete metastasectomy 3
in mRCC patients in terms of overall survival, cancer-specific survival and delay of systemic therapy.
Radiotherapy to bone and brain metastases from RCC can induce significant relief from local 3
symptoms (e.g. pain).
Recommendations grade
Consider local therapy for metastatic disease (including metastasectomy) in patients with weak ↑
a favourable risk profile in whom complete resection is achievable or when local symptoms
need to be controlled.
Stereotactic radiotherapy for clinically relevant bone or brain metastases can be considered weak ↑
for local control and symptom relief.
7.4.1.1 Summary of evidence and recommendation for systemic therapy for advanced/metastatic renal cell
cancer
Summary of evidence LE
In metastatic RCC, 5-FU combined with immunotherapy has equivalent efficacy to INF-α. 1b
In metastatic RCC, chemotherapy is otherwise not effective with the exception of gemcitabine and 3
doxorubicine in sarcomatoid and rapidly progressive disease.
Recommendations grade
Do not offer chemotherapy as first-line therapy in patients with metastatic clear-cell renal cell strong ↓↓
cancer (RCC).
Consider offering a combination of gemcitabine and doxorubicin to patients with sarcomatoid weak ↑
or rapidly progressive RCC.
Table 7.1: The Metastatic Renal Cancer Database Consortium (IMDC) risk model [364]
7.4.2.2 Interleukin-2
Interleukin-2 has been used to treat mRCC since 1985, with response rates ranging from 7% to 27% [363,
365, 366]. Complete and durable responses have been achieved with high-dose bolus IL-2, however IL-2
remains the only drug to date that can cure a small percentage of RCC patients. [367]. The toxicity of IL-2 is
substantially greater than that of IFN-α [358].
Summary of evidence LE
Interferon-α monotherapy is inferior to VEG-targeted therapy or mTOR inhibition in mRCC. 1b
Interleukin-2 monotherapy may have an effect in selected cases (good PS, ccRCC, lung metastases 2
only).
IL-2 has more side-effects than IFN-α. 2
High dose (HD)-IL-2 is associated with durable complete responses in a limited number of patients. 1b
However, no clinical factors or biomarkers exist to accurately predict a durable response in patients
treated with HD-IL-2.
Bevacizumab plus IFN-α is more effective than IFN-α treatment-naïve, low-risk and intermediate-risk 1b
ccRCC.
Vaccination therapy with tumour antigen 5T4 showed no survival benefit over first-line standard 1b
therapy.
Cytokine combinations, with or without additional chemotherapy, do not improve OS compared with 1b
monotherapy.
Nivolumab leads to superior OS compared to everolimus in patients failing one or two lines of VEGF- 1b
targeted therapy.
Recommendations grade
Offer nivolumab after one or two lines of vascular endothelial growth factor-targeted therapy strong ↑↑
in metastatic RCC.
Do not offer monotherapy with interferon-α or high-dose bolus interleukin-2 as first-line weak ↓
therapy in metastatic RCC.
In major trials leading to registration of the approved targeted agents, patients were stratified according to the
MSKCC risk model [356] (Table 7.1). Since the MSKCC (Motzer) criteria were developed during the cytokine
era, the IMDC risk model has been established and validated to aid accurate prognosis of patients treated
in the era of targeted therapy. Neutrophilia and thrombocytosis have been added to the list of MSKCC risk
factors, while LDH has been removed [364].
The IMDC published data on conditional survival which may be used in patient counselling [377]. The IMDC risk
model has been validated and compared with the Cleveland Clinic Foundation (CCF) model, the French model,
MSKCC model, and the International Kidney Cancer Working Group (IKCWG) model. The IMDC model did not
differ from the other models, indicating that a ceiling has been reached in predicting prognosis based solely
on clinical factors [378]. Both the MSKCC and IMDC developed models for second-line treatment in the era of
targeted therapy based, in part, on their risk models for treatment-naïve patients [379].
7.4.3.1.2 Sunitinib
Sunitinib is an oral tyrosine kinase (TK) inhibitor and has anti-tumour and anti-angiogenic activity. Sunitinib
as second-line monotherapy (after cytokines) in patients with mRCC demonstrated a partial response in
34-40% and stable disease at > 3 months in 27-29% of patients [382]). First-line monotherapy with sunitinib
demonstrated significantly longer PFS compared with IFN-α. Overall survival was greater in patients treated
with sunitinib (26.4) vs. INF-α (21.8 months) despite crossover [383].
In the EFFECT trial, sunitinib 50 mg/day (four weeks on/two weeks off) was compared with
continuous uninterrupted sunitinib 37.5 mg/day in patients with cc-mRCC [384]. Median time to progression
(TTP) with sunitinib 50 mg was numerically longer than the 37.5 mg arm (9.9 months vs. 7.1 months). No
significant differences in OS were seen (23.1 vs. 23.5 months; p = 0.615). Toxicity was comparable in both
arms. Because of the non-significant, but numerically longer TTP with the standard 50 mg dosage, the authors
recommended using this regimen. Alternate scheduling of sunitinib (two weeks on/one week off) is being used
to manage toxicity, but robust data to support its use is lacking [385].
7.4.3.1.3 Pazopanib
Pazopanib is an oral angiogenesis inhibitor. In a trial of pazopanib vs. placebo in treatment-naïve mRCC
patients and cytokine-treated patients, a significant improvement in PFS and tumour response was observed
[386]. Median PFS with pazopanib compared with placebo was:
• 9.2 vs. 4.2 months in the overall study population;
• 11.1 vs. 2.8 months for the treatment-naïve subpopulation;
• 7.4 vs. 4.2 months for the cytokine-pre-treated subpopulation.
A trial comparing pazopanib with sunitinib (COMPARZ) established pazopanib as another first-line option. It
showed that pazopanib was not associated with significantly worse PFS or OS compared to sunitinib. The two
drugs had different toxicity profiles [387], and QoL was better with pazopanib. In another patient-preference
study (PISCES), patients preferred pazopanib to sunitinib (70% vs. 22%: p < 0.05) due to symptomatic toxicity
[388]. Both studies were limited in that intermittent therapy (sunitinib) was compared with continuous therapy
(pazopanib).
7.4.3.1.4 Axitinib
Axitinib is an oral selective second-generation inhibitor of VEGFR-1, -2, and -3. Axitinib was first evaluated as
second-line treatment. In the AXIS trial, axitinib was compared to sorafenib in patients with previously failed
cytokine treatment or targeted agents (mainly sunitinib) [389].
The overall median PFS was greater for axitinib than sorafenib. The difference in PFS was greatest
in patients in whom cytokine treatment had failed. For those in whom sunitinib had failed, axitinib was
associated with a greater PFS than sorafenib (4.8 vs. 3.4 months). Axitinib showed > Grade 3 diarrhoea in
11%, hypertension in 16%, and fatigue in 11%. Across all grades, nausea was recorded in 32%, vomiting in
24%, and asthenia in 21%. Overall survival was a secondary end-point of the trial in which crossover was not
permitted. Final analysis of OS showed no significant differences between axitinib or sorafenib [390, 391].
7.4.3.1.5 Cabozantinib
Cabozantinib is an oral inhibitor of TK, including MET, VEGF and AXL. Cabozantinib was investigated in a
phase I study in patients resistant to VEGFR and mTOR inhibitors demonstrating objective responses and
disease control [171]. Based on these results a randomised phase III trial investigated cabozantinib vs.
everolimus in patients with ccRCC failing one or more VEGF-targeted therapies (METEOR) [64]. Cabozantinib
delayed PFS compared to everolimus in VEGF-targeted therapy refractory disease by 42% (HR: 0.58 95% CI:
0.45-0.75) [64] (LE: 1b). The median PFS for cabozantinib was 7.4 months (95% CI: 5.6-9.1) vs. 3.8 months
(95% CI: 3.7-5.4) for everolimus. The trial recruited 658 patients although PFS was assessed on the first 375
patients. The median OS was 21.4 months (95% CI: 18.7 to not estimable) with cabozantinib and 16.5 months
(95% CI 14.7-18.8) with everolimus in VEGF- resistant RCC. The HR for death was 0.66 (95% CI: 0.53-0.83; p =
0.0003) [393]. Grade 3 or 4 adverse events were reported in 74% with cabozantinib and 65% with everolimus.
Adverse events were managed with dose reductions; doses were reduced in 60% of the patients who received
cabozantinib. Discontinuation due to toxicity was not significantly different for the two drugs. The trial included
16% MSKCC poor-risk patients.
7.4.3.1.6 Lenvatinib
Lenvatinib is an oral multi-target TKI of VEGFR1, VEGFR2, and VEGFR3, with inhibitory activity against
fibroblast growth factor receptors (FGFR1, FGFR2, FGFR3, and FGFR4), platelet growth factor receptor α
(PDGFRα), re-arranged during transfection (RET), and receptor for stem cell factor (KIT). It has recently been
investigated in randomised phase II study in combination with everolimus vs. lenvatinib or everolimus alone
(see Section 7.4.6.1.1.5 for discussion of results).
7.4.5.2 Everolimus
Everolimus is an oral mTOR inhibitor, which is established in the treatment of VEGF-refractory disease. The
RECORD-1 study compared everolimus + best supportive care (BSC) vs. placebo + BSC in patients with
previously failed anti-VEGFR treatment (or previously intolerant of VEGF-targeted therapy) [399]. The initial data
showed a median PFS of four months vs. 1.9 months for everolimus and placebo, respectively [399]. This was
extended to 4.9 months in the final analysis (HR: 0.33) [400]. Subset analysis of PFS for patients receiving only
one previous VEFG TKI was 5.4 months [401]. This included some patients who were intolerant rather than
progressed on therapy (PFS was also 5.4 months) [402]. RECORD-1 included patients who failed multiple lines
of VEGF-targeted therapy, and received everolimus in a third- and fourth-line setting [399].
The RECORD-3 randomised phase II study of sequential first-line sunitinib and second-line everolimus vs.
sequential first-line everolimus and second-line sunitinib in treatment-naïve mRCC reported a higher median
Tolerability is an important consideration when recommendations cannot be made for efficacy alone. Both
everolimus and sorafenib have been outperformed by other agents in VEGF-refractory disease and should
not be the standard of care in pure VEGF-refractory disease where superior alternatives are available. It is not
currently possible to determine therapy based on baseline characteristics or biomarker expression for any of
the above drugs.
Direct comparison of RECORD-1, Checkmate-25 and METEOR data with AXIS data is not advised
due to differences in patient populations [389-391, 399].
INTORSECT compared temsirolimus vs. sorafenib after disease progression on sunitinib [398]. Median PFS
was higher, but not significant, in the temsirolimus group. However, there was a significant difference in OS in
favour of sorafenib. Neither of these agents are recommended or widely used in this setting. These data are not
necessarily relevant to other mTOR inhibitors such as everolimus.
Based on difference in OS, recommendations can currently be made as to the best sequence of targeted
therapy (Figure 7.1). Two major trials, testing nivolumab and cabozantinib, have changed treatment paradigms
in VEGF-refractory RCC (LE: 1a). There is a strong rationale for using both drugs in sequence in the second and
third line following VEGF-targeted therapy. This creates a new a standard for the majority of patients.
The most common non-clear-cell subtypes are papillary type 1 and non-type 1 papillary RCCs. There are small
single-arm trials for sunitinib and everolimus [413-416]. A trial of both types of pRCC treated with everolimus
(RAPTOR) [416], showed a median PFS of 3.7 months per central review in the intention-to-treat population
with a median OS of 21.0 months.
Another trial investigated foretinib (a dual MET/VEGFR2 inhibitor) in patients with pRCC. Toxicity
was acceptable with a high relative risk in patients with germline MET mutations [417]. However, a randomised
phase II trial of everolimus vs. sunitinib (ESPN) with crossover design in non-cc-mRCC including 73 patients
(27 with pRCC) was stopped after a futility analysis for PFS and OS [418]. The final results presented at the
2014 annual meeting of the American Society of Clinical Oncology showed a non-significant trend favouring
sunitinib (6.1 vs. 4.1 months). Based on a SR including subgroup analysis of the ESPN, RECORD-3 and
another phase II trial (ASPEN) sunitinib and everolimus remain options in this population, with a preference for
sunitinib [136, 419, 420]. Patients with non-cc-mRCC should be referred to a clinical trial where appropriate.
Collecting-duct cancers are resistant to systemic therapy. There is a lack of data to support specific
therapy in these patients. There is limited data supporting the use of targeted therapy in other histological
subtypes such as chromophobe tumours [362, 411].
axitinib
or everolimus2 everolimus
or sorafenib3 or sorafenib
and intermediate-risk disease) and temsirolimus (poor-risk disease) have not been widely used as first-line
therapy in the pivotal VEGF-resistant trials and therefore recommendations are not possible.
Table 7.3: EAU 2017 evidence-based recommendations for systemic therapy in patients with mRCC
RCC MSKCC risk First-line LE^ Second-Line LE^ Third-line* LE^ Later LE
type group [356] after VEGF lines
therapy*
Clear Favourable, sunitinib 1b based on OS: after VEGF any 4
cell* intermediate pazopanib 1b nivolumab 2b therapy: targeted
and poor bevacizumab 1b cabozantinib 2b nivolumab 2b agent
+ IFN-α based on PFS: cabozantinib 2b
(favourable- axitinib 2b everolimus& 2b
intermediate sorafenib# 2b
only) everolimus& 2b after VEGF
and mTOR
therapy:
sorafenib 1b
after
VEGF and
nivolumab:
cabozantinib 4
axitinib 4
everolimus 4
Clear poor¶ temsirolimus 1b any targeted 4
cell* sunitinib 2b agent
pazopanib 2b
7.4.6.3 Summary of evidence and recommendations for systemic therapy in metastatic renal cell cancer
Summary of evidence LE
VEGF and TKIs increase PFS and/or OS as both first-line and second-line treatments for clear-cell 1b
mRCC.
Axitinib has proven efficacy and superiority in PFS as a second-line treatment after failure of cytokines 1b
and VEGF-targeted therapy in comparison with sorafenib.
Sunitinib is more effective than IFN-α in treatment-naïve patients. 1b
Bevacizumab plus IFN-α is more effective than IFN-α in treatment-naïve low-risk and intermediate-risk 1b
patients.
pazopanib is superior to placebo in both naïve mRCC patients and post-cytokine patients. 1b
First line pazopanib is not inferior to sunitinib in clear-cell mRCC patients. 1b
Temsirolimus monotherapy prolongs OS compared to IFN-α in poor-risk mRCC. 1b
Nivolumab is superior to everolimus in terms of OS and adverse events in patients failing one or two 1b
lines of VEGF-targeted therapy.
Cabozantinib is superior to everolimus in terms of PFS and OS in patients failing one or more lines of 1b
VEGF-targeted therapy.
Everolimus prolongs PFS in patients who have previously failed or are intolerant of VEGF-targeted 1b
therapy when compared to placebo.
Sorafenib has broad activity in a spectrum of settings in ccRCC patients previously treated with 4
cytokine or targeted therapies. It is inferior to axitinib in both sunitinib or cytokine pre-treated patients.
Both mTOR inhibitors (everolimus and temsirolimus) and VEFG-targeted therapies (sunitinib or 3
sorafenib) can be used in non-clear cell RCC.
No combination has proven to be better than single-agent therapy, with the exception of the 1a
combination of lenvatinib plus everolimus.
The largest series on the treatment of isolated recurrence was published in 2009 [423]. In 2,945 patients
who underwent nephrectomy the authors identified 54 isolated local recurrences in the renal fossa. These,
however, included recurrences to the ipsilateral adrenal and LNs. Exclusively retrospective non-comparative
data exist which suggest that aggressive local resection offers durable local tumour control and improves
survival. Adverse prognostic factors were, a positive surgical margin after resection, the size of the recurrence
and sarcomatoid histologic features [423]. In cases where complete surgical removal is not feasible due to
advanced tumour growth and pain, palliative treatments including radiation treatment can be considered.
Summary of evidence LE
Isolated recurrence in the local renal fossa is rare. 3
Patients who undergo resection of local recurrences in the absence of sarcomatoid features may 3
benefit from durable local control and improved survival.
Recommendation grade
Offer surgical resection of local recurrent disease, when feasible. weak ↑
There is no consensus on surveillance after RCC treatment, and there is no evidence that early vs. later
diagnosis of recurrences improves survival. However, follow-up is important to increase the available
information on RCC, and should be performed by a urologist, who should record the time to recurrence or
the development of metastases. Patients undergoing follow-up seem to have a longer OS when compared to
patients not undergoing routine follow-up [424].
An individualised, risk-based, approach to RCC surveillance was recently proposed. The authors use
competing risk models, incorporating patient age, pathologic stage, relapse location and comorbidities,
to calculate when the risk of non-RCC death exceeds the risk of RCC recurrence [425]. For patients with
low-stage disease but with a Charlson comorbidity index > 2, the risk of non-RCC death exceeded that of
abdominal recurrence risk already one month after surgery, regardless of patient age.
Renal function is assessed by the measurement of serum creatinine and eGFR. Repeated long-term monitoring
of eGFR is indicated in case of impaired renal function before, or after, surgery. Renal function [426, 427] and
non-cancer survival [196, 428, 429] can be optimised by performing NSS, whenever possible, for T1 and T2
tumours [430] (LE: 3). Recurrence after PN is rare, but early diagnosis is useful, as the most effective treatment
is redux surgery [431, 432]. Recurrence in the contralateral kidney is also rare and might be related to positive
margins, multifocality, and grade [433] (LE: 3). Surveillance can identify local recurrences or metastases at an
early stage. In metastatic disease, extended tumour growth can limit the opportunity for surgical resection,
which is considered the standard therapy in cases of resectable and preferably solitary lesions. In addition,
early diagnosis of tumour recurrence may enhance the efficacy of systemic treatment if the tumour burden is
low.
• The sensitivity of chest radiography and US for small metastases is poor. Surveillance with these imaging
modalities should not be done [436].
• In low-risk tumours, surveillance intervals should be adapted taking into account radiation exposure and
benefit. To reduce radiation exposure, MRI can be used outside the thorax.
• When the risk of relapse is intermediate or high, CT of the chest and abdomen should be performed.
• Surveillance should also include evaluation of renal function and cardiovascular risk factors.
• Positron-emission tomography and PET-CT as well as bone scintigraphy should not be used in RCC
surveillance, due to their limited specificity and sensitivity.
• The risk of acute renal failure seems to be negligible in patients with a GFR > 20 mL/min and chronic renal
impairment [437].
Controversy exists on the optimal duration of follow-up. Some argue that follow-up with imaging is not cost-
effective after five years; however, late metastases are more likely to be solitary and justify more aggressive
therapy with curative intent. In addition, patients with tumours that develop in the contralateral kidney can be
treated with NSS if the tumours are detected early. For tumours < 4 cm, there is no difference between PN and
RN with regard to recurrences during follow up [438] (LE: 3).
Several authors [182, 184, 439, 440], have designed scoring systems and nomograms to quantify
the likelihood of patients developing tumour recurrences, metastases, and subsequent death. These systems
have been compared and validated [441] (LE: 2). Using prognostic variables, several stage-based surveillance
Table 8.1: P
roposed surveillance schedule following treatment for RCC, taking into account patient risk
profile and treatment efficacy
Summary of evidence LE
Surveillance can detect local recurrence or metastatic disease while the patient is still surgically 4
curable.
After NSS, there is an increased risk of recurrence for larger (> 7 cm) tumours, or when there is a 3
positive surgical margin.
Patients undergoing surveillance have a better overall survival than patients not undergoing 3
surveillance.
Recommendations grade
Base follow-up after RCC on the risk of recurrence. strong ↑↑
For low-risk disease, computed tomography (CT)/magnetic resonance imaging (MRI) can be weak ↑
used infrequently.
In intermediate-risk patients, offer intensified follow-up, including chest and abdominal CT/ weak ↑
MRI scans at regular intervals in accordance with a risk-stratified nomogram.
In high-risk patients, include chest and abdominal CT/MRI scans in follow-up examinations. weak ↑
Intensify follow-up in patients after NSS for tumours > 7 cm or in patients with a positive weak ↑
surgical margin.
Base risk stratification on pre-existing classification systems such as the University of strong ↑↑
California Los Angeles integrated staging system integrated risk assessment score (http://
urology.ucla.edu/body.cfm?id=443).
UISS = University of California Los Angeles integrated staging system.
2. METHODS 7
2.1 Review 7
2.2 Future goals 7
5. DIAGNOSTIC EVALUATION 13
5.1 Clinical examination 13
5.2 Imaging of the testis 13
5.3 Serum tumour markers at diagnosis 13
5.4 Inguinal exploration and orchiectomy 13
5.5 Organ-sparing surgery 13
5.6 Pathological examination of the testis 14
5.7 Germ cell tumours histological markers 14
5.8 Diagnosis and treatment of germ cell neoplasia in situ (GCNIS) 15
5.9 Screening 15
5.10 Guidelines for the diagnosis and staging of testicular cancer 15
6. PROGNOSIS 16
6.1 Risk factors for metastatic relapse in clinical stage I 16
7. DISEASE MANAGEMENT 16
7.1 Impact on fertility and fertility-associated issues 16
7.2 Stage I Germ cell tumours 16
7.2.1 Stage I seminoma 16
7.2.1.1 Surveillance 16
7.2.1.2 Adjuvant chemotherapy 17
7.2.1.3 Adjuvant radiotherapy and risk-adapted treatment 17
7.2.1.4 Risk-adapted treatment 17
7.2.1.5 Guidelines for the treatment of stage I seminoma 17
7.2.2 NSGCT clinical stage I 17
7.2.2.1 Surveillance 18
7.2.2.2 Adjuvant chemotherapy 18
7.2.2.3 Risk-adapted treatment 18
7.2.2.4 Retroperitoneal lymph node dissection 19
7.2.2.5 Guidelines for the treatment of stage 1 non-seminomatous germ
cell tumour 19
7.2.2.6 Risk-adapted treatment for clinical stage 1 based on
vascular invasion 20
7.3 Metastatic germ cell tumours 21
7.3.1 CS1S with (persistently) elevated serum tumour markers 21
7.3.2 Metastatic disease (stage IIA/B) 21
10. REFERENCES 36
• Section 5.7 - Germ cell tumours histological markers. This is a new table.
• Table 7.2 - An alternative schedule for salvage chemotherapy has been included.
• Chapter 8 - Section 8.1 Rationale for follow up, has been completely replaced, including three new tables,
based on the findings of an ESMO Testis Cancer Consensus Committee.
Recommendations GR
Advise patients with a familiar history of testis cancer, as well as their family members, to A
perform regular testicular self-examination.
Recommendations LE GR
Initially offer radiotherapy for seminoma CS IIA. 1a A
When necessary, use chemotherapy as a salvage treatment with the same schedule
as for the corresponding prognostic groups of NSGCT.
Initially offer chemotherapy in seminoma stage CS IIB (BEP x 3 or etoposide, cisplatin 1a A
(EP) x 4, in good prognosis) as an alternative to radiotherapy.
Table 8.1: R
ecommended minimal follow-up for seminoma stage I on active surveillance or after
adjuvant treatment (carboplatin or radiotherapy)
Table 8.2: Recommended minimal follow-up for non-seminoma stage I on active surveillance
Table 8.3: R
ecommended minimal follow up after adjuvant treatment or complete remission for
advanced disease (excluded: poor prognosis and no remission)
Recommendations in this text are assessed according to their level of evidence (LE) and Guidelines are
given a grade of recommendation (GR), according to a classification system modified from the Oxford Centre
for Evidence-Based Medicine Levels of Evidence [2]. Additional information can be found in the general
Methodology section of this print, and online at the EAU website: http://uroweb.org/guidelines/.
A list of associations endorsing the EAU Guidelines can also be viewed online at the above address.
2.1 Review
This document was subjected to peer review prior to publication in 2015.
At diagnosis, 1-2% of cases are bilateral and the predominant histology is germ cell tumour (90-95% of cases)
[4]. Peak incidence is in the third decade of life for non-seminoma, and in the fourth decade for pure seminoma.
Testicular cancers (TC) show excellent cure rates based on, their chemosensitivity especially to cisplatin-based
chemotherapy [9], careful staging at diagnosis, adequate early treatment based on a multidisciplinary approach
and strict follow-up and salvage therapies. A decrease in the meantime of delay to diagnosis and treatment
has been observed. Although early stages can be successfully treated in a non-reference centre, the relapse
rate is higher [10, 11]. In poor prognosis non-seminomatous germ cell tumours (NSGCT), overall survival
(OS) within a clinical trial depends on the number of patients treated at the participating centre (worse if < 5
patients enrolled) [12]. In the same context, the frequency of post-chemotherapy residual tumour resection is
associated with peri-operative mortality and OS [13, 14]. Establishment of second-opinion clinics for testicular
cancer patients may prevent over- and under-treatment [15].
Epidemiological risk factors for the development of testicular tumours are components of the testicular
dysgenesis syndrome (i.e. cryptorchidism, hypospadias, decreased spermatogenesis evidenced by sub- or
infertility) [22, 23], familial history of testicular tumours among first-grade relatives and the presence of a
contralateral tumour or GCNIS [16, 22, 24-28]. A recent systematic review confirmed the association between
height and TGCT with an odds ratio (OR) of 1.13 per 5 cm increase in height [29].
Seminoma
• Embryonal carcinoma
• Yolk sac tumour, post-pubertal type
• Trophoblastic tumours
• Teratoma, post-pubertal type
• Teratoma with somatic-type malignancies
• Mixed germ cell tumours
A chest CT is the most sensitive way to evaluate the thorax and mediastinal nodes. This exploration is
recommended in all patients with TC as up to 10% of cases can present with small subpleural nodes that are
not visible on an X-ray [42]. A CT has high sensitivity, but low specificity.
There is no evidence to support the use of fluorodeoxyglucose-positron emission tomography
(PET) (FDG-PET) in the staging of testis cancer [43, 44]. It is recommended in the follow up of patients with
seminoma with a residual mass larger than 3 cm and should not be performed before eight weeks after
Test Recommendation GR
Serum tumour markers Alpha-fetoprotein A
human chorionic gonadotrophin (hCG)
Lactate dehydrogenase
Abdominopelvic computed tomography (CT) All patients A
Chest CT All patients A
Testis ultrasound (bilateral) All patients A
Bone scan or magnetic resonance imaging (MRI) columna In case of symptoms
Brain scan (CT/MRI) In case of symptoms and patients with
metastatic disease with multiple lung
metastases and/or high beta-hCG
values.
Further investigations
Fertility investigations: B
Total testosterone
Luteinising hormone
Follicle-stimulating hormone
Semen analysis
Discuss sperm banking with all men prior to starting treatment for testicular cancer. A
Table 4.2: TNM classification for testicular cancer (UICC, 2017, 8th edn. [30])
pT - Primary Tumour1
pTX Primary tumour cannot be assessed (see note 1)
pT0 No evidence of primary tumour (e.g. histological scar in testis)
pTis Intratubular germ cell neoplasia (carcinoma in situ)
pT1 Tumour limited to testis and epididymis without vascular/lymphatic invasion; tumour may
invade tunica albuginea but not tunica vaginalis*
pT2 Tumour limited to testis and epididymis with vascular/lymphatic invasion, or tumour
extending through tunica albuginea with involvement of tunica vaginalis
pT3 Tumour invades spermatic cord with or without vascular/lymphatic invasion
pT4 Tumour invades scrotum with or without vascular/lymphatic invasion
N - Regional Lymph Nodes - Clinical
NX Regional lymph nodes cannot be assessed
N0 No regional lymph node metastasis
N1 Metastasis with a lymph node mass 2 cm or less in greatest dimension or multiple lymph
nodes, none more than 2 cm in greatest dimension
N2 Metastasis with a lymph node mass more than 2 cm but not more than 5 cm in greatest
dimension, or multiple lymph nodes, any one mass more than 2 cm but not more than 5 cm
in greatest dimension.
1 Except for pTis and pT4, where radical orchidectomy is not always necessary for classification purposes, the
extent of the primary tumour is classified after radical orchidectomy; see pT. In other circumstances, TX is used
if no radical orchidectomy has been performed.
According to the 2009 TNM classification, stage I testicular cancer includes the following substages:
Stage grouping
Stage 0 pTis N0 M0 S0
Stage I pT1-T4 N0 M0 SX
Stage IA pT1 N0 M0 S0
Stage IB pT2 - pT4 N0 M0 S0
Stage IS Any patient/TX N0 M0 S1-3
Stage II Any patient/TX N1-N3 M0 SX
Stage IIA Any patient/TX N1 M0 S0
Any patient/TX N1 M0 S1
Stage IIB Any patient/TX N2 M0 S0
Any patient/TX N2 M0 S1
Stage II Any patient/TX N3 M0 S0
Any patient/TX N3 M0 S1
Stage III Any patient/TX Any N M1a SX
Stage IIIA Any patient/TX Any N M1a S0
Any patient/TX Any N M1a S1
Stage IIIB Any patient/TX N1-N3 M0 S2
Any patient/TX Any N M1a S2
Stage IIIC Any patient/TX N1-N3 M0 S3
Any patient/TX Any N M1a S3
Any patient/TX Any N M1b Any S
In large population-based patient series, 75-80% of seminoma patients, and about 55% of patients with
NSGCT cancer have stage I disease at diagnosis [48, 49]. True stage IS (persistently elevated or increasing
serum marker levels after orchiectomy) is found in about 5% of non-seminoma patients.
In 1997, the IGCCCG defined a prognostic factor-based staging system for metastatic testis tumours based
on identification of clinically independent adverse factors. This staging system has been incorporated into
the TNM Classification and uses histology, location of the primary tumour, location of metastases and pre-
chemotherapy marker levels in serum as prognostic factors to categorise patients into ‘good’, ‘intermediate’ or
‘poor’ prognosis (Table 4.3) [33].
Table 4.3: P
rognostic-based staging system for metastatic germ cell cancer
(International Germ Cell Cancer Collaborative Group [50])*
Good-prognosis group
Non-seminoma (56% of cases) All of the following criteria:
5-year PFS 89% • Testis/retro-peritoneal primary
5-year survival 92% • No non-pulmonary visceral metastases
• AFP < 1,000 ng/mL
• hCG < 5,000 IU/L (1,000 ng/mL)
• LDH < 1.5 x ULN
Seminoma (90% of cases) All of the following criteria:
5-year PFS 82% • Any primary site
5-year survival 86% • No non-pulmonary visceral metastases
• Normal AFP
• Any hCG
• Any LDH
Intermediate prognosis group
Non-seminoma (28% of cases) Any of the following criteria:
5-year PFS 75% • Testis/retro-peritoneal primary
5-year survival 80% • No non-pulmonary visceral metastases
• AFP 1,000 - 10,000 ng/mL or
• hCG 5,000 - 50,000 IU/L or
• LDH 1.5 - 10 x ULN
Seminoma (10% of cases) All of the following criteria:
5-year PFS 67% • Any primary site
5-year survival 72% • Non-pulmonary visceral metastases
• Normal AFP
• Any hCG
• Any LDH
Poor prognosis group
Non-seminoma (16% of cases) Any of the following criteria:
5-year PFS 41% • Mediastinal primary
5-year survival 48% • Non-pulmonary visceral metastases
• AFP > 10,000 ng/mL or
• hCG > 50,000 IU/L (10,000 ng/mL) or
• LDH > 10 x ULN
Seminoma No patients classified as poor prognosis
*Pre-chemotherapy serum tumour markers should be assessed immediately prior to the administration of
chemotherapy (same day). PFS = progression-free survival; AFP = alpha-fetoprotein; hCG = human chorionic
gonadotrophin; LDH = lactate dehydrogenase.
Tumour markers are of value for diagnosis (before orchiectomy) as well as for prognosis (after orchiectomy).
They are increased in approximately every second patient with TC [51, 60]. Alpha-fetoprotein and hCG are
increased in 50-70% and in 40-60% of patients with NSGCT, respectively. About 90% of NSGCT present with
a rise in one or both of the markers. Up to 30% of seminomas can present or develop an elevated hCG level
during the course of the disease [31].
Lactase dehydrogenase is a less specific marker, its concentration being proportional to tumour
volume. Its level may be elevated in 80% of patients with advanced TC [31]. Of note, negative marker levels do
not exclude the diagnosis of a germ cell tumour. Placental alkaline phosphatase (PLAP), is an optional marker
in monitoring patients with pure seminoma, but not recommended in smokers [61].
Cytogenetic and molecular markers are available in specific centres, but at present only contribute
to research. There is preliminary evidence that some micro-RNAs (miRNA 371-373) may be of diagnostic value
in the future [62].
Marker GCNIS Seminoma Post- Embryonal Tropho- Tropho- Sperma- Pre- Sex cord
puberal Carcinoma blastic blastic tocytic puberal gonadal
yolk sac Cyto Syncytio tumour yolk sac stromal
tumour tumour tumours
OCT3/4 100% 100% - 90% - -- - -
SALL 4 90% 100% 90% 90% + - 50-90% 100% -
(weak)
Glypican3 - - 100% 8% 100% 100% - -
(irregular) (irregular)
CD30 - < 10% < 10% 100% - - - -
AFP - - 80% 33% - - - - -
β-hCG - - - - - 100% - -
CD117 100% 90/100% 60% - - - +/- (weak) -
(focal)
PLAP 100% 86/95% 53% 86% +/- 100% - -
α-inhibin - - - - - +/- - + Sertoli;
30-50%
Leydig;
100%
Calretinin - - - - - - - 100%
AE1/AE3 - 20/36% + (focal) 95% +/- +/- - Sertoli:
(weak) 64%
Leydig:
42%
EMA - 2% 5% 2% 46% +/-
CEA - - 11% - - 25% -
GATA 3 - - 100% 40% (focal) + 100%
hPL - - - - - + - -
CgA Sertoli:
82%
Leydig:
92%
Once GCNIS is diagnosed, local radiotherapy (16-20 Gy in fractions of 2 Gy) is the treatment of choice in the
case of a solitary testis. Testicular radiotherapy in a solitary testis will result in infertility and increased long-term
risk of Leydig cell insufficiency [37, 69, 75, 76]. Fertile patients who wish to father children may delay radiation
therapy and be followed by regular testicular US [72]. Chemotherapy is significantly less effective and the cure
rates are dose-dependent [77].
If GCNIS is diagnosed and the contralateral testis is healthy, the options for management are
orchiectomy or close observation (with a 5-year risk of developing TC of 50%) [78].
5.9 Screening
There are no high level evidence studies proving the advantages of screening programmes [79], but it has been
demonstrated that stage and prognosis are directly related to early diagnosis. In the presence of clinical risk
factors, and especially in patients with a family history of testis cancer, family members and the patient should
be informed about the importance of physical self-examination [80].
Recommendations GR
Perform testicular ultrasound in all patients with suspicion of testicular cancer. A
Offer biopsy of the contralateral testis and discuss its consequences with patients at high risk for A
contralateral germ cell neoplasia in situ.
Perform orchiectomy and pathological examination of the testis to confirm the diagnosis and to define A
the local extension (pT category). In a life-threatening situation due to extensive metastasis, start
chemotherapy before orchiectomy.
Perform serum determination of tumour markers (alpha-fetoprotein, human chorionic gonadotrophin, A
and lactate dehydrogenase), both before and five-seven days after orchiectomy for staging and
prognostic reasons.
Assess the state of the retroperitoneal, mediastinal and supraclavicular nodes and viscera in testicular A
cancer.
Advise patients with a familiar history of testis cancer, as well as their family members, to perform A
regular testicular self-examination.
For non-seminoma stage I, vascular invasion of the primary tumour in blood or lymphatic vessels is the most
important predictor of occult metastatic disease. The proliferation rate, as well as the percentage of embryonal
carcinoma, are additional predictors that improve upon the positive and negative predictive value of vascular
invasion [86]. Whether the absence of teratoma (as qualitative data, as opposed to the more subjective
assessment of percentage of embryonal carcinoma) can independently complement vascular invasion as a
predictive factor of relapse requires validation [87].
The significant prognostic pathological risk factors for stage I TC are listed in Table 6.1.
Table 6.1: Risk factors for occult metastatic disease in stage I testicular cancer
7. DISEASE MANAGEMENT
7.1 Impact on fertility and fertility-associated issues
Sperm abnormalities are frequently found in patients with testis tumours. Furthermore, chemotherapy and
radiation treatment can additionally impair fertility, however long-term infertility is rare after radiotherapy and
dose-cumulative-dependant after chemotherapy [88, 89]. In patients in the reproductive age group, pre-
treatment fertility assessment (testosterone, luteinising hormone [LH] and follicle stimulating hormone [FSH]
levels) should be performed, and semen analysis and cryopreservation should be offered. If cryopreservation
is desired, it should preferably be performed before orchiectomy, but in any case prior to chemotherapy
[75, 88-91]. In cases of bilateral orchiectomy or low testosterone levels after treatment of GCNIS, life-long
testosterone supplementation is necessary [92]. Patients with unilateral or bilateral orchiectomy should be
offered a testicular prosthesis [93]. For more detailed information, the reader is referred to the EAU Male
Infertility Guidelines [94].
7.2.1.1 Surveillance
Several prospective non-randomised surveillance studies have been conducted during the past decade, the
largest study from Canada with > 1,500 patients [98]. Previous analyses from four studies showed an actuarial
five-year relapse-free rate of 82.3%. The Princess Margaret Hospital series (n = 1,559) showed an overall
relapse rate in unselected patients of 16.8%. The actuarial relapse rate is in the order of 15-20% at five years,
The overall cancer-specific survival (CSS) rate reported under surveillance performed by experienced centres
is 97-100% for seminoma stage I [99, 100]. The main drawback of surveillance is the need for more intensive
follow-up, especially with repeated imaging examinations of the retroperitoneal lymph nodes.
With regard to the irradiation dose, a large Medical Research Council (MRC) randomised trial of 20 Gy vs.
30 Gy PA radiation in stage I seminoma showed non-inferiority in terms of recurrence rates [107]. The rate
of severe radiation induced long-term toxicity is less than 2%. Moderate chronic gastrointestinal (GI) side-
effects are seen in about 5% of patients, and moderate acute GI toxicity in about 60% [106]. The main
concern surrounding adjuvant radiotherapy is the increased risk of radiation-induced second non-germ cell
malignancies [109-111].
A scrotal shield should be considered during adjuvant radiotherapy in order to prevent scattered
radiation toxicity in the contralateral testis [109].
Recommendations GR
Offer surveillance as a management option if facilities are available and the patient is compliant. A*
Offer one course at area under curve (AUC) 7, if carboplatin chemotherapy is considered. A
Do not perform adjuvant treatment in patients at very low risk (no risk factors). A
Do not perform radiotherapy as adjuvant treatment. A
*Upgraded following panel consensus.
7.2.2.1 Surveillance
Improvements in clinical staging and follow-up methods, and the availability of effective salvage treatment with
cisplatin-based chemotherapy and post-chemotherapy surgery, have led to studies of only close surveillance
after orchiectomy in CS1 NSGCT patients. The largest reports of the surveillance strategy indicate a cumulative
relapse rate of about 30%, with 80% of relapses occurring during the first twelve months of follow up, 12%
during the second year and 6% during the third year, decreasing to 1% during the fourth and fifth years,
and occasionally even later [114, 115]. Approximately 35% of relapsing patients have normal levels of serum
tumour markers at relapse, with 60% of relapses occurring in the retroperitoneum. Despite very close follow-
up, 11% of relapsing patients presented with large-volume recurrent disease.
The somewhat lower relapse rates reported from surveillance studies compared with some series of patients
staged by RPLND [116] can be explained by the fact that some patients (presumably at higher risk) are
excluded once surveillance is advised. Based on the overall CSS data, surveillance within an experienced
surveillance programme can safely be offered to patients with non-risk stratified CSI non-seminoma as long
as they are compliant and informed about the expected recurrence rate as well as the salvage treatment [117,
118].
In 2008, a randomised trial of nerve-sparing RPLND or one course of BEP as adjuvant treatment in CS1
NSGCT without risk-adaption reported [124]. Adjuvant chemotherapy significantly increased the two-year
recurrence-free survival rate to 99.41% (CI: 95.87%, 99.92%) as opposed to surgery, which had a two-year
recurrence-free survival rate of 92.37% (CI: 87.21%, 95.50%). The difference was 7.04%, (CI: 2.52%, 11.56%)
and, therefore, the main endpoint of the trial was reached. The hazard ratio to experience a tumour recurrence
with surgery as opposed to chemotherapy was 7.937, (CI: 1.808, 34.48). Of the 174 patients having received
one course of BEP, 43% had high-risk features (> pT1) [124].
A community-based prospective study recommended one course of BEP in LVI+ patients, while LVI-patients
chose between surveillance and BEP x 1 [125]. The relapse-rate of the 490 patients who received BEP x 1
at five years was 3.2% for LVI+ patients and 1.6% for LVI- patients. After a median follow up of 8.1 years the
relapse rate was 2.3%, 3.4% and 1.3% for all, LVI+, and LVI-, respectively [126]. These numbers imply that
> 90% of relapses were prevented by adjuvant chemotherapy and, importantly, no relapses were observed
later than 3.3 years. Reduction from two to one cycle of BEP improves the risk-benefit ratio of adjuvant
chemotherapy considerably.
In addition, it is important to be aware of slow-growing retroperitoneal teratomas after primary
chemotherapy [109]. Until now, only a limited number of patients with long-term follow-up and toxicity data
have been reported on [127].
The results of cost analyses comparing surveillance, RPLND and primary chemotherapy show different
results among the reported studies, possibly because of differences in intensity and costs related to follow-
up procedures [128]. With low frequency follow-up CTs (a surveillance strategy which has been proven to be
effective in non-seminoma CS1), the costs of follow up can be considerably reduced [129].
The follow-up after RPLND is simpler and less costly than that carried out during post-orchiectomy surveillance
because of the reduced need for abdominal CT scans [136]. If there is an indication to perform a staging
RPLND, a laparoscopic or robot-assisted RPLND is feasible in expert hands. This minimal-invasive approach
cannot be recommended as the standard approach outside of a specialised laparoscopic centre [137].
7.2.2.5 Guidelines for the treatment of stage 1 non-seminomatous germ cell tumour
Recommendations LE GR
Inform patients with stage 1 non-seminomatous germ cell tumour (NSGCT) about all adjuvant 2a A*
treatment options after orchiectomy (surveillance, adjuvant chemotherapy, and retroperitoneal
lymph node dissection [RPLND]) including treatment-specific recurrence rates as well as acute
and long-term side effects.
In patients with stage 1 NSGCT, offer surveillance or risk-adapted treatment based on vascular 2a A*
invasion (see below).
If patients are not willing to undergo surveillance, offer one course of cisplatin, etoposide, 1b A*
bleomycin (BEP) as an adjuvant treatment alternative since it has proven to be superior to
RPLND in terms of recurrence rates.
In patients with marker-positive recurrent and/or progressing lesion during surveillance, 2a A
perform salvage treatment consisting of three or four courses of BEP chemotherapy according
to the International Germ Cell Cancer Collaborative Group classification, followed by post-
chemotherapy retroperitoneal lymph node dissection if necessary.
*Upgraded following panel consensus.
Recommendations LE GR
Stage IA (pT1, no vascular invasion): low risk
Offer surveillance if the patient is willing and able to comply. 2a A
In low-risk patients not willing (or unsuitable) to undergo surveillance, offer adjuvant 2a A*
chemotherapy with one course of cisplatin, etoposide, bleomycin (BEP).
Stage IB (pT2-pT4): high risk
Offer primary chemotherapy with one course of BEP. 2a A*
Inform patients having adjuvant chemotherapy about the advantages and disadvantages of 2a A*
one vs. two cycles of BEP.
Offer surveillance to patients not willing to undergo adjuvant chemotherapy. A*
Offer nerve-sparing retroperitoneal lymph node dissection to highly selected patients only; A*
those with contraindication to adjuvant chemotherapy and unwilling to accept surveillance.
*Upgraded following panel consensus.
Figure 1: Risk-adapted treatment in patients with clinical stage 1 non-seminoma NSGCT CS1 [138]*
Non-seminoma CS1
Low-risk High-risk
No vascular invasion Vascular invasion present
OR
Adjuvant Adjuvant
Nerve-sparing (NS) NS
Surveillance Chemotherapy Chemotherapy Surveillance
RPLND RPLND
1 cycle BEP 1 cycle BEP
Relapse
*All treatment options will need discussing with individual patients, to allow for them to make an informed
decision as to their further care.
In relapsed patients a new prognostic score has been developed including response to first-line therapy which
can be used to estimate patient outcome following salvage chemotherapy (see below).
A population-based study reported on persistently elevated LDH or β-hCG in 19 and 15% of stage I seminoma
patients, respectively. These patients frequently had more advanced T stage, but both CSS and OS did not
differ from stage I A/B patients independent of treatment [142].
In all patients with germ cell tumours and rising markers, only after orchidectomy, a repeated imaging to detect
metastasis is justified in order to individually tailor treatment.
Until recently, the standard treatment for stage IIA/B seminoma has been radiotherapy with reported relapse
rates of 9-24% [143, 144]. Accumulating data on long-term morbidity, such as increased risk of cardiovascular
events and increased risk of second malignancies following radiotherapy has led to concern. One study
displaying a long-term follow-up of 19 years, reports a mortality not due to seminoma seven-fold greater
than mortality due to seminoma [145]. Most reports refer to patients irradiated with larger target volumes
and higher doses but there are also more recent studies reporting on patients treated with more modern
radiotherapy [146]. The radiation dose recommended in stage IIA and IIB is 30 Gy and 36 Gy, respectively.
The standard radiation field compared with stage I will be extended from the PA region to the ipsilateral iliac
field. In stage IIB, the lateral borders should include the metastatic lymph nodes with a safety margin of
1.0-1.5 cm. This technique yields a relapse-free survival in stage IIA and IIB of 92% and 90%, respectively
[143, 144]. Conversely, dose reduction to 27 Gy has been associated with 11% of relapses in stage IIA patients
[100, 146].
In patients with stage IIA/B seminoma, chemotherapy with three courses of BEP or four courses of etoposide
and cisplatin (EP), in cases with contraindications to bleomycin, is an alternative to radiotherapy. There are
no randomised studies comparing radiotherapy vs. chemotherapy. A recent meta-analysis of thirteen high
quality studies compared efficacy and toxicity of radiotherapy and chemotherapy in stage IIA and IIB patients
[147]. Radiotherapy and chemotherapy appeared to be similarly effective in both stages. Nonetheless a non-
significant trend toward a greater efficacy of chemotherapy (HR: 2.17) was shown in stage IIB seminoma. Acute
toxicity was almost exclusively reported following chemotherapy, while long-term toxicity was more frequent
Single-agent carboplatin is not an alternative to standard EP or BEP chemotherapy for metastatic disease
[148].
Figure 2: Treatment options in patients with seminoma clinical stage IIA and B
either or either or
Follow-up Follow-up
If surveillance is chosen, one follow-up evaluation after six weeks is indicated to document whether the lesion
is growing, remaining stable or shrinking. A shrinking lesion is probably non-malignant in origin and should be
observed further. A stable or growing lesion indicates either teratoma or an undifferentiated malignant tumour.
If the lesion is growing without a corresponding increase in the tumour markers AFP or ß-hCG, teratoma
is suspected. In such cases “nerve-sparing” RPLND represents the first treatment option and should be
performed by an experienced surgeon [149]. Patients with a growing lesion and a concomitant increase in
the tumour markers AFP or ß-hCG require primary chemotherapy according to the treatment algorithm for
patients with metastatic disease and IGCCCG recommendations (Figure 2). A CT-or US-guided biopsy, if
technically possible, may represent an alternative to surveillance strategy in stage IIA non-seminoma patients.
When a marker negative stage IIA/B relapse is diagnosed two or more years following initial diagnosis, a CT-or
US-guided biopsy should be advised to confirm the diagnosis of germ cell tumour (GCT) relapse. There is
insufficient published data on PET scans in this situation to provide a recommendation on.
Primary chemotherapy and primary ‘nerve-sparing’ RPLND are comparable options in terms of outcome, but
early and long-term side-effects and toxicity are different, allowing for involvement of the patient in selecting
the treatment of choice [150]. The cure rate with either approach will be close to 98% [151-153].
either or
Chemotherapy Follow-up
NS-RPLND
BEP X 3 After 6 weeks
Residual
tumour PS I PS IIA/B PD NC Regression
either or + marker -
3 cycles
Follow-up PEB +/-
Independant NS-RPLND Further
2 cycles Resection or chemo- NS-RPLND Follow-up
Resection of vascular Follow-up BEP of residual therapy
invasion tumour
BEP = cisplatin, etoposide, bleomycin; NS = nerve-sparing; RPLND = retroperitoneal lymph node dissection;
PS = pathological stage; PD = progressive disease; NC = no change.
*Plus hydration.
In selected cases where bleomycin is contraindicated, EP x 4 can be given [139, 159]. A randomised trial
from the French Groupe d’Etude des Tumeurs Genito-Urinaires (GETUG) suggested that when BEP is used in
this setting the mortality rate was half that of EP, although the difference did not reach statistical significance
[161]. Furthermore, the incidence of active cancer in the retroperitoneal specimen at post-chemotherapy
retroperitoneal lymph node dissection was, however, to significantly higher in patients who received EP x 4
as compared to BEP x 3 (31.9% vs. 7.8%, p. < 0.0.01) [162, 163]. The risk of requiring post-RPLND adjuvant
chemotherapy could be higher after EP x 4 which could thereby offset a hoped-for less toxic treatment.
Higher age is an adverse factor for the efficacy of BEP x 3 [164].
Therapy should be given without reduction of the doses at 21-day intervals; delaying the following
chemotherapy cycle is justified only in cases of fever with granulocytopenia < 1,000/mm3 or thrombocytopenia
< 100,000/IU. Neutropenia without fever is not by itself a reason to delay the next cycle. There is no indication
for prophylactic application of haematopoietic growth factors such as granulocyte colony-stimulating factor
(G-CSF). However, if infectious complications have occurred during chemotherapy or the treatment interval was
delayed due to myelotoxicity, prophylactic administration of G-CSF is recommended for the following cycles
[165].
Since a matched-pair analysis comparing high-dose to conventional treatment resulted in a better survival rate
[34, 177], poor prognosis patients should still be treated in ongoing prospective trials or registries, whenever
possible. Patients meeting ‘poor-prognosis’ criteria should be transferred to a reference centre as a better
outcome was reported for intermediate and poor prognosis patients who had been treated within a clinical
trial in a high volume centre [12, 155]. There are no general recommendations for treatment modifications for
patients with a poor general condition (Karnofsky < 50%) or extended liver infiltration (> 50%), but two small
reports indicate that a first cycle of dose-reduced therapy may reduce acute mortality without compromising
long-term outcome. However, the number of subsequent cycles of full-dose therapy should not be reduced
after a first low-dose induction cycle [178, 179].
Patients with extended pulmonary infiltration are at risk for acute respiratory distress syndrome:
adapting the doses of the BEP regimen in the first cycle of chemotherapy (only three days of EP without
bleomycin) was suggested to reduce the risk of early death in this setting [178].
Patients with clear upfront progression (primary cisplatin refractory) should be switched to experimental
new drug trials [183]. Patients with slow marker decline after the first one-two cycles of chemotherapy are
candidates for dose intensification (see Section 7.4.3.1.5.). Patients with a low-level hCG marker plateau post-
treatment should be observed to see whether complete normalisation occurs. In patients with a low plateau
serum AFP level after chemotherapy, surgery of residual masses should be performed, with post-surgery AFP
monitoring. Salvage chemotherapy is indicated for documented marker rise only [184, 185].
7.4.2.2 Non-seminoma
Following first-line BEP chemotherapy, only 6-10% of residual masses contain viable cancer, 50% contain
mature teratoma, and 40% contain necrotic-fibrotic tissue [194]. FDG-PET is not indicated to re-stage patients
after chemotherapy [47]. In cases of complete remission after first line chemotherapy (no visible tumour),
tumour resection is not indicated [195, 196]. Residual tumour resection is mandatory in all patients with a
residual mass > 1 cm in the short axis at cross-sectional CT imaging [197-200].
The role of surgery is debated in patients with retroperitoneal residual lesions < 1 cm. There is still a risk
of residual cancer or teratoma although the vast majority of patients (> 70%) harbour fibro-necrotic tissue
[201]. Proponents of post-chemotherapy-RPLND for all patients refer to the fact that both teratoma and vital
malignant germ cell tumours are still found after radiologic complete remission in lesions < 10 mm [202]. The
alternative is to put patients with residual disease < 1 cm on an observation protocol based on recurrence data
of 6-9% depending on the time of follow-up [195, 196]. In the series with a longer observation of 15.5 years,
12 of 141 patients (9%) relapsed after having achieved a complete response after primary treatment [196], but
eight of the 12 relapsing patients were cured. Therefore, patients treated with first-line chemotherapy should
be informed about this life-long risk of recurrence in the order of 10% before consenting to observe residual
lesions < 1 cm. Patients after salvage chemotherapy or high-dose chemotherapy in first or subsequent salvage
situations harbour vital tumour at a much higher rate [203]. Therefore, there is an indication to perform surgery
in salvage patients even with residual disease < 1 cm [195, 196].
If residual surgery is indicated, all areas of primary metastatic sites must be completely resected within two-six
weeks of completion of chemotherapy. If technically feasible, a bilateral nerve-sparing procedure should be
performed. There is growing evidence that template resections with unilateral preservation of nerves in selected
patients yield equivalent long-term results compared to bilateral systematic resections in all patients. The mere
resection of the residual tumour (so called lumpectomy) should not be performed [196, 201, 204-207].
Table 7.2: Standard PEI/VIP, TIP and GIP chemotherapy (interval 21 days)
The International Prognostic Factors Study Group score, comprised of seven important factors, is listed in
Table 7.3. Using these factors, 5 risk groups (very low risk = -1 points; low risk = 0 points; intermediate-risk =
1-2 points, high risk = 3-4 points; and very high risk > 5 points) were identified with significant differences in
PFS and OS. Table 4.3 illustrates the five risk groups and the corresponding two-year PFS and three-year OS
rates [235].
Table 7.3: The International Prognostic Factors Study Group Score Construction [228]
Points -1 0 1 2 3
Variable
Histology Seminoma Non-seminoma
Primary site Gonadal Retroperitoneal Mediastinal
Response CR/PRm- PRm+/SD PD
PFI > 3 months < 3 months
AFP salvage Normal < 1000 1000
hCG salvage < 1000 1000
LBB No Yes
AFP = alpha-fetoprotein; hCG = human chorionic gonadotrophin; LBB = liver, bone, brain metastases;
PD = progressive disease; PFI = progression-free interval.
Refractory disease: Patients relapsing within four-eight weeks after platinum-based therapy or who are
progressing despite platinum-based therapy as well as those relapsing shortly after HD chemotherapy are
considered cisplatinum refractory. For those patients, combinations of gemcitabine and oxaliplatin or the triple
combination of gemcitabine, oxaliplatin and paclitaxel have resulted in response rates of 25-45%. Targeted
agents have mostly failed [236-238]. Cisplatin re-challenge in association with gemcitabine and paclitaxel,
could be considered in patients with good renal function [239].
Patients with a good response undergoing subsequent resection of residual tumour lesions may
still have a 15-20% chance of long-term cure [219, 240]. Immunotherapy with PD1- checkpoint inhibitors is
currently studied due a substantial expression of PDL1 in germ cell tumours, in most series about 50% of
tumour cells or tumour infiltration cells express PDL1.
7.4.5.1 Late relapse (> two years after end of first-line treatment)
Late relapse is defined as recurrence more than two years following cure after chemotherapy for metastatic
TC, with, or without, residual tumour surgery and occurs, according to a pooled analysis, in 1.4% and 3.2%
in seminoma and non-seminoma patients, respectively [241, 242]. If feasible, all lesions of late relapsing non-
seminoma patients should be removed by radical surgery.
Patients with rapidly rising hCG may benefit from induction salvage chemotherapy before complete
resection, but in most patients surgery should be performed irrespective of the level of their tumour markers
in order to completely resect all undifferentiated germ-cell tumour, mature teratoma with or without somatic
transformation [204, 243, 244].
Survival strongly depends on the histology of the removed lesions rather than on the initial germ
cell cancer. Interestingly, in a population-based study all late-relapsing seminoma patients had viable germ cell
tumour, whereas teratoma or necrosis was found in half of the patients with initial non-seminoma [245].
If the lesions are not completely resectable, biopsies should be obtained for histological
assessment, and salvage chemotherapy should be initiated according to the histological results. In these
cases, consultation of an experienced pathologist is required to avoid misinterpretation of the therapeutic
morphological changes in the germ cell neoplasms [246]. If the patient responds to salvage chemotherapy,
secondary surgery should be conducted whenever possible. In the case of unresectable, but localised,
refractory disease, stereotactic or conventional radiotherapy may be considered. To avoid excess mortality, late
relapses should be treated only at centres experienced in managing such patients [247].
Recommendations LE GR
Treat low volume non-seminomatous germ cell tumour (NSGCT) stage IIA/B with elevated 2 A
markers like ‘good or intermediate prognosis’ advanced NSGCT, with three or four cycles of
cisplatin, etoposide, bleomycin (BEP).
In stage IIA/B NSGCT without marker elevation, exclude marker negative embryonal carcinoma 3 B
by obtaining histology by either retroperitoneal lymph node dissection (RPLND) or biopsy. If
not possible, repeat staging after six weeks of surveillance before making a final decision on
further treatment.
In metastatic NSGCT with an intermediate prognosis, treat with four courses of standard BEP. 1 A
In metastatic NSGCT with a poor prognosis, treat with one cycle of BEP, followed by tumour 1 A
marker assessment after three weeks: in the case of an unfavourable decline, initiate
chemotherapy intensification. In the case of a favourable decline, continue BEP up to a total of
four cycles.
Perform surgical resection of residual masses after chemotherapy in NSGCT in the case of 2 A
visible residual masses and when serum levels of tumour markers are normal or normalising.
Initially offer radiotherapy for seminoma CS IIA. 2 B
When necessary, use chemotherapy as a salvage treatment with the same schedule as for the
corresponding prognostic groups of NSGCT.
Initially offer chemotherapy in seminoma stage CS IIB (BEP x 3 or etoposide, cisplatin x 4, in 1a A
good prognosis) as an alternative to radiotherapy.
Treat seminoma stage IIC and higher, with primary chemotherapy according to the same 1 A
principles used for NSGCT.
It is important to note that patients not achieving a complete remission or presenting with poor prognosis
disease should be followed up individually in specialised centres.
Generally, MRI of the abdomen can be used instead of CT in experienced centres. Regarding the use of
US of the contralateral testis, the majority of the consensus meeting participants voted against repeat US
investigation, both in case of negative biopsy (21/31) and also if no contralateral biopsy has been performed
(17/32).
Follow up for relapse beyond five years is generally not recommended. A very late relapse (VLR) after five years
is a rare event occurring in approximately 0.5% of patients according to a population-based analysis [245]. The
aim of follow up beyond five years therefore shifts to detection of late side effects of treatment.
Most patients with VLR are diagnosed due to symptoms, however in up to 50% elevated tumour markers can
be found in both seminomatous and non-seminomatous germ cell tumours [245, 259]. Patient education about
relapse symptoms and physician awareness is a very important part of survivorship management. The early
use of imaging and tumour markers in case of suspicion of relapse is encouraged.
Table 8.1: R
ecommended minimal follow-up for seminoma stage I on active surveillance or after
adjuvant treatment (carboplatin or radiotherapy)
Table 8.2: Recommended minimal follow-up for non-seminoma stage I on active surveillance
Table 8.3: R
ecommended minimal follow up after adjuvant treatment or complete remission for
advanced disease (excluded: poor prognosis and no remission)
8.2.2 Leukaemia
In a series of 40,576 TC survivors, the observed/expected ratio for developing a leukaemia, mostly acute
myeloid (AML) and lymphoblastic leukaemia was 2.6 [271]. The risk of AML seems to be both related to the
dose of cisplatin and etoposide. Doses of etoposide exceeding 2 g/m2 have been shown to increase the
subsequent risk of AML [272]. It is important to keep in mind that the majority of TC patients do receive much
lower doses of etoposide such that the absolute risk of AML after three to four courses of BEP is very low, and
in patients requiring high-dose chemotherapy with cumulative etoposide doses exceeding this threshold, less
than 1.5% have been reported to suffer from AML. There is a cumulative dose-disease relationship regarding
cisplatin and AML. Chemotherapy-induced leukaemia is usually diagnosed within the first ten years after
treatment for TC and has a very poor prognosis [273].
8.2.3 Infections
Chemotherapy-treated TC survivors (TCSs) have a higher risk of dying from infections than the normal
population, (SMR 2.48, 95% CI: 1.70 to 3.50) [274]. This is possibly due to long-term depression of the
bone-marrow, but also complications of subsequent salvage treatment (which was not reliably registered)
or extensive or subsequent surgical treatment might lie behind these numbers. Furthermore, asymptomatic
pulmonary fibrosis by mediastinal radiotherapy and/or bleomycin may render TCSs vulnerable to potentially
deadly pneumonias many years after treatment.
8.2.7 Neurotoxicity
Cisplatin induces a symmetric dose-dependent sensory, distal, length-dependent glove and stocking
paraesthesias, affecting 29% of TCSs who received cisplatin-based chemotherapy as opposed to 10% after
orchiectomy alone [289]. Application of five or more cycles increases the frequency of this symptom to 46%.
Paclitaxel-induced acute neuropathy consists of an acute pain syndrome, which usually develops within three
days of paclitaxel administration, or within a week. Platinum is measurable in the serum of TCSs many years
after its application and the intensity of paraesthesias is more strongly associated with platinum serum level
than with the cumulative dose of applied cisplatin [284].
8.2.8 Ototoxicity
Cisplatin-induced ototoxicity comprises tinnitus and hearing impairment, particularly frequencies of 4,000 Hz
and higher, and is caused by damage to the outer hair cells in the inner ear [290-292]. Both hearing impairment
and tinnitus are considerably increased after application of 50 mg/m2 cisplatin over two days as compared
to 20 mg/m2 over five days (odds ratio 5.1 and 7.3, respectively), indicating a higher impact of serum peak
concentrations than cumulative doses [289]. A significant association between glutathione S-transferases
(GST) genotypes and the risk of cisplatin-induced ototoxicity has been demonstrated [293, 294]. Hopefully,
increasing insight into the pathogenesis of and vulnerability for this complication will lead to more individualised
treatment in the future.
8.2.9 Nephrotoxicity
Cisplatin-based chemotherapy may lead to long-term renal function impairment in 20-30% of TCSs [289-292].
In TC patients, reduced renal elimination of cisplatin and bleomycin might increase the risk of other toxicities,
e.g. bleomycin-related pneumonitis [295, 296]. However, a comprehensive assessment of 1,206 Danish TCSs
did not reveal a significant association between chemotherapy-induced impaired renal function and other
toxicities [279]. Renal recovery was poor after 5 or more cycles of BEP as compared to after BEP x3 [279].
8.2.10 Hypogonadism
Testicular endocrine dysfunction comprises insufficient testosterone production and/or compensatory
increased Luteinizing hormone (LH) levels. Subnormal testosterone levels have been reported in TCSs treated
with chemotherapy, when compared to those treated with surgery only or the general population [262, 297].
A recent systematic review [285] analysing the impact of previously identified pathologic risk factors on
harbouring occult metastatic disease (OMD) in patients with CS I testicular stromal tumours showed an
increased risk of occult metastatic disease for each additional risk factor (P < .001). Five-year occult metastatic
disease-free survival was 98.1% for those with < 2 risk factors vs. 44.9% for those with ≥ 2 risk factors
(P < .001). Whilst the existing literature does not support making firm recommendations, it seems to be of
interest to risk-stratify patients for future research and initiate adjuvant therapy in higher-risk patients.
These data support the importance of large databases to evaluate the efficacy of treatment in rare neoplasms.
9.2.3 Diagnosis
Patients either present with a painless enlarged testis or the tumour is found incidentally on US. In up to 80%
of cases, hormonal disorders with high oestrogen and oestradiol levels, low testosterone, and increased levels
of LH and FSH are reported [306, 307], while negative results are always obtained for the testicular germ cell
tumour-markers AFP, hCG, LDH and PLAP. Up to 10% of adult patients present with gynaecomastia [307, 308].
Diagnostic work-up must include markers, hormones (at least testosterone, LH and FSH; if not conclusive, also
oestrogen, oestradiol, progesterone and cortisol), US of both testes, and CT of chest and abdomen. On US,
it may be possible to observe well-defined, small, hypoechoic lesions with hypervascularisation, however, the
appearance is variable and is indistinguishable from germ-cell tumours [309]. Contrast-enhanced US [310] or
contrast-enhanced MRI [311] may improve the diagnosis. The proportion of metastatic tumours in all published
case reports is less than 10%. In three old series with long follow-up, eighteen metastatic tumours were found
in a total of 83 cases (21.7%) [302, 304, 312], while 5 recently published studies with long follow-up reported
only 2 metastatic tumours in 156 patients (1.3%) [113, 307, 308, 313, 314].
9.3.2.1 Classification
Three subtypes have been described [316]:
• classic Sertoli cell tumour [315];
• large cell calcifying form with characteristic calcifications [319, 320];
• sclerosing form [321, 322].
9.3.3 Diagnosis
Patients present either with an enlarged testis or the tumour is found incidentally on US. Most classic
Sertoli cell tumours are unilateral and unifocal. Hormonal disorders are infrequent, although gynaecomastia
is sometimes seen [315]. The testicular tumour-markers AFP, hCG, LDH and PLAP are always negative.
Diagnostic work-up must include tumour markers, hormones (at least testosterone, LH and FSH; if not
conclusive, also oestrogen, oestradiol, progesterone and cortisol), US of both testes and CT of chest and
The large cell calcifying form is diagnosed in younger men and is associated with genetic dysplastic syndromes
(Carney’s complex [324] and Peutz-Jeghers syndrome [325]) or, in about 40% of cases, endocrine disorders.
Forty-four percent of cases are bilateral, either synchronous or metachronous, and 28% show multifocality with
good prognosis [320].
Up to 20% of the large cell calcifying forms are malignant. It has been suggested that discrimination
between an early and late onset type may define a different risk for metastatic disease (5.5% compared to
23%) [316].
The sclerosing subtype is very rare, unilateral, with a mean age around 40 years and metastases are infrequent
[322].
When diagnosed and treated early, long-term favourable outcomes are seen at follow-up in Leydig cell
tumours, even with its potential metastatic behaviour. In stromal tumours with histological signs of malignancy,
especially in older patients, orchidectomy and early retroperitoneal lymphadenectomy may be an option to
prevent metastases [113, 327] or to achieve long-term cure in stage IIA cases [328]. Prophylactic RPLND is
unjustified for patients with CS I disease without high-risk features [329].
Tumours that have metastasised to lymph nodes, lung, liver or bone respond poorly to
chemotherapy or radiation and survival is poor [113, 327]. No recommendations are available for the treatment
of these patients.
Malignant tumours represent around 20% of cases. Lymphovascular invasion, necrosis, infiltrative borders and
size > 4 cm may help in identifying cases with aggressive behaviour. Mitotic counts vary and do not appear to
be of prognostic significance [333].
9.9 Tumours containing germ cell and sex cord/gonadal stroma (gonadoblastoma)
Some patients with disorders of sex development (DSDs) have abnormal gonadal development with ambiguous
genitalia and an increased risk of germ-cell tumours. If the arrangement of the germ cells is in a nested
pattern and the rest of the tumour is composed of sex cord/gonadal stroma, the term gonadoblastoma is
used. Bilateral tumours are present in 40% of cases. The prognosis correlates with the invasive growth of the
germinal component [336, 337].
In the case of a diffuse arrangement of the different components, there are some doubts about the
neoplastic nature of the germinal cells and some authors consider them to be entrapped rather than neoplastic
[338].
10. REFERENCES
1. Albers, P., et al. Guidelines on Testicular Cancer: 2015 Update. Eur Urol, 2015. 68: 1054.
https://www.ncbi.nlm.nih.gov/pubmed/26297604
2. Phillips, B., et al. Oxford Centre for Evidence-based Medicine Levels of Evidence. Updated by
Jeremy Howick March 2009.
http://www.cebm.net/oxford-centre-evidence-based-medicine-levels-evidence-march-2009/
3. Marconi, L., et al. Tumour size and rete testis invasion in the radical orchiectomy specimens
of patients with clinical stage I seminoma testis undergoing active surveillance risk factors for
developing disease recurrence. PROSPERO International prospective register of systematic reviews,
2017.
https://www.crd.york.ac.uk/PROSPERO/display_record.asp?ID=CRD42017056975.
4. La Vecchia, C., et al. Cancer mortality in Europe, 2000-2004, and an overview of trends since 1975.
Ann Oncol, 2010. 21: 1323.
https://www.ncbi.nlm.nih.gov/pubmed/19948741
5. Rosen, A., et al. Global trends in testicular cancer incidence and mortality. Eur Urol, 2011. 60: 374.
https://www.ncbi.nlm.nih.gov/pubmed/21612857
6. Jemal, A., et al. Cancer statistics, 2009. CA Cancer J Clin, 2009. 59: 225.
https://www.ncbi.nlm.nih.gov/pubmed/19474385
7. Nigam, M., et al. Increasing incidence of testicular cancer in the United States and Europe between
1992 and 2009. World J Urol, 2014.
https://www.ncbi.nlm.nih.gov/pubmed/25030752
8. Ghazarian, A.A., et al. Recent trends in the incidence of testicular germ cell tumors in the United
States. Andrology, 2015. 3: 13.
https://www.ncbi.nlm.nih.gov/pubmed/25331158
9. Hoffmann, R., et al. Innovations in health care and mortality trends from five cancers in seven
European countries between 1970 and 2005. Int J Public Health, 2014. 59: 341.
https://www.ncbi.nlm.nih.gov/pubmed/23989709
2. METHODS 4
2.1 Data identification 4
2.2 Review 4
2.3 Future goals 4
6. DISEASE MANAGEMENT 12
6.1 Treatment of the primary tumour 12
6.1.1 Treatment of superficial non-invasive disease (CIS) 12
6.1.2 Treatment of invasive disease confined to the glans (category Ta/T1a) 12
6.1.3 Results of different surgical organ-preserving treatments 13
6.1.3.1 Laser therapy 13
6.1.3.2 Moh’s micrographic surgery 13
6.1.3.3 Glans resurfacing 13
6.1.3.4 Glansectomy 14
6.1.3.5 Partial penectomy 14
6.1.3.6 Summary of results of surgical techniques 14
6.1.4 Results of radiotherapy for T1 and T2 disease 14
6.1.5 Summary of treatment recommendations for non-invasive and
localised superficially invasive penile cancer 15
6.1.5.1 Treatment of invasive disease confined to the corpus
spongiosum/glans (T2) 15
6.1.5.2 Treatment of disease invading the corpora cavernosa and/or
urethra (T2/T3) 15
7. FOLLOW-UP 21
7.1 Rationale for follow-up 21
7.1.1 When and how to follow-up 21
7.1.2 Recurrence of the primary tumour 21
7.1.3 Regional recurrence 21
7.1.4 Guidelines for follow-up in penile cancer 22
7.2 Quality of life 22
7.2.1 Consequences after penile cancer treatment 22
7.2.2 Sexual activity and quality of life after laser treatment 22
7.2.3 Sexual activity after glans resurfacing 22
7.2.4 Sexual activity after glansectomy 22
7.2.5 Sexual function after partial penectomy 23
7.2.6 Quality of life after partial penectomy 23
7.3 Total phallic reconstruction 23
7.4 Specialised care 23
8. REFERENCES 23
9. CONFLICT OF INTEREST 33
2. METHODS
2.1 Data identification
A systematic literature search on penile cancer was performed between August 2008 and November 2013.
All articles relating to penile cancer (n = 1,602) in the relevant literature databases were reviewed and 352
papers were considered suitable for addition to the research base of the Guidelines. Fully revised Guidelines
were produced using the updated research base, together with several national and international guidelines
on penile cancer (National Comprehensive Cancer Network [2], French Association of Urology [3] and the
European Society of Medical Oncology [4]). Recommendations in this text are assessed according to their
level of evidence (LE) and Guidelines are given a grade of recommendation (GR), according to a classification
system modified from the Oxford Centre for Evidence-Based Medicine Levels of Evidence [5]. Additional
information can be found in the general Methodology section of this print, and online at the EAU website:
http://uroweb.org/guideline/. A list of Associations endorsing the EAU Guidelines can also be viewed online at
the above address.
2.2 Review
This document was subjected to independent peer review prior to publication in 2014.
3.2 Epidemiology
In the Western World, primary penile cancer is uncommon, with an overall incidence of < 1.00/100,000 males
in Europe and the USA [7, 8] although there are several geographical areas in Europe with an incidence over
1.00/100,000 (Figure 1) [9]. In North America [7], the incidence of penile cancer is also affected by race and
ethnicity, with the incidence highest in white Hispanics (1.01/100,000) compared to Alaskans, Native American
Indians (0.77/100,000), African Americans (0.62/100,000) and white non-Hispanics (0.51/100,000), respectively.
In contrast, other parts of the world, such as South America, South East Asia and parts of Africa, have a much
higher incidence, with penile cancer accounting for 1-2% of malignant diseases in men [9].
Penile cancer is common in regions with a high prevalence of human papilloma virus (HPV), which
may account for the variation in incidence, as the worldwide HPV prevalence varies considerably [7]. The
annual age-adjusted incidence is 0.7-3.0/100,000 men in India, 8.3/100,000 men in Brazil and even higher in
Uganda, where it is the most commonly diagnosed male cancer [9, 10]. The majority of knowledge about penile
cancer comes from countries with a high incidence rate.
There is also a less noticeable variation in incidence between European regions (Figure 1). At least
one third of cases can be attributed to HPV-related carcinogenesis. There is no data linking penile cancer to
human immunodeficiency virus (HIV) or acquired immune deficiency syndrome (AIDS).
In the USA, the overall age-adjusted incidence rate decreased from 1973 to 2002 from 0.84/100,000
in 1973-1982 to 0.69/100,000 in 1983-1992, and to 0.58/100,000 in 1993-2002 [7]. In Europe, the overall
incidence has been stable from the 1980s until 2013 [8], with an increased incidence reported in Denmark [11]
and the UK. A UK longitudinal study confirmed a 21% increase in incidence from 1979-2009 [12].
The incidence of penile cancer increases with age [8]. The peak age is during the sixth decade of
life, though the disease does occur in younger men [13].
Spain, Albacete
Malta
Switzerland, Neuchatel
France, Haut-Rhin
Italy, Ragusa Province
UK, Scotland
Denmark
Austria, Tyrol
Norway
Spain, Asturias
France, Bas-Rhin
UK, England
Estonia
Slovakia
Switzerland, Ticino
The Netherlands
Belgium Flanders (excl. Limburg)
Italy, Torino
Poland, Warsaw city
Germany, Saarland
Portugal, Vila Nova de Gaia
Slovenia
Italy, Sassari
0 0.5 1.0 1.5 2.0
Table 1: Recognised aetiological and epidemiological risk factors for penile cancer
Human papilloma virus infection (HPV) is an important risk factor; HPV DNA was found in 70-100% of intra-
epithelial neoplasia and in 30-40% of invasive penile cancer tissue samples (LE: 2a). It is thought to be a
cofactor in the carcinogenesis of some variants of penile SCC [20] through interaction with oncogenes and
tumour suppressor genes (P53, Rb genes) [26]. The commonest HPV subtypes in penile cancer are types 16
and 18 [27] and the risk of penile cancer is increased in patients with condyloma acuminata [28] (LE: 2b).
3.4 Pathology
Squamous cell carcinoma accounts for > 95% of cases of penile malignancies (Tables 2 and 3). It is not known
how often SCC is preceded by premalignant lesions (Table 3) [37-40]. Some variants of primary penile cancer
have not yet been included in the World Health Organisation (WHO) classification, including pseudohyperplastic
carcinoma, carcinoma cuniculatum, pseudoglandular carcinoma, and warty-basaloid carcinoma.
There are many mixed forms of SCC, including the warty-basaloid form (50-60% of mixed penile
SCC), usual-verrucous (hybrid), usual-warty, usual-basaloid or usual-papillary and other rarer combinations.
Other penile malignant lesions include melanocytic lesions, mesenchymal tumours, lymphomas
and metastases which are unrelated to penile cancer, and rarer. Aggressive penile sarcoma has been reported.
Penile metastases from other neoplasias often have a prostatic or colorectal origin.
Lesions sporadically associated with squamous cell carcinoma (SCC) of the penis:
• Cutaneous horn of the penis
• Bowenoid papulosis of the penis
• Lichen sclerosus (balanitis xerotica obliterans)
Premalignant lesions (up to one-third transform to invasive SCC):
• Intra-epithelial neoplasia grade III
• Giant condylomata (Buschke-Löwenstein)
• Erythroplasia of Queyrat
• Bowen’s disease
• Paget’s disease (intradermal ADK)
3.4.3 Grading
The Tumour, Node, Metastasis (TNM) classification for penile cancer includes tumour grade, due to its
prognostic relevance (Table 4). Both Broder’s classification and the WHO grading system for grading penile
cancer are highly observer dependent and are no longer used [44].
Biopsy size is important; in biopsies with an average size of 0.1 cm, it is difficult to evaluate the depth of
invasion in 91% of biopsies. The grade at biopsy and in the final specimen may differ in up to 30% of cases
with failure to detect cancer in 3.5% of cases [37]. Furthermore, vascular and lymphatic tumour emboli
were detected in only 9-11% of cases. Although a punch biopsy may be sufficient for superficial lesions, an
excisional biopsy is preferred as it should be deep enough to properly assess the degree of invasion and stage.
Table 4: 2016 TNM clinical and pathological classification of penile cancer [63]
Clinical classification
T - Primary Tumour
TX Primary tumour cannot be assessed
T0 No evidence of primary tumour
Tis Carcinoma in situ
Ta Non-invasive verrucous carcinoma*
T1 Tumour invades subepithelial connective tissue
T1a Tumour invades subepithelial connective tissue without lymphovascular invasion and is not
poorly differentiated (T1G1-2)
T1b Tumour invades subepithelial connective tissue with lymphovascular invasion or is poorly
differentiated (T1G3-4)
T2 Tumour invades corpus spongiosum with or without invasion of the urethra
T3 Tumour invades corpus cavernosum with or without invasion of the urethra
T4 Tumour invades other adjacent structures
N - Regional Lymph Nodes
NX Regional lymph nodes cannot be assessed
N0 No palpable or visibly enlarged inguinal lymph nodes
N1 Palpable mobile unilateral inguinal lymph node
N2 Palpable mobile multiple or bilateral inguinal lymph nodes
N3 Fixed inguinal nodal mass or pelvic lymphadenopathy, unilateral or bilateral
M - Distant Metastasis
M0 No distant metastasis
M1 Distant metastasis
Pathological classification
The pT categories correspond to the clinical T categories. The pN categories are based upon biopsy or
surgical excision
pN - Regional Lymph Nodes
pNX Regional lymph nodes cannot be assessed
pN0 No regional lymph node metastasis
pN1 Metastasis in one or two inguinal lymph nodes
pN2 Metastasis in more than two unilateral inguinal nodes or bilateral inguinal lymph nodes
pN3 Metastasis in pelvic lymph node(s), unilateral or bilateral extranodal extension of regional lymph node
metastasis
pM - Distant Metastasis
pM0 No distant metastasis
pM1 Distant metastasis
G - Histopathological Grading
GX Grade of differentiation cannot be assessed
G1 Well differentiated
G2 Moderately differentiated
G3-4 Poorly differentiated/undifferentiated
The further diagnostic management of patients with normal inguinal nodes should be guided by pathological
risk factors. Lymphovascular invasion, local stage and grade are risk factors for the likelihood of lymphatic
metastasis [72, 73]. Existing nomograms are not accurate enough. Invasive lymph node staging is required in
patients at intermediate or high risk of lymphatic spread (see Section 6.2).
5.4 Summary of evidence and recommendations for the diagnosis and staging of penile
cancer
Recommendations GR
Primary tumour
Perform a physical examination, record morphology, extent and invasion of penile structures. C
Obtain MRI with artificial erection in cases for which organ-preserving surgery is intended.
Inguinal lymph nodes
Perform a physical examination of both groins, record the number, laterality and characteristics of C
inguinal nodes and:
• if nodes are not palpable, offer invasive lymph node staging in high-risk patients;
• if nodes are palpable, stage with a pelvic computed tomography (CT) or positron
emissiontomography (PET)/CT.
Distant metastases
In N+ patients, obtain an abdominopelvic CT scan and chest X-ray for systemic staging. Alternatively, C
stage with a PET/CT scan.
In patients with systemic disease or with relevant symptoms, obtain a bone scan.
6. DISEASE MANAGEMENT
6.1 Treatment of the primary tumour
Treatment of the primary penile cancer lesion aims to remove the tumour completely, while preserving as much
of the penis as possible without compromising radicality. Local recurrence has little effect on long-term survival
so that organ preservation strategies can be used [80].
The overall quality of the available research evidence is low. There are no randomised controlled
trials or observational studies for surgical management of localised penile cancer nor studies comparing
surgical and non-surgical modalities.
Penile preservation appears to be superior in functional and cosmetic outcomes. It is the primary
treatment method for men with localised penile cancer. However, there are no randomised studies comparing
organ-preserving and ablative treatment strategies, only retrospective studies with a LE: 3, or less.
Histological diagnosis with local staging must be obtained in all cases, especially if considering non-
surgical treatment modalities. Treatment of the primary tumour and of the regional nodes can be staged. It is
mandatory to remove all malignant tissue with negative surgical margins. Patients must be counselled about all
relevant treatment modalities.
Local treatment modalities for small and localised penile cancer include excisional surgery, external
beam radiotherapy (EBRT), brachytherapy and laser ablation.
6.1.5.2 Treatment of disease invading the corpora cavernosa and/or urethra (T2/T3)
Partial amputation with a tumour-free margin and reconstruction is standard [114]. A surgical margin of 5 mm is
considered safe [84, 85]. Patients should remain under close follow-up. Radiotherapy is an option.
6.2.1 Management of patients with clinically normal inguinal lymph nodes (cN0)
Risk stratification for the management of patients with clinically normal lymph nodes depends on stage, grade
and the presence or absence of lymphovascular invasion in the primary tumour [84]. Tumours with low risk
of metastatic disease are those with superficial penile cancer (pTa, pTis) and low grade. pT1 tumours are a
heterogeneous risk group: low risk if they are well differentiated (pT1G1) intermediate-risk group (pT1G2) [85] or
high risk (pT1G3 and all higher stages).
Early inguinal lymphadenectomy in clinically node-negative patients is far superior for long-term
patient survival compared to therapeutic lymphadenectomy when regional nodal recurrence occurs [86, 87].
One prospective study comparing bilateral lymphadenectomy, radiotherapy and surveillance in clinically
node-negative patients reported that five-year OS was significantly better with inguinal lymphadenectomy
vs. immediate inguinal radiotherapy or that observed with a surveillance strategy (74% vs. 66% and 63%,
respectively) [88].
6.2.1.1 Surveillance
The surveillance of regional lymph nodes carries the risk of regional recurrence arising later from existing
micrometastatic disease. Patient survival is over 90% with early lymphadenectomy and below 40% with
lymphadenectomy for later regional recurrence [89, 90]. This risk must be taken into account when considering
surveillance and informing the patient. Surveillance can only be recommended in patients with pTis and pTa
penile cancer and with the appropriate caveats in pT1G1 tumours [89-91]. A prerequisite for surveillance is
good patient information and compliance.
node biopsy is not reliable in patients with palpably enlarged and suspicious inguinal lymph nodes and should
not be used [123] (LE: 3).
6.2.5 The role of radiotherapy for the treatment of lymph node disease
The use of radiotherapy for nodal disease follows tradition and single-institution policies and is not evidence
based. Despite the lack of data, radiotherapy is widely used in some European countries to manage regional
lymph node metastasis in penile cancer.
It has not been reported that neoadjuvant or adjuvant radiotherapy improves oncological outcome
in node-positive penile cancer [145]. One prospective trial found that inguinal node dissection was superior to
inguinal radiotherapy [146]. Another study reported poor long-term survival in patients with adjuvant inguinal
and pelvic radiotherapy [147]. Adjuvant chemotherapy has been reported to be far superior to adjuvant
radiotherapy after radical inguinal lymphadenectomy in node-positive patients in one retrospective series [140].
Using the National Cancer Institute Surveillance, Epidemiology and End Results (SEER) Program database,
treatment results of 2,458 penile cancer patients treated with either surgery alone or surgery plus EBRT showed
that the addition of adjuvant radiotherapy ‘had neither a harmful nor a beneficial effect on CSS’ [148].
Due to the lack of evidence, radiotherapy in the treatment of lymph node disease in penile cancer
is not generally recommended. Prophylactic radiotherapy for cN0 disease is not indicated. Adjuvant inguinal
radiotherapy may be considered as an option in selected patients with extracapsular nodal extension (cN3) or
as a palliative treatment for surgically irresectable disease.
6.3 Chemotherapy
6.3.1 Adjuvant chemotherapy in node-positive patients after radical inguinal lymphadenectomy
Multimodal treatment can improve patient outcome in many tumour types. Adjuvant chemotherapy after
resection of nodal metastases in penile carcinoma has been reported in a few small and heterogeneous series
[141, 149-152]. Comparing different small-scale clinical studies is fraught with difficulty.
The value of adjuvant chemotherapy after radical inguinal lymphadenectomy in node-positive penile
cancer was demonstrated by an Italian group who reported long-term (DFS) of 84% in 25 consecutive patients
treated with twelve adjuvant weekly courses of vincristine, bleomycin, and methotrexate (VBM) during the
period 1979-1990 and compared this to a historical control group of 38 consecutive node-positive patients with
radical lymphadenectomy (with- or without adjuvant inguinal radiotherapy) who had achieved a DFS rate of
only 39% [141].
This group has also published results of a chemotherapy regimen adjuvant to radical
lymphadenectomy in stage pN2-3 patients receiving three courses of cisplatin and 5-fluorouracil (5-FU) which
they had been using since 1991 with lower toxicity and even better results compared to VBM [151] (LE: 2b).
The same group has been using an adjuvant taxane-based regimen since 2004, cisplatin, 5-FU plus paclitaxel
or docetaxel (TPF), in nineteen node-positive patients receiving three to four cycles of TPF after resection of
pN2-3 disease [152]. Of those patients, 52.6% were disease-free after a median follow up of 42 months and
tolerability was good. Results of adjuvant treatment with paclitaxel and cisplatin also improved outcome [153].
The use of adjuvant chemotherapy is recommended, in particular when the administration of the
triple combination chemotherapy is feasible, and curative treatment is aimed for (LE: 2b). No data for the
adjuvant chemotherapeutic treatment of penile carcinoma in stage pN1 are available. The administration of an
adjuvant treatment in pN1 disease is therefore recommended only in clinical trials.
Recommendations LE GR
Treat patients with pN2-3 tumours with adjuvant chemotherapy (three-four cycles of cisplatin, 2b C
5-fluorouracil, paclitaxel or docetaxel).
Treat patients with non-resectable or recurrent lymph node metastases with neoadjuvant 2a B
chemotherapy (4 cycles of a cisplatin and taxane-based regimen) followed by radical surgery.
Treat patients with systemic disease and a limited metastatic load with chemotherapy. 3 C
8. REFERENCES
1. Hakenberg, O.W., et al. EAU guidelines on penile cancer: 2014 update. Eur Urol, 2015. 67: 142.
http://www.ncbi.nlm.nih.gov/pubmed/25457021
2. Clark, P.E., et al. Penile cancer: Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw,
2013. 11: 594.
http://www.ncbi.nlm.nih.gov/pubmed/23667209
3. Souillac, I., et al. [Penile cancer in 2010: update from the Oncology Committee of the French
Association of Urology: external genital organs group (CCAFU-OGE)]. Prog Urol, 2011. 21: 909.
http://www.ncbi.nlm.nih.gov/pubmed/22118355
4. Van Poppel, H., et al. Penile cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and
follow-up. Ann Oncol, 2013. 24 Suppl 6: vi115.
http://www.ncbi.nlm.nih.gov/pubmed/23975666
5. Phillips B, et al. Oxford Centre for Evidence-based Medicine Levels of Evidence. Updated by
Jeremy Howick March 2009. 1998.
http://www.cebm.net/oxford-centre-evidence-based-medicine-levels-evidence-march-2009
6. Robinson, R., et al. What are the risks and benefits of adjuvant radiotherapy after inguinal
lymphadenectomy for penile cancer? 2015. PROSPERO CRD42015024904.
https://www.crd.york.ac.uk/PROSPERO/display_record.asp?ID=CRD42015024904
7. Backes, D.M., et al. Systematic review of human papillomavirus prevalence in invasive penile
cancer. Cancer Causes Control, 2009. 20: 449.
http://www.ncbi.nlm.nih.gov/pubmed/19082746
1. INTRODUCTION 4
1.1 Aim and objectives 4
1.2 Panel composition 4
1.3 Available publications 4
1.4 Publication history 4
2. METHODS 4
2.1 Introduction 4
2.2 Review 4
2.3 Patients to whom the guidelines apply 4
4. DIAGNOSTIC EVALUATION 6
4.1 Medical History 6
4.2 Symptom score questionnaires 7
4.2.1 The International Prostate Symptom Score (IPSS) 7
4.2.2 The International Consultation on Incontinence Questionnaire (ICIQ-MLUTS) 7
4.2.3 Danish Prostate Symptom Score (DAN-PSS) 7
4.3 Frequency volume charts and bladder diaries 7
4.4 Physical examination and digital-rectal examination 7
4.4.1 Digital-rectal examination and prostate size evaluation 7
4.5 Urinalysis 8
4.6 Prostate-specific antigen (PSA) 8
4.6.1 PSA and the prediction of prostatic volume 8
4.6.2 PSA and the probability of PCa 8
4.6.3 PSA and the prediction of BPO-related outcomes 8
4.7 Renal function measurement 9
4.8 Post-void residual urine 9
4.9 Uroflowmetry 9
4.10 Imaging 10
4.10.1 Upper urinary tract 10
4.10.2 Prostate 10
4.10.2.1 Prostate size and shape 10
4.10.3 Voiding cysto-urethrogram 10
4.11 Urethrocystoscopy 10
4.12 Urodynamics 11
4.12.1 Diagnosing bladder outlet obstruction 11
4.12.2 Videourodynamics 11
4.13 Non-invasive tests in diagnosing bladder outlet obstruction in men with LUTS 12
4.13.1 Prostatic configuration/intravesical prostatic protrusion (IPP) 12
4.13.2 Bladder/detrusor wall thickness and ultrasound-estimated bladder weight 12
4.13.3 Non-invasive pressure-flow testing 12
4.13.4 The diagnostic performance of non-invasive tests in diagnosing bladder outlet
obstruction in men with LUTS compared with pressure-flow studies 12
5. DISEASE MANAGEMENT 14
5.1 Conservative treatment 14
5.1.1 Watchful waiting 14
5.1.2 Behavioural and dietary modifications 14
5.1.3 Practical considerations 14
5.2 Pharmacological treatment 14
5.2.1 α1-Adrenoceptor antagonists (α1-blockers) 14
5.2.2 5α-reductase inhibitors 16
5.2.3 Muscarinic receptor antagonists 17
5.2.4 Phosphodiesterase 5 inhibitors 18
5.2.5 Plant extracts - phytotherapy 19
2 MANAGEMENT OF NON-NEUROGENIC MALE LOWER URINARY TRACT SYMPTOMS (LUTS) - UPDATE MARCH 2017
5.2.6 Beta-3 agonist 20
5.2.7 Combination therapies 20
5.2.7.1 α1-blockers + 5α-reductase inhibitors 20
5.2.7.2 α1-blockers + muscarinic receptor antagonists 22
5.3 Surgical treatment 22
5.3.1 Transurethral resection of the prostate and transurethral incision of the prostate 22
5.3.1.1 Modifications of TURP: bipolar TURP 23
5.3.2 Open prostatectomy 24
5.3.3 Transurethral microwave therapy (TUMT) 25
5.3.4 Transurethral needle ablation of the prostate 26
5.3.5 Laser treatments of the prostate 26
5.3.5.1 Holmium laser enucleation and holmium laser resection of the prostate 26
5.3.5.2 532 nm (‘Greenlight’) laser vaporisation of prostate 27
5.3.5.3 Diode laser vaporisation of the prostate 28
5.3.5.4 Thulium:yttrium-aluminium-garnet laser (Tm:YAG) 29
5.3.6 Prostatic stents 30
5.3.7 Prostatic urethral lift 30
5.3.8 Novel interventions 31
5.3.8.1 Intra-prostatic injections 31
5.3.8.2 Minimal invasive simple prostatectomy 32
5.4 Patient selection 32
5.5 Management of Nocturia in men with lower urinary tract symptoms 34
5.5.1 Diagnostic assessment 35
5.5.2 Medical conditions and sleep disorders Shared Care Pathway 36
5.5.3 Treatment for Nocturia 37
5.5.3.1 Antidiuretic therapy 37
5.5.3.2 Medications to treat LUTD 38
5.5.3.3 Other medications 38
6. FOLLOW-UP 38
6.1 Watchful waiting (behavioural) 38
6.2 Medical treatment 38
6.3 Surgical treatment 39
7. REFERENCES 39
8. CONFLICT OF INTEREST 63
MANAGEMENT OF NON-NEUROGENIC MALE LOWER URINARY TRACT SYMPTOMS (LUTS) - UPDATE MARCH 2017 3
1. INTRODUCTION
1.1 Aim and objectives
Lower urinary tract symptoms (LUTS) are a common complaint in adult men with a major impact on quality of
life (QoL), and substantial economic burden. The present Guidelines offer practical evidence-based guidance
on the assessment and treatment of men aged 40 years or older with various non-neurogenic benign forms
of LUTS. The understanding of the LUT as a functional unit, and the multifactorial aetiology of associated
symptoms, means that LUTS now constitute the main focus, rather than the former emphasis on Benign
Prostatic Hyperplasia (BPH). It must be emphasised that clinical guidelines present the best evidence available
to the experts. However, following guideline recommendations will not necessarily result in the best outcome.
Guidelines can never replace clinical expertise when making treatment decisions for individual patients, but
rather help to focus decisions - also taking personal values and preferences/individual circumstances of
patients into account. Guidelines are not mandates and do not purport to be a legal standard of care.
2. METHODS
2.1 Introduction
For the 2017 Management of Non-Neurogenic Male LUTS Guidelines, new and relevant evidence has
been identified, collated and appraised through a structured assessment of the literature. A broad and
comprehensive literature search, covering all sections of the Non-Neurogenic Male LUTS Guidelines was
performed. The search was limited to studies representing high levels of evidence, i.e. systematic reviews with
meta-analysis, randomised controlled trials (RCTs), and prospective non-randomised comparative studies,
published in the English language. Databases searched included Medline, EMBASE, and the Cochrane
Libraries, covering a time frame between April 1st 2015 and May 31st 2016. A total of 1,622 unique records
were identified, retrieved and screened for relevance. A detailed search strategy is available online: http://www.
uroweb.org/guideline/ treatment-of-non-neurogenic-male-luts/supplementary-material.
References used in this text are assessed according to their level of evidence (LE) and Guidelines
are given a grade of recommendation (GR), according to a classification system modified from the Oxford
Centre for Evidence-Based Medicine Levels of Evidence [1]. Additional methodology information can be
found in the general Methodology section of this print, and online at the EAU website: http://www.uroweb.
org/guidelines/. A list of all Associations endorsing the EAU Guidelines can also be viewed online at the above
address.
2.2 Review
The Non-Neurogenic Male LUTS Guidelines were peer reviewed prior to publication in 2016.
4 MANAGEMENT OF NON-NEUROGENIC MALE LOWER URINARY TRACT SYMPTOMS (LUTS) - UPDATE MARCH 2017
non-neurogenic and non-malignant conditions such as LUTS/Benign Prostatic Obstruction (BPO), detrusor
overactivity/overactive bladder (OAB), or nocturnal polyuria. Men with other contexts of LUT disease (e.g.
concomitant neurological diseases, young age, prior LUT disease or surgery) usually require a more extensive
work-up, which is not covered in these Guidelines, but may include several tests mentioned in the following
sections. EAU Guidelines on Neuro-Urology, Urinary Incontinence, Urological Infections, Urolithiasis, or
malignant diseases of the LUT have been developed by other EAU Guidelines Panels and are available online:
www.uroweb.org/guidelines/.
The definitions of the most common conditions related to male LUTS are presented below:
• Acute retention of urine is defined as a painful, palpable or percussible bladder, when the patient is
unable to pass any urine [2];
• Chronic retention of urine is defined as a non-painful bladder, which remains palpable or percussible after
the patient has passed urine. Such patients may be incontinent [2];
• Bladder outlet obstruction is the generic term for obstruction during voiding and is characterised
by increasing detrusor pressure and reduced urine flow rate. It is usually diagnosed by studying the
synchronous values of flow-rate and detrusor pressure [2];
• Benign prostatic obstruction is a form of BOO and may be diagnosed when the cause of outlet
obstruction is known to be BPE [2]. In the Guidelines either the term BPO or BOO is used as reported by
the original studies;
• Benign prostatic hyperplasia is a term used (and reserved) for the typical histological pattern, which
defines the disease;
• Detrusor overactivity (DO) is a urodynamic observation characterised by involuntary detrusor contractions
during the filling phase which may be spontaneous or provoked [2];
• Overactive bladder syndrome is characterised by urinary urgency, with or without urgency urinary
incontinence, usually with increased daytime frequency and nocturia, if there is no proven infection or
other obvious pathology [14].
Figure 1 illustrates the potential causes of LUTS. In any man complaining of LUTS, it is common for more than
one of these factors to be present.
MANAGEMENT OF NON-NEUROGENIC MALE LOWER URINARY TRACT SYMPTOMS (LUTS) - UPDATE MARCH 2017 5
Figure 1: Causes of male lower urinary tract symptoms (LUTS)
Benign
prostatic
Detrusor obstruction
under- Others
activity
Overactive
bladder / Distal
detrusor ureteric
overactivity stone
Nocturnal Bladder
polyuria LUTS tumour
Chronic
pelvic pain Urethral
syndrome stricture
Neurogenic Foreign
bladder body
dysfunction Urinary
tract
infection
4. DIAGNOSTIC EVALUATION
Tests are useful for diagnosis, monitoring, assessing the risk of disease progression, treatment planning, and
the prediction of treatment outcomes. The clinical assessment of patients with LUTS has two main objectives:
• to identify the differential diagnoses, since the origin of male LUTS is multifactorial, the relevant EAU
Guidelines on the management of applicable conditions should be followed in these cases;
• to define the clinical profile (including the risk of disease progression) of men with LUTS in order to
provide appropriate care.
Recommendation LE GR
Take a complete medical history from men with LUTS. 4 A*
*Upgraded based on Panel consensus.
6 MANAGEMENT OF NON-NEUROGENIC MALE LOWER URINARY TRACT SYMPTOMS (LUTS) - UPDATE MARCH 2017
4.2 Symptom score questionnaires
All published guidelines for male LUTS/BPH recommend using validated symptom score questionnaires [15,
17]. Several questionnaires have been developed which are sensitive to symptom changes and can be used
to monitor treatment [20-26]. Symptom scores are helpful in quantifying LUTS and in identifying which type
of symptoms are predominant, yet they are not disease-, or age-specific. A systematic review evaluating
the diagnostic accuracy of individual symptoms and questionnaires, compared with urodynamic studies
(the reference standard) for the diagnosis of BOO in males with LUTS found that individual symptoms and
questionnaires for diagnosing BOO were not significantly associated with one another [27].
Recommendation LE GR
Use a validated symptom score questionnaire including quality of life assessment during the 3 B
assessment of male LUTS and for re-evaluation during and/or after treatment.
Recommendations LE GR
Use a bladder diary to assess male LUTS with a prominent storage component or nocturia. 3 B
Tell the patient to complete a bladder diary for the duration of at least three days. 2b B
MANAGEMENT OF NON-NEUROGENIC MALE LOWER URINARY TRACT SYMPTOMS (LUTS) - UPDATE MARCH 2017 7
has been developed to help urologists estimate prostate volume more accurately [38]. One study concluded
that DRE was sufficient to discriminate between prostate volumes > or < than 50 mL [39].
Recommendation LE GR
Perform a physical examination including digital rectal examination in the assessment of male 3 B
LUTS.
4.5 Urinalysis
Urinalysis (dipstick or sediment) must be included in the primary evaluation of any patient presenting with LUTS
to identify conditions, such as urinary tract infections (UTI), microhaematuria and diabetes mellitus. If abnormal
findings are detected further tests are recommended according to other EAU Guidelines, including Guidelines
on urinary tract cancers and urological infections [40-43].
Urinalysis is recommended in most Guidelines in the primary management of patients with LUTS
[44, 45]. There is limited evidence, yet general expert consensus that the benefits outweigh the costs [46]. The
value of urinary dipstick/microscopy for diagnosing UTI in men with LUTS without acute frequency and dysuria
has recently been questioned [47].
Recommendation LE GR
Use urinalysis (by dipstick or urinary sediment) in the assessment of male LUTS. 3 A*
*Upgraded based on Panel consensus.
Recommendations LE GR
Measure prostate-specific antigen (PSA) if a diagnosis of prostate cancer will change 1b A
management.
Measure PSA if it assists in the treatment and/or decision making process. 1b A
8 MANAGEMENT OF NON-NEUROGENIC MALE LOWER URINARY TRACT SYMPTOMS (LUTS) - UPDATE MARCH 2017
4.7 Renal function measurement
Renal function may be assessed by serum creatinine or estimated glomerular filtration rate (eGFR).
Hydronephrosis, renal insufficiency or urinary retention are more prevalent in patients with signs or symptoms
of BPO [61]. Even though BPO may be responsible for these complications, there is no conclusive evidence on
the mechanism [62].
One study reported that 11% of men with LUTS had renal insufficiency [61]. Neither symptom score
nor QoL was associated with the serum creatinine level. Diabetes mellitus or hypertension were the most
likely causes of the elevated creatinine concentration. Comiter et al. [63] reported that non-neurogenic voiding
dysfunction is not a risk factor for elevated creatinine levels. Koch et al. [64] concluded that only those with an
elevated creatinine level require investigational ultrasound (US) of the kidney.
In the Olmsted County community-dwelling men, there was a cross-sectional association between
signs and symptoms of BPO (though not prostate volume) and chronic kidney disease (CKD) [65]. In 2,741
consecutive patients who presented with LUTS, decreased Qmax, a history of hypertension and/or diabetes
were associated with CKD [66]. Another study demonstrated a correlation between Qmax and eGFR in middle-
aged men with moderate-to-severe LUTS [67]. Patients with renal insufficiency are at an increased risk of
developing post-operative complications [68].
Recommendation LE GR
Assess renal function if renal impairment is suspected based on history and clinical 3 A*
examination, or in the presence of hydronephrosis, or when considering surgical treatment for
male LUTS.
*Upgraded based on Panel consensus.
Recommendation LE GR
Measure post-void residual in the assessment of male LUTS. 3 B
4.9 Uroflowmetry
Urinary flow rate assessment is a widely used non-invasive urodynamic test. Key parameters are Qmax and
flow pattern. Uroflowmetry parameters should preferably be evaluated with voided volume > 150 mL. As Qmax
is prone to within-subject variation [73, 74], it is useful to repeat uroflowmetry measurements, especially if
thevoided volume is < 150 mL, or Qmax or flow pattern is abnormal.
The diagnostic accuracy of uroflowmetry for detecting BOO varies considerably, and is substantially
influenced by threshold values. A threshold Qmax of 10 mL/s has a specificity of 70%, a PPV of 70% and a
sensitivity of 47% for BOO. The specificity using a threshold Qmax of 15 mL/s was 38%, the PPV 67% and
the sensitivity 82% [75]. If Qmax is > 15 mL/s, physiological compensatory processes mean that BOO cannot
be excluded. Low Qmax can arise as a consequence of BOO [76], detrusor underactivity or an under-filled
bladder [77]. Therefore, it is limited as a diagnostic test as it is unable to discriminate between the underlying
mechanisms. Specificity can be improved by repeated flow rate testing. Uroflowmetry can be used for
monitoring treatment outcomes [78] and correlating symptoms with objective findings.
MANAGEMENT OF NON-NEUROGENIC MALE LOWER URINARY TRACT SYMPTOMS (LUTS) - UPDATE MARCH 2017 9
Recommendation LE GR
Uroflowmetry in the initial assessment of male LUTS may be performed and should be 2b B
performed prior to any treatment.
4.10 Imaging
4.10.1 Upper urinary tract
Routine imaging of the upper urinary tract in men with LUTS is not recommended, as these men are not at
increased risk for upper tract malignancy or other abnormalities when compared to the overall population [64,
79-81]. Several arguments support the use of renal US in preference to intravenous urography (IVU). Ultrasound
allows for better characterisation of renal masses, the possibility of investigating the liver and retroperitoneum,
and simultaneous evaluation of the bladder, PVR and prostate, together with a lower cost, radiation dose and
less side effects [79].
Recommendation LE GR
Perform ultrasound of the upper urinary tract in men with LUTS and a large post-void residual, 3 B
or haematuria, or a history of urolithiasis.
4.10.2 Prostate
Imaging of the prostate can be performed by transabdominal US, TRUS, computed tomography (CT),
and magnetic resonance imaging (MRI). However, in daily practice, prostate imaging is performed by
transabdominal US or TRUS [79].
Recommendations LE GR
Perform imaging of the prostate (either by transrectal or transabdominal ultrasound) when 3 B
considering medical treatment for male LUTS, if it assists in the choice of the appropriate drug.
Perform imaging of the prostate (either by transrectal or transabdominal ultrasound) when 3 B
considering surgical treatment.
4.11 Urethrocystoscopy
Patients with a history of microscopic or gross haematuria, urethral stricture, or bladder cancer, who present
with LUTS, should undergo urethrocystoscopy during diagnostic evaluation.
Shoukry et al. evaluated 122 patients with LUTS using uroflowmetry and urethrocystoscopy [84].
The pre-operative Qmax was normal in 25% of 60 patients who had no bladder trabeculation, 21% of 73
patients with mild trabeculation and 12% of 40 patients with marked trabeculation on cystoscopy. All 21
patients who presented with diverticula had a reduced Qmax.
Anikwe showed that there was no significant correlation between the degree of bladder
trabeculation (graded from I to IV), and the pre-operative Qmax value in 39 symptomatic men aged 53-83 years
[85]. The largest study published on this issue examined the relation of urethroscopic findings to urodynamic
studies in 492 elderly men with LUTS [86]. The authors noted a correlation between cystoscopic appearance
(grade of bladder trabeculation and urethral occlusion) and urodynamic indices, DO and low compliance. It
should be noted, however, that BOO was present in 15% of patients with normal cystoscopic findings, while
8% of patients had no obstruction, even in the presence of severe trabeculation [86].
10 MANAGEMENT OF NON-NEUROGENIC MALE LOWER URINARY TRACT SYMPTOMS (LUTS) - UPDATE MARCH 2017
Recommendation LE GR
Perform urethrocystoscopy in men with LUTS to exclude suspected bladder or urethral 3 B
pathology and/or prior to minimally invasive/surgical therapies if the findings may change
treatment.
4.12 Urodynamics
In male LUTS, the most widespread invasive urodynamic techniques employed are filling cystometry and
pressure flow studies (PFS). The major goal of urodynamics is to explore the functional mechanisms of LUTS
and to identify risk factors for adverse outcomes (for informed/shared decision-making). Most terms and
conditions (e.g. DO, low compliance, BOO/BPO, DUA) are defined by urodynamic investigation.
4.12.2 Videourodynamics
Videourodynamics provides additional anatomical and functional information and may be recommended if the
clinician considers this is needed to understand the pathophysiological mechanism of an individual patient’s
LUTS.
Recommendations LE GR
Perform pressure-flow studies (PFS) only in individual patients with specific indications prior to 3 B
invasive treatment or when evaluation of the underlying pathophysiology of LUTS is warranted.
Perform PFS in men who have had previously unsuccessful (invasive) treatment for LUTS. 3 B
When considering invasive treatment, pressure-flow studies may be used for patients who 3 C
cannot void > 150 mL.
When considering invasive treatment in men with bothersome voiding LUTS, PFS may be 3 C
performed in men with a post-void residual > 300 mL.
When considering invasive treatment in men with bothersome, predominantly voiding LUTS, 3 C
PFS may be performed in men aged > 80 years.
When considering invasive treatment in men with bothersome, predominantly voiding LUTS, 3 B
perform PFS in men aged < 50 years.
MANAGEMENT OF NON-NEUROGENIC MALE LOWER URINARY TRACT SYMPTOMS (LUTS) - UPDATE MARCH 2017 11
4.13 Non-invasive tests in diagnosing bladder outlet obstruction in men with LUTS
4.13.1 Prostatic configuration/intravesical prostatic protrusion (IPP)
Prostatic configuration can be evaluated with TRUS, using the concept of the presumed circle area ratio
(PCAR) [95]. The PCAR evaluates how closely the transverse US image of the prostate approaches a circular
shape. The ratio tends toward one as the prostate becomes more circular. The sensitivity of PCAR was 77% for
diagnosing BPO when PCAR was > 0.8, with 75% specificity [95].
Ultrasound measurement of IPP assesses the distance between the tip of the prostate median
lobe and bladder neck in the midsagittal plane, using a suprapubically positioned US scanner, with a bladder
volume of 150-250 mL; grade I protrusion is 0-4.9 mm, grade II is 5-10 mm and grade III is > 10 mm.
Intravesical prostatic protrusion correlates well with BPO (presence and severity) on urodynamic
testing, with a PPV of 94% and a NPV of 79% [96]. Intravesical prostatic protrusion may also correlate with
prostate volume, DO, bladder compliance, detrusor pressure at maximum urinary flow, BOO index and PVR,
and negatively correlates with Qmax [97]. Furthermore, IPP also appears to successfully predict the outcome
of a trial without catheter (TWOC) after AUR [98, 99]. However, no information with regard to intra- or inter-
observer variability and learning curve is yet available. Therefore, IPP may be a feasible option to infer BPO in
men with LUTS. The role of IPP as a non-invasive alternative to PFS in the assessment of male LUTS is under
evaluation.
4.13.4 The diagnostic performance of non-invasive tests in diagnosing bladder outlet obstruction in
men with LUTS compared with pressure-flow studies
The diagnostic performance of non-invasive tests in diagnosing BOO in men with LUTS compared with PFS
has been investigated by a systematic review performed by the Panel [116].
A total of 42 studies were included in this review, this summary print version is supplemented by a
detailed online version (http://uroweb.org/guideline/treatment-of-non-neurogenic-male-luts/). The majority were
prospective cohort studies, and the diagnostic accuracy of the following non-invasive tests were assessed:
penile cuff test; uroflowmetry; detrusor/bladder wall thickness; bladder weight; external condom catheter
method; IPP; doppler US; prostate volume/height; near-infrared spectroscopy. Overall, although the majority of
studies have a low risk of bias, data regarding the diagnostic accuracy of these non-invasive tests is limited by
the heterogeneity of the studies in terms of the threshold values used to define BOO, the different urodynamic
definitions of BOO used across different studies and the small number of studies for each test. It was found
that specificity, sensitivity, PPV and NPV of the non-invasive tests were highly variable. Therefore, even though
12 MANAGEMENT OF NON-NEUROGENIC MALE LOWER URINARY TRACT SYMPTOMS (LUTS) - UPDATE MARCH 2017
several tests have shown promising results regarding non-invasive diagnosis of BOO, invasive urodynamics
remains the modality of choice.
Recommendation LE GR
None of the non-invasive tests in diagnosing bladder outlet obstruction in men with LUTS can 1a B
currently be recommended as an alternative to pressure-flow studies.
Yes
Abnormal DRE Significant PVR
Suspicion of
neurological disease
High PSA
Abnormal urinalysis FVC in cases of predominant
US of kidneys storage LUTS/nocturia
+/- Renal function US assessment of prostate
assessment Uroflowmetry
Evaluate according to
relevant guidelines or
clinical standard Benign conditions of
Medical treatment
according to treatment bladder and/or prostate
algorithm with baseline values
PLAN TREATMENT
Treat underlying
condition
(if any, otherwise Endoscopy (if test would alter the
return to initial choice of surgical modality)
assessment) Pressure flow studies (see text for
specific indications)
DRE = digital-rectal examination; FVC = frequency volume chart; LUTS = lower urinary tract symptoms;
PCa = prostate cancer; PSA = prostate specific antigen; PVR = post-void residual; US = ultrasound.
MANAGEMENT OF NON-NEUROGENIC MALE LOWER URINARY TRACT SYMPTOMS (LUTS) - UPDATE MARCH 2017 13
5. DISEASE MANAGEMENT
5.1 Conservative treatment
5.1.1 Watchful waiting
Many men with LUTS are not troubled enough by their symptoms to need drug treatment or surgical
intervention. All men with LUTS should be formally assessed prior to any allocation of treatment in order
to establish symptom severity and to differentiate between men with uncomplicated (the majority) and
complicated LUTS. Watchful waiting is a viable option for many men with non-bothersome LUTS as few will
progress to AUR and complications (e.g. renal insufficiency or stones) [117, 118], whilst others can remain
stable for years [119]. In one study, approximately 85% of men with mild LUTS were stable on WW at one year
[120].
A study comparing WW and transurethral resection of the prostate (TURP) in men with moderate
LUTS showed the surgical group had improved bladder function (flow rates and PVR volumes), especially
in those with high levels of bother; 36% of WW patients crossed over to surgery within five years, leaving
64% doing well in the WW group [121, 122]. Increasing symptom bother and PVR volumes are the strongest
predictors of clinical failure. Men with mild-to-moderate uncomplicated LUTS who are not too troubled by their
symptoms are suitable for WW.
There now exists evidence (LE: 1b) that self-management as part of WW reduces both symptoms and
progression [123, 124] (online supplementary Table S.12). Men randomised to three self-management sessions
in addition to standard care had better symptom improvement and QoL than men treated with standard care
only for up to a year [123].
Recommendations LE GR
Offer men with mild/moderate symptoms, minimally bothered by their symptoms, watchful 1b A
waiting.
Offer men with LUTS lifestyle advice prior to or concurrent with treatment. 1b A
14 MANAGEMENT OF NON-NEUROGENIC MALE LOWER URINARY TRACT SYMPTOMS (LUTS) - UPDATE MARCH 2017
α1-adrenoceptors located outside the prostate (e.g. urinary bladder and/or spinal cord)
and α1-adrenoceptor subtypes (α1B- or α1D-adrenoceptors) may play a role as mediators of effects.
α1-adrenoceptors in blood vessels, other non-prostatic smooth muscle cells, and the central nervous system
may mediate adverse events.
α1-blockers currently available are: alfuzosin hydrochloride (alfuzosin); doxazosin mesylate
(doxazosin); silodosin; tamsulosin hydrochloride (tamsulosin); terazosin hydrochloride (terazosin). α1-blockers
exist in different formulations (online supplementary Table S.13). Although different formulations result in
different pharmacokinetic and tolerability profiles, the overall clinical impact of the different formulations is
modest.
Efficacy: Indirect comparisons and limited direct comparisons between α1-blockers demonstrate that all
α1-blockers have a similar efficacy in appropriate doses [129]. Effects take a few weeks to develop fully, but
significant efficacy over placebo can occur within hours to days [130].
Controlled studies show that α1-blockers typically reduce IPSS by approximately 30-40%
and increase Qmax by approximately 20-25% (online supplementary Table S.14). However, considerable
improvements also occurred in the corresponding placebo arms [55, 130]. In open-label studies, an IPSS
improvement of up to 50% and Qmax increase of up to 40% were documented [55, 130].
α1-blockers can reduce both storage and voiding LUTS. Prostate size does not affect α1-blocker
efficacy in studies with follow-up periods of less then one year, but α1-blockers do seem to be more efficacious
in patients with smaller prostates (< 40 mL) in longer-term studies [56, 131-134]. α1-blocker efficacy is similar
across age groups [130]. α1-blockers neither reduce prostate size nor prevent AUR in long-term studies
[132-134]. Nevertheless, IPSS reduction and Qmax improvement during α1-blocker treatment appears to be
maintained over at least four years.
Tolerability and safety: Tissue distribution, subtype selectivity, and pharmacokinetic profiles of certain
formulations may contribute to the tolerability profile of specific drugs. The most frequent adverse events of
α1-blockers are asthenia, dizziness and (orthostatic) hypotension. Vasodilating effects are most pronounced
with doxazosin and terazosin, and are less common for alfuzosin and tamsulosin [135]. Patients with
cardiovascular comorbidity and/or vaso-active co-medication may be susceptible to α1-blocker-induced
vasodilatation [136]. In contrast, the frequency of hypotension with the α1A- selective blocker silodosin is
comparable with placebo [137]. In a large retrospective cohort analysis of men aged > 66 years treated with α
blockers, the risks of falling (odds ratio [OR] 1.14) and of sustaining a fracture (OR 1.16) was increased, most
likely as a result of induced hypotension [138].
An adverse ocular event termed intra-operative floppy iris syndrome (IFIS) was reported in 2005,
affecting cataract surgery [139]. A meta-analysis on IFIS after alfuzosin, doxazosin, tamsulosin or terazosin
exposure showed an increased risk for all α1-blockers [140]. However, the OR for IFIS was much higher for
tamsulosin. It appears prudent not to initiate α1-blocker treatment prior to scheduled cataract surgery, and the
ophthalmologist should be informed about α1-blocker use.
A systematic review concluded that α1-blockers do not adversely affect libido, have a small
beneficial effect on erectile function, but sometimes cause abnormal ejaculation [141]. Originally, abnormal
ejaculation was thought to be retrograde, but more recent data demonstrate that it is due to a decrease or
absence of seminal fluid during ejaculation, with young age being an apparent risk factor. In a recent meta-
analysis ejaculatory dysfunction (EjD) was significantly more common with α1-blockers than with placebo (OR
5.88). In particular, EjD was significantly more commonly related with tamsulosin or silodosin (OR: 8.57 and
32.5) than placebo, while both doxazosin and terazosin (OR 0.80 and 1.78) were associated with a low risk of
EjD [142]. In the meta-regression, the occurrence of EjD was independently associated with the improvement of
urinary symptoms and flow rate, suggesting that the more effective the α1-blocker is the greater the incidence
of EjD.
Practical considerations: α1-blockers are often considered the first line drug treatment of male LUTS because
of their rapid onset of action, good efficacy, and low rate and severity of adverse events. However, α1-blockers
do not prevent occurrence of urinary retention or need for surgery. Ophthalmologists should be informed about
α1-blocker use prior to cataract surgery. Elderly patients treated with non-selective α1-blockers should be
informed about the risk of orthostatic hypotension. Sexually active patients treated with selective α1-blockers
should be counselled about the risk of EjD.
MANAGEMENT OF NON-NEUROGENIC MALE LOWER URINARY TRACT SYMPTOMS (LUTS) - UPDATE MARCH 2017 15
Recommendations LE GR
Offer α1-blockers to men with moderate-to-severe LUTS. 1a A
Counsel patients about the treatment related side effects associated with selective versus non- 1a A
selective α-blockers.
Two 5α-reductase inhibitors (5-ARIs) are available for clinical use: dutasteride and finasteride (online
supplementary Table S.15). Finasteride inhibits only 5α-reductase type 2, whereas dutasteride inhibits
5α-reductase types 1 and 2 with similar potency (dual 5-ARI). 5-ARIs act by inducing apoptosis of prostate
epithelial cells [144] leading to prostate size reduction of about 18-28% and a decrease in circulating PSA
levels of about 50% after six to twelve months of treatment [145]. Mean prostate volume reduction and PSA
decrease may be even more pronounced after long-term treatment. Continuous treatment reduces the serum
DHT concentration by approximately 70% with finasteride and 95% with dutasteride. However, prostate DHT
concentration is reduced to a similar level (85-90%) by both 5-ARIs.
Efficacy: Clinical effects relative to placebo are seen after a minimum treatment duration of at least six to
twelve months. After two to four years of treatment, 5-ARIs improve IPSS by approximately 15-30%, decrease
prostate volume by 18-28%, and increase Qmax by 1.5-2.0 mL/s in patients with LUTS due to prostate
enlargement (online supplementary Table S.16) [56, 133, 134, 146-152]. A indirect comparison and one direct
comparative trial (twelve months duration) indicate that dutasteride and finasteride are equally effective in the
treatment of LUTS [145, 153]. Symptom reduction depends on initial prostate size.
Finasteride may not be more efficacious than placebo in patients with prostates < 40 mL [154].
However, dutasteride seems to reduce IPSS, prostate volume, and the risk of AUR, and to increase Qmax
even in patients with prostate volumes of between 30 and 40 mL at baseline [155, 156]. A long-term trial with
dutasteride in symptomatic men with prostate volumes > 30 mL and increased risk for disease progression
showed that dutasteride reduced LUTS at least as much as, or even more effectively than, the α1-blocker
tamsulosin [133, 152, 157]. The greater the baseline prostate volume (or serum PSA concentration), the faster
and more pronounced the symptomatic benefit of dutasteride as compared to tamsulosin.
5-ARIs, but not α1-blockers, reduce the long-term (> one year) risk of AUR or need for surgery [56,
150, 158]. In the PLESS study, finasteride treatment reduced the relative risk of AUR by 57%, and surgery by
55% at four years, compared with placebo [150]. In the MTOPS study, a significant reduction in the risk of AUR
and surgery in the finasteride arm compared with placebo was reported (68% and 64%, respectively) [56].
A pooled analysis of randomised trials with two-year follow-up data, reported that treatment with finasteride
significantly decreased the occurrence of AUR by 57%, and surgical intervention by 34%, in moderately
symptomatic LUTS [159]. Dutasteride has also demonstrated efficacy in reducing the risks for AUR and BPH-
related surgery. Open-label trials have demonstrated relevant changes in urodynamic parameters [160, 161].
Finasteride might reduce blood loss during transurethral prostate surgery, probably due to its effects
on prostatic vascularisation [162].
Tolerability and safety: The most relevant adverse effects of 5-ARIs are related to sexual function, and
include reduced libido, erectile dysfunction (ED) and less frequently, ejaculation disorders such as retrograde
ejaculation, ejaculation failure, or decreased semen volume [56, 134, 145]. The incidence of sexual dysfunction
and other adverse events is low and even decreased with trial duration. Gynaecomastia (with breast or nipple
tenderness) develops in 1-2% of patients.
Data from two trials on PCa chemoprevention (the Prostate Cancer Prevention Trial and the
Reduction by Dutasteride of Prostate Cancer Events trial) found a higher incidence of high-grade cancers
in the 5-ARIs arms [163, 164]. Although no causal relationship with high-grade PCa has been proven, men
taking 5-ARIs should be followed-up regularly using serial PSA testing and any confirmed PSA increase should
be evaluated accordingly. There is a long-standing debate regarding potential cardiovascular side effects of
5-ARIs, in particular dutasteride [165]. In a five year population-based study performed in Taiwan, Hsieh et
al. could not identify an association between the use of 5-ARIs and increased cardiovascular side effects, in
elderly men (> 65 years) [165].
Practical considerations: Treatment with 5-ARIs should be considered in men with moderate-to-severe LUTS
16 MANAGEMENT OF NON-NEUROGENIC MALE LOWER URINARY TRACT SYMPTOMS (LUTS) - UPDATE MARCH 2017
and an enlarged prostate (> 40 mL) and/or elevated PSA concentration (> 1.4-1.6 ng/mL). 5α-reductase
inhibitors can prevent disease progression with regard to acute urinary retention and the need for surgery. Due
to the slow onset of action, they are suitable only for long-term treatment (years). Their effect on the serum PSA
concentration needs to be considered in relation to PCa screening.
Recommendations LE GR
Use 5α-reductase inhibitors in men who have moderate-to-severe LUTS and an enlarged 1b A
prostate (> 40 mL).
Counsel patients about the delayed symptom improvement with 5α-reductase inhibitors. 1a A
Efficacy: Antimuscarinics were mainly tested in females in the past, as it was believed that LUTS in men were
caused by the prostate, so should be treated with prostate-specific drugs. However, there is no scientific data
for this assumption [172]. A sub-analysis of an open-label trial of OAB patients showed that age but not gender
had an impact on urgency, frequency, or urgency incontinence [173]. In a pooled analysis, which included a
sub-analysis of male patients, fesoterodine 8 mg was superior to tolterodine extended release (ER) 4 mg for the
improvement of severe urgency episodes/24 hours and the OAB-q Symptom Bother score at week twelve, the
urinary retention rate was around 2% [174].
The efficacy of antimuscarinics as single agents in men with OAB in the absence of BOO have
been tested (online supplementary Table S.18) [175-180]. Most trials lasted only twelve weeks. Four post
hoc analyses of large RCTs on the treatment of OAB in women and men without presumed BOO were
performed focusing only on the men [176, 178, 181]. Tolterodine can significantly reduce urgency incontinence,
daytime or 24-hour frequency and urgency-related voiding whilst improving patient perception of treatment
benefit. Solifenacin significantly improved mean patient perception of bladder condition scores, mean
OAB questionnaire scores, and overall perception of bladder problems. Fesoterodine improved micturition
frequency, urgency episodes, and urgency urinary incontinence (UUI) episodes. In open-label trials with
tolterodine, daytime frequency, nocturia, UUI, and IPSS were significantly reduced compared with baseline
values after 12-25 weeks [177, 180].
In the Tolterodine and Tamsulosin in Men with LUTS including OAB: Evaluation of Efficacy and
Safety Study, men who received tolterodine monotherapy saw improvement only in urgency incontinence, but
not urgency, IPSS (total or storage subscore), or the overall percentage of patients reporting treatment benefit
compared with placebo [179].
A further analysis showed that men with PSA levels of < 1.3 ng/mL (smaller prostates) might benefit
more from antimuscarinic drugs [182]. Two other studies found a positive effect of antimuscarinics in patients
with OAB and concomitant BPO [180, 183]. In a small RCT without placebo, propiverine improved frequency
and urgency episodes [183]. In an open-label study, tolterodine decreased 24-hour micturition, nocturia and
American Urological Association Symptom Index scores [180].
Tolerability and safety: Antimuscarinic drug trials generally show approximately 3-10% withdrawals, which
is similar to placebo. Drug-related adverse events include dry mouth (up to 16%), constipation (up to 4%),
micturition difficulties (up to 2%), nasopharyngitis (up to 3%), and dizziness (up to 5%).
Increased PVR in men without BOO is minimal and similar to placebo. Nevertheless, fesoterodine
8 mg showed higher PVRs (+20.2 mL) than placebo (-0.6 mL) or fesoterodine 4 mg (+9.6 mL) [179]. Incidence
of urinary retention in men without BOO was similar to placebo for tolterodine (0-1.3% vs. 0-1.4%). With
fesoterodine 8 mg, 5.3% had symptoms, which was higher than placebo or fesoterodine 4 mg (both 0.8%).
MANAGEMENT OF NON-NEUROGENIC MALE LOWER URINARY TRACT SYMPTOMS (LUTS) - UPDATE MARCH 2017 17
These symptoms appeared during the first two weeks of treatment and mainly affected men aged 66 years or
older.
Theoretically antimuscarinics might decrease bladder strength, and hence might be associated with
PVR urine or urinary retention. A twelve week safety study on men with mild to moderate BOO showed that
tolterodine increased the PVR (49 mL vs. 16 mL) but not acute urinary retention (3% in both arms) [184]. The
urodynamic effects included larger bladder volumes at first detrusor contraction, higher maximum cystometric
capacity, and decreased bladder contractility index. Qmax was unchanged. This trial indicated that short-term
treatment with antimuscarinics in men with BOO is safe [184].
Practical considerations: Not all antimuscarinics have been tested in elderly men, and long-term studies on
the efficacy of muscarinic receptor antagonists in men of any age with LUTS are not yet available. In addition,
only patients with low PVR volumes at baseline were included in the studies. These drugs should therefore be
prescribed with caution, and regular re-evaluation of IPSS and PVR urine is advised. Men should be advised to
discontinue medication if worsening voiding LUTS or urinary stream is noted after initiation of therapy.
Recommendations LE GR
Use muscarinic receptor antagonists in men with moderate-to-severe LUTS who mainly have 1b B
bladder storage symptoms.
Prescribe antimuscarinics with caution in men with a post-void residual volume > 150 mL. 4 C
Available drugs: Although clinical trials of several selective oral PDE5Is have been conducted in men with
LUTS, only tadalafil (5 mg once daily) has been licensed for the treatment of male LUTS.
Efficacy: Several RCTs have demonstrated that PDE5Is reduce IPSS, storage and voiding LUTS, and improve
QoL (online supplementary Table S.19). However, Qmax did not significantly differ from placebo in most trials. In
a meta-analysis, PDE5Is were found to improve IPSS and IIEF score, but not Qmax [188].
Tadalafil 5 mg reduces IPSS by 22-37% (online supplementary Table S.19), and improvement
may be seen within a week of initiation of treatment [189]. A three point or greater total IPSS improvement
was observed in 59.8% of tadalafil treated men within one week and in 79.3% within four weeks [190]. The
maximum trial (open label) duration was 52 weeks [191]. A subgroup analysis of pooled data from four RCTs
demonstrated a significant reduction in LUTS, regardless of baseline severity, age, previous use of α-blockers
or PDE5Is, total testosterone level or predicted prostate volume [192]. In a recent post hoc analysis of
pooled data from four RCTs, tadalafil was shown to also be effective in men with cardiovascular risk factors/
comorbidities except for patients receiving more than one antihypertensive medication. The use of diuretics
may contribute to patients’ perception of a negated efficacy [193]. Among sexually active men > 45 years with
comorbid LUTS/BPH and ED, tadalafil improved both conditions [194].
An integrated data analyses from four placebo controlled clinical studies showed that total IPSS
improvement was largely attributed to direct (92.5%, p < 0.001) vs. indirect (7.5%, p = 0.32) treatment effects
via IIEF-EF improvement [195]. Another analysis showed a small but significant increase in Qmax without any
effect on PVR [196].
A combination of PDE5Is and α-blockers has also been evaluated. A meta-analysis of five RCTs
(two studies with tadalafil 20 mg, two with sildenafil 25 mg, and one with vardenafil 20 mg), showed that
combination therapy significantly improved IPSS score (-1.8), IIEF score (+3.6) and Qmax (+1.5 mL/s) compared
with α-blockers alone [188]. The effects of tadalafil 5 mg combined with finasteride 5 mg were assessed in a
26-week placebo-controlled RCT. The combination of tadalafil and finasteride provided an early improvement in
urinary symptoms (p < 0.022 after 4, 12 and 26 weeks), with a significant improvement of storage and voiding
symptoms and QoL. Combination therapy was well tolerated and improved erectile function [197]. However,
only tadalafil 5 mg has been licensed in the context of LUTS management while data on combinations of
PDE5Is and other LUTS medications is emerging.
18 MANAGEMENT OF NON-NEUROGENIC MALE LOWER URINARY TRACT SYMPTOMS (LUTS) - UPDATE MARCH 2017
Tolerability and safety: Reported adverse effects in RCTs comparing the effect of all PDE5Is vs. placebo in men
with LUTS include flushing, gastroesophageal reflux, headache, dyspepsia, back pain and nasal congestion
[188]. Discontinuation rate due to adverse effects for tadalafil was 2.0% [198] and did not differ by age, LUTS
severity, testosterone levels, or prostate volume in the pooled data analyses [192].
PDE5Is are contraindicated in patients using nitrates, the potassium channel opener nicorandil,
or the α1-blockers doxazosin and terazosin. They are also contraindicated in patients who have unstable
angina pectoris, have had a recent myocardial infarction (< three months) or stroke (< six months), myocardial
insufficiency (New York Heart Association stage > 2), hypotension, poorly controlled blood pressure, significant
hepatic or renal insufficiency, or if anterior ischaemic optic neuropathy with sudden loss of vision is known or
was reported after previous use of PDE5Is.
Practical considerations: To date, only tadalafil 5 mg once daily has been officially licensed for the treatment of
male LUTS with or without ED. The meta-regression suggested that younger men with low body mass index
and more severe LUTS benefit the most from treatment with PDE5Is [188]. Long-term experience with tadalafil
in men with LUTS is limited to one trial with a one year follow-up [191], therefore conclusions about its efficacy
or tolerability greater than one year are not possible. There is limited information on reduction of prostate size
and no data on disease progression.
Recommendation LE GR
Use phosphodiesterase type 5 inhibitors in men with moderate-to-severe LUTS with or without 1a A
erectile dysfunction.
Efficacy: The extracts of the same plant produced by different companies do not necessarily have the same
biological or clinical effects, therefore the effects of one brand cannot be extrapolated to others [202]. In
addition, batches from the same producer may contain different concentrations of active ingredients [203].
A review of recent extraction techniques and their impact on the composition/biological activity of Serenoa
repens based available products showed that results from different clinical trials must be compared strictly
according to the same validated extraction technique and/or content of active compounds [204]. Thus the
pharmacokinetic properties can vary significantly.
Online supplementary Table S.20 presents the trials with the highest LE for each plant extract.
In general, no phytotherapeutic agent has been shown to reduce prostate size, and no trial has proven a
reduction of BOO or a decrease in disease progression.
A cochrane meta-analyses suggest that men treated with Pygeum africanum were twice as likely
to report symptom improvement whilst men treated with Secale cereale were twice as likely to benefit from
therapy compared to placebo and that Serenoa repens was not superior to placebo, finasteride, or tamsulosin
for IPSS (similar levels of IPSS improvements in trials with finasteride or tamsulosin might be interpreted as
treatment equivalence) [205-207].
Recently, short-term studies on the combination of plant extracts with tamsulosin have been
published with promising results [208, 209]. Combination treatment with Serenoa Repens (SeR), lycopene (Ly),
selenium (Se) and tamsulosin was more effective than single therapies (SeR-Ly-Se or tamsulosin) in improving
IPSS and increasing Qmax in patients with LUTS at twelve months. The combination treatment of Serenoa
repens and tamsulosin was shown to be more effective than tamsulosin monotherapy in reducing storage
symptoms but changes in IPSS, voiding subscore, QoL, Qmax, PVR, PSA, and prostate volume showed no
significant differences between the two groups.
MANAGEMENT OF NON-NEUROGENIC MALE LOWER URINARY TRACT SYMPTOMS (LUTS) - UPDATE MARCH 2017 19
Tolerability and safety: Side-effects during phytotherapy are generally mild and comparable to placebo. Serious
adverse events were not related to the study medication. Gastrointestinal complaints were the most commonly
reported. In formulations with Hypoxis rooperi, ED was reported in 0.5% of patients.
Practical considerations: Phytotherapeutic agents are a heterogeneous group and may contain differing
concentrations of active ingredients. Hence, meta-analyses may not be justified and results of any analyses
have to be interpreted with caution.
Panel interpretation: The Guidelines Panel has not made any specific recommendations on phytotherapy for
the treatment of male LUTS due to product heterogeneity, a limited regulatory framework, and methodological
limitations of the published trials and meta-analyses.
Efficacy: Mirabegron 50 mg is the first clinically available beta-3 agonist with approval for use in adults with
OAB. Mirabegron has undergone extensive evaluation in RCTs conducted in Europe, Australia, North America
and Japan [210-214]. Mirabegron demonstrated significant efficacy in treating the symptoms of OAB, including
micturition frequency, urgency incontinence, and urgency and also patient perception of treatment benefit.
These studies had a predominantly female study population.
Mirabegron as an add-on therapy has been studied in OAB patients with incontinence despite
antimuscarinic therapy [215], again in a predominantly-female study population. An Asian study with a higher
proportion of male subjects (approximately one third) reported superiority over placebo in reducing frequency
of micturition, but did not report the results separately for the genders [216].
Tolerability and safety: The most common treatment-related adverse events in the mirabegron groups were
hypertension, UTI, headache and nasopharyngitis [210-213]. Mirabegron is contraindicated in patients with
severe uncontrolled hypertension (systolic blood pressure > 180 mmHg or diastolic blood pressure > 110
mmHg, or both). Blood pressure should be measured before starting treatment and monitored regularly during
treatment. The proportion of patients with dry mouth and constipation in the mirabegron groups was notably
lower than reported in RCTs of other OAB agents or of the active control tolterodine [210]. Evaluation of
urodynamic parameters in men with combined BOO and OAB concluded that mirabegron did not adversely
affect voiding urodynamic parameters compared to placebo in terms of Qmax, detrusor pressure at maximum
flow and bladder contractility index [217]. The overall change in PVR with mirabegron is small [217].
Practical considerations: Long-term studies on the efficacy and safety of mirabegron in men of any age with
LUTS are not yet available. Studies on the use of mirabegron in combination with other pharmacotherapeutic
agents for male LUTS are pending. However, pharmacokinetic interaction upon add-on of mirabegron or
tamsulosin to existing tamsulosin or mirabegron therapy does not cause clinically relevant changes in safety
profiles [218]. One small study has looked at change in symptom scores in men receiving mirabegron with
tamsulosin 0.2 mg daily [219]. A phase four study, with a small proportion of male subjects, reported addition of
mirabegron in people with persisting urgency despite solifenacin in a Japanese population [220].
Recommendation LE GR
Use beta-3 agonists in men with moderate-to-severe LUTS who mainly have bladder storage 1b B
symptoms.
Efficacy: Several studies have investigated the efficacy of combination therapy against an α1-blocker, 5-ARI or
placebo alone (online supplementary Table S.21). Initial studies with follow-up periods of six to twelve months
demonstrated that the α1-blocker was superior to finasteride in symptom reduction, whereas combination
therapy of both agents was not superior to α1-blocker monotherapy [147, 148, 221]. In studies with a placebo
20 MANAGEMENT OF NON-NEUROGENIC MALE LOWER URINARY TRACT SYMPTOMS (LUTS) - UPDATE MARCH 2017
arm, the α1-blocker was consistently more effective than placebo, but finasteride was not. Data at one year in
the MTOPS study showed similar results [56].
Long-term data (four years) from MTOPS, and Combination of Avodart and Tamsulosin (CombAT)
studies showed that combination treatment is superior to monotherapy for symptoms and Qmax, and superior
to α-blocker alone in reducing the risk of AUR or need for surgery [56, 133, 134].
The CombAT study demonstrated that combination treatment is superior to either monotherapy
regarding symptoms and flow rate starting from month nine, and superior to α1-blocker for AUR and the
need for surgery after eight months [134]. Thus the differences in MTOPS may reflect different inclusion and
exclusion criteria and baseline patient characteristics.
Discontinuation of the α1-blocker after six to nine months of combination therapy was investigated
by an RCT and an open-label multicentre trial [222, 223]. The first trial evaluated the combination of tamsulosin
with dutasteride and the impact of tamsulosin discontinuation after six months [222], with almost three-
quarters of patients reporting no worsening of symptoms. However, patients with severe symptoms (IPSS > 20)
at baseline may benefit from longer combination therapy.
A more recent trial evaluated the symptomatic outcome of finasteride monotherapy at three
and nine months after discontinuation of nine-month combination therapy [223]. LUTS improvement
after combination therapy was sustained at three months (IPSS difference 1.24) and nine months (IPSS
difference 0.4). The limitations of the studies include the short duration and the short follow-up period after
discontinuation.
In both the MTOPS and CombAT studies, combination therapy was superior to monotherapy in preventing
clinical progression as defined by an IPSS increase of at least four points, AUR, UTI, incontinence, or an
increase in creatinine > 50%. The MTOPS study found that the risk of long-term clinical progression (primarily
due to increasing IPSS) was reduced by 66% with combined therapy vs. placebo and to a greater extent than
with either finasteride or doxazosin monotherapy (34% and 39%, respectively) [56]. In addition, finasteride
(alone or in combination), but not doxazosin, significantly reduced both the risks of AUR and the need for BPH
related surgery over the four-year study. In the CombAT study, combination therapy reduced the relative risks
of AUR by 68%, BPH-related surgery by 71%, and symptom deterioration by 41% compared with tamsulosin,
after four years [224]. To prevent one case of urinary retention and/or surgical treatment thirteen patients need
to be treated for four years with dutasteride and tamsulosin combination therapy compared to tamsulosin
monotherapy while the absolute risk reduction (risk difference) was 7.7%.
The CONDUCT study compared efficacy and safety of a fixed-dose combination of dutasteride and tamsulosin
to a WW approach with the potential initiation of tamsulosin (step-up approach) in a two year RCT with a total
of 742 patients. In both arms detailed lifestyle advice was given. This fixed-dose combination resulted in a
rapid and sustained improvement in men with moderate LUTS at risk of disease progression, the difference
in IPSS at 24 months was 1.8 points (p < 0.001) [225]. Furthermore, tamsulosin plus dutasteride significantly
reduced the relative risk of clinical progression (mainly characterised as a worsening in symptoms) by 43.1%
when compared with WW, with an absolute risk reduction of 11.3% (number needed to treat [NNT] = 9).
The influence of baseline variables on changes in IPSS after combination therapy with dutasteride
plus tamsulosin or either monotherapy was tested based on the four year results of the CombAT study.
Combination therapy provided consistent improvement of LUTS over tamsulosin across all analysed baseline
variables at 48 months [226].
More recently, a combination of the 5-ARI, finasteride, and tadalafil 5 mg was tested in a large scale
RCT against finasteride monotherapy. This study supports the concept of this novel combination therapy and is
described in more detail in the chapter on PDE5Is [197].
Tolerability and safety: Adverse events for both drug classes have been reported with combination treatment
[56, 133, 134]. The adverse events observed during combination treatment were typical of α1-blockers and
5-ARIs. The frequency of adverse events was significantly higher for combination therapy.
Practical considerations: Compared with α1-blockers or 5-ARI monotherapy, combination therapy results in
a greater improvement in LUTS and increase in Qmax, and is superior in prevention of disease progression.
However, combination therapy is also associated with a higher rate of adverse events. Combination therapy
should therefore be prescribed primarily in men who have moderate-to-severe LUTS and are at risk of disease
progression (higher prostate volume, higher PSA concentration, advanced age, higher PVR, lower Qmax, etc.).
Combination therapy should only be used when long-term treatment (more than twelve months) is intended
and patients should be informed about this. Discontinuation of the α1-blocker after six months might be
considered in men with moderate LUTS.
MANAGEMENT OF NON-NEUROGENIC MALE LOWER URINARY TRACT SYMPTOMS (LUTS) - UPDATE MARCH 2017 21
Recommendation LE GR
Use combination treatment of an α1-blocker and 5α-reductase inhibitor in men with moderate- 1b A
to-severe LUTS and risk of disease progression (e.g. prostate volume > 40 mL).
Efficacy: Several RCTs and prospective studies investigated combination therapy, lasting four to twelve
weeks, either as an initial treatment in men with OAB and presumed BPO or as a sequential treatment for
storage symptoms persisting while on an α1-blocker [179, 180, 224, 227-233] (online supplementary Table
S.22). One trial used the α1-blocker naftopidil (not registered in most European countries) with and without
antimuscarinics [234]. A high proportion of men with voiding and storage LUTS need to add anticholinergics
after α1-blocker monotherapy, particularly those with longer duration of symptoms at presentation, and men
with storage symptoms and a small prostate volume [235].
Combination treatment is more efficacious in reducing urgency, UUI, voiding frequency, nocturia, or
IPSS compared with α1-blockers or placebo alone, and improves QoL [179, 236]. Symptom improvement is
higher regardless of PSA concentration, whereas tolterodine alone improved symptoms mainly in men with a
serum PSA of < 1.3 ng/mL [182].
Persistent LUTS during α1-blocker treatment can be reduced by the additional use
of an antimuscarinic, [180, 224, 227, 233, 237, 238]. Two systematic reviews of the efficacy and safety
of antimuscarinics in men suggested that combination treatment provides significant benefit [239, 240].
Effectiveness of therapy is evident primarily in those men with moderate-to-severe storage LUTS [241]. Long
term use of combination therapy has been reported in patients receiving treatment for up to a year, showing
symptomatic response is maintained, with a low incidence of AUR [242]. In men with moderate-to-severe
storage symptoms, voiding symptoms and PVR < 150 mL, the reduction in symptoms using combination
therapy is associated with patient-relevant improvements in health related quality of life (HRQoL) compared
with placebo and α1-blocker monotherapy [243].
Tolerability and safety: Adverse events of both drug classes are seen with combined treatment using
α1-blockers and antimuscarinics. The most common side-effect is xerostomia. Some side-effects (e.g.
xerostomia or ejaculation failure) may show increased incidence which cannot simply be explained by
summing the incidence with the drugs used separately. Increased PVR may be seen, but is usually not clinically
significant, and risk of AUR is low [239, 240]. Antimuscarinics do not cause evident deterioration in maximum
flow rate used in conjunction with an α1-blocker in men with OAB symptoms [236, 244].
A recent RCT investigated safety in terms of maximum detrusor pressure and Qmax for solifenacin
(6 mg or 9 mg) with tamsulosin in men with LUTS and BOO compared with placebo [245]. The combination
therapy was not inferior to placebo for the primary urodynamic variables; Qmax was increased versus placebo
[245].
Practical considerations: Class effects are likely to underlie efficacy and QoL using an α1-blocker and
antimuscarinic. Trials used mainly storage symptom endpoints, were of short duration, and included only men
with low PVR volumes at baseline. Therefore, measuring PVR is recommended during combination treatment.
Recommendations LE GR
Use combination treatment of an α1-blocker with a muscarinic receptor antagonist in patients 1b B
with moderate-to-severe LUTS if relief of storage symptoms has been insufficient with
monotherapy with either drug.
Prescribe combination treatment with caution in men with a post-void residual volume 2b B
> 150 mL.
22 MANAGEMENT OF NON-NEUROGENIC MALE LOWER URINARY TRACT SYMPTOMS (LUTS) - UPDATE MARCH 2017
Efficacy: In a recent analysis of 20 contemporary RCTs with a maximum follow-up of five years, TURP resulted
in a substantial mean Qmax improvement (+162%), a significant reduction in IPSS (-70%), QoL score (-69%),
and PVR (-77%) [246]. TURP delivers durable outcomes as shown by studies with a follow-up of 8-22 years.
There are no similar data on durability for any other surgical treatment for BPO [247]. One study with a mean
follow-up of thirteen years reported a significant and sustained decrease in most symptoms and improvement
in urodynamic parameters. Failures were associated with DUA rather than re-development of BPO [92].
Online supplementary Table S.24 presents RCTs comparing TUIP with TURP [248-255]. A meta-
analysis of short- and long-term data from ten RCTs found similar LUTS improvements and lower but
insignificant improvements in Qmax for TUIP [250]. In this meta-analysis, an upper limit of prostate size was
reported as an entry criterion for eight studies with five < 30 mL and three < 60 mL.
A second prostatic operation, usually re-TURP, has been reported at a constant annual rate of
approximately 1-2%. A review analysing 29 RCTs found a retreatment rate of 2.6% after a mean follow-up of
sixteen months [256]. In a large-scale study of 20,671 men, the overall retreatment rates (re-TURP, urethrotomy
and bladder neck incision) were 5.8%, 12.3%, and 14.7%, at one, five, and eight years follow-up, respectively,
and the respective incidence of re-TURP was 2.9%, 5.8% and 7.4% [257]. A meta-analysis of six trials showed
that re-operation was more common after TUIP (18.4%) than after TURP (7.2%) [250].
Tolerability and safety: Peri-operative mortality and morbidity have decreased over time, but the latter
remains considerable (0.1% and 11.1%, respectively) [258]. The possibility of increased long-term mortality
compared to open surgery [259] has not been verified [260-262]. Data from 20,671 TURPs and 2,452 open
prostatectomies (OP) showed that short- and long-term procedural mortality was similar (0.7% vs. 0.9% at 90
days, 2.8% vs. 2.7% at one year, 12.7% vs. 11.8% at five years, 20% vs. 20.9% at eight years) and that the
eight year myocardial infarction rates were identical (4.8% vs. 4.9%) [257].
The risk of TUR-syndrome decreased to < 1.1% [256, 263]. No case has been recorded after TUIP.
Data from 10,654 TURPs reported bleeding requiring transfusion in 2.9% [258]. The risk after TUIP is negligible.
Similar results for TURP complications were reported by an analysis of contemporary RCTs using TURP as a
comparator: bleeding requiring transfusion 2% (0-9%), TUR-syndrome 0.8% (0-5%), AUR 4.5% (0-13.3%), clot
retention 4.9% (0-39%), and UTI 4.1% (0-22%) [246]. Long-term complications comprise urinary incontinence
(1.8% after TUIP vs. 2.2% after TURP), urinary retention and UTIs, bladder neck contracture (BNC) (4.7% after
TURP), urethral stricture (3.8% after TURP vs. 4.1% after TUIP), retrograde ejaculation (65.4% after TURP vs.
18.2% after TUIP), and ED (6.5% after TURP) [256].
Practical considerations: TURP and TUIP are effective treatments for moderate-to-severe LUTS secondary
to BPO. The choice should be based primarily on prostate volume (< 30 mL and 30-80 mL suitable for TUIP
and TURP, respectively). No studies on the optimal cut-off value exist but the complication rates increase with
prostate size [258]. The upper limit for TURP is suggested as 80 mL (based on Panel expert opinion, under the
assumption that this limit depends on the surgeon’s experience, resection speed, and choice of resectoscope
size).
Efficacy: Bipolar TURP is the most widely and thoroughly investigated alternative to M-TURP. Results from
> 40 RCTs [266] have been reported, of which around half have been pooled in RCT-based meta-analyses [246,
267-270]. Early pooled results concluded that no clinically relevant differences exist in short-term (up to twelve
months) efficacy (IPSS, QoL score and Qmax) [268]. Subsequent meta-analyses supported these conclusions
[246, 267, 269, 270], though trial quality was generally poor. Data from RCTs with a follow-up of 12-60 months
show no differences in efficacy parameters (online supplementary Table S.25) [271-277].
A meta-analysis has been recently conducted to specifically evaluate the quasi-bipolar Transurethral
Resection in Saline (TURis, Olympus Medical) system vs. M-TURP, (http://www.nice.org.uk/guidance/mtg23/
MANAGEMENT OF NON-NEUROGENIC MALE LOWER URINARY TRACT SYMPTOMS (LUTS) - UPDATE MARCH 2017 23
resources/the-turis-system-for-transurethral-resection-of-the-prostate-64371933166021). Ten unique RCTs
(1,870 patients) were included. It was concluded that TURis was of equivalent efficacy to M-TURP.
Tolerability and safety: Early pooled results concluded that no differences exist in short-term (up to twelve
months) urethral stricture/BNC rates, but B-TURP is preferable due to a more favourable peri-operative
safety profile (elimination of TUR-syndrome; lower clot retention/blood transfusion rates; shorter irrigation,
catheterisation, and possibly hospitalisation times) [268]. Subsequent meta-analyses supported these
conclusions [246, 267, 269, 270]. However, trial quality was relatively poor and limited follow-up might cause
under-reporting of late complications, such as urethral stricture/BNC [268]. Data from individual RCTs with a
follow-up of 12-60 months showed no differences in urethral stricture/BNC rates [270] (online supplementary
Table S.25). However, in a recent RCT, a significantly higher stricture (urethral stricture + BNC) rate was
detected for the first time in the B-TURP arm [278]. In this trial, 136 patients were randomised 1:1 to B-TURP
(TURis) or M-TURP arm and followed up for 36 months. The primary endpoint was safety, including long-term
complications such as strictures (urethral stricture + BNC). A significant difference in stricture rates favouring
M-TURP was detected (6.6% vs. 19.0%). When patients were stratified according to prostate volume, no
difference was detected in stricture rates between the arms in those with a prostate volume of up to 70 mL
(TURis 3/40 [7.5%] vs. M-TURP: 3/39 [7.7%]; P = 1.00). However, in patients with prostate volume > 70 mL, a
significantly higher stricture rate was seen in those submitted to TURis (9/23 [39.1] vs. 1/22 [4.6%]; P = 0.01).
Furthermore, in another RCT, a significantly higher BNC (but not urethral stricture) rate was detected for the
first time in the B-TURP arm [279]. In this trial 137 patients were randomised 1:1 to B-TURP (performed with
a “true” bipolar system [Gyrus PK SuperPulse, Olympus Medical]) or M-TURP arm and followed up to twelve
months [279]. A significant difference in BNC rates favouring M-TURP was detected (0.0% vs. 8.5%; P=0.02),
reinforcing a previously expressed potential association of BNC formation with the extremely focused electrical
activity of a “true” bipolar system at the prostate level and thus, in close proximity to the bladder neck [276].
A RCT using the erectile function domain of the IIEF (IIEF-ED) showed that M-TURP and B-TURP
have a similar effect on erectile function [280]. A comparative evaluation of the effects on overall sexual
function, quantified with IIEF-15, showed no differences between B-TURP and M-TURP at twelve months
follow-up (erection, orgasmic function, sexual desire, intercourse satisfaction, overall satisfaction) [281].
A meta-analysis (http://www.nice.org.uk/guidance/mtg23/resources/the-turis-system-
fortransurethral-resection-of-the-prostate-64371933166021) has shown that TURis reduces the risk of TUR-
syndrome and the need for blood transfusion compared to M-TURP. It is plausible that TURis reduces length of
hospital stay and re-admissions after surgery, although the evidence on these outcomes is limited.
Practical considerations: B-TURP offers an attractive alternative to M-TURP in patients with moderate-to-
severe LUTS secondary to BPO, with similar efficacy but lower peri-operative morbidity [268]. The duration
of improvements with B-TURP were documented in a number of RCTs with a follow-up of greater than twelve
months. Mid-term results (up to five years) for B-TURP showed that safety and efficacy are comparable to
M-TURP. The choice of B-TURP should be based on equipment availability, surgeon’s experience, and patient’s
preference.
Recommendations LE GR
Offer transurethral incision of the prostate to surgically treat moderate-to-severe LUTS in men 1a A
with prostate size < 30 mL, without a middle lobe.
Offer bipolar- or monopolar- transurethral resection of the prostate to surgically treat moderate- 1a A
to-severe LUTS in men with prostate size of 30-80 mL.
Efficacy: A few RCTs showed that holmium laser enucleation of the prostate (HoLEP), photoselective
vaporisation of the prostate (PVP) and more recently, enucleation of the prostate using bipolar circuitry lead
to similar outcomes compared to OP in men with large glands at a significantly lower complication rate [282-
289]. Open prostatectomy reduces LUTS by 63-86% (12.5-23.3 IPSS points), improves QoL score by 60-87%,
increases mean Qmax by 375% (+16.5-20.2 mL/s), and reduces PVR by 86-98% [282-284, 290, 291]. Efficacy is
maintained for up to six years [292].
Two RCT-based meta-analysis evaluated the overall efficacy of endoscopic enucleation of the
24 MANAGEMENT OF NON-NEUROGENIC MALE LOWER URINARY TRACT SYMPTOMS (LUTS) - UPDATE MARCH 2017
prostate (EEP) vs. OP for treating patients with large glands [293, 294]. The larger study included RCTs
involving 758 patients. Five RCTs compared OP with HoLEP [282, 283, 287] and four RCTs compared OP with
EEP using bipolar circuitry [272-274, 278]. Open prostatectomy was performed via a transvesical approach
in all RCTs. At 3-, 6-, 12- and 24-month follow-up, there were no significant differences in Qmax between EEP
and OP. Post-void residual, PSA, IPSS and QoL score also showed no significant difference at 1-, 3-, 6- and
12-months. Furthermore, IIEF also showed no significant difference at 3-, 6- and 12- months. It was concluded
that EEP appears to be an effective minimally invasive option for treating large prostates.
Tolerability and safety: Open prostatectomy mortality has decreased significantly during the past two decades
(< 0.25%) [291]. The estimated transfusion rate is about 7-14% [282, 290, 291, 293]. Long-term complications
include transient urinary incontinence (up to 10%), BNC and urethral stricture (about 6%) [282-284, 293, 295].
Two recent RCT-based meta-analysis evaluated the overall safety of EEP vs. OP for treating patients
with large glands [293, 294]. Operation time was significantly longer for EEP, due to a significantly longer
operation time needed for HoLEP (no difference was detected between OP and EEP using bipolar circuitry).
Catheterisation and hospitalisation time was significantly shorter with EEP whilst IIEF-5 showed no significant
difference between OP and EEP at twelve months [283, 286, 294]. Endoscopic enucleation of the prostate
was also associated with fewer blood transfusions but there were no significant differences regarding other
complications. It was concluded that EEP appears to be a minimally invasive option for treating large prostates.
Practical considerations: Open prostatectomy is the most invasive surgical method but it is an effective and
durable procedure for the treatment of LUTS/BPO. Endoscopic enucleation techniques require experience and
relevant endoscopic skills. In the absence of an endourological armamentarium including a holmium laser or a
bipolar system, OP is the surgical treatment of choice for men with prostates > 80 mL.
Recommendation LE GR
Offer endoscopic enucleation of the prostate or open prostatectomy to treat moderate-to- 1a A
severe LUTS in men with prostate size > 80 mL.
Efficacy: A systematic review and meta-analysis assessed therapeutic efficacy in different devices/software,
including Prostatron (Prostasoft 2.0 and 2.5) and ProstaLund Feedback (online supplementary Table S.27)
[281]. Symptom score after TUMT decreased by 65% in twelve months, compared to 77% after TURP.
Transurethral resection of the prostate also achieved greater improvement in Qmax (119% vs. 70%) [296].
In one pooled analysis of three studies (two RCTs and one cohort study), with a twelve month
follow-up, responder rate was 85.3% for ProstaLund Feedback TUMT (PLFT) and 85.9% for TURP [297]. The
IPSS showed a subjective, non-inferior improvement with PLFT [297]. However, although both PLFT and TURP
improved Qmax significantly, PLFT was inferior.
Previously, urinary retention was considered a contraindication for TUMT. Nowadays, LE:2b
studies have reported a 77-93% short-term success rate for TUMT, defined as the percentage of patients
who regained their ability to void spontaneously [298-301]. In one study with longer follow-up, cumulative
retreatment risk at five years was estimated to be 42% for those without retention and 59% for those with
retention at the baseline [302].
An RCT-based systematic review [296] (though the trials had different follow-up periods) found that
TUMT patients (7.54/100 person-years) were more likely than TURP patients (1.05/100 person-years) to require
retreatment for symptoms.
In a multicentre RCT with a five year follow-up, no significant differences were found in Qmax and
IPSS between TUMT (PLFT; the Core-Therm device) and TURP. Additional treatment was needed in 10% after
TUMT and in 4.3% after TURP. However, one must be cautious when interpreting these data because there
was substantial loss to follow-up; less than half of the patients were analysed at four to five years. In addition,
patients who remained in the study were likely to represent the best data (responders).
Tolerability and safety: Treatment is well tolerated, although most patients experience perineal discomfort and
urinary urgency, and require pain medication for therapy. Pooled morbidity data comparing TUMT and TURP
have been published [296, 297, 303]. In the Cochrane review of RCTs, catheterisation time, dysuria/urgency
MANAGEMENT OF NON-NEUROGENIC MALE LOWER URINARY TRACT SYMPTOMS (LUTS) - UPDATE MARCH 2017 25
and urinary retention rates were significantly smaller with TURP. On the other hand, hospitalisation time,
haematuria, clot retention, transfusion, TUR-syndrome, sexual dysfunction and retreatment rates for urethral
stricture/BNC were significantly smaller for TUMT [296].
Practical considerations: Endoscopy prior to TUMT is essential to identify the presence of a prostate middle
lobe or an insufficient length of the prostatic urethra. Due to the low peri- and post-operative morbidity and
lack of need for anaesthesia, TUMT is a true outpatient procedure and an option for (elderly) patients with
comorbidities or greater anaesthesia risks [304].
Recommendations LE GR
Transurethral microwave therapy achieves symptom improvement comparable with, 1a A
transurethral resection of the prostate (TURP) but transurethral microwave therapy is
associated with decreased morbidity and lower flow improvements.
Durability is in favour of TURP which has lower retreatment rates compared to transurethral 1a A
microwave therapy.
Efficacy: A meta-analysis of two RCTs, two non-randomised comparative and ten single-arm studies showed
that TUNA™ achieved a 50% decrease in IPSS and a 70% improvement in Qmax at one year [305]. These
findings are supported by a more recent meta-analysis of 35 studies (9 comparative, 26 non-comparative)
[306]. Transurethral needle ablation of the prostate significantly improved IPSS and Qmax, but compared to
TURP these improvements were significantly lower at twelve months. Mean differences in TURP vs. TUNA™
were 4.7 for IPSS and 5.9 mL/s for Qmax [306].
Clinical studies on the impact of TUNA™ on BPO [307, 308] showed a significant decrease in
maximum detrusor pressure or detrusor pressure at Qmax. However, one out of six patients were still obstructed
at one year [307].
The overall retreatment rate after TUNA™ was 19% based on an analysis of seventeen non-
comparative studies (median follow-up unreported; only three out of seventeen studies had follow-up
exceeding two years [306]); a rate considerably higher than that seen with TURP.
Tolerability and safety: Transient urinary retention and storage LUTS are common for weeks post-operatively
[309, 310]. Generally, TUNA™ is associated with fewer adverse events compared to TURP, including mild
haematuria, UTIs, strictures, incontinence, ED, and ejaculation disorders [305].
Practical considerations: Transurethral needle ablation of the prostate can be performed as a day-case
procedure under local anaesthesia or sedation [309]. However, TUNA™ is not suitable for prostates > 75 mL
or isolated bladder neck obstruction. In addition, TUNA™ cannot effectively treat prostatic middle lobes. There
are also concerns about the durability of the effects achieved by TUNA™.
Recommendations LE GR
Transurethral needle ablation is a minimally invasive alternative with decreased morbidity 1a A
compared to transurethral resection of the prostate (TURP) but with less efficacy
Durability is in favour of TURP with lower retreatment rates compared to transurethral needle 1a A
ablation.
26 MANAGEMENT OF NON-NEUROGENIC MALE LOWER URINARY TRACT SYMPTOMS (LUTS) - UPDATE MARCH 2017
Efficacy: In a meta-analysis of studies comparing HoLRP with TURP, no difference in symptom improvement
could be detected at six or twelve months post-operatively (online supplementary Table S.29) [312]. One RCT
comparing TURP with HoLRP with a minimum follow-up of four years showed no difference in urodynamics
after 48 months [313]. Three meta-analyses covering trials on HoLEP vs. TURP found that symptom
improvement was comparable or superior with HoLEP (online supplementary Table S.29) [314-316]. One RCT
comparing photoselective vaporisation of the prostate (PVP) and HoLEP in patients with prostates > 60 mL
showed comparable symptom improvement but significantly higher flow rates and lower PVR volume after
HoLEP [317]. Another RCT on HoLAP and 80-W PVP showed comparable functional improvement within a
median follow-up of 71 months [318].
RCTs indicate that HoLEP is as effective as OP for improving micturition in large prostates [282,
283], with similar re-operation rates after five years (5% vs. 6.7%, respectively) [282]. One RCT comparing
HoLEP with TURP in a small number of patients with a seven year follow-up found that the functional long term
results of HoLEP were comparable with TURP [319]. A retrospective study of HoLEP with the longest follow-up
of up to ten years (mean 62 months) reported durable functional results with low re-operation rates [320].
Tolerability and safety: Dysuria is the most common post-operative complication [311, 314]. Compared to
TURP, HoLRP has shorter catheterisation and hospitalisation times [312, 321]. Potency, continence, and major
morbidity at 48 months were identical between HoLRP and TURP [313]. Three meta-analyses found that
HoLEP has shorter catheterisation time and hospital stay, reduced blood loss, and fewer blood transfusions,
but a longer operation time compared with TURP [314-316]. In a meta-analysis, no significant differences were
noted between HoLEP and TURP for urethral stricture (2.6% vs. 4.4%), stress urinary incontinence (1.5% vs.
1.5%), and re-intervention (4.3% vs. 8.8%) [300]. HoLEP is superior to OP for blood loss, catheterisation and
hospitalisation time [282, 283].
HoLEP has been safely performed in patients using anticoagulant medications [322, 323]. In a study
of 83 patients, blood transfusion was required in seven patients (8%) [324]. A retrospective study compared the
safety results of HoLEP in 39 patients who were on anticoagulant therapy at the time of their surgery, and 37
controls [323]. No transfusions were required and bleeding complication rates were not significantly different
[323]. Short-term studies showed that patients with urinary retention could be treated with HoLEP [325, 326].
The impact on erectile function and retrograde ejaculation is comparable between HoLEP and
TURP/OP [283, 327]. Erectile function did not decrease from baseline in either group; three quarters of sexually
active patients had retrograde ejaculation after HoLEP.
Practical considerations: Holmium laser operations are surgical procedures that require experience and
relevant endoscopic skills. The experience of the surgeon was the most important factor affecting the overall
occurrence of complications [322, 328].
Efficacy: A meta-analysis of the nine available RCTs comparing PVP using the 80-W and 120-W lasers with
TURP was performed in 2012 (online supplementary Table S.29) [329]. No differences were found in Qmax
and IPSS between 80-W-PVP and TURP, but only three RCTs provided sufficient twelve month data to be
included in the meta-analysis [330-332]. With the 180-W (XPS) laser efficacy is comparable to TURP in terms
of IPSS, Qmax, PVR volume, prostate volume reduction, PSA decrease and QoL questionnaires. The XPS laser
prostatectomy is superior to TURP in terms of catheterisation time, length of hospital stay and time to stable
health status.
The longest RCT using the 80-W KTP laser has a follow-up of only twelve months [330]. A case
series showed durable functional outcomes with the 80-W KTP laser, with an overall retreatment rate of 8.9%
at five years [333]. Another case series of 500 patients treated with the 80-W system with a mean follow-up of
30.6 months reported a retreatment rate of 14.8% [334]. At twelve months self-reported urinary incontinence
was 2.9% with XPS and 3.0% with TURP. Surgical re-intervention was comparably low after twelve months for
both XPS and TURP.
Significant improvements in voiding parameters at a follow-up of twelve months were demonstrated
urodynamically [335]. The longest RCT comparing the 120-W HPS laser with TURP had a follow-up of 36
months and showed a comparable improvement in IPSS, Qmax, and PVR [336]. The re-operation rate was
MANAGEMENT OF NON-NEUROGENIC MALE LOWER URINARY TRACT SYMPTOMS (LUTS) - UPDATE MARCH 2017 27
higher after PVP (11% vs. 1.8%; p = 0.04) [336]. Similar improvement of IPSS, QoL, Qmax, or urodynamic
parameters was reported from two RCTs with a maximum follow-up of 24 months [331, 337].
A multicentre case series of the 180-W laser demonstrated comparable safety and symptom
improvement for the 180-W laser and the former Greenlight laser systems [338].
Tolerability and safety: A meta-analysis of the RCTs comparing the 80-W and 120-W lasers with TURP showed
a significantly longer operating time but shorter catheterisation time and length of hospital stay after PVP [329].
Blood transfusions and clot retention were less with PVP. No difference was noted in post-operative urinary
retention, infection, meatal stenosis, urethral stricture, or bladder neck stenosis [329]. According to the Goliath
Study, 180-W Greenlight laser prostatectomy is non-inferior to TURP in terms of peri-operative complications,
including post-operative dysuria rate (XPS 19.1%;TURP 21.8%). Post-operative Clavien III re-interventions are
more likely within the first 30 days after TURP compared to XPS (3.8% vs. 9.8%; p = 0.04), but comparable
after twelve months follow-up. There are more severe bleeding complications within 30 days after TURP and
more mild bleeding complications after XPS laser prostatectomy over twelve months, leading to a comparable
overall incidence between both techniques.
The Greenlight laser appears to be safe in high-risk patients under anticoagulation treatment [339-
343]. In one study, anticoagulant patients had significantly higher rates of bladder irrigation (17.2%) compared
with those not taking anticoagulants (5.4%) [342]. Safety in patients with urinary retention, or prostates > 80 mL
was shown in various prospective non-randomised trials [343-345].
The impact of Greenlight laser on sexual function and abnormal ejaculation was similar to that of
TURP after twelve months [346]. In addition, no difference was reported between OP/TURP and Greenlight
PVP for erectile function [347, 348], IIEF-5 scores are maintained after treatment. However, in patients with pre-
operative IIEF-5 > 19, the post-operative IIEF-5 scores were significantly decreased at 6, 12, and 24 months
[349].
Practical considerations: The 180-W XPS laser should be regarded as the reference for Greenlight laser
prostatectomy. However, many former studies were done with the out-dated 80-W and 120-W lasers therefore,
results need to be interpreted accordingly. Long-term results from the Goliath Study (180-W XPS vs. TURP) are
pending. The intermediate two year follow-up data showed efficacy and safety outcomes similar to TURP [350].
Efficacy: Case series, and two comparative studies of vaporisation using a 980 nm diode laser or a 120-W HPS
laser, are available [352-358]. Quality of life, IPSS, Qmax, and PVR improved significantly in all studies compared
to baseline and were similar for both laser, at six and twelve months [352, 353].
One RCT with a twelve month follow-up compared the 980 nm diode laser with bipolar enucleation
and found equal clinical outcome [359]. One small RCT with a six month follow-up comparing laser enucleation
using a 1,318 nm diode laser with B-TURP reported similar efficacy (online supplementary Table S.29) [360].
This data is further supported by one RCT, comparing 980 nm diode laser vaporisation vs. TURP within a two
year follow-up [361]. Redo TURP was more frequent in the diode laser group (online supplementary Table S.29)
[359].
Tolerability and safety: Published studies on 980 nm laser vaporisation indicate high haemostatic potential,
although anticoagulants or platelet aggregation inhibitors were taken in 24% and 52% of patients, respectively
[352, 353]. Post-operatively, a high rate of dysuria was reported [352-354, 361]. Fibre modifications led to
a significant reduction in surgical time [355]. Furthermore, the literature on diode vaporisation reports high
re-operation rates (8-33%) and persisting stress urinary incontinence (9.1%) [352-354, 361]. In contrast, the
two RCTs on diode laser enucleation showed that blood loss, hospitalisation and catheterisation time were in
favour of diode laser enucleation, with equivalent clinical outcome for either bipolar enucleation [359] or TURP
[360] during follow-up.
Practical considerations: Diode laser vaporisation leads to immediate improvement of LUTS due to BPO and
provides good haemostatic properties. Diode laser enucleation seems to offer similar efficacy and safety when
compared to either TURP or bipolar enucleation. Based on the limited number, mainly low quality RCTs and
controversial data on the retreatment rate, results for diode laser vaporisation should be evaluated in further
higher quality RCTs.
28 MANAGEMENT OF NON-NEUROGENIC MALE LOWER URINARY TRACT SYMPTOMS (LUTS) - UPDATE MARCH 2017
5.3.5.4 Thulium:yttrium-aluminium-garnet laser (Tm:YAG)
Mechanism of action: In the Tm:YAG laser, a wavelength between 1,940 and 2,013 nm is emitted in continuous
wave mode. The laser is primarily used in front-fire applications [351, 362]. Different applications, ranging
from vaporisation (ThuVaP), vaporesection (ThuVaRP), and enucleation (ThuVEP/ThuLEP: similar enucleating
techniques) are published.
Efficacy: One RCT with a four year follow-up comparing ThuVARP to M-TURP, showed comparable efficacy
and favourable re-operation rates in the ThuVaRP group [363] (online supplementary Table S.29). One RCT and
one non-RCT compared ThuVaRP with M-TURP [364, 365], while two RCTs comparing ThuVaRP and B-TURP
were published recently [366, 367]. In summary, studies show comparable improvement of symptoms and
voiding parameters. There are only a few case studies on ThuVEP showing a significant improvement in IPSS,
Qmax, and PVR after treatment [368-371]. ThuLEP and HoLEP were compared in one RCT with eighteen months
follow-up with comparable outcomes in both arms (online supplementary Table S.29) [356]. Furthermore,
ThuLEP and bipolar enucleation were compared in one RCT with twelve months follow-up. The outcome
showed no difference with regard to efficacy whilst the decrease in hemoglobin level and catheter time were
significantly lower for ThulEP [372].
Tolerability and safety: Thulium laser prostatectomy shows high intra-operative safety in RCTs [363, 364], as
well as in case series in patients with large prostates [368] and anticoagulation or bleeding disorders [369,
373]. Catheterisation time, hospital stay, and blood loss were shorter compared to TURP [364-366]. The
rate of post-operative urethral strictures after ThuVaRP was 1.9%, the rate of bladder neck contracture was
1.8%, and the re-operation rate was 0-7.1% during follow-up [364, 365, 374]. Urethral stricture after ThuVEP
occurred in 1.6%, and the overall retreatment rate was 3.4% (mean follow-up 16.5 months) [375]. No urethral
and bladder neck strictures after ThuLEP were reported during the eighteen months follow-up [376]. Recently,
a study focused on post-operative complications after ThuVEP (vapoenucleation) reported adverse events in
31% of cases, with 6.6% complications greater then Clavien grade II [377]. One case control study on ThuVEP
with 48-month follow-up reported long-term durability of voiding improvements and overall re-operation rates
of 2.4% [373]. Two studies (one case control, one RCT vs. TURP) addressed the impact of ThuVEP on sexual
function, demonstrating no effect on erectile function with increased prevalence of retrograde ejaculation post-
operatively [378, 379].
A prospective multicentre study on ThuVARP, including 2,216 patients, showed durable post-
operative improvement in IPSS, QoL, Qmax, and PVR for the entire eight years of follow-up. Urethral stricture
and bladder neck contracture accounted for 2.6 % and 1.6 % of patients, respectively. Persistent stress
incontinence was found in 0.1 % whilst, re-operation due to BPH recurrence was required in 1.2 % patients
[380].
In two RCTs on ThuLEP versus TURP, one RCT on ThuLEP versus bipolar enucleation and one RCT
on ThuLEP versus HoLEP, ThuLEP appeared to be equivalent with regard to clinical efficacy and superior with
regard to intra-operative haemostasis. The same was demonstrated for ThuVEP vs. TURP in one RCT [381].
Practical considerations: The limited number of RCTs and only a few studies with long-term follow-up (up to 48
months) support the efficacy of thulium laser prostatectomy therefore, there is a need for ongoing confirmation.
MANAGEMENT OF NON-NEUROGENIC MALE LOWER URINARY TRACT SYMPTOMS (LUTS) - UPDATE MARCH 2017 29
Recommendations LE GR
Holmium laser enucleation and 532-nm laser vaporisation of the prostate are alternatives to 1a A
transurethral resection of the prostate (TURP) in men with moderate-to-severe LUTS leading to
immediate, objective, and subjective improvements comparable with TURP.
The short-term and mid-term functional results of 532-nm laser vaporisation of the prostate are 1b A
comparable with TURP.
The long-term functional results of holmium laser enucleation are comparable with TURP or 1b A
open prostatectomy.
Thulium enucleation may be an alternative to TURP and holmium laser enucleation in men 1b A
with moderate-to-severe LUTS leading to immediate and mid-term objective and subjective
improvements.
Diode laser operations lead to short-term objective and subjective improvement. 1b B
Tm:YAG vaporesection is an alternative to TURP for small- and medium-size prostates. 1b A
With regard to intra-operative safety and haemostatic properties, diode and thulium lasers 3 C
appear to be safe.
With regard to intra-operative safety, 532-nm laser vaporisation is superior to TURP. 1b A
532-nm laser vaporisation should be considered in patients receiving anticoagulant medication 3 B
or with a high cardiovascular risk.
Efficacy: Several small case studies on a range of stents of different designs and materials provide low level
evidence for their use. Online supplementary Table S.30 describes the most important studies [382, 383, 385-
388]. There was a substantial loss to follow-up in all studies. There are no studies comparing stents with sham
or other treatment modalities, and only one RCT compared two versions of a prostatic stent for BPO [389].
The main representative of the permanent stents is the UroLume prosthesis. A systematic review
identified 20 case series (990 patients), with differing follow-ups [390]. These studies reported relevant
symptom improvement and Qmax increase [390]. The pooled data from studies with patients who were catheter
dependent showed that 84% of patients (148/176) regained the ability to void spontaneously after UroLume
treatment [390, 391].
The data on non-epithelialising prostatic stents was summarised in a systematic review on the
efficacy of Memokath, a self-expanding metallic prostatic stent [392]. Overall, IPSS was reduced by 11-19
points and Qmax increased by 3-11 mL/s [392].
Tolerability and safety: In general, stents are subject to misplacement, migration, and poor tolerability because
of exacerbation of LUTS and encrustation [384]. The most immediate and common adverse events include
perineal pain or bladder storage symptoms.
Practical considerations: Due to common side effects and a high migration rate, prostatic stents have a limited
role in the treatment of moderate-to-severe LUTS. Temporary stents can provide short-term relief from LUTS
secondary to BPO in patients temporarily unfit for surgery or after minimally invasive treatment [384].
Recommendation LE GR
Offer prostatic stents as an alternative to catheterisation in men unfit for surgery. 3 C
30 MANAGEMENT OF NON-NEUROGENIC MALE LOWER URINARY TRACT SYMPTOMS (LUTS) - UPDATE MARCH 2017
Efficacy: The available studies on PUL are presented in online supplementary Table S.31 [393-398]. In
general, PUL achieves a significant improvement in IPSS (-39% to -52%), Qmax (+32% to +59%) and QoL
(-48% to -53%). There is only one RCT comparing PUL with sham [393]. The primary endpoint was meet
at three months with a 50% reduction in AUA-SI from 22.1 to 11.0 points and remained stable up to twelve
months. Change for AUA-SI was 88% greater for the treatment group than sham control. Also Qmax increased
significantly from 8.1 to 12.4 mL/s relative to baseline at three months and this result could still be confirmed at
twelve months. The difference in clinical response for Qmax between both groups was of statistical significance.
A relevant benefit with regard to PVR was not demonstrated compared to baseline nor relative to sham control.
An RCT of 80 patients, conducted in nine European countries, comparing PUL to TURP was
published in 2015. At twelve months, IPSS improvement was -11.4 for PUL and -15.4 for TURP. There was no
retrograde ejaculation among PUL patients, while 40% of TURP patients lost the ability to ejaculate. Surgical
recovery was measured using a validated instrument and confirmed that recovery from PUL is more rapid and
more extensive in the first three to six months [399]. However, TURP resulted in much greater improvements in
Qmax (+13.7 ± 10.4 mL/s) after twelve months compared to PUL. (4.0 ± 4.8 mL/s).
In a recent meta-analysis of retrospective and prospective trials, pooled estimates showed an
overall improvement following PUL, including IPSS (-7.2 to -8.7 points), Qmax (3.8 to 4.0 mL/s), and QoL (-2.2 to
-2.4 points) [398]. Sexual function was preserved with a small improvement estimated at twelve months.
A multi-centre, randomised and blinded trial of PUL in men with bothersome LUTS due to BPH
showed that at three years, average improvements from baseline were significant for total IPSS (41.1%), QoL
(48.8%), Qmax (53.1%) and individual IPSS symptoms. Symptomatic improvement was independent of prostate
size. There were no de novo, sustained ejaculatory or erectile dysfunction events and all sexual function
assessments showed average stability or improvement after PUL [400].
Tolerability and safety: The most common complications reported post-operatively included haematuria (16-
63%), dysuria (25-58%), pelvic pain (5-17.9%), urgency (7.1-10%), transient incontinence (3.6-16%), and UTI
(2.9-11%). Most symptoms were mild-to-moderate in severity and resolved within two to four weeks after the
procedure.
Prostatic urethral lift seems to have no significant impact on sexual function. Evaluation of sexual
function as measured by IIEF-5, Male Sexual Health Questionnaire-Ejaculatory Dysfunction, and Male Sexual
Health Questionnaire-Bother in patients undergoing PUL showed that erectile and ejaculatory function were
preserved [393-397].
Practical considerations: An obstructed/protruding median lobe cannot be effectively treated, and the
effectiveness in large prostate glands has not been shown yet. Long-term studies are needed to evaluate the
duration of the effect in comparison to other techniques.
Recommendation LE GR
Offer Prostatic urethral lift (Urolift®) to men with LUTS interested in preserving ejaculatory 1a B
function, with prostates < 70 mL and no middle lobe. Inform patients that long-term effects
have not been evaluated.
Efficacy: Results from clinical trials have shown only modest clinical benefits, that do not seem to be superior
to placebo, for BoNT-A [402, 403] (see online supplementary Table S.32). A recent systematic review and meta-
analysis showed no differences in efficacy compared with placebo, and concluded that there is no evidence of
clinical benefits in medical practice [404]. With regard to NX-1207 and PRX302, the positive results from Phase
II-studies have not be confirmed in Phase III-trials thus far [405, 406].
MANAGEMENT OF NON-NEUROGENIC MALE LOWER URINARY TRACT SYMPTOMS (LUTS) - UPDATE MARCH 2017 31
Safety: Studies including safety assessments have reported only a few mild and self-limiting adverse events for
all injectable drugs [401]. Furthermore, a recent systematic review and meta-analysis showed low incident rates
of procedure-related adverse events [404].
Practical considerations: Although experimental evidence for compounds such as NX-1207, PRX302 and
BoNT-A was promising for their transition to clinical use, randomised, controlled studies of all three of these
injectable agents have not been able to reveal any significant clinical benefits.
Recommendation LE GR
Do not offer Botulinum toxin injection treatment to patients with male LUTS. 1a B
Efficacy: A recent systematic review and meta-analysis showed that in 27 observational studies including
764 patients, the mean increase in Qmax was 14.3 mL/s (95% CI 13.1-15.6), and the mean improvement in
IPSS was 17.2 (95% CI 15.2-19.2). Mean duration of operation was 141 min (95% CI 124-159), and the mean
intra-operative blood loss was 284 mL (95% CI 243-325). One hundred and four patients (13.6%) developed a
surgical complication. In comparative studies to OP, length of hospital stay (WMD -1.6 days, p = 0.02), length of
catheter use (WMD -1.3 days, p = 0.04) and estimated blood loss (WMD -187 mL, p = 0.015) were significantly
lower in the MISP group, while the duration of operation was longer than in OP (WMD 37.8 min, p < 0.0001).
There were no differences in improvements in Qmax, IPSS and peri-operative complications between both
procedures (see online supplementary Table S.33).
Two recent retrospective series on RASP are now available which were not included in the meta-
analysis which confirm these findings [409, 410]. The largest retrospective series reports 1,330 consecutive
cases including 487 robotic (36.6%) and 843 laparoscopic (63.4%) simple prostatectomy cases. The authors
confirm that both techniques can be safely and effectively done in selected centres [409]. Technical variations
also include an intrafasical (IF) approach. Comparing laproscopic, robotic and robotic IF simple prostatectomy,
the IF-RSP technique is safe and effective, with results at one year follow-up for continence, IPSS and Sexual
Health Inventory for Men scores similar to those for the LSP and RSP techniques [411].
Tolerability and safety: In the largest series, the post-operative complication rate was 10.6% (7.1% for LSP and
16.6% for RASP), most of the complications being of low grade. The most common complications in the RASP
series were hematuria requiring irrigation, UTI and AUR; in the LSP series, the most common complications
were UTI, ileus and AUR.
Practical considerations: Data on MISP are increasing from selected centres. MISP seems comparable to OP in
terms of efficacy and safety, providing similar improvements in Qmax and IPSS [412]. However, most studies are
of a retrospective nature. High quality studies are needed to compare the efficacy, safety, and hospitalisation
times of MISP and both OP and endoscopic methods. Long-term outcomes, learning curve and cost of MISP
should also be evaluated.
Evidence Statement LE
Minimal invasive simple prostatectomy seems to be feasible in men with prostate sizes > 80 mL 2a
needing surgical treatment; however, RCTs are needed.
32 MANAGEMENT OF NON-NEUROGENIC MALE LOWER URINARY TRACT SYMPTOMS (LUTS) - UPDATE MARCH 2017
Figure 3 provides a flow chart illustrating treatment choice according to evidence-based medicine and patient
profiles.
Surgical treatment is usually required when patients have experienced recurrent or refractory urinary
retention, overflow incontinence, recurrent UTIs, bladder stones or diverticula, treatment-resistant macroscopic
haematuria due to BPH/BPE, or dilatation of the upper urinary tract due to BPO, with or without renal
insufficiency (absolute operation indications, need for surgery).
Additionally, surgery is usually needed when patients have not obtained adequate relief from
LUTS or PVR using conservative or medical treatments (relative operation indications). The choice of
surgical technique depends on prostate size, comorbidities of the patient, ability to have anaesthesia,
patients’ preferences, willingness to accept surgery-associated specific side-effects, availability of the surgical
armamentarium, and experience of the surgeon with these surgical techniques. An algorithm for surgical
approaches according to evidence-based medicine and the patient’s profile is provided in figure 4.
Figure 3: T
reatment algorithm of male LUTS using medical and/or conservative treatment options.
Treatment decisions depend on results assessed during initial evaluation.
Note that patients’ preferences may result in different treatment decisions.
Male LUTS
(without indications for surgery)
Bothersome
no symptoms? yes
Nocturnal
no polyuria yes
predominant
Prostate
no volume yes
> 40 mL?
yes
Residual
storage
symptoms
MANAGEMENT OF NON-NEUROGENIC MALE LOWER URINARY TRACT SYMPTOMS (LUTS) - UPDATE MARCH 2017 33
Figure 4: T
reatment algorithm of bothersome LUTS refractory to conservative/medical treatment or in
cases of absolute operation indications. The flowchart was stratified by the patient’s ability to
have anaesthesia, cardiovascular risk, and prostate size.
Male LUTS
with absolute indications for surgery or non-responders to medical treatment or those
who do not want medical treatment but request active treatment
High-risk
low high
patients?
Can have
yes surgery under no
anaesthesia?
Can stop
yes no
anticoagulation/
antiplatelet therapy
Prostate
< 30 mL volume > 80 mL
30 – 80 mL
(1) Current standard/first choice. The alternative treatments are presented in alphabetical order.
Notice: Readers are strongly recommended to read the full text that highlights the current
position of each treatment in detail.
34 MANAGEMENT OF NON-NEUROGENIC MALE LOWER URINARY TRACT SYMPTOMS (LUTS) - UPDATE MARCH 2017
print version is supplemented by a detailed online version (http://uroweb.org/guideline/ treatment-of-non-
neurogenic-maleluts/).
Nocturia is defined as the complaint of waking at night to void [2]. It reflects the relationship
between the amount of urine produced while asleep, and the ability of the bladder to store the urine received.
Nocturia can occur as part of lower urinary tract dysfunction (LUTD), such as OAB and chronic pelvic pain
syndrome. Nocturia can also occur in association with other forms of LUTD, such as BOO, but here it is
debated whether the link is one of causation or simply the co-existence of two common conditions. Crucially,
nocturia may have behavioural, sleep disturbance (primary or secondary) or systemic causes unrelated to
LUTD (Table 1). Differing causes often co-exist and each has to be considered in all cases. Only where LUTD is
contributory should nocturia be termed a LUTS.
MANAGEMENT OF NON-NEUROGENIC MALE LOWER URINARY TRACT SYMPTOMS (LUTS) - UPDATE MARCH 2017 35
Figure 5. Evaluation of Nocturia in non-neurogenic Male LUTS.
Significant PVR
• US assessment of prostate
• Uroflowmetry
• US of kidneys +/- renal
function assessment
• FVC with predominant storage LUTS
Interventional LUTS
treatment
(Indirect MoA for
nocturia)
Assessment must establish whether the patient has polyuria, LUTS, sleep disorder or a combination. Therapy
may be driven by the bother it causes, but non-bothersome nocturia may warrant assessment of a frequency
volume chart (indicated by the dotted line) depending on history and clinical examination since potential
presence of a serious underlying medical condition must be considered.
FVC = frequency volume chart; DRE = digital rectal examination; NP = nocturnal polyuria; MoA = mechanism of
action; PVR = post-void residual.
36 MANAGEMENT OF NON-NEUROGENIC MALE LOWER URINARY TRACT SYMPTOMS (LUTS) - UPDATE MARCH 2017
expertise is available (Figure 6). They should not proceed along any LUTD management pathway unless a
causative link with LUTD is justifiably suspected, and systemic or sleep abnormalities have been considered.
In patients with non-bothersome nocturia, the medical evaluation (history and physical examination)
should consider the possibility of early stages of systemic disease, and whether there is possibility of earlier
diagnosis or therapy adjustment.
Some important potentially treatable non-urological causes of nocturia include; obstructive sleep
apnoea (OSA), congestive cardiac failure, poorly controlled diabetes mellitus and medications (e.g. diuretics, or
lithium).
Figure 6: S
hared care pathway for nocturia, highlighting the need to manage potentially complex
patients using relevant expertise for the causative factors.
Practical considerations
Desmopressin is taken once daily before sleeping. Because the optimal dose differs between patients,
desmopressin treatment should be initiated at a low dose (0.1 mg/day) and may be gradually increased up to
a dosage of 0.4 mg/day every week until maximum efficacy is reached. Patients should avoid drinking fluids at
least one hour before and for eight hours after dosing. In men aged 65 years or older, desmopressin should not
be used if the serum sodium concentration is below normal: all patients should be monitored for hyponatremia.
Men with nocturia should be advised regarding off-label use.
MANAGEMENT OF NON-NEUROGENIC MALE LOWER URINARY TRACT SYMPTOMS (LUTS) - UPDATE MARCH 2017 37
5.5.3.2 Medications to treat LUTD
Where LUTD is diagnosed and considered causative of nocturia, relevant medications for storage (and voiding)
LUTS may be considered. However, effect size of these medications is generally small, or not significantly
different from placebo when used to treat nocturia. Applicable medications include; selective α1-adrenergic
antagonists [415], antimuscarinics [416-418], 5α-reductase inhibitors [419] and PDE5Is [420].
Recommendations LE GR
Treatment should aim to address underlying causative factors, which may be behavioural, 4 A*
systemic condition(s), sleep disorders, lower urinary tract dysfunction, or a combination of
factors.
Discuss lifestyle changes to reduce nocturnal urine volume and episodes of nocturia, and 3 A*
improve sleep quality.
Desmopressin may be prescribed to decrease nocturia due to nocturnal polyuria in men 1a A
under the age of 65. Screening for hyponatremia must be undertaken at baseline, during dose
titration and during treatment.
α1-adrenergic antagonists may be offered to men with nocturia associated with LUTS. 1b B
Antimuscarinic drugs may be offered to men with nocturia associated with overactive bladder. 1b B
5α-reductase inhibitors may be offered to men with nocturia who have moderate-to-severe 1b C
LUTS and an enlarged prostate (> 40 mL).
Do not offer phosphodiesterase type 5 inhibitors for the treatment of nocturia. 1b B
A trial of timed diuretic therapy may be offered to men with nocturia due to nocturnal polyuria. 1b C
Screening for hyponatremia should be undertaken at baseline and during treatment.
Agents to promote sleep may be used to aid return to sleep in men with nocturia. 2 C
*Upgraded based on Panel consensus.
6. FOLLOW-UP
6.1 Watchful waiting (behavioural)
Patients who elect to pursue a WW policy should be reviewed at six months and then annually, provided there
is no deterioration of symptoms or development of absolute indications for surgical treatment. The following
are recommended at follow-up visits: history, IPSS, uroflowmetry, and PVR volume.
38 MANAGEMENT OF NON-NEUROGENIC MALE LOWER URINARY TRACT SYMPTOMS (LUTS) - UPDATE MARCH 2017
months subsequently. The following tests are recommended at follow-up visits: serum-sodium concentration
and frequency volume chart. The follow-up sequence should be restarted after dose escalation.
Recommendation LE GR
Follow-up for all conservative, medical, or operative treatment modalities is based on empirical 3-4 C
data or theoretical considerations, but not on evidence-based studies.
7. REFERENCES
1. Phillips B, et al. Oxford Centre for Evidence-based Medicine Levels of Evidence. Updated by
Jeremy Howick March 2009. 1998.
http://www.cebm.net/oxford-centre-evidence-based-medicine-levels-evidence-march-2009/
2. Abrams, P., et al. The standardisation of terminology of lower urinary tract function: report from the
Standardisation Sub-committee of the International Continence Society. Neurourol Urodyn, 2002.
21: 167.
https://www.ncbi.nlm.nih.gov/pubmed/11857671
3. Martin, S.A., et al. Prevalence and factors associated with uncomplicated storage and voiding lower
urinary tract symptoms in community-dwelling Australian men. World J Urol, 2011. 29: 179.
https://www.ncbi.nlm.nih.gov/pubmed/20963421
4. Société Internationale d’Urologie (SIU), Lower Urinary Tract Symptoms (LUTS) : An International
Consultation on Male LUTS. , C. Chapple & P. Abrams, Editors. 2013.
http://www.siuurology.org/themes/web/assets/files/ICUD/pdf/Male%20Lower%20Urinary%20
Tract%20Symptoms%20(LUTS).pdf
5. Kupelian, V., et al. Prevalence of lower urinary tract symptoms and effect on quality of life in a
racially and ethnically diverse random sample: the Boston Area Community Health (BACH) Survey.
Arch Intern Med, 2006. 166: 2381.
https://www.ncbi.nlm.nih.gov/pubmed/17130393
6. Agarwal, A., et al. What is the most bothersome lower urinary tract symptom? Individual- and
population-level perspectives for both men and women. Eur Urol, 2014. 65: 1211.
https://www.ncbi.nlm.nih.gov/pubmed/24486308
7. De Ridder, D., et al. Urgency and other lower urinary tract symptoms in men aged >/= 40 years: a
Belgian epidemiological survey using the ICIQ-MLUTS questionnaire. Int J Clin Pract, 2015. 69: 358.
https://www.ncbi.nlm.nih.gov/pubmed/25648652
8. Taub, D.A., et al. The economics of benign prostatic hyperplasia and lower urinary tract symptoms
in the United States. Curr Urol Rep, 2006. 7: 272.
https://www.ncbi.nlm.nih.gov/pubmed/16930498
9. Gacci, M., et al. Metabolic syndrome and benign prostatic enlargement: a systematic review and
meta-analysis. BJU Int, 2015. 115: 24.
https://www.ncbi.nlm.nih.gov/pubmed/24602293
10. Kogan, M.I., et al. Epidemiology and impact of urinary incontinence, overactive bladder, and other
lower urinary tract symptoms: results of the EPIC survey in Russia, Czech Republic, and Turkey.
Curr Med Res Opin, 2014. 30: 2119.
https://www.ncbi.nlm.nih.gov/pubmed/24932562
11. Chapple, C.R., et al. Lower urinary tract symptoms revisited: a broader clinical perspective.
Eur Urol, 2008. 54: 563.
https://www.ncbi.nlm.nih.gov/pubmed/18423969
MANAGEMENT OF NON-NEUROGENIC MALE LOWER URINARY TRACT SYMPTOMS (LUTS) - UPDATE MARCH 2017 39
12. Ficarra, V., et al. The role of inflammation in lower urinary tract symptoms (LUTS) due to benign
prostatic hyperplasia (BPH) and its potential impact on medical therapy. Curr Urol Rep, 2014. 15:
463.
https://www.ncbi.nlm.nih.gov/pubmed/25312251
13. He, Q., et al. Metabolic syndrome, inflammation and lower urinary tract symptoms: possible
translational links. Prostate Cancer Prostatic Dis, 2016. 19: 7.
https://www.ncbi.nlm.nih.gov/pubmed/26391088
14. Drake, M.J. Do we need a new definition of the overactive bladder syndrome? ICI-RS 2013.
Neurourology and Urodynamics, 2014. 33: 622.
http://www.ncbi.nlm.nih.gov/pubmed/24838519
15. Novara, G., et al. Critical Review of Guidelines for BPH Diagnosis and Treatment Strategy.
Eur Urol Suppl 2006. 4: 418.
http://eu-acme.org/europeanurology/upload_articles/Novara2.pdf
16. McVary, K.T., et al. Update on AUA guideline on the management of benign prostatic hyperplasia.
J Urol, 2011. 185: 1793.
https://www.ncbi.nlm.nih.gov/pubmed/21420124
17. Bosch, J., et al. Etiology, Patient Assessment and Predicting Outcome from Therapy. International
Consultation on Urological Diseases Male LUTS Guideline 2013, 2013. 37
18. Martin, R.M., et al. Lower urinary tract symptoms and risk of prostate cancer: the HUNT 2 Cohort,
Norway. Int J Cancer, 2008. 123: 1924.
https://www.ncbi.nlm.nih.gov/pubmed/18661522
19. Young, J.M., et al. Are men with lower urinary tract symptoms at increased risk of prostate cancer?
A systematic review and critique of the available evidence. BJU Int, 2000. 85: 1037.
https://www.ncbi.nlm.nih.gov/pubmed/10848691
20. Barqawi, A.B., et al. Methods of developing UWIN, the modified American Urological Association
symptom score. J Urol, 2011. 186: 940.
https://www.ncbi.nlm.nih.gov/pubmed/21791346
21. Barry, M.J., et al. The American Urological Association symptom index for benign prostatic
hyperplasia. The Measurement Committee of the American Urological Association. J Urol, 1992.
148: 1549.
https://www.ncbi.nlm.nih.gov/pubmed/1279218
22. Donovan, J.L., et al. Scoring the short form ICSmaleSF questionnaire. International Continence
Society. J Urol, 2000. 164: 1948.
https://www.ncbi.nlm.nih.gov/pubmed/11061889
23. Epstein, R.S., et al. Validation of a new quality of life questionnaire for benign prostatic hyperplasia.
J Clin Epidemiol, 1992. 45: 1431.
https://www.ncbi.nlm.nih.gov/pubmed/1281223
24. Homma, Y., et al. Symptom assessment tool for overactive bladder syndrome--overactive bladder
symptom score. Urology, 2006. 68: 318.
https://www.ncbi.nlm.nih.gov/pubmed/16904444
25. Schou, J., et al. The value of a new symptom score (DAN-PSS) in diagnosing uro-dynamic
infravesical obstruction in BPH. Scand J Urol Nephrol, 1993. 27: 489.
https://www.ncbi.nlm.nih.gov/pubmed/7512747
26. Homma, Y., et al. Core Lower Urinary Tract Symptom score (CLSS) questionnaire: a reliable tool in
the overall assessment of lower urinary tract symptoms. Int J Urol, 2008. 15: 816.
https://www.ncbi.nlm.nih.gov/pubmed/18657204
27. D’Silva, K.A., et al. Does this man with lower urinary tract symptoms have bladder outlet
obstruction?: The Rational Clinical Examination: a systematic review. JAMA, 2014. 312: 535.
https://www.ncbi.nlm.nih.gov/pubmed/25096693
28. Bryan, N.P., et al. Frequency volume charts in the assessment and evaluation of treatment: how
should we use them? Eur Urol, 2004. 46: 636.
https://www.ncbi.nlm.nih.gov/pubmed/15474275
29. Gisolf, K.W., et al. Analysis and reliability of data from 24-hour frequency-volume charts in men with
lower urinary tract symptoms due to benign prostatic hyperplasia. Eur Urol, 2000. 38: 45.
https://www.ncbi.nlm.nih.gov/pubmed/10859441
30. Cornu, J.N., et al. A contemporary assessment of nocturia: definition, epidemiology,
pathophysiology, and management--a systematic review and meta-analysis. Eur Urol, 2012. 62:
877.
https://www.ncbi.nlm.nih.gov/pubmed/22840350
40 MANAGEMENT OF NON-NEUROGENIC MALE LOWER URINARY TRACT SYMPTOMS (LUTS) - UPDATE MARCH 2017
31. Weiss, J.P. Nocturia: “do the math”. J Urol, 2006. 175: S16.
https://www.ncbi.nlm.nih.gov/pubmed/16458734
32. Weiss, J.P., et al. Nocturia Think Tank: focus on nocturnal polyuria: ICI-RS 2011.
Neurourol Urodyn, 2012. 31: 330.
https://www.ncbi.nlm.nih.gov/pubmed/22415907
33. Vaughan, C.P., et al. Military exposure and urinary incontinence among American men. J Urol, 2014.
191: 125.
https://www.ncbi.nlm.nih.gov/pubmed/23871759
34. Bright, E., et al. Urinary diaries: evidence for the development and validation of diary content,
format, and duration. Neurourol Urodyn, 2011. 30: 348.
https://www.ncbi.nlm.nih.gov/pubmed/21284023
35. Yap, T.L., et al. A systematic review of the reliability of frequency-volume charts in urological
research and its implications for the optimum chart duration. BJU Int, 2007. 99: 9.
https://www.ncbi.nlm.nih.gov/pubmed/16956355
36. Weissfeld, J.L., et al. Quality control of cancer screening examination procedures in the Prostate,
Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. Control Clin Trials, 2000. 21: 390s.
https://www.ncbi.nlm.nih.gov/pubmed/11189690
37. Roehrborn, C.G. Accurate determination of prostate size via digital rectal examination and
transrectal ultrasound. Urology, 1998. 51: 19.
https://www.ncbi.nlm.nih.gov/pubmed/9586952
38. Roehrborn, C.G., et al. Interexaminer reliability and validity of a three-dimensional model to assess
prostate volume by digital rectal examination. Urology, 2001. 57: 1087.
https://www.ncbi.nlm.nih.gov/pubmed/11377314
39. Bosch, J.L., et al. Validity of digital rectal examination and serum prostate specific antigen in the
estimation of prostate volume in community-based men aged 50 to 78 years: the Krimpen Study.
Eur Urol, 2004. 46: 753.
https://www.ncbi.nlm.nih.gov/pubmed/15548443
40. Burger, M., et al. ICUD-EAU International Consultation on Bladder Cancer 2012: Non-muscle-
invasive urothelial carcinoma of the bladder. Eur Urol, 2013. 63: 36.
https://www.ncbi.nlm.nih.gov/pubmed/22981672
41. Bonkat, et. al. EAU Guidelines on Urological Infections. In: EAU Guidelines, edition presented at the
annual EAU Congress London 2017. ISBN 978-90-79754-91-5.
http://uroweb.org/guidelines/
42. Palou, J., et al. ICUD-EAU International Consultation on Bladder Cancer 2012: Urothelial carcinoma
of the prostate. Eur Urol, 2013. 63: 81.
https://www.ncbi.nlm.nih.gov/pubmed/22938869
43. Roupret, M., et al. European guidelines on upper tract urothelial carcinomas: 2013 update.
Eur Urol, 2013. 63: 1059.
https://www.ncbi.nlm.nih.gov/pubmed/23540953
44. Roehrborn, C.G., et al. Guidelines for the diagnosis and treatment of benign prostatic hyperplasia: a
comparative, international overview. Urology, 2001. 58: 642.
https://www.ncbi.nlm.nih.gov/pubmed/11711329
45. Abrams, P., et al. Evaluation and treatment of lower urinary tract symptoms in older men.
J Urol, 2013. 189: S93.
https://www.ncbi.nlm.nih.gov/pubmed/23234640
46. European urinalysis guidelines. Scand J Clin Lab Invest Suppl, 2000. 231: 1.
https://www.ncbi.nlm.nih.gov/pubmed/12647764
47. Khasriya, R., et al. The inadequacy of urinary dipstick and microscopy as surrogate markers of
urinary tract infection in urological outpatients with lower urinary tract symptoms without acute
frequency and dysuria. J Urol, 2010. 183: 1843.
https://www.ncbi.nlm.nih.gov/pubmed/20303096
48. Roehrborn, C.G., et al. Serum prostate-specific antigen as a predictor of prostate volume in men
with benign prostatic hyperplasia. Urology, 1999. 53: 581.
https://www.ncbi.nlm.nih.gov/pubmed/10096388
49. Bohnen, A.M., et al. Serum prostate-specific antigen as a predictor of prostate volume in the
community: the Krimpen study. Eur Urol, 2007. 51: 1645.
https://www.ncbi.nlm.nih.gov/pubmed/17320271
50. Kayikci, A., et al. Free prostate-specific antigen is a better tool than total prostate-specific antigen at
predicting prostate volume in patients with lower urinary tract symptoms. Urology, 2012. 80: 1088.
https://www.ncbi.nlm.nih.gov/pubmed/23107399
MANAGEMENT OF NON-NEUROGENIC MALE LOWER URINARY TRACT SYMPTOMS (LUTS) - UPDATE MARCH 2017 41
51. Morote, J., et al. Prediction of prostate volume based on total and free serum prostate-specific
antigen: is it reliable? Eur Urol, 2000. 38: 91.
https://www.ncbi.nlm.nih.gov/pubmed/10859448
52. Heidenreich, A., et al. EAU guidelines on prostate cancer part 1: screening, diagnosis, and local
treatment with curative intent-update 2013. Eur Urol, 2014. 65: 124.
https://www.ncbi.nlm.nih.gov/pubmed/24207135
53. Roehrborn, C.G., et al. Serum prostate specific antigen is a strong predictor of future prostate
growth in men with benign prostatic hyperplasia. PROSCAR long-term efficacy and safety study.
J Urol, 2000. 163: 13.
https://www.ncbi.nlm.nih.gov/pubmed/10604304
54. Roehrborn, C.G., et al. Serum prostate-specific antigen and prostate volume predict long-term
changes in symptoms and flow rate: results of a four-year, randomized trial comparing finasteride
versus placebo. PLESS Study Group. Urology, 1999. 54: 662.
https://www.ncbi.nlm.nih.gov/pubmed/10510925
55. Djavan, B., et al. Longitudinal study of men with mild symptoms of bladder outlet obstruction
treated with watchful waiting for four years. Urology, 2004. 64: 1144.
https://www.ncbi.nlm.nih.gov/pubmed/15596187
56. McConnell, J.D., et al. The long-term effect of doxazosin, finasteride, and combination therapy on
the clinical progression of benign prostatic hyperplasia. N Engl J Med, 2003. 349: 2387.
https://www.ncbi.nlm.nih.gov/pubmed/14681504
57. Roehrborn, C.G. Alfuzosin 10 mg once daily prevents overall clinical progression of benign prostatic
hyperplasia but not acute urinary retention: results of a 2-year placebo-controlled study.
BJU Int, 2006. 97: 734.
https://www.ncbi.nlm.nih.gov/pubmed/16536764
58. Jacobsen, S.J., et al. Treatment for benign prostatic hyperplasia among community dwelling men:
the Olmsted County study of urinary symptoms and health status. J Urol, 1999. 162: 1301.
https://www.ncbi.nlm.nih.gov/pubmed/10492184
59. Lim, K.B., et al. Comparison of intravesical prostatic protrusion, prostate volume and serum
prostatic-specific antigen in the evaluation of bladder outlet obstruction. Int J Urol, 2006. 13: 1509.
https://www.ncbi.nlm.nih.gov/pubmed/17118026
60. Meigs, J.B., et al. Risk factors for clinical benign prostatic hyperplasia in a community-based
population of healthy aging men. J Clin Epidemiol, 2001. 54: 935.
https://www.ncbi.nlm.nih.gov/pubmed/11520654
61. Gerber, G.S., et al. Serum creatinine measurements in men with lower urinary tract symptoms
secondary to benign prostatic hyperplasia. Urology, 1997. 49: 697.
https://www.ncbi.nlm.nih.gov/pubmed/9145973
62. Oelke, M., et al. Can we identify men who will have complications from benign prostatic obstruction
(BPO)? ICI-RS 2011. Neurourol Urodyn, 2012. 31: 322.
https://www.ncbi.nlm.nih.gov/pubmed/22415947
63. Comiter, C.V., et al. Urodynamic risk factors for renal dysfunction in men with obstructive and
nonobstructive voiding dysfunction. J Urol, 1997. 158: 181.
https://www.ncbi.nlm.nih.gov/pubmed/9186351
64. Koch, W.F., et al. The outcome of renal ultrasound in the assessment of 556 consecutive patients
with benign prostatic hyperplasia. J Urol, 1996. 155: 186.
https://www.ncbi.nlm.nih.gov/pubmed/7490828
65. Rule, A.D., et al. The association between benign prostatic hyperplasia and chronic kidney disease
in community-dwelling men. Kidney Int, 2005. 67: 2376.
https://www.ncbi.nlm.nih.gov/pubmed/15882282
66. Hong, S.K., et al. Chronic kidney disease among men with lower urinary tract symptoms due to
benign prostatic hyperplasia. BJU Int, 2010. 105: 1424.
https://www.ncbi.nlm.nih.gov/pubmed/19874305
67. Lee, J.H., et al. Relationship of estimated glomerular filtration rate with lower urinary tract
symptoms/benign prostatic hyperplasia measures in middle-aged men with moderate to severe
lower urinary tract symptoms. Urology, 2013. 82: 1381.
https://www.ncbi.nlm.nih.gov/pubmed/24063940
68. Mebust, W.K., et al. Transurethral prostatectomy: immediate and postoperative complications. A
cooperative study of 13 participating institutions evaluating 3,885 patients. J Urol, 1989. 141: 243.
https://www.ncbi.nlm.nih.gov/pubmed/2643719
42 MANAGEMENT OF NON-NEUROGENIC MALE LOWER URINARY TRACT SYMPTOMS (LUTS) - UPDATE MARCH 2017
69. Rule, A.D., et al. Longitudinal changes in post-void residual and voided volume among community
dwelling men. J Urol, 2005. 174: 1317.
https://www.ncbi.nlm.nih.gov/pubmed/16145411
70. Sullivan, M.P., et al. Detrusor contractility and compliance characteristics in adult male patients with
obstructive and nonobstructive voiding dysfunction. J Urol, 1996. 155: 1995.
https://www.ncbi.nlm.nih.gov/pubmed/8618307
71. Oelke, M., et al. Diagnostic accuracy of noninvasive tests to evaluate bladder outlet obstruction in
men: detrusor wall thickness, uroflowmetry, postvoid residual urine, and prostate volume.
Eur Urol, 2007. 52: 827.
https://www.ncbi.nlm.nih.gov/pubmed/17207910
72. Mochtar, C.A., et al. Post-void residual urine volume is not a good predictor of the need for invasive
therapy among patients with benign prostatic hyperplasia. J Urol, 2006. 175: 213.
https://www.ncbi.nlm.nih.gov/pubmed/16406914
73. Jorgensen, J.B., et al. Age-related variation in urinary flow variables and flow curve patterns in
elderly males. Br J Urol, 1992. 69: 265.
https://www.ncbi.nlm.nih.gov/pubmed/1373664
74. Kranse, R., et al. Causes for variability in repeated pressure-flow measurements. Urology, 2003. 61:
930.
https://www.ncbi.nlm.nih.gov/pubmed/12736007
75. Reynard, J.M., et al. The ICS-’BPH’ Study: uroflowmetry, lower urinary tract symptoms and bladder
outlet obstruction. Br J Urol, 1998. 82: 619.
https://www.ncbi.nlm.nih.gov/pubmed/9839573
76. Idzenga, T., et al. Accuracy of maximum flow rate for diagnosing bladder outlet obstruction can be
estimated from the ICS nomogram. Neurourol Urodyn, 2008. 27: 97.
https://www.ncbi.nlm.nih.gov/pubmed/17600368
77. Siroky, M.B., et al. The flow rate nomogram: I. Development. J Urol, 1979. 122: 665.
https://www.ncbi.nlm.nih.gov/pubmed/159366
78. Siroky, M.B., et al. The flow rate nomogram: II. Clinical correlation. J Urol, 1980. 123: 208.
https://www.ncbi.nlm.nih.gov/pubmed/7354519
79. Grossfeld, G.D., et al. Benign prostatic hyperplasia: clinical overview and value of diagnostic
imaging. Radiol Clin North Am, 2000. 38: 31.
https://www.ncbi.nlm.nih.gov/pubmed/10664665
80. Thorpe, A., et al. Benign prostatic hyperplasia. Lancet, 2003. 361: 1359.
https://www.ncbi.nlm.nih.gov/pubmed/12711484
81. Wilkinson, A.G., et al. Is pre-operative imaging of the urinary tract worthwhile in the assessment of
prostatism? Br J Urol, 1992. 70: 53.
https://www.ncbi.nlm.nih.gov/pubmed/1379105
82. Loch, A.C., et al. Technical and anatomical essentials for transrectal ultrasound of the prostate.
World J Urol, 2007. 25: 361.
https://www.ncbi.nlm.nih.gov/pubmed/17701043
83. Stravodimos, K.G., et al. TRUS versus transabdominal ultrasound as a predictor of enucleated
adenoma weight in patients with BPH: a tool for standard preoperative work-up? Int Urol Nephrol,
2009. 41: 767.
https://www.ncbi.nlm.nih.gov/pubmed/19350408
84. Shoukry, I., et al. Role of uroflowmetry in the assessment of lower urinary tract obstruction in adult
males. Br J Urol, 1975. 47: 559.
https://www.ncbi.nlm.nih.gov/pubmed/1191927
85. Anikwe, R.M. Correlations between clinical findings and urinary flow rate in benign prostatic
hypertrophy. Int Surg, 1976. 61: 392.
https://www.ncbi.nlm.nih.gov/pubmed/61184
86. el Din, K.E., et al. The correlation between urodynamic and cystoscopic findings in elderly men with
voiding complaints. J Urol, 1996. 155: 1018.
https://www.ncbi.nlm.nih.gov/pubmed/8583551
87. Oelke, M., et al. Age and bladder outlet obstruction are independently associated with detrusor
overactivity in patients with benign prostatic hyperplasia. Eur Urol, 2008. 54: 419.
https://www.ncbi.nlm.nih.gov/pubmed/18325657
88. Oh, M.M., et al. Is there a correlation between the presence of idiopathic detrusor overactivity and
the degree of bladder outlet obstruction? Urology, 2011. 77: 167.
https://www.ncbi.nlm.nih.gov/pubmed/20934743
MANAGEMENT OF NON-NEUROGENIC MALE LOWER URINARY TRACT SYMPTOMS (LUTS) - UPDATE MARCH 2017 43
89. Jeong, S.J., et al. Prevalence and Clinical Features of Detrusor Underactivity among Elderly with
Lower Urinary Tract Symptoms: A Comparison between Men and Women. Korean J Urol, 2012. 53:
342.
https://www.ncbi.nlm.nih.gov/pubmed/22670194
90. Thomas, A.W., et al. The natural history of lower urinary tract dysfunction in men: the influence of
detrusor underactivity on the outcome after transurethral resection of the prostate with a minimum
10-year urodynamic follow-up. BJU Int, 2004. 93: 745.
https://www.ncbi.nlm.nih.gov/pubmed/15049984
91. Al-Hayek, S., et al. Natural history of detrusor contractility--minimum ten-year urodynamic follow-up
in men with bladder outlet obstruction and those with detrusor. Scand J Urol Nephrol Suppl, 2004:
101.
https://www.ncbi.nlm.nih.gov/pubmed/15545204
92. Thomas, A.W., et al. The natural history of lower urinary tract dysfunction in men: minimum 10-year
urodynamic followup of transurethral resection of prostate for bladder outlet obstruction.
J Urol, 2005. 174: 1887.
https://www.ncbi.nlm.nih.gov/pubmed/16217330
93. Clement, K.D., et al. Invasive urodynamic studies for the management of lower urinary tract
symptoms (LUTS) in men with voiding dysfunction. Cochrane Database Syst Rev, 2015: CD011179.
https://www.ncbi.nlm.nih.gov/pubmed/25918922
94. Stohrer, M., et al. EAU guidelines on neurogenic lower urinary tract dysfunction. Eur Urol, 2009. 56:
81.
https://www.ncbi.nlm.nih.gov/pubmed/19403235
95. Kojima, M., et al. Correlation of presumed circle area ratio with infravesical obstruction in men with
lower urinary tract symptoms. Urology, 1997. 50: 548.
https://www.ncbi.nlm.nih.gov/pubmed/9338730
96. Chia, S.J., et al. Correlation of intravesical prostatic protrusion with bladder outlet obstruction.
BJU Int, 2003. 91: 371.
https://www.ncbi.nlm.nih.gov/pubmed/12603417
97. Keqin, Z., et al. Clinical significance of intravesical prostatic protrusion in patients with benign
prostatic enlargement. Urology, 2007. 70: 1096.
https://www.ncbi.nlm.nih.gov/pubmed/18158025
98. Mariappan, P., et al. Intravesical prostatic protrusion is better than prostate volume in predicting the
outcome of trial without catheter in white men presenting with acute urinary retention: a prospective
clinical study. J Urol, 2007. 178: 573.
https://www.ncbi.nlm.nih.gov/pubmed/17570437
99. Tan, Y.H., et al. Intravesical prostatic protrusion predicts the outcome of a trial without catheter
following acute urine retention. J Urol, 2003. 170: 2339.
https://www.ncbi.nlm.nih.gov/pubmed/14634410
100. Arnolds, M., et al. Positioning invasive versus noninvasive urodynamics in the assessment of
bladder outlet obstruction. Curr Opin Urol, 2009. 19: 55.
https://www.ncbi.nlm.nih.gov/pubmed/19057217
101. Manieri, C., et al. The diagnosis of bladder outlet obstruction in men by ultrasound measurement of
bladder wall thickness. J Urol, 1998. 159: 761.
https://www.ncbi.nlm.nih.gov/pubmed/9474143
102. Kessler, T.M., et al. Ultrasound assessment of detrusor thickness in men-can it predict bladder
outlet obstruction and replace pressure flow study? J Urol, 2006. 175: 2170.
https://www.ncbi.nlm.nih.gov/pubmed/16697831
103. Blatt, A.H., et al. Ultrasound measurement of bladder wall thickness in the assessment of voiding
dysfunction. J Urol, 2008. 179: 2275.
https://www.ncbi.nlm.nih.gov/pubmed/18423703
104. Oelke, M. International Consultation on Incontinence-Research Society (ICI-RS) report on non-
invasive urodynamics: the need of standardization of ultrasound bladder and detrusor wall thickness
measurements to quantify bladder wall hypertrophy. Neurourol Urodyn, 2010. 29: 634.
https://www.ncbi.nlm.nih.gov/pubmed/20432327
105. Kojima, M., et al. Ultrasonic estimation of bladder weight as a measure of bladder hypertrophy in
men with infravesical obstruction: a preliminary report. Urology, 1996. 47: 942.
https://www.ncbi.nlm.nih.gov/pubmed/8677600
106. Kojima, M., et al. Noninvasive quantitative estimation of infravesical obstruction using ultrasonic
measurement of bladder weight. J Urol, 1997. 157: 476.
https://www.ncbi.nlm.nih.gov/pubmed/8996337
44 MANAGEMENT OF NON-NEUROGENIC MALE LOWER URINARY TRACT SYMPTOMS (LUTS) - UPDATE MARCH 2017
107. Akino, H., et al. Ultrasound-estimated bladder weight predicts risk of surgery for benign prostatic
hyperplasia in men using alpha-adrenoceptor blocker for LUTS. Urology, 2008. 72: 817.
https://www.ncbi.nlm.nih.gov/pubmed/18597835
108. McIntosh, S.L., et al. Noninvasive assessment of bladder contractility in men. J Urol, 2004. 172:
1394.
https://www.ncbi.nlm.nih.gov/pubmed/15371853
109. Drinnan, M.J., et al. Inter-observer agreement in the estimation of bladder pressure using a penile
cuff. Neurourol Urodyn, 2003. 22: 296.
https://www.ncbi.nlm.nih.gov/pubmed/12808703
110. Griffiths, C.J., et al. A nomogram to classify men with lower urinary tract symptoms using urine flow
and noninvasive measurement of bladder pressure. J Urol, 2005. 174: 1323.
https://www.ncbi.nlm.nih.gov/pubmed/16145412
111. Clarkson, B., et al. Continuous non-invasive measurement of bladder voiding pressure using an
experimental constant low-flow test. Neurourol Urodyn, 2012. 31: 557.
https://www.ncbi.nlm.nih.gov/pubmed/22190105
112. Van Mastrigt, R., et al. Towards a noninvasive urodynamic diagnosis of infravesical obstruction.
BJU Int, 1999. 84: 195.
https://www.ncbi.nlm.nih.gov/pubmed/10444152
113. Pel, J.J., et al. Development of a non-invasive strategy to classify bladder outlet obstruction in male
patients with LUTS. Neurourol Urodyn, 2002. 21: 117.
https://www.ncbi.nlm.nih.gov/pubmed/11857664
114. Shinbo, H., et al. Application of ultrasonography and the resistive index for evaluating bladder outlet
obstruction in patients with benign prostatic hyperplasia. Curr Urol Rep, 2011. 12: 255.
https://www.ncbi.nlm.nih.gov/pubmed/21475953
115. Ku, J.H., et al. Correlation between prostatic urethral angle and bladder outlet obstruction index in
patients with lower urinary tract symptoms. Urology, 2010. 75: 1467.
https://www.ncbi.nlm.nih.gov/pubmed/19962734
116. Malde, S., et al. Systematic Review of the Performance of Noninvasive Tests in Diagnosing Bladder
Outlet Obstruction in Men with Lower Urinary Tract Symptoms. Eur Urol, 2016.
https://www.ncbi.nlm.nih.gov/pubmed/27687821
117. Ball, A.J., et al. The natural history of untreated “prostatism”. Br J Urol, 1981. 53: 613.
https://www.ncbi.nlm.nih.gov/pubmed/6172172
118. Kirby, R.S. The natural history of benign prostatic hyperplasia: what have we learned in the last
decade? Urology, 2000. 56: 3.
https://www.ncbi.nlm.nih.gov/pubmed/11074195
119. Isaacs, J.T. Importance of the natural history of benign prostatic hyperplasia in the evaluation of
pharmacologic intervention. Prostate Suppl, 1990. 3: 1.
https://www.ncbi.nlm.nih.gov/pubmed/1689166
120. Netto, N.R., Jr., et al. Evaluation of patients with bladder outlet obstruction and mild international
prostate symptom score followed up by watchful waiting. Urology, 1999. 53: 314.
https://www.ncbi.nlm.nih.gov/pubmed/9933046
121. Flanigan, R.C., et al. 5-year outcome of surgical resection and watchful waiting for men with
moderately symptomatic benign prostatic hyperplasia: a Department of Veterans Affairs cooperative
study. J Urol, 1998. 160: 12.
https://www.ncbi.nlm.nih.gov/pubmed/9628595
122. Wasson, J.H., et al. A comparison of transurethral surgery with watchful waiting for moderate
symptoms of benign prostatic hyperplasia. The Veterans Affairs Cooperative Study Group on
Transurethral Resection of the Prostate. N Engl J Med, 1995. 332: 75.
https://www.ncbi.nlm.nih.gov/pubmed/7527493
123. Brown, C.T., et al. Self management for men with lower urinary tract symptoms: randomised
controlled trial. Bmj, 2007. 334: 25.
https://www.ncbi.nlm.nih.gov/pubmed/17118949
124. Yap, T.L., et al. The impact of self-management of lower urinary tract symptoms on frequency-
volume chart measures. BJU Int, 2009. 104: 1104.
https://www.ncbi.nlm.nih.gov/pubmed/19485993
125. Brown, C.T., et al. Defining the components of a self-management programme for men with
uncomplicated lower urinary tract symptoms: a consensus approach. Eur Urol, 2004. 46: 254.
https://www.ncbi.nlm.nih.gov/pubmed/15245822
MANAGEMENT OF NON-NEUROGENIC MALE LOWER URINARY TRACT SYMPTOMS (LUTS) - UPDATE MARCH 2017 45
126. Michel, M.C., et al. Alpha1-, alpha2- and beta-adrenoceptors in the urinary bladder, urethra and
prostate. Br J Pharmacol, 2006. 147 Suppl 2: S88.
https://www.ncbi.nlm.nih.gov/pubmed/16465187
127. Kortmann, B.B., et al. Urodynamic effects of alpha-adrenoceptor blockers: a review of clinical trials.
Urology, 2003. 62: 1.
https://www.ncbi.nlm.nih.gov/pubmed/12837408
128. Barendrecht, M.M., et al. Do alpha1-adrenoceptor antagonists improve lower urinary tract
symptoms by reducing bladder outlet resistance? Neurourol Urodyn, 2008. 27: 226.
https://www.ncbi.nlm.nih.gov/pubmed/17638312
129. Djavan, B., et al. State of the art on the efficacy and tolerability of alpha1-adrenoceptor antagonists
in patients with lower urinary tract symptoms suggestive of benign prostatic hyperplasia. Urology,
2004. 64: 1081.
https://www.ncbi.nlm.nih.gov/pubmed/15596173
130. Michel, M.C., et al. Comparison of tamsulosin efficacy in subgroups of patients with lower urinary
tract symptoms. Prostate Cancer Prostatic Dis, 1998. 1: 332.
https://www.ncbi.nlm.nih.gov/pubmed/12496876
131. Boyle, P., et al. Meta-analysis of randomized trials of terazosin in the treatment of benign prostatic
hyperplasia. Urology, 2001. 58: 717.
https://www.ncbi.nlm.nih.gov/pubmed/11711348
132. Roehrborn, C.G. Three months’ treatment with the alpha1-blocker alfuzosin does not affect total or
transition zone volume of the prostate. Prostate Cancer Prostatic Dis, 2006. 9: 121.
https://www.ncbi.nlm.nih.gov/pubmed/16304557
133. Roehrborn, C.G., et al. The effects of dutasteride, tamsulosin and combination therapy on lower
urinary tract symptoms in men with benign prostatic hyperplasia and prostatic enlargement: 2-year
results from the CombAT study. J Urol, 2008. 179: 616.
https://www.ncbi.nlm.nih.gov/pubmed/18082216
134. Roehrborn, C.G., et al. The effects of combination therapy with dutasteride and tamsulosin on
clinical outcomes in men with symptomatic benign prostatic hyperplasia: 4-year results from the
CombAT study. Eur Urol, 2010. 57: 123.
https://www.ncbi.nlm.nih.gov/pubmed/19825505
135. Nickel, J.C., et al. A meta-analysis of the vascular-related safety profile and efficacy of alpha-
adrenergic blockers for symptoms related to benign prostatic hyperplasia. Int J Clin Pract, 2008. 62:
1547.
https://www.ncbi.nlm.nih.gov/pubmed/18822025
136. Barendrecht, M.M., et al. Treatment of lower urinary tract symptoms suggestive of benign prostatic
hyperplasia: the cardiovascular system. BJU Int, 2005. 95 Suppl 4: 19.
https://www.ncbi.nlm.nih.gov/pubmed/15871732
137. Chapple, C.R., et al. Silodosin therapy for lower urinary tract symptoms in men with suspected
benign prostatic hyperplasia: results of an international, randomized, double-blind, placebo- and
active-controlled clinical trial performed in Europe. Eur Urol, 2011. 59: 342.
https://www.ncbi.nlm.nih.gov/pubmed/21109344
138. Welk, B., et al. The risk of fall and fracture with the initiation of a prostate-selective alpha antagonist:
a population based cohort study. BMJ, 2015. 351: h5398.
https://www.ncbi.nlm.nih.gov/pubmed/26502947
139. Chang, D.F., et al. Intraoperative floppy iris syndrome associated with tamsulosin. J Cataract Refract
Surg, 2005. 31: 664.
https://www.ncbi.nlm.nih.gov/pubmed/15899440
140. Chatziralli, I.P., et al. Risk factors for intraoperative floppy iris syndrome: a meta-analysis.
Ophthalmology, 2011. 118: 730.
https://www.ncbi.nlm.nih.gov/pubmed/21168223
141. van Dijk, M.M., et al. Effects of alpha(1)-adrenoceptor antagonists on male sexual function. Drugs,
2006. 66: 287.
https://www.ncbi.nlm.nih.gov/pubmed/16526818
142. Gacci, M., et al. Impact of medical treatments for male lower urinary tract symptoms due to benign
prostatic hyperplasia on ejaculatory function: a systematic review and meta-analysis.
J Sex Med, 2014. 11: 1554.
https://www.ncbi.nlm.nih.gov/pubmed/24708055
143. Andriole, G., et al. Dihydrotestosterone and the prostate: the scientific rationale for 5alpha-reductase
inhibitors in the treatment of benign prostatic hyperplasia. J Urol, 2004. 172: 1399.
https://www.ncbi.nlm.nih.gov/pubmed/15371854
46 MANAGEMENT OF NON-NEUROGENIC MALE LOWER URINARY TRACT SYMPTOMS (LUTS) - UPDATE MARCH 2017
144. Rittmaster, R.S., et al. Evidence for atrophy and apoptosis in the prostates of men given finasteride.
J Clin Endocrinol Metab, 1996. 81: 814.
https://www.ncbi.nlm.nih.gov/pubmed/8636309
145. Naslund, M.J., et al. A review of the clinical efficacy and safety of 5alpha-reductase inhibitors for the
enlarged prostate. Clin Ther, 2007. 29: 17.
https://www.ncbi.nlm.nih.gov/pubmed/17379044
146. Andersen, J.T., et al. Can finasteride reverse the progress of benign prostatic hyperplasia? A two-
year placebo-controlled study. The Scandinavian BPH Study Group. Urology, 1995. 46: 631.
https://www.ncbi.nlm.nih.gov/pubmed/7495111
147. Kirby, R.S., et al. Efficacy and tolerability of doxazosin and finasteride, alone or in combination, in
treatment of symptomatic benign prostatic hyperplasia: the Prospective European Doxazosin and
Combination Therapy (PREDICT) trial. Urology, 2003. 61: 119.
https://www.ncbi.nlm.nih.gov/pubmed/12559281
148. Lepor, H., et al. The efficacy of terazosin, finasteride, or both in benign prostatic hyperplasia.
Veterans Affairs Cooperative Studies Benign Prostatic Hyperplasia Study Group.
N Engl J Med, 1996. 335: 533.
https://www.ncbi.nlm.nih.gov/pubmed/8684407
149. Marberger, M.J. Long-term effects of finasteride in patients with benign prostatic hyperplasia: a
double-blind, placebo-controlled, multicenter study. PROWESS Study Group. Urology, 1998. 51:
677.
https://www.ncbi.nlm.nih.gov/pubmed/9610579
150. McConnell, J.D., et al. The effect of finasteride on the risk of acute urinary retention and the need
for surgical treatment among men with benign prostatic hyperplasia. Finasteride Long-Term Efficacy
and Safety Study Group. N Engl J Med, 1998. 338: 557.
https://www.ncbi.nlm.nih.gov/pubmed/9475762
151. Nickel, J.C., et al. Efficacy and safety of finasteride therapy for benign prostatic hyperplasia: results
of a 2-year randomized controlled trial (the PROSPECT study). PROscar Safety Plus Efficacy
Canadian Two year Study. Cmaj, 1996. 155: 1251.
https://www.ncbi.nlm.nih.gov/pubmed/8911291
152. Roehrborn, C.G., et al. Efficacy and safety of a dual inhibitor of 5-alpha-reductase types 1 and 2
(dutasteride) in men with benign prostatic hyperplasia. Urology, 2002. 60: 434.
https://www.ncbi.nlm.nih.gov/pubmed/12350480
153. Nickel, J.C., et al. Comparison of dutasteride and finasteride for treating benign prostatic
hyperplasia: the Enlarged Prostate International Comparator Study (EPICS). BJU Int, 2011. 108: 388.
https://www.ncbi.nlm.nih.gov/pubmed/21631695
154. Boyle, P., et al. Prostate volume predicts outcome of treatment of benign prostatic hyperplasia with
finasteride: meta-analysis of randomized clinical trials. Urology, 1996. 48: 398.
https://www.ncbi.nlm.nih.gov/pubmed/8804493
155. Gittelman, M., et al. Dutasteride improves objective and subjective disease measures in men with
benign prostatic hyperplasia and modest or severe prostate enlargement. J Urol, 2006. 176: 1045.
https://www.ncbi.nlm.nih.gov/pubmed/16890688
156. Roehrborn, C.G., et al. Long-term sustained improvement in symptoms of benign prostatic
hyperplasia with the dual 5alpha-reductase inhibitor dutasteride: results of 4-year studies. BJU Int,
2005. 96: 572.
https://www.ncbi.nlm.nih.gov/pubmed/16104912
157. Roehrborn, C.G., et al. The influence of baseline parameters on changes in international prostate
symptom score with dutasteride, tamsulosin, and combination therapy among men with
symptomatic benign prostatic hyperplasia and an enlarged prostate: 2-year data from the CombAT
study. Eur Urol, 2009. 55: 461.
https://www.ncbi.nlm.nih.gov/pubmed/19013011
158. Roehrborn, C.G. BPH progression: concept and key learning from MTOPS, ALTESS, COMBAT, and
ALF-ONE. BJU Int, 2008. 101 Suppl 3: 17.
https://www.ncbi.nlm.nih.gov/pubmed/18307681
159. Andersen, J.T., et al. Finasteride significantly reduces acute urinary retention and need for surgery in
patients with symptomatic benign prostatic hyperplasia. Urology, 1997. 49: 839.
https://www.ncbi.nlm.nih.gov/pubmed/9187688
160. Kirby, R.S., et al. Long-term urodynamic effects of finasteride in benign prostatic hyperplasia: a pilot
study. Eur Urol, 1993. 24: 20.
https://www.ncbi.nlm.nih.gov/pubmed/7689971
MANAGEMENT OF NON-NEUROGENIC MALE LOWER URINARY TRACT SYMPTOMS (LUTS) - UPDATE MARCH 2017 47
161. Tammela, T.L., et al. Long-term effects of finasteride on invasive urodynamics and symptoms in the
treatment of patients with bladder outflow obstruction due to benign prostatic hyperplasia.
J Urol, 1995. 154: 1466.
https://www.ncbi.nlm.nih.gov/pubmed/7544845
162. Donohue, J.F., et al. Transurethral prostate resection and bleeding: a randomized, placebo
controlled trial of role of finasteride for decreasing operative blood loss. J Urol, 2002. 168: 2024.
https://www.ncbi.nlm.nih.gov/pubmed/12394700
163. Andriole, G.L., et al. Effect of dutasteride on the risk of prostate cancer. N Engl J Med, 2010. 362:
1192.
https://www.ncbi.nlm.nih.gov/pubmed/20357281
164. Thompson, I.M., et al. The influence of finasteride on the development of prostate cancer.
N Engl J Med, 2003. 349: 215.
https://www.ncbi.nlm.nih.gov/pubmed/12824459
165. Hsieh, T.F., et al. Use of 5-alpha-reductase inhibitors did not increase the risk of cardiovascular
diseases in patients with benign prostate hyperplasia: a five-year follow-up study. PLoS One, 2015.
10: e0119694.
https://www.ncbi.nlm.nih.gov/pubmed/25803433
166. Chess-Williams, R., et al. The minor population of M3-receptors mediate contraction of human
detrusor muscle in vitro. J Auton Pharmacol, 2001. 21: 243.
https://www.ncbi.nlm.nih.gov/pubmed/12123469
167. Matsui, M., et al. Multiple functional defects in peripheral autonomic organs in mice lacking
muscarinic acetylcholine receptor gene for the M3 subtype. Proc Natl Acad Sci U S A, 2000. 97:
9579.
https://www.ncbi.nlm.nih.gov/pubmed/10944224
168. Kono, M., et al. Central muscarinic receptor subtypes regulating voiding in rats. J Urol, 2006. 175:
353.
https://www.ncbi.nlm.nih.gov/pubmed/16406941
169. Wuest, M., et al. Effect of rilmakalim on detrusor contraction in the presence and absence of
urothelium. Naunyn Schmiedebergs Arch Pharmacol, 2005. 372: 203.
https://www.ncbi.nlm.nih.gov/pubmed/16283254
170. Goldfischer, E.R., et al. Efficacy and safety of oxybutynin topical gel 3% in patients with urgency
and/or mixed urinary incontinence: A randomized, double-blind, placebo-controlled study.
Neurourology and Urodynamics, 2015. 34: 37.
https://www.ncbi.nlm.nih.gov/pubmed/24133005
171. Baldwin, C.M., et al. Transdermal oxybutynin. Drugs, 2009. 69: 327.
https://www.ncbi.nlm.nih.gov/pubmed/19275276
172. Chapple, C.R., et al. A shifted paradigm for the further understanding, evaluation, and treatment of
lower urinary tract symptoms in men: focus on the bladder. Eur Urol, 2006. 49: 651.
https://www.ncbi.nlm.nih.gov/pubmed/16530611
173. Michel, M.C., et al. Does gender or age affect the efficacy and safety of tolterodine? J Urol, 2002.
168: 1027.
https://www.ncbi.nlm.nih.gov/pubmed/12187215
174. Chapple, C., et al. Fesoterodine clinical efficacy and safety for the treatment of overactive bladder
in relation to patient profiles: a systematic review. Curr Med Res Opin, 2015. 31: 1201.
https://www.ncbi.nlm.nih.gov/pubmed/25798911
175. Dmochowski, R., et al. Efficacy and tolerability of tolterodine extended release in male and female
patients with overactive bladder. Eur Urol, 2007. 51: 1054.
https://www.ncbi.nlm.nih.gov/pubmed/17097217
176. Herschorn, S., et al. Efficacy and tolerability of fesoterodine in men with overactive bladder: a
pooled analysis of 2 phase III studies. Urology, 2010. 75: 1149.
https://www.ncbi.nlm.nih.gov/pubmed/19914702
177. Hofner, K., et al. Safety and efficacy of tolterodine extended release in men with overactive bladder
symptoms and presumed non-obstructive benign prostatic hyperplasia. World J Urol, 2007. 25:
627.
https://www.ncbi.nlm.nih.gov/pubmed/17906864
178. Roehrborn, C.G., et al. Efficacy and tolerability of tolterodine extended-release in men with
overactive bladder and urgency urinary incontinence. BJU Int, 2006. 97: 1003.
https://www.ncbi.nlm.nih.gov/pubmed/16643482
48 MANAGEMENT OF NON-NEUROGENIC MALE LOWER URINARY TRACT SYMPTOMS (LUTS) - UPDATE MARCH 2017
179. Kaplan, S.A., et al. Tolterodine and tamsulosin for treatment of men with lower urinary tract
symptoms and overactive bladder: a randomized controlled trial. Jama, 2006. 296: 2319.
https://www.ncbi.nlm.nih.gov/pubmed/17105794
180. Kaplan, S.A., et al. Tolterodine extended release attenuates lower urinary tract symptoms in men
with benign prostatic hyperplasia. J Urol, 2005. 174: 2273.
https://www.ncbi.nlm.nih.gov/pubmed/16280803
181. Kaplan, S.A., et al. Solifenacin treatment in men with overactive bladder: effects on symptoms and
patient-reported outcomes. Aging Male, 2010. 13: 100.
https://www.ncbi.nlm.nih.gov/pubmed/20001469
182. Roehrborn, C.G., et al. Effects of serum PSA on efficacy of tolterodine extended release with or
without tamsulosin in men with LUTS, including OAB. Urology, 2008. 72: 1061.
https://www.ncbi.nlm.nih.gov/pubmed/18817961
183. Yokoyama, T., et al. Naftopidil and propiverine hydrochloride for treatment of male lower urinary
tract symptoms suggestive of benign prostatic hyperplasia and concomitant overactive bladder: a
prospective randomized controlled study. Scand J Urol Nephrol, 2009. 43: 307.
https://www.ncbi.nlm.nih.gov/pubmed/19396723
184. Abrams, P., et al. Safety and tolerability of tolterodine for the treatment of overactive bladder in men
with bladder outlet obstruction. J Urol, 2006. 175: 999.
https://www.ncbi.nlm.nih.gov/pubmed/16469601
185. Giuliano, F., et al. The mechanism of action of phosphodiesterase type 5 inhibitors in the treatment
of lower urinary tract symptoms related to benign prostatic hyperplasia. Eur Urol, 2013. 63: 506.
https://www.ncbi.nlm.nih.gov/pubmed/23018163
186. Morelli, A., et al. Phosphodiesterase type 5 expression in human and rat lower urinary tract tissues
and the effect of tadalafil on prostate gland oxygenation in spontaneously hypertensive rats.
J Sex Med, 2011. 8: 2746.
https://www.ncbi.nlm.nih.gov/pubmed/21812935
187. Vignozzi, L., et al. PDE5 inhibitors blunt inflammation in human BPH: a potential mechanism of
action for PDE5 inhibitors in LUTS. Prostate, 2013. 73: 1391.
https://www.ncbi.nlm.nih.gov/pubmed/23765639
188. Gacci, M., et al. A systematic review and meta-analysis on the use of phosphodiesterase 5 inhibitors
alone or in combination with alpha-blockers for lower urinary tract symptoms due to benign
prostatic hyperplasia. Eur Urol, 2012. 61: 994.
https://www.ncbi.nlm.nih.gov/pubmed/22405510
189. Oelke, M., et al. Monotherapy with tadalafil or tamsulosin similarly improved lower urinary tract
symptoms suggestive of benign prostatic hyperplasia in an international, randomised, parallel,
placebo-controlled clinical trial. Eur Urol, 2012. 61: 917.
https://www.ncbi.nlm.nih.gov/pubmed/22297243
190. Oelke, M., et al. Time to onset of clinically meaningful improvement with tadalafil 5 mg once daily
for lower urinary tract symptoms secondary to benign prostatic hyperplasia: analysis of data pooled
from 4 pivotal, double-blind, placebo controlled studies. J Urol, 2015. 193: 1581.
https://www.ncbi.nlm.nih.gov/pubmed/25437533
191. Donatucci, C.F., et al. Tadalafil administered once daily for lower urinary tract symptoms secondary
to benign prostatic hyperplasia: a 1-year, open-label extension study. BJU Int, 2011. 107: 1110.
https://www.ncbi.nlm.nih.gov/pubmed/21244606
192. Porst, H., et al. Efficacy and safety of tadalafil 5 mg once daily for lower urinary tract symptoms
suggestive of benign prostatic hyperplasia: subgroup analyses of pooled data from 4 multinational,
randomized, placebo-controlled clinical studies. Urology, 2013. 82: 667.
https://www.ncbi.nlm.nih.gov/pubmed/23876588
193. Vlachopoulos, C., et al. Impact of cardiovascular risk factors and related comorbid conditions and
medical therapy reported at baseline on the treatment response to tadalafil 5 mg once-daily in
men with lower urinary tract symptoms associated with benign prostatic hyperplasia: an integrated
analysis of four randomised, double-blind, placebo-controlled, clinical trials. Int J Clin Pract, 2015.
69: 1496.
https://www.ncbi.nlm.nih.gov/pubmed/26299520
194. Porst, H., et al. Effects of tadalafil on lower urinary tract symptoms secondary to benign prostatic
hyperplasia and on erectile dysfunction in sexually active men with both conditions: analyses of
pooled data from four randomized, placebo-controlled tadalafil clinical studies. J Sex Med, 2013.
10: 2044.
https://www.ncbi.nlm.nih.gov/pubmed/23782459
MANAGEMENT OF NON-NEUROGENIC MALE LOWER URINARY TRACT SYMPTOMS (LUTS) - UPDATE MARCH 2017 49
195. Brock, G.B., et al. Direct effects of tadalafil on lower urinary tract symptoms versus indirect effects
mediated through erectile dysfunction symptom improvement: integrated data analyses from 4
placebo controlled clinical studies. J Urol, 2014. 191: 405.
https://www.ncbi.nlm.nih.gov/pubmed/24096120
196. Roehrborn, C.G., et al. Effects of tadalafil once daily on maximum urinary flow rate in men with lower
urinary tract symptoms suggestive of benign prostatic hyperplasia. J Urol, 2014. 191: 1045.
https://www.ncbi.nlm.nih.gov/pubmed/24445278
197. Casabe, A., et al. Efficacy and safety of the coadministration of tadalafil once daily with finasteride
for 6 months in men with lower urinary tract symptoms and prostatic enlargement secondary to
benign prostatic hyperplasia. J Urol, 2014. 191: 727.
https://www.ncbi.nlm.nih.gov/pubmed/24096118
198. Gacci, M., et al. The use of a single daily dose of tadalafil to treat signs and symptoms of benign
prostatic hyperplasia and erectile dysfunction. Res Rep Urol, 2013. 5: 99.
https://www.ncbi.nlm.nih.gov/pubmed/24400241
199. Madersbacher, S., et al. Plant extracts: sense or nonsense? Curr Opin Urol, 2008. 18: 16.
https://www.ncbi.nlm.nih.gov/pubmed/18090484
200. Buck, A.C. Is there a scientific basis for the therapeutic effects of serenoa repens in benign prostatic
hyperplasia? Mechanisms of action. J Urol, 2004. 172: 1792.
https://www.ncbi.nlm.nih.gov/pubmed/15540722
201. Levin, R.M., et al. A scientific basis for the therapeutic effects of Pygeum africanum and Serenoa
repens. Urol Res, 2000. 28: 201.
https://www.ncbi.nlm.nih.gov/pubmed/10929430
202. Habib, F.K., et al. Not all brands are created equal: a comparison of selected components of
different brands of Serenoa repens extract. Prostate Cancer Prostatic Dis, 2004. 7: 195.
https://www.ncbi.nlm.nih.gov/pubmed/15289814
203. Scaglione, F., et al. Comparison of the potency of different brands of Serenoa repens extract on
5alpha-reductase types I and II in prostatic co-cultured epithelial and fibroblast cells. Pharmacology,
2008. 82: 270.
https://www.ncbi.nlm.nih.gov/pubmed/18849646
204. De Monte, C., et al. Modern extraction techniques and their impact on the pharmacological profile
of Serenoa repens extracts for the treatment of lower urinary tract symptoms. BMC Urol, 2014. 14:
63.
https://www.ncbi.nlm.nih.gov/pubmed/25112532
205. Tacklind, J., et al. Serenoa repens for benign prostatic hyperplasia. Cochrane Database Syst Rev,
2012. 12: Cd001423.
https://www.ncbi.nlm.nih.gov/pubmed/23235581
206. Wilt, T., et al. Pygeum africanum for benign prostatic hyperplasia. Cochrane Database Syst Rev,
2002: Cd001044.
https://www.ncbi.nlm.nih.gov/pubmed/11869585
207. Wilt, T., et al. Cernilton for benign prostatic hyperplasia. Cochrane Database Syst Rev, 2000:
Cd001042.
https://www.ncbi.nlm.nih.gov/pubmed/10796739
208. Morgia, G., et al. Serenoa repens, lycopene and selenium versus tamsulosin for the treatment of
LUTS/BPH. An Italian multicenter double-blinded randomized study between single or combination
therapy (PROCOMB trial). Prostate, 2014. 74: 1471.
https://www.ncbi.nlm.nih.gov/pubmed/25154739
209. Ryu, Y.W., et al. Comparison of tamsulosin plus serenoa repens with tamsulosin in the treatment of
benign prostatic hyperplasia in Korean men: 1-year randomized open label study. Urol Int, 2015. 94:
187.
https://www.ncbi.nlm.nih.gov/pubmed/25614155
210. Chapple, C.R., et al. Randomized double-blind, active-controlled phase 3 study to assess 12-month
safety and efficacy of mirabegron, a beta(3)-adrenoceptor agonist, in overactive bladder. Eur Urol,
2013. 63: 296.
https://www.ncbi.nlm.nih.gov/pubmed/23195283
211. Herschorn, S., et al. A phase III, randomized, double-blind, parallel-group, placebo-controlled,
multicentre study to assess the efficacy and safety of the beta(3) adrenoceptor agonist, mirabegron,
in patients with symptoms of overactive bladder. Urology, 2013. 82: 313.
https://www.ncbi.nlm.nih.gov/pubmed/23769122
50 MANAGEMENT OF NON-NEUROGENIC MALE LOWER URINARY TRACT SYMPTOMS (LUTS) - UPDATE MARCH 2017
212. Khullar, V., et al. Efficacy and tolerability of mirabegron, a beta(3)-adrenoceptor agonist, in patients
with overactive bladder: results from a randomised European-Australian phase 3 trial. Eur Urol,
2013. 63: 283.
https://www.ncbi.nlm.nih.gov/pubmed/23182126
213. Nitti, V.W., et al. Results of a randomized phase III trial of mirabegron in patients with overactive
bladder. J Urol, 2013. 189: 1388.
https://www.ncbi.nlm.nih.gov/pubmed/23079373
214. Yamaguchi, O., et al. Efficacy and Safety of the Selective beta3 -Adrenoceptor Agonist Mirabegron
in Japanese Patients with Overactive Bladder: A Randomized, Double-Blind, Placebo-Controlled,
Dose-Finding Study. Low Urin Tract Symptoms, 2015. 7: 84.
https://www.ncbi.nlm.nih.gov/pubmed/26663687
215. Drake, M.J., et al. Efficacy and Safety of Mirabegron Add-on Therapy to Solifenacin in Incontinent
Overactive Bladder Patients with an Inadequate Response to Initial 4-Week Solifenacin
Monotherapy: A Randomised Double-blind Multicentre Phase 3B Study (BESIDE). Eur Urol, 2016.
70: 136.
https://www.ncbi.nlm.nih.gov/pubmed/26965560
216. Kuo, H.C., et al. Results of a randomized, double-blind, parallel-group, placebo- and active-
controlled, multicenter study of mirabegron, a beta3-adrenoceptor agonist, in patients with
overactive bladder in Asia. Neurourol Urodyn, 2015. 34: 685.
https://www.ncbi.nlm.nih.gov/pubmed/25130281
217. Nitti, V.W., et al. Urodynamics and safety of the beta(3)-adrenoceptor agonist mirabegron in males
with lower urinary tract symptoms and bladder outlet obstruction. J Urol, 2013. 190: 1320.
https://www.ncbi.nlm.nih.gov/pubmed/23727415
218. Van Gelderen, M., et al. Absence of clinically relevant cardiovascular interaction upon add-on of
mirabegron or tamsulosin to an established tamsulosin or mirabegron treatment in healthy middle-
aged to elderly men. International Journal of Clinical Pharmacology and Therapeutics, 2014. 52:
693.
https://www.ncbi.nlm.nih.gov/pubmed/24755125
219. Ichihara, K., et al. A randomized controlled study of the efficacy of tamsulosin monotherapy and
its combination with mirabegron for overactive bladder induced by benign prostatic obstruction.
Journal of Urology, 2015. 193: 921.
https://www.ncbi.nlm.nih.gov/pubmed/25254938
220. Yamaguchi, O., et al. Safety and efficacy of mirabegron as ‘add-on’ therapy in patients with
overactive bladder treated with solifenacin: a post-marketing, open-label study in Japan (MILAI
study). BJU Int, 2015. 116: 612.
https://www.ncbi.nlm.nih.gov/pubmed/25639296
221. Debruyne, F.M., et al. Sustained-release alfuzosin, finasteride and the combination of both in the
treatment of benign prostatic hyperplasia. European ALFIN Study Group. Eur Urol, 1998. 34: 169.
https://www.ncbi.nlm.nih.gov/pubmed/9732187
222. Barkin, J., et al. Alpha-blocker therapy can be withdrawn in the majority of men following initial
combination therapy with the dual 5alpha-reductase inhibitor dutasteride. Eur Urol, 2003. 44: 461.
https://www.ncbi.nlm.nih.gov/pubmed/14499682
223. Nickel, J.C., et al. Finasteride monotherapy maintains stable lower urinary tract symptoms in men
with benign prostatic hyperplasia following cessation of alpha blockers. Can Urol Assoc J, 2008. 2:
16.
https://www.ncbi.nlm.nih.gov/pubmed/18542722
224. Athanasopoulos, A., et al. Combination treatment with an alpha-blocker plus an anticholinergic for
bladder outlet obstruction: a prospective, randomized, controlled study. J Urol, 2003. 169: 2253.
https://www.ncbi.nlm.nih.gov/pubmed/12771763
225. Roehrborn, C.G., et al. Efficacy and safety of a fixed-dose combination of dutasteride and
tamsulosin treatment (Duodart® ) compared with watchful waiting with initiation of tamsulosin
therapy if symptoms do not improve, both provided with lifestyle advice, in the management of
treatment-naive men with moderately symptomatic benign prostatic hyperplasia: 2-year CONDUCT
study results. BJU Int, 2015. 116: 450.
https://www.ncbi.nlm.nih.gov/pubmed/25565364
226. Roehrborn, C.G., et al. Influence of baseline variables on changes in International Prostate Symptom
Score after combined therapy with dutasteride plus tamsulosin or either monotherapy in patients
with benign prostatic hyperplasia and lower urinary tract symptoms: 4-year results of the CombAT
study. BJU Int, 2014. 113: 623.
https://www.ncbi.nlm.nih.gov/pubmed/24127818
MANAGEMENT OF NON-NEUROGENIC MALE LOWER URINARY TRACT SYMPTOMS (LUTS) - UPDATE MARCH 2017 51
227. Chapple, C., et al. Tolterodine treatment improves storage symptoms suggestive of overactive
bladder in men treated with alpha-blockers. Eur Urol, 2009. 56: 534.
https://www.ncbi.nlm.nih.gov/pubmed/19070418
228. Kaplan, S.A., et al. Safety and tolerability of solifenacin add-on therapy to alpha-blocker treated men
with residual urgency and frequency. J Urol, 2009. 182: 2825.
https://www.ncbi.nlm.nih.gov/pubmed/19837435
229. Lee, J.Y., et al. Comparison of doxazosin with or without tolterodine in men with symptomatic
bladder outlet obstruction and an overactive bladder. BJU Int, 2004. 94: 817.
https://www.ncbi.nlm.nih.gov/pubmed/15476515
230. Lee, K.S., et al. Combination treatment with propiverine hydrochloride plus doxazosin controlled
release gastrointestinal therapeutic system formulation for overactive bladder and coexisting benign
prostatic obstruction: a prospective, randomized, controlled multicenter study. J Urol, 2005. 174:
1334.
https://www.ncbi.nlm.nih.gov/pubmed/16155414
231. MacDiarmid, S.A., et al. Efficacy and safety of extended-release oxybutynin in combination with
tamsulosin for treatment of lower urinary tract symptoms in men: randomized, double-blind,
placebo-controlled study. Mayo Clin Proc, 2008. 83: 1002.
https://www.ncbi.nlm.nih.gov/pubmed/18775200
232. Saito, H., et al. A comparative study of the efficacy and safety of tamsulosin hydrochloride (Harnal
capsules) alone and in combination with propiverine hydrochloride (BUP-4 tablets) in patients with
prostatic hypertrophy associated with pollakisuria and/or urinary incontinence. Jpn J Urol Surg,
1999. 12: 525. (No abstract available).
233. Yang, Y., et al. Efficacy and safety of combined therapy with terazosin and tolteradine for patients
with lower urinary tract symptoms associated with benign prostatic hyperplasia: a prospective
study. Chin Med J (Engl), 2007. 120: 370.
https://www.ncbi.nlm.nih.gov/pubmed/17376305
234. Maruyama, O., et al. Naftopidil monotherapy vs naftopidil and an anticholinergic agent combined
therapy for storage symptoms associated with benign prostatic hyperplasia: A prospective
randomized controlled study. Int J Urol, 2006. 13: 1280.
https://www.ncbi.nlm.nih.gov/pubmed/17010005
235. Lee, H.N., et al. Rate and associated factors of solifenacin add-on after tamsulosin monotherapy
in men with voiding and storage lower urinary tract symptoms. International Journal of Clinical
Practice, 2015. 69: 444.
https://www.ncbi.nlm.nih.gov/pubmed/25363606
236. van Kerrebroeck, P., et al. Combination therapy with solifenacin and tamsulosin oral controlled
absorption system in a single tablet for lower urinary tract symptoms in men: efficacy and safety
results from the randomised controlled NEPTUNE trial. Eur Urol, 2013. 64: 1003.
https://www.ncbi.nlm.nih.gov/pubmed/23932438
237. Kaplan, S.A., et al. Add-on fesoterodine for residual storage symptoms suggestive of overactive
bladder in men receiving alpha-blocker treatment for lower urinary tract symptoms. BJU Int, 2012.
109: 1831.
https://www.ncbi.nlm.nih.gov/pubmed/21966995
238. Kim, T.H., et al. Comparison of the efficacy and safety of tolterodine 2 mg and 4 mg combined
with an alpha-blocker in men with lower urinary tract symptoms (LUTS) and overactive bladder: a
randomized controlled trial. BJU Int, 2016. 117: 307.
https://www.ncbi.nlm.nih.gov/pubmed/26305143
239. Athanasopoulos, A., et al. The role of antimuscarinics in the management of men with symptoms
of overactive bladder associated with concomitant bladder outlet obstruction: an update. Eur Urol,
2011. 60: 94.
https://www.ncbi.nlm.nih.gov/pubmed/21497434
240. Kaplan, S.A., et al. Antimuscarinics for treatment of storage lower urinary tract symptoms in men: a
systematic review. Int J Clin Pract, 2011. 65: 487.
https://www.ncbi.nlm.nih.gov/pubmed/21210910
241. Van Kerrebroeck, P., et al. Efficacy and safety of solifenacin plus tamsulosin OCAS in men with
voiding and storage lower urinary tract symptoms: results from a phase 2, dose-finding study
(SATURN). Eur Urol, 2013. 64: 398.
https://www.ncbi.nlm.nih.gov/pubmed/23537687
52 MANAGEMENT OF NON-NEUROGENIC MALE LOWER URINARY TRACT SYMPTOMS (LUTS) - UPDATE MARCH 2017
242. Drake, M.J., et al. Long-term safety and efficacy of single-tablet combinations of solifenacin and
tamsulosin oral controlled absorption system in men with storage and voiding lower urinary tract
symptoms: Results from the NEPTUNE study and NEPTUNE II open-label extension. European
Urology, 2015. 67: 262.
https://www.ncbi.nlm.nih.gov/pubmed/25070148
243. Drake, M.J., et al. Responder and health-related quality of life analyses in men with lower urinary
tract symptoms treated with a fixed-dose combination of solifenacin and tamsulosin OCAS: results
from the NEPTUNE study. BJU Int, 2015.
https://www.ncbi.nlm.nih.gov/pubmed/25907003
244. Gong, M., et al. Tamsulosin combined with solifenacin versus tamsulosin monotherapy for male
lower urinary tract symptoms: a meta-analysis. Curr Med Res Opin, 2015. 31: 1781.
https://www.ncbi.nlm.nih.gov/pubmed/26211817
245. Kaplan, S.A., et al. Solifenacin plus tamsulosin combination treatment in men with lower urinary
tract symptoms and bladder outlet obstruction: a randomized controlled trial. Eur Urol, 2013. 63:
158.
https://www.ncbi.nlm.nih.gov/pubmed/22831853
246. Ahyai, S.A., et al. Meta-analysis of functional outcomes and complications following transurethral
procedures for lower urinary tract symptoms resulting from benign prostatic enlargement. Eur Urol,
2010. 58: 384.
https://www.ncbi.nlm.nih.gov/pubmed/20825758
247. Reich, O., et al. Techniques and long-term results of surgical procedures for BPH. Eur Urol, 2006.
49: 970.
https://www.ncbi.nlm.nih.gov/pubmed/16481092
248. Dorflinger, T., et al. Transurethral prostatectomy compared with incision of the prostate in the
treatment of prostatism caused by small benign prostate glands. Scand J Urol Nephrol, 1992. 26:
333.
https://www.ncbi.nlm.nih.gov/pubmed/1284003
249. Jahnson, S., et al. Transurethral incision versus resection of the prostate for small to medium benign
prostatic hyperplasia. Br J Urol, 1998. 81: 276.
https://www.ncbi.nlm.nih.gov/pubmed/9488072
250. Lourenco, T., et al. The clinical effectiveness of transurethral incision of the prostate: a systematic
review of randomised controlled trials. World J Urol, 2010. 28: 23.
https://www.ncbi.nlm.nih.gov/pubmed/20033744
251. Riehmann, M., et al. Transurethral resection versus incision of the prostate: a randomized,
prospective study. Urology, 1995. 45: 768.
https://www.ncbi.nlm.nih.gov/pubmed/7538238
252. Saporta, L., et al. Objective and subjective comparison of transurethral resection, transurethral
incision and balloon dilatation of the prostate. A prospective study. Eur Urol, 1996. 29: 439.
https://www.ncbi.nlm.nih.gov/pubmed/8791051
253. Soonawalla, P.F., et al. Transurethral incision versus transurethral resection of the prostate.
A subjective and objective analysis. Br J Urol, 1992. 70: 174.
https://www.ncbi.nlm.nih.gov/pubmed/1382793
254. Tkocz, M., et al. Comparison of long-term results of transurethral incision of the prostate with
transurethral resection of the prostate, in patients with benign prostatic hypertrophy. Neurourol
Urodyn, 2002. 21: 112.
https://www.ncbi.nlm.nih.gov/pubmed/11857663
255. Yang, Q., et al. Transurethral incision compared with transurethral resection of the prostate for
bladder outlet obstruction: a systematic review and meta-analysis of randomized controlled trials.
J Urol, 2001. 165: 1526.
https://www.ncbi.nlm.nih.gov/pubmed/11342911
256. Madersbacher, S., et al. Is transurethral resection of the prostate still justified? BJU Int, 1999. 83:
227.
https://www.ncbi.nlm.nih.gov/pubmed/10233485
257. Madersbacher, S., et al. Reoperation, myocardial infarction and mortality after transurethral and
open prostatectomy: a nation-wide, long-term analysis of 23,123 cases. Eur Urol, 2005. 47: 499.
https://www.ncbi.nlm.nih.gov/pubmed/15774249
258. Reich, O., et al. Morbidity, mortality and early outcome of transurethral resection of the prostate: a
prospective multicenter evaluation of 10,654 patients. J Urol, 2008. 180: 246.
https://www.ncbi.nlm.nih.gov/pubmed/18499179
MANAGEMENT OF NON-NEUROGENIC MALE LOWER URINARY TRACT SYMPTOMS (LUTS) - UPDATE MARCH 2017 53
259. Roos, N.P., et al. Mortality and reoperation after open and transurethral resection of the prostate for
benign prostatic hyperplasia. N Engl J Med, 1989. 320: 1120.
https://www.ncbi.nlm.nih.gov/pubmed/2469015
260. Hahn, R.G., et al. Incidence of acute myocardial infarction and cause-specific mortality after
transurethral treatments of prostatic hypertrophy. Urology, 2000. 55: 236.
https://www.ncbi.nlm.nih.gov/pubmed/10688086
261. Holman, C.D., et al. Mortality and prostate cancer risk in 19,598 men after surgery for benign
prostatic hyperplasia. BJU Int, 1999. 84: 37.
https://www.ncbi.nlm.nih.gov/pubmed/10444122
262. Shalev, M., et al. Long-term incidence of acute myocardial infarction after open and transurethral
resection of the prostate for benign prostatic hyperplasia. J Urol, 1999. 161: 491.
https://www.ncbi.nlm.nih.gov/pubmed/9915433
263. Rassweiler, J., et al. Complications of transurethral resection of the prostate (TURP)--incidence,
management, and prevention. Eur Urol, 2006. 50: 969.
https://www.ncbi.nlm.nih.gov/pubmed/16469429
264. Issa, M.M. Technological advances in transurethral resection of the prostate: bipolar versus
monopolar TURP. J Endourol, 2008. 22: 1587.
https://www.ncbi.nlm.nih.gov/pubmed/18721041
265. Rassweiler, J., et al. Bipolar transurethral resection of the prostate--technical modifications and early
clinical experience. Minim Invasive Ther Allied Technol, 2007. 16: 11.
https://www.ncbi.nlm.nih.gov/pubmed/17365673
266. Mamoulakis, C., et al. Bipolar versus monopolar transurethral resection of the prostate for lower
urinary tract symptoms secondary to benign prostatic obstruction. Cochrane Database Syst Rev,
2014. 1.
http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD009629.pub3/abstract
267. Burke, N., et al. Systematic review and meta-analysis of transurethral resection of the prostate
versus minimally invasive procedures for the treatment of benign prostatic obstruction. Urology,
2010. 75: 1015.
https://www.ncbi.nlm.nih.gov/pubmed/19854492
268. Mamoulakis, C., et al. Bipolar versus monopolar transurethral resection of the prostate: a systematic
review and meta-analysis of randomized controlled trials. Eur Urol, 2009. 56: 798.
https://www.ncbi.nlm.nih.gov/pubmed/19595501
269. Omar, M.I., et al. Systematic review and meta-analysis of the clinical effectiveness of bipolar
compared with monopolar transurethral resection of the prostate (TURP). BJU Int, 2014. 113: 24.
https://www.ncbi.nlm.nih.gov/pubmed/24053602
270. Cornu, J.N., et al. A Systematic Review and Meta-analysis of Functional Outcomes and
Complications Following Transurethral Procedures for Lower Urinary Tract Symptoms Resulting
from Benign Prostatic Obstruction: An Update. Eur Urol, 2015. 67: 1066.
https://www.ncbi.nlm.nih.gov/pubmed/24972732
271. Autorino, R., et al. Four-year outcome of a prospective randomised trial comparing bipolar
plasmakinetic and monopolar transurethral resection of the prostate. Eur Urol, 2009. 55: 922.
https://www.ncbi.nlm.nih.gov/pubmed/19185975
272. Chen, Q., et al. Bipolar transurethral resection in saline vs traditional monopolar resection of the
prostate: results of a randomized trial with a 2-year follow-up. BJU Int, 2010. 106: 1339.
https://www.ncbi.nlm.nih.gov/pubmed/20477825
273. Fagerstrom, T., et al. Complications and clinical outcome 18 months after bipolar and monopolar
transurethral resection of the prostate. J Endourol, 2011. 25: 1043.
https://www.ncbi.nlm.nih.gov/pubmed/21568691
274. Geavlete, B., et al. Bipolar plasma vaporization vs monopolar and bipolar TURP-A prospective,
randomized, long-term comparison. Urology, 2011. 78: 930.
https://www.ncbi.nlm.nih.gov/pubmed/2180212
275. Giulianelli, R., et al. Comparative randomized study on the efficaciousness of endoscopic bipolar
prostate resection versus monopolar resection technique. 3 year follow-up. Arch Ital Urol Androl,
2013. 85: 86.
https://www.ncbi.nlm.nih.gov/pubmed/23820656
276. Mamoulakis, C., et al. Midterm results from an international multicentre randomised controlled trial
comparing bipolar with monopolar transurethral resection of the prostate. Eur Urol, 2013. 63: 667.
https://www.ncbi.nlm.nih.gov/pubmed/23102675
54 MANAGEMENT OF NON-NEUROGENIC MALE LOWER URINARY TRACT SYMPTOMS (LUTS) - UPDATE MARCH 2017
277. Xie, C.Y., et al. Five-year follow-up results of a randomized controlled trial comparing bipolar
plasmakinetic and monopolar transurethral resection of the prostate. Yonsei Med J, 2012. 53: 734.
https://www.ncbi.nlm.nih.gov/pubmed/22665339
278. Komura, K., et al. Incidence of urethral stricture after bipolar transurethral resection of the prostate
using TURis: results from a randomised trial. BJU Int, 2015. 115: 644.
https://www.ncbi.nlm.nih.gov/pubmed/24909399
279. Stucki, P., et al. Bipolar versus monopolar transurethral resection of the prostate: a prospective
randomized trial focusing on bleeding complications. J Urol, 2015. 193: 1371.
https://www.ncbi.nlm.nih.gov/pubmed/25464004
280. Akman, T., et al. : a prospective randomized comparative study. BJU Int, 2013. 111: 129.Effects of
bipolar and monopolar transurethral resection of the prostate on urinary and erectile function
https://www.ncbi.nlm.nih.gov/pubmed/22672229
281. Mamoulakis, C., et al. Bipolar vs monopolar transurethral resection of the prostate: evaluation of
the impact on overall sexual function in an international randomized controlled trial setting. BJU Int,
2013. 112: 109.
https://www.ncbi.nlm.nih.gov/pubmed/23490008
282. Kuntz, R.M., et al. Holmium laser enucleation of the prostate versus open prostatectomy for
prostates greater than 100 grams: 5-year follow-up results of a randomised clinical trial. Eur Urol,
2008. 53: 160.
https://www.ncbi.nlm.nih.gov/pubmed/17869409
283. Naspro, R., et al. Holmium laser enucleation of the prostate versus open prostatectomy for
prostates >70 g: 24-month follow-up. Eur Urol, 2006. 50: 563.
https://www.ncbi.nlm.nih.gov/pubmed/16713070
284. Skolarikos, A., et al. Eighteen-month results of a randomized prospective study comparing
transurethral photoselective vaporization with transvesical open enucleation for prostatic adenomas
greater than 80 cc. J Endourol, 2008. 22: 2333.
https://www.ncbi.nlm.nih.gov/pubmed/18837655
285. Ou, R., et al. Transurethral enucleation and resection of the prostate vs transvesical prostatectomy
for prostate volumes >80 mL: a prospective randomized study. BJU Int, 2013. 112: 239.
https://www.ncbi.nlm.nih.gov/pubmed/23795788
286. Rao, J.M., et al. Plasmakinetic enucleation of the prostate versus transvesical open prostatectomy
for benign prostatic hyperplasia >80 mL: 12-month follow-up results of a randomized clinical trial.
Urology, 2013. 82: 176.
https://www.ncbi.nlm.nih.gov/pubmed/23601443
287. Zhang, Y., et al. [Transurethral holmium laser enucleation for prostate adenoma greater than 100 g].
Zhonghua Nan Ke Xue, 2007. 13: 1091.
https://www.ncbi.nlm.nih.gov/pubmed/18284057
288. Geavlete, B., et al. Bipolar plasma enucleation of the prostate vs open prostatectomy in large benign
prostatic hyperplasia cases - a medium term, prospective, randomized comparison. BJU Int, 2013.
111: 793.
https://www.ncbi.nlm.nih.gov/pubmed/23469933
289. Geavlete, B., et al. Bipolar vaporization, resection, and enucleation versus open prostatectomy:
optimal treatment alternatives in large prostate cases? J Endourol, 2015. 29: 323.
https://www.ncbi.nlm.nih.gov/pubmed/25111385
290. Varkarakis, I., et al. Long-term results of open transvesical prostatectomy from a contemporary
series of patients. Urology, 2004. 64: 306.
https://www.ncbi.nlm.nih.gov/pubmed/15302484
291. Gratzke, C., et al. Complications and early postoperative outcome after open prostatectomy in
patients with benign prostatic enlargement: results of a prospective multicenter study. J Urol, 2007.
177: 1419.
https://www.ncbi.nlm.nih.gov/pubmed/17382744
292. Chen, S., et al. Plasmakinetic enucleation of the prostate compared with open prostatectomy for
prostates larger than 100 grams: a randomized noninferiority controlled trial with long-term results at
6 years. Eur Urol, 2014. 66: 284.
https://www.ncbi.nlm.nih.gov/pubmed/24502959
293. Li, M., et al. Endoscopic enucleation versus open prostatectomy for treating large benign prostatic
hyperplasia: a meta-analysis of randomized controlled trials. PLoS One, 2015. 10: e0121265.
https://www.ncbi.nlm.nih.gov/pubmed/25826453
MANAGEMENT OF NON-NEUROGENIC MALE LOWER URINARY TRACT SYMPTOMS (LUTS) - UPDATE MARCH 2017 55
294. Lin, Y., et al. Transurethral enucleation of the prostate versus transvesical open prostatectomy for
large benign prostatic hyperplasia: a systematic review and meta-analysis of randomized controlled
trials. World J Urol, 2016. 34: 1207.
https://www.ncbi.nlm.nih.gov/pubmed/26699627
295. Tubaro, A., et al. A prospective study of the safety and efficacy of suprapubic transvesical
prostatectomy in patients with benign prostatic hyperplasia. J Urol, 2001. 166: 172.
https://www.ncbi.nlm.nih.gov/pubmed/11435849
296. Hoffman, R.M., et al. Microwave thermotherapy for benign prostatic hyperplasia. Cochrane
Database Syst Rev, 2012. 9: Cd004135.
https://www.ncbi.nlm.nih.gov/pubmed/22972068
297. Gravas, S., et al. Seeking evidence that cell kill guided thermotherapy gives results not inferior
to those of transurethral prostate resection: results of a pooled analysis of 3 studies of feedback
transurethral microwave thermotherapy. J Urol, 2005. 174: 1002.
https://www.ncbi.nlm.nih.gov/pubmed/16094023
298. Aagaard, M.F., et al. Transurethral microwave thermotherapy treatment of chronic urinary retention in
patients unsuitable for surgery. Scand J Urol, 2014. 48: 290.
https://www.ncbi.nlm.nih.gov/pubmed/24102183
299. Kellner, D.S., et al. Efficacy of high-energy transurethral microwave thermotherapy in alleviating
medically refractory urinary retention due to benign prostatic hyperplasia. Urology, 2004. 64: 703.
https://www.ncbi.nlm.nih.gov/pubmed/15491705
300. Naqvi, S.A., et al. High-energy microwave thermotherapy in patients in urinary retention. J Endourol,
2000. 14: 677.
https://www.ncbi.nlm.nih.gov/pubmed/11083411
301. Schelin, S. Microwave thermotherapy in patients with benign prostatic hyperplasia and chronic
urinary retention. Eur Urol, 2001. 39: 400.
https://www.ncbi.nlm.nih.gov/pubmed/11306877
302. Gravas, S., et al. Durability of 30-minute high-energy transurethral microwave therapy for treatment
of benign prostatic hyperplasia: a study of 213 patients with and without urinary retention. Urology,
2007. 69: 854.
https://www.ncbi.nlm.nih.gov/pubmed/17482921
303. de la Rosette, J.J., et al. Transurethral microwave thermotherapy: the gold standard for minimally
invasive therapies for patients with benign prostatic hyperplasia? J Endourol, 2003. 17: 245.
https://www.ncbi.nlm.nih.gov/pubmed/12816589
304. D’Ancona, F.C., et al. Results of high-energy transurethral microwave thermotherapy in patients
categorized according to the American Society of Anesthesiologists operative risk classification.
Urology, 1999. 53: 322.
https://www.ncbi.nlm.nih.gov/pubmed/9933048
305. Boyle, P., et al. A meta-analysis of trials of transurethral needle ablation for treating symptomatic
benign prostatic hyperplasia. BJU Int, 2004. 94: 83.
https://www.ncbi.nlm.nih.gov/pubmed/15217437
306. Bouza, C., et al. Systematic review and meta-analysis of Transurethral Needle Ablation in
symptomatic Benign Prostatic Hyperplasia. BMC Urol, 2006. 6: 14.
https://www.ncbi.nlm.nih.gov/pubmed/16790044
307. Campo, B., et al. Transurethral needle ablation (TUNA) of the prostate: a clinical and urodynamic
evaluation. Urology, 1997. 49: 847.
https://www.ncbi.nlm.nih.gov/pubmed/9187689
308. Steele, G.S., et al. Transurethral needle ablation of the prostate: a urodynamic based study with
2-year followup. J Urol, 1997. 158: 1834.
https://www.ncbi.nlm.nih.gov/pubmed/9334612
309. Chapple, C.R., et al. Transurethral needle ablation (TUNA). A critical review of radiofrequency
thermal therapy in the management of benign prostatic hyperplasia. Eur Urol, 1999. 35: 119.
https://www.ncbi.nlm.nih.gov/pubmed/9933805
310. Schatzl, G., et al. The early postoperative morbidity of transurethral resection of the prostate and of
4 minimally invasive treatment alternatives. J Urol, 1997. 158: 105.
https://www.ncbi.nlm.nih.gov/pubmed/9186334
311. Gilling, P.J., et al. Combination holmium and Nd:YAG laser ablation of the prostate: initial clinical
experience. J Endourol, 1995. 9: 151.
https://www.ncbi.nlm.nih.gov/pubmed/7633476
56 MANAGEMENT OF NON-NEUROGENIC MALE LOWER URINARY TRACT SYMPTOMS (LUTS) - UPDATE MARCH 2017
312. Tooher, R., et al. A systematic review of holmium laser prostatectomy for benign prostatic
hyperplasia. J Urol, 2004. 171: 1773.
https://www.ncbi.nlm.nih.gov/pubmed/15076275
313. Westenberg, A., et al. Holmium laser resection of the prostate versus transurethral resection of the
prostate: results of a randomized trial with 4-year minimum long-term followup. J Urol, 2004. 172:
616.
https://www.ncbi.nlm.nih.gov/pubmed/15247745
314. Lourenco, T., et al. Alternative approaches to endoscopic ablation for benign enlargement of the
prostate: systematic review of randomised controlled trials. Bmj, 2008. 337: a449.
https://www.ncbi.nlm.nih.gov/pubmed/18595932
315. Tan, A., et al. Meta-analysis of holmium laser enucleation versus transurethral resection of the
prostate for symptomatic prostatic obstruction. Br J Surg, 2007. 94: 1201.
https://www.ncbi.nlm.nih.gov/pubmed/17729384
316. Yin, L., et al. Holmium laser enucleation of the prostate versus transurethral resection of the
prostate: a systematic review and meta-analysis of randomized controlled trials. J Endourol, 2013.
27: 604.
https://www.ncbi.nlm.nih.gov/pubmed/23167266
317. Elmansy, H., et al. Holmium laser enucleation versus photoselective vaporization for prostatic
adenoma greater than 60 ml: preliminary results of a prospective, randomized clinical trial. J Urol,
2012. 188: 216.
https://www.ncbi.nlm.nih.gov/pubmed/22591968
318. Elshal, A.M., et al. Two laser ablation techniques for a prostate less than 60 mL: lessons learned 70
months after a randomized controlled trial. Urology, 2013. 82: 416.
https://www.ncbi.nlm.nih.gov/pubmed/23791215
319. Gilling, P.J., et al. Long-term results of a randomized trial comparing holmium laser enucleation of
the prostate and transurethral resection of the prostate: results at 7 years. BJU Int, 2012. 109: 408.
https://www.ncbi.nlm.nih.gov/pubmed/21883820
320. Elmansy, H.M., et al. Holmium laser enucleation of the prostate: long-term durability of clinical
outcomes and complication rates during 10 years of followup. J Urol, 2011. 186: 1972.
https://www.ncbi.nlm.nih.gov/pubmed/21944127
321. Gilling, P.J., et al. Holmium: YAG laser resection of the prostate (HoLRP) versus transurethral
electrocautery resection of the prostate (TURP): a prospective randomized, urodynamicbased
clinical trial. J Urol, 1997. 157: 149A. [No abstract available]
322. Elzayat, E.A., et al. Holmium laser enucleation of the prostate (HoLEP): long-term results,
reoperation rate, and possible impact of the learning curve. Eur Urol, 2007. 52: 1465.
https://www.ncbi.nlm.nih.gov/pubmed/17498867
323. Tyson, M.D., et al. Safety of holmium laser enucleation of the prostate in anticoagulated patients.
J Endourol, 2009. 23: 1343.
https://www.ncbi.nlm.nih.gov/pubmed/
324. Elzayat, E., et al. Holmium laser enucleation of the prostate in patients on anticoagulant therapy or
with bleeding disorders. J Urol, 2006. 175: 1428.
https://www.ncbi.nlm.nih.gov/pubmed/16516015
325. Elzayat, E.A., et al. Holmium laser enucleation of prostate for patients in urinary retention. Urology,
2005. 66: 789.
https://www.ncbi.nlm.nih.gov/pubmed/16230139
326. Peterson, M.D., et al. Holmium laser enucleation of the prostate for men with urinary retention.
J Urol, 2005. 174: 998.
https://www.ncbi.nlm.nih.gov/pubmed/16094022
327. Briganti, A., et al. Impact on sexual function of holmium laser enucleation versus transurethral
resection of the prostate: results of a prospective, 2-center, randomized trial. J Urol, 2006. 175:
1817.
https://www.ncbi.nlm.nih.gov/pubmed/16600770
328. Du, C., et al. Holmium laser enucleation of the prostate: the safety, efficacy, and learning experience
in China. J Endourol, 2008. 22: 1031.
https://www.ncbi.nlm.nih.gov/pubmed/18377236
329. Thangasamy, I.A., et al. Photoselective vaporisation of the prostate using 80-W and 120-W laser
versus transurethral resection of the prostate for benign prostatic hyperplasia: a systematic review
with meta-analysis from 2002 to 2012. Eur Urol, 2012. 62: 315.
https://www.ncbi.nlm.nih.gov/pubmed/22575913
MANAGEMENT OF NON-NEUROGENIC MALE LOWER URINARY TRACT SYMPTOMS (LUTS) - UPDATE MARCH 2017 57
330. Bouchier-Hayes, D.M., et al. A randomized trial of photoselective vaporization of the prostate using
the 80-W potassium-titanyl-phosphate laser vs transurethral prostatectomy, with a 1-year follow-up.
BJU Int, 2010. 105: 964.
https://www.ncbi.nlm.nih.gov/pubmed/19912196
331. Capitan, C., et al. GreenLight HPS 120-W laser vaporization versus transurethral resection of the
prostate for the treatment of lower urinary tract symptoms due to benign prostatic hyperplasia: a
randomized clinical trial with 2-year follow-up. Eur Urol, 2011. 60: 734.
https://www.ncbi.nlm.nih.gov/pubmed/21658839
332. Skolarikos, A., et al., 80W PVP versus TURP: results of a randomized prospective study at 12
months of follow-up. , in Abstract presented at: American Urological Association annual meeting.
2008: Orlando, FL, USA.
333. Hai, M.A. Photoselective vaporization of prostate: five-year outcomes of entire clinic patient
population. Urology, 2009. 73: 807.
https://www.ncbi.nlm.nih.gov/pubmed/19200589
334. Ruszat, R., et al. GreenLight laser vaporization of the prostate: single-center experience and long-
term results after 500 procedures. Eur Urol, 2008. 54: 893.
https://www.ncbi.nlm.nih.gov/pubmed/18486311
335. Hamann, M.F., et al. Functional outcome following photoselective vaporisation of the prostate (PVP):
urodynamic findings within 12 months follow-up. Eur Urol, 2008. 54: 902.
https://www.ncbi.nlm.nih.gov/pubmed/18502565
336. Al-Ansari, A., et al. GreenLight HPS 120-W laser vaporization versus transurethral resection of the
prostate for treatment of benign prostatic hyperplasia: a randomized clinical trial with midterm
follow-up. Eur Urol, 2010. 58: 349.
https://www.ncbi.nlm.nih.gov/pubmed/20605316
337. Pereira-Correia, J.A., et al. GreenLight HPS 120-W laser vaporization vs transurethral resection of
the prostate (<60 mL): a 2-year randomized double-blind prospective urodynamic investigation.
BJU Int, 2012. 110: 1184.
https://www.ncbi.nlm.nih.gov/pubmed/22257240
338. Bachmann, A., et al. 180-W XPS GreenLight laser therapy for benign prostate hyperplasia: early
safety, efficacy, and perioperative outcome after 201 procedures. Eur Urol, 2012. 61: 600.
https://www.ncbi.nlm.nih.gov/pubmed/22153927
339. Chung, D.E., et al. Outcomes and complications after 532 nm laser prostatectomy in anticoagulated
patients with benign prostatic hyperplasia. J Urol, 2011. 186: 977.
https://www4.ncbi.nlm.nih.gov/pubmed/21791350
340. Reich, O., et al. High power (80 W) potassium-titanyl-phosphate laser vaporization of the prostate in
66 high risk patients. J Urol, 2005. 173: 158.
https://www.ncbi.nlm.nih.gov/pubmed/15592063
341. Ruszat, R., et al. Safety and effectiveness of photoselective vaporization of the prostate (PVP) in
patients on ongoing oral anticoagulation. Eur Urol, 2007. 51: 1031.
https://www.ncbi.nlm.nih.gov/pubmed/16945475
342. Sandhu, J.S., et al. Photoselective laser vaporization prostatectomy in men receiving anticoagulants.
J Endourol, 2005. 19: 1196.
https://www.ncbi.nlm.nih.gov/pubmed/16359214
343. Woo, H., et al. Outcome of GreenLight HPS 120-W laser therapy in specific patient populations:
those in retention, on anticoagulants, and with large prostates (>80 ml). Eur Urol Suppl 2008. 7: 378.
http://www.europeanurology.com/article/S1569-9056(08)00027-4/abstract/outcome-of-greenlight-
hps-120-w-laser-therapy-in-specific-patient-populations-those-in-retention-on-anticoagulants-and-
with-large-prostates-x02265-80ml
344. Rajbabu, K., et al. Photoselective vaporization of the prostate with the potassium-titanyl-phosphate
laser in men with prostates of >100 mL. BJU Int, 2007. 100: 593.
https://www.ncbi.nlm.nih.gov/pubmed/17511771
345. Ruszat, R., et al. Photoselective vaporization of the prostate: subgroup analysis of men with
refractory urinary retention. Eur Urol, 2006. 50: 1040.
https://www.ncbi.nlm.nih.gov/pubmed/16481099
346. Horasanli, K., et al. Photoselective potassium titanyl phosphate (KTP) laser vaporization versus
transurethral resection of the prostate for prostates larger than 70 mL: a short-term prospective
randomized trial. Urology, 2008. 71: 247.
https://www.ncbi.nlm.nih.gov/pubmed/18308094
58 MANAGEMENT OF NON-NEUROGENIC MALE LOWER URINARY TRACT SYMPTOMS (LUTS) - UPDATE MARCH 2017
347. Alivizatos, G., et al. Transurethral photoselective vaporization versus transvesical open enucleation
for prostatic adenomas >80ml: 12-mo results of a randomized prospective study. Eur Urol, 2008. 54:
427.
https://www.ncbi.nlm.nih.gov/pubmed/18069117
348. Bouchier-Hayes, D.M., et al. KTP laser versus transurethral resection: early results of a randomized
trial. J Endourol, 2006. 20: 580.
https://www.ncbi.nlm.nih.gov/pubmed/16903819
349. Bruyere, F., et al. Influence of photoselective vaporization of the prostate on sexual function: results
of a prospective analysis of 149 patients with long-term follow-up. Eur Urol, 2010. 58: 207.
https://www.ncbi.nlm.nih.gov/pubmed/20466480
350. Thomas, J.A., et al. A Multicenter Randomized Noninferiority Trial Comparing GreenLight-XPS Laser
Vaporization of the Prostate and Transurethral Resection of the Prostate for the Treatment of Benign
Prostatic Obstruction: Two-yr Outcomes of the GOLIATH Study. Eur Urol, 2016. 69: 94.
https://www.ncbi.nlm.nih.gov/pubmed/26283011
351. Bach, T., et al. Laser treatment of benign prostatic obstruction: basics and physical differences.
Eur Urol, 2012. 61: 317.
https://www.ncbi.nlm.nih.gov/pubmed/22033173
352. Chiang, P.H., et al. GreenLight HPS laser 120-W versus diode laser 200-W vaporization of the
prostate: comparative clinical experience. Lasers Surg Med, 2010. 42: 624.
https://www.ncbi.nlm.nih.gov/pubmed/20806388
353. Ruszat, R., et al. Prospective single-centre comparison of 120-W diode-pumped solid-state high-
intensity system laser vaporization of the prostate and 200-W high-intensive diode-laser ablation of
the prostate for treating benign prostatic hyperplasia. BJU Int, 2009. 104: 820.
https://www.ncbi.nlm.nih.gov/pubmed/19239441
354. Seitz, M., et al. The diode laser: a novel side-firing approach for laser vaporisation of the human
prostate--immediate efficacy and 1-year follow-up. Eur Urol, 2007. 52: 1717.
https://www.ncbi.nlm.nih.gov/pubmed/17628326
355. Shaker, H.S., et al. Quartz head contact laser fiber: a novel fiber for laser ablation of the prostate
using the 980 nm high power diode laser. J Urol, 2012. 187: 575.
https://www.ncbi.nlm.nih.gov/pubmed/22177175
356. Erol, A., et al. High power diode laser vaporization of the prostate: preliminary results for benign
prostatic hyperplasia. J Urol, 2009. 182: 1078.
https://www.ncbi.nlm.nih.gov/pubmed/ 19616811
357. Hruby, S., et al. Eraser laser enucleation of the prostate: technique and results. Eur Urol, 2013. 63:
341.
https://www.ncbi.nlm.nih.gov/pubmed/22959050
358. Leonardi, R. Preliminary results on selective light vaporization with the side-firing 980 nm diode laser
in benign prostatic hyperplasia: an ejaculation sparing technique. Prostate Cancer Prostatic Dis,
2009. 12: 277.
https://www.ncbi.nlm.nih.gov/pubmed/19322136
359. Xu, A., et al. A randomized trial comparing diode laser enucleation of the prostate with plasmakinetic
enucleation and resection of the prostate for the treatment of benign prostatic hyperplasia.
J Endourol, 2013. 27: 1254.
https://www.ncbi.nlm.nih.gov/pubmed/23879477
360. Lusuardi, L., et al. Safety and efficacy of Eraser laser enucleation of the prostate: preliminary report.
J Urol, 2011. 186: 1967.
https://www.ncbi.nlm.nih.gov/pubmed/21944122
361. Razzaghi, M.R., et al. Diode laser (980 nm) vaporization in comparison with transurethral resection
of the prostate for benign prostatic hyperplasia: randomized clinical trial with 2-year follow-up.
Urology, 2014. 84: 526.
https://www.ncbi.nlm.nih.gov/pubmed/25168526
362. Tiburtius, C., et al. A prospective, randomized comparison of a 1940 nm and a 2013 nm thulium:
yttrium-aluminum-garnet laser device for Thulium VapoEnucleation of the prostate (ThuVEP): First
results. Indian J Urol, 2015. 31: 47.
https://www.ncbi.nlm.nih.gov/pubmed/25624576
363. Cui, D., et al. A randomized trial comparing thulium laser resection to standard transurethral
resection of the prostate for symptomatic benign prostatic hyperplasia: four-year follow-up results.
World J Urol, 2014. 32: 683.
https://www.ncbi.nlm.nih.gov/pubmed/23913094
MANAGEMENT OF NON-NEUROGENIC MALE LOWER URINARY TRACT SYMPTOMS (LUTS) - UPDATE MARCH 2017 59
364. Fu, W.J., et al. Comparison of 2-microm continuous wave laser vaporesection of the prostate and
transurethral resection of the prostate: a prospective nonrandomized trial with 1-year follow-up.
Urology, 2010. 75: 194.
https://www.ncbi.nlm.nih.gov/pubmed/19819535
365. Xia, S.J., et al. Thulium laser versus standard transurethral resection of the prostate: a randomized
prospective trial. Eur Urol, 2008. 53: 382.
https://www.ncbi.nlm.nih.gov/pubmed/17566639
366. Peng, B., et al. A comparative study of thulium laser resection of the prostate and bipolar
transurethral plasmakinetic prostatectomy for treating benign prostatic hyperplasia. BJU Int, 2013.
111: 633.
https://www.ncbi.nlm.nih.gov/pubmed/23107074
367. Yang, Z., et al. Thulium laser enucleation versus plasmakinetic resection of the prostate: a
randomized prospective trial with 18-month follow-up. Urology, 2013. 81: 396.
https://www.ncbi.nlm.nih.gov/pubmed/23374815
368. Bach, T., et al. Thulium:YAG vapoenucleation in large volume prostates. J Urol, 2011. 186: 2323.
https://www.ncbi.nlm.nih.gov/pubmed/22014812
369. Hauser, S., et al. Thulium laser (Revolix) vapoenucleation of the prostate is a safe procedure in
patients with an increased risk of hemorrhage. Urol Int, 2012. 88: 390.
https://www.ncbi.nlm.nih.gov/pubmed/22627127
370. Netsch, C., et al. Comparison of 120-200 W 2 mum thulium:yttrium-aluminum-garnet
vapoenucleation of the prostate. J Endourol, 2012. 26: 224.
https://www.ncbi.nlm.nih.gov/pubmed/22191688
371. Netsch, C., et al. 120-W 2-microm thulium:yttrium-aluminium-garnet vapoenucleation of the
prostate: 12-month follow-up. BJU Int, 2012. 110: 96.
https://www.ncbi.nlm.nih.gov/pubmed/22085294
372. Feng, L., et al. Thulium Laser Enucleation Versus Plasmakinetic Enucleation of the Prostate:
A Randomized Trial of a Single Center. J Endourol, 2016. 30: 665.
https://www.ncbi.nlm.nih.gov/pubmed/26886719
373. Netsch, C., et al. Safety and effectiveness of Thulium VapoEnucleation of the prostate (ThuVEP) in
patients on anticoagulant therapy. World J Urol, 2014. 32: 165.
https://www.ncbi.nlm.nih.gov/pubmed/23657354
374. Szlauer, R., et al. Endoscopic vaporesection of the prostate using the continuous-wave 2-microm
thulium laser: outcome and demonstration of the surgical technique. Eur Urol, 2009. 55: 368.
https://www.ncbi.nlm.nih.gov/pubmed/19022557
375. Bach, T., et al. Thulium:YAG laser enucleation (VapoEnucleation) of the prostate: safety and
durability during intermediate-term follow-up. World J Urol, 2010. 28: 39.
https://www.ncbi.nlm.nih.gov/pubmed/19669645
376. Zhang, F., et al. Thulium laser versus holmium laser transurethral enucleation of the prostate:
18-month follow-up data of a single center. Urology, 2012. 79: 869.
https://www.ncbi.nlm.nih.gov/pubmed/22342411
377. Gross, A.J., et al. Complications and early postoperative outcome in 1080 patients after thulium
vapoenucleation of the prostate: results at a single institution. Eur Urol, 2013. 63: 859.
https://www.ncbi.nlm.nih.gov/pubmed/23245687
378. Tiburtius, C., et al. Impact of thulium VapoEnucleation of the prostate on erectile function: a
prospective analysis of 72 patients at 12-month follow-up. Urology, 2014. 83: 175.
https://www.ncbi.nlm.nih.gov/pubmed/ https://www.ncbi.nlm.nih.gov/pubmed/24103563
379. Wang, Y., et al. Impact of 120-W 2-mum continuous wave laser vapoenucleation of the prostate on
sexual function. Lasers Med Sci, 2014. 29: 689.
https://www.ncbi.nlm.nih.gov/pubmed/23828495
380. Sun, F., et al. Long-term results of thulium laser resection of the prostate: a prospective study at
multiple centers. World J Urol, 2015. 33: 503.
https://www.ncbi.nlm.nih.gov/pubmed/25487702
381. Chang, C.H., et al. Vapoenucleation of the prostate using a high-power thulium laser: a one-year
follow-up study. BMC Urol, 2015. 15: 40.
https://www.ncbi.nlm.nih.gov/pubmed/25956819
382. Corica, A.P., et al. A novel temporary prostatic stent for the relief of prostatic urethral obstruction.
BJU Int, 2004. 93: 346.
https://www.ncbi.nlm.nih.gov/pubmed/14764134
60 MANAGEMENT OF NON-NEUROGENIC MALE LOWER URINARY TRACT SYMPTOMS (LUTS) - UPDATE MARCH 2017
383. Guazzoni, G., et al. A modified prostatic UroLume Wallstent for healthy patients with symptomatic
benign prostatic hyperplasia: a European Multicenter Study. Urology, 1994. 44: 364.
https://www.ncbi.nlm.nih.gov/pubmed/7521092
384. Vanderbrink, B.A., et al. Prostatic stents for the treatment of benign prostatic hyperplasia. Curr Opin
Urol, 2007. 17: 1.
https://www.ncbi.nlm.nih.gov/pubmed/17143103
385. Gesenberg, A., et al. Management of benign prostatic hyperplasia in high risk patients: long-term
experience with the Memotherm stent. J Urol, 1998. 160: 72.
https://www.ncbi.nlm.nih.gov/pubmed/9628608
386. Kaplan, S.A., et al. Long-term experience utilizing a new balloon expandable prostatic
endoprosthesis: the Titan stent. North American Titan Stent Study Group. Urology, 1995. 45: 234.
https://www.ncbi.nlm.nih.gov/pubmed/7855972
387. Perry, M.J., et al. Thermo-expandable intraprostatic stents in bladder outlet obstruction: an 8-year
study. BJU Int, 2002. 90: 216.
https://www.ncbi.nlm.nih.gov/pubmed/12133055
388. van Dijk, M.M., et al. The bell-shaped nitinol prostatic stent in the treatment of lower urinary tract
symptoms: experience in 108 patients. Eur Urol, 2006. 49: 353.
https://www.ncbi.nlm.nih.gov/pubmed/16426738
389. Kijvikai, K., et al. Clinical utility of “blind placement” prostatic stent in patients with benign prostatic
obstruction: a prospective study. Urology, 2006. 68: 1025.
https://www.ncbi.nlm.nih.gov/pubmed/17113894
390. Armitage, J.N., et al. Epithelializing stent for benign prostatic hyperplasia: a systematic review of the
literature. J Urol, 2007. 177: 1619.
https://www.ncbi.nlm.nih.gov/pubmed/17437773
391. Masood, S., et al. The 12-year outcome analysis of an endourethral wallstent for treating benign
prostatic hyperplasia. BJU Int, 2004. 94: 1271.
https://www.ncbi.nlm.nih.gov/pubmed/15610103
392. Armitage, J.N., et al. The thermo-expandable metallic stent for managing benign prostatic
hyperplasia: a systematic review. BJU Int, 2006. 98: 806.
https://www.ncbi.nlm.nih.gov/pubmed/16879446
393. Chin, P.T., et al. Prostatic urethral lift: two-year results after treatment for lower urinary tract
symptoms secondary to benign prostatic hyperplasia. Urology, 2012. 79: 5.
https://www.ncbi.nlm.nih.gov/pubmed/22202539
394. McNicholas, T.A., et al. Minimally invasive prostatic urethral lift: surgical technique and multinational
experience. Eur Urol, 2013. 64: 292.
https://www.ncbi.nlm.nih.gov/pubmed/23357348
395. Roehrborn, C.G., et al. The prostatic urethral lift for the treatment of lower urinary tract symptoms
associated with prostate enlargement due to benign prostatic hyperplasia: the L.I.F.T. Study. J Urol,
2013. 190: 2161.
https://www.ncbi.nlm.nih.gov/pubmed/23764081
396. Woo, H.H., et al. Safety and feasibility of the prostatic urethral lift: a novel, minimally invasive
treatment for lower urinary tract symptoms (LUTS) secondary to benign prostatic hyperplasia (BPH).
BJU Int, 2011. 108: 82.
https://www.ncbi.nlm.nih.gov/pubmed/21554526
397. Woo, H.H., et al. Preservation of sexual function with the prostatic urethral lift: a novel treatment for
lower urinary tract symptoms secondary to benign prostatic hyperplasia. J Sex Med, 2012. 9: 568.
https://www.ncbi.nlm.nih.gov/pubmed/22172161
398. Perera, M., et al. Prostatic urethral lift improves urinary symptoms and flow while preserving sexual
function for men with benign prostatic hyperplasia: a systematic review and meta-analysis. Eur Urol,
2015. 67: 704.
https://www.ncbi.nlm.nih.gov/pubmed/25466940
399. Sonksen, J., et al. Prospective, Randomized, Multinational Study of Prostatic Urethral Lift Versus
Transurethral Resection of the Prostate: 12-month Results from the BPH6 Study. Eur Urol, 2015. 68:
643.
https://www.ncbi.nlm.nih.gov/pubmed/25937539
400. Roehrborn, C.G., et al. Three year results of the prostatic urethral L.I.F.T. study. Can J Urol, 2015. 22:
7772.
https://www.ncbi.nlm.nih.gov/pubmed/25937539
MANAGEMENT OF NON-NEUROGENIC MALE LOWER URINARY TRACT SYMPTOMS (LUTS) - UPDATE MARCH 2017 61
401. Magistro, G., et al. New intraprostatic injectables and prostatic urethral lift for male LUTS. Nat Rev
Urol, 2015. 12: 461.
https://www.ncbi.nlm.nih.gov/pubmed/26195444
402. Marberger, M., et al. A randomized double-blind placebo-controlled phase 2 dose-ranging study of
onabotulinumtoxinA in men with benign prostatic hyperplasia. Eur Urol, 2013. 63: 496.
https://www.ncbi.nlm.nih.gov/pubmed/9610579
403. McVary, K.T., et al. A multicenter, randomized, double-blind, placebo controlled study of
onabotulinumtoxinA 200 U to treat lower urinary tract symptoms in men with benign prostatic
hyperplasia. J Urol, 2014. 192: 150.
https://www.ncbi.nlm.nih.gov/pubmed/24508634
404. Shim, S.R., et al. Efficacy and safety of botulinum toxin injection for benign prostatic hyperplasia: a
systematic review and meta-analysis. Int Urol Nephrol, 2016. 48: 19.
https://www.ncbi.nlm.nih.gov/pubmed/26560471
405. Elhilali, M.M., et al. Prospective, randomized, double-blind, vehicle controlled, multicenter phase
IIb clinical trial of the pore forming protein PRX302 for targeted treatment of symptomatic benign
prostatic hyperplasia. J Urol, 2013. 189: 1421.
https://www.ncbi.nlm.nih.gov/pubmed/23142202
406. Denmeade, S.R., et al. Phase 1 and 2 studies demonstrate the safety and efficacy of intraprostatic
injection of PRX302 for the targeted treatment of lower urinary tract symptoms secondary to benign
prostatic hyperplasia. Eur Urol, 2011. 59: 747.
https://www.ncbi.nlm.nih.gov/pubmed/21129846
407. Mariano, M.B., et al. Laparoscopic prostatectomy with vascular control for benign prostatic
hyperplasia. J Urol, 2002. 167: 2528.
https://www.ncbi.nlm.nih.gov/pubmed/11992078
408. Sotelo, R., et al. Robotic simple prostatectomy. J Urol, 2008. 179: 513.
https://www.ncbi.nlm.nih.gov/pubmed/18076926
409. Autorino, R., et al. Perioperative Outcomes of Robotic and Laparoscopic Simple Prostatectomy:
A European-American Multi-institutional Analysis. Eur Urol, 2015. 68: 86.
https://www.ncbi.nlm.nih.gov/pubmed/25484140
410. Pokorny, M., et al. Robot-assisted Simple Prostatectomy for Treatment of Lower Urinary Tract
Symptoms Secondary to Benign Prostatic Enlargement: Surgical Technique and Outcomes in a
High-volume Robotic Centre. Eur Urol, 2015. 68: 451.
https://www.ncbi.nlm.nih.gov/pubmed/25887786
411. Martin Garzon, O.D., et al. One-Year Outcome Comparison of Laparoscopic, Robotic, and Robotic
Intrafascial Simple Prostatectomy for Benign Prostatic Hyperplasia. J Endourol, 2016. 30: 312.
https://www.ncbi.nlm.nih.gov/pubmed/26463701
412. Lucca, I., et al. Outcomes of minimally invasive simple prostatectomy for benign prostatic
hyperplasia: a systematic review and meta-analysis. World J Urol, 2015. 33: 563.
https://www.ncbi.nlm.nih.gov/pubmed/24879405
413. Marshall, S.D., et al. Nocturia: Current Levels of Evidence and Recommendations From the
International Consultation on Male Lower Urinary Tract Symptoms. Urology, 2015.
https://www.ncbi.nlm.nih.gov/pubmed/25881866
414. Cannon, A., et al. Desmopressin in the treatment of nocturnal polyuria in the male. BJU Int, 1999.
84: 20.
https://www.ncbi.nlm.nih.gov/pubmed/10444118
415. Djavan, B., et al. The impact of tamsulosin oral controlled absorption system (OCAS) on nocturia
and the quality of sleep: Preliminary results of a pilot study. European Urology, Supplements, 2005.
4: 1119.
http://www.europeanurology.com/article/S1569-9056(04)00127-7/abstract/the-impact-of-
tamsulosin-oral-controlled-absorption-system-ocas-on-nocturia-and-the-quality-of-sleep-
preliminary-results-of-a-pilot-study
416. Yokoyama, O., et al. Efficacy of fesoterodine on nocturia and quality of sleep in Asian patients with
overactive bladder. Urology, 2014. 83: 750.
https://www.ncbi.nlm.nih.gov/pubmed/24518285
417. Yokoyama, O., et al. Efficacy of solifenacin on nocturia in Japanese patients with overactive bladder:
impact on sleep evaluated by bladder diary. J Urol, 2011. 186: 170.
https://www.ncbi.nlm.nih.gov/pubmed/21575976
418. Johnson, T.M., 2nd, et al. The effect of doxazosin, finasteride and combination therapy on nocturia
in men with benign prostatic hyperplasia. J Urol, 2007. 178: 2045.
https://www.ncbi.nlm.nih.gov/pubmed/17869295
62 MANAGEMENT OF NON-NEUROGENIC MALE LOWER URINARY TRACT SYMPTOMS (LUTS) - UPDATE MARCH 2017
419. Oelke, M., et al. Impact of dutasteride on nocturia in men with lower urinary tract symptoms
suggestive of benign prostatic hyperplasia (LUTS/BPH): a pooled analysis of three phase III studies.
World J Urol, 2014. 32: 1141.
https://www.ncbi.nlm.nih.gov/pubmed/24903347
420. Oelke, M., et al. Effects of tadalafil on nighttime voiding (nocturia) in men with lower urinary tract
symptoms suggestive of benign prostatic hyperplasia: a post hoc analysis of pooled data from four
randomized, placebo-controlled clinical studies. World J Urol, 2014. 32: 1127.
https://www.ncbi.nlm.nih.gov/pubmed/24504761
421. Drake, M.J., et al. Melatonin pharmacotherapy for nocturia in men with benign prostatic
enlargement. J Urol, 2004. 171: 1199.
https://www.ncbi.nlm.nih.gov/pubmed/14767300
422. Reynard, J.M., et al. A novel therapy for nocturnal polyuria: a double-blind randomized trial of
frusemide against placebo. Br J Urol, 1998. 81: 215.
https://www.ncbi.nlm.nih.gov/pubmed/9488061
423. Falahatkar, S., et al. Celecoxib for treatment of nocturia caused by benign prostatic hyperplasia: a
prospective, randomized, double-blind, placebo-controlled study. Urology, 2008. 72: 813.
https://www.ncbi.nlm.nih.gov/pubmed/18692876
424. Sigurdsson, S., et al. A parallel, randomized, double-blind, placebo-controlled study to investigate
the effect of SagaPro on nocturia in men. Scand J Urol, 2013. 47: 26.
https://www.ncbi.nlm.nih.gov/pubmed/23323790
8. CONFLICT OF INTEREST
All members of the EAU Non-neurogenic Male LUTS Guidelines Panel have provided disclosure statements
on all relationships that they have that might be perceived to be a potential source of a conflict of interest.
This information is publically accessible through the EAU website: http://www.uroweb.org/guidelines/. These
Guidelines were developed with the financial support of the EAU. No external sources of funding and support
have been involved. The EAU is a non-profit organisation, and funding is limited to administrative assistance
and travel and meeting expenses. No honoraria or other reimbursements have been provided.
MANAGEMENT OF NON-NEUROGENIC MALE LOWER URINARY TRACT SYMPTOMS (LUTS) - UPDATE MARCH 2017 63
64 MANAGEMENT OF NON-NEUROGENIC MALE LOWER URINARY TRACT SYMPTOMS (LUTS) - UPDATE MARCH 2017
EAU Guidelines on
Urinary
Incontinence
in Adults
F.C. Burkhard (Chair), J.L.H.R. Bosch, F. Cruz, G.E. Lemack,
A.K. Nambiar, N. Thiruchelvam, A. Tubaro,
Guidelines Associates: D. Ambühl, D. Bedretdinova, F. Farag,
B.B. Rozenberg
2. METHODS 10
2.1 Introduction 10
2.2 Review 10
2.3 Terminology 10
3. DIAGNOSTIC EVALUATION 11
3.1 History and physical examination 11
3.2 Patient questionnaires 11
3.2.1 Questions 11
3.2.2 Evidence 11
3.3 Voiding diaries 13
3.3.1 Question 13
3.3.2 Evidence 13
3.4 Urinalysis and urinary tract infection 13
3.4.1 Question 13
3.4.2 Evidence 13
3.5 Post-void residual volume 14
3.5.1 Question 14
3.5.2 Evidence 14
3.6 Urodynamics 15
3.6.1 Question 15
3.6.2 Evidence 15
3.6.2.1 Variability 15
3.6.2.2 Diagnostic accuracy 15
3.6.2.3 Question 15
3.6.2.4 Evidence 15
3.6.2.5 Question 15
3.6.2.6 Evidence 15
3.6.2.7 Question 16
3.6.2.8 Evidence 16
3.6.2.9 Question 16
3.6.2.10 Evidence 16
3.6.3 Research priority 17
3.7 Pad testing 17
3.7.1 Questions 17
3.7.2 Evidence 17
3.7.3 Research priority 17
3.8 Imaging 18
3.8.1 Questions 18
3.8.2 Evidence 18
3.8.3 Research priority 18
4. DISEASE MANAGEMENT 19
4.1 Conservative management 19
4.1.1 Simple clinical interventions 19
4.1.1.1 Underlying disease/cognitive impairment 19
4.1.1.1.1 Question 19
4.1.1.1.2 Evidence 19
4.1.1.2 Adjustment of other (non-incontinence) medication 19
4.1.1.2.1 Question 19
4.1.1.2.2 Evidence 20
5. REFERENCES 66
6. CONFLICT OF INTEREST 91
The elderly
The Panel decided to include a separate but complimentary set of recommendations referring to the elderly
population within each section. Older people with UI deserve special consideration for a number of reasons.
Physiological changes with natural ageing mean that all types of UI become more common with increasing
age. Urinary incontinence commonly co-exists with other comorbid conditions, reduced mobility, and impaired
cognition and may require specific interventions, such as assisted toileting.
For the elderly person expectations of assessment and treatment may need to be modified to fit in with specific
circumstances, needs, and preferences, while also taking into account any loss of capacity for consent. When
the urologist is dealing with a frail elderly patient with urinary incontinence, collaboration with other healthcare
professionals such as elderly care physicians is recommended.
It must be emphasised that clinical guidelines present the best evidence available to the experts.
However, following guideline recommendations will not necessarily result in the best outcome. Guidelines
can never replace clinical expertise when making treatment decisions for individual patients, but rather help
to focus decisions - also taking personal values and preferences/individual circumstances of patients into
account. Guidelines are not mandates and do not purport to be a legal standard of care.
Summary of evidence LE
There is limited evidence that one antimuscarinic drug is superior to an alternative antimuscarinic drug for 1b
cure or improvement of urgency urinary incontinence.
Higher doses of antimuscarinic drugs are more effective to cure or improve urgency urinary incontinence, 1b
but with a higher risk of side effects.
Once daily (extended release) formulations are associated with lower rates of adverse events compared to 1b
immediate release ones, although similar discontinuation rates are reported in clinical trials.
Dose escalation of antimuscarinic drugs may be appropriate in selected patients to improve treatment 1b
effect although higher rates of adverse events can be expected.
Transdermal oxybutynin (patch) is associated with lower rates of dry mouth than oral antimuscarinic drugs, 1b
but has a high rate of withdrawal due to skin reaction.
Recommendations GR
Offer antimuscarinic drugs for adults with urgency urinary incontinence who failed conservative treatment. A
Consider extended release formulations in patients who do not tolerate immediate release antimuscarinics. A
If antimuscarinic treatment proves ineffective, consider dose escalation or offering an alternative treatment. B
Consider using transdermal oxybutynin if oral antimuscarinic agents cannot be tolerated due to dry mouth. B
Offer and encourage early review (of efficacy and side effects) of patients on antimuscarinic medication for C
urgency urinary incontinence.
Summary of evidence LE
Adherence to antimuscarinic treatment is low and decreases over time because of lack of efficacy, adverse 2
events and/or cost.
Most patients will stop antimuscarinic agents within the first three months. 2
4.2.5 Antimuscarinic and beta3 agonist agents, the elderly and cognition
Summary of evidence LE
Antimuscarinic drugs are effective in elderly patients. 1b
Mirabegron has been shown to efficacious and safe in elderly patients. 1b
In older people, the cognitive impact of drugs which have anticholinergic effects is cumulative and 2
increases with length of exposure.
Oxybutynin may worsen cognitive function in elderly patients. 2
Solifenacin, darifenacin, fesoterodine and trospium have been shown not to cause cognitive dysfunction in 1b
elderly people in short-term studies.
Recommendations GR
In older people being treated for urinary incontinence, every effort should be made to employ C
nonpharmacological treatments first.
Long-term antimuscarinic treatment should be used with caution in elderly patients especially those who B*
are at risk of, or have, cognitive dysfunction.
When prescribing antimuscarinic for urgency urinary incontinence, consider the total antimuscarinic load in C
older people on multiple drugs.
Consider the use of Mirabegron in elderly patients if additional antimuscarinic load is to be avoided. C
*Recommendation based on expert opinion.
Summary of evidence LE
Mirabegron is better than placebo and as efficacious as antimuscarinics for improvement of urgency 1a
urinary incontinence symptoms.
Adverse event rates with mirabegron are similar to placebo. 1a
Patients inadequately treated with solifenacin 5 mg may benefit more from the addition of mirabegron than 1b
dose escalation of solifenacin.
Recommendation GR
In patients with urgency urinary incontinence and an inadequate response to conservative treatments, offer A
mirabegron unless they have uncontrolled hypertension.
Summary of evidence LE
Duloxetine, 40 mg twice daily improves stress urinary incontinence in women. 1a
Duloxetine causes significant gastrointestinal and central nervous system (CNS) side effects leading to a 1a
high rate of treatment discontinuation, although these symptoms are limited to the first weeks of treatment.
Recommendations GR
Duloxetine can be used with caution to treat women with symptoms of stress urinary incontinence. A
Duloxetine should be initiated using dose titration because of high adverse event rates. A
4.2.8 Oestrogen
Recommendation GR
Vaginal oestrogen therapy for vulvovaginal atrophy should be prescribed long-term. In women with a C
history of breast cancer, the treating oncologist needs to be consulted.
Recommendations GR
Consider offering desmopressin to patients requiring occasional short-term relief from daytime urinary A
incontinence and inform them that this drug is not licensed for this indication.
Monitor plasma sodium levels in patients on desmopressin. A*
*Recommendation based on expert opinion.
Recommendation GR
Offer antimuscarinic drugs or beta3 agonists to patients with urgency-predominant mixed urinary A*
incontinence.
*Recommendation based on expert opinion.
Summary of evidence LE
Duloxetine, either alone or combined with conservative treatment, can hasten recovery of continence but 1b
does not improve continence rate following prostate surgery.
Recommendation GR
Consider offering duloxetine to hasten recovery of continence after prostate surgery but inform the patient B
about the possible adverse events.
2. METHODS
2.1 Introduction
For the 2017 Urinary Incontinence Guidelines, the literature has been assessed for Section 4.2 –
Pharmacological management. Databases searched included Medline, EMBASE, and the Cochrane Libraries,
covering a time frame between January 2012 and April 20th, 2016. A total of 1164 unique records were
identified, retrieved and screened for relevance. A detailed search strategy is available online: https://uroweb.
org/guideline/urinary-incontinence/?type=appendices-publications.
A systematic review was performed assessing nocturia and nocturnal incontinence in both men and women, in
collaboration with the EAU Non-Neurogenic Male LUTS Guidelines Panel [6].
Due to the paucity of literature addressing nocturnal incontinence, the Panel did not include new
information on this topic. The findings relating to nocturia in males are presented in the Non-Neurogenic Male
LUTS Guidelines.
References used in this text are assessed according to their level of evidence (LE) and Guidelines are given
a grade of recommendation (GR), according to a classification system modified from the Oxford Centre for
Evidence-Based Medicine Levels of Evidence [7]. Additional methodology information can be found in the
general Methodology section of this print, and online at the EAU website: http://www.uroweb.org/guideline/.
A list of Associations endorsing the EAU Guidelines can also be viewed online at the above address.
In this edition the Panel has continued to focus, largely, on the management of a ‘standard’ patient. The
Panel has referred in places to patients with ‘complicated incontinence’, by which we mean patients with
associated morbidity, a history of previous pelvic surgery, surgery for UI, radiotherapy and women with
associated genitourinary prolapse. An appendix is included on non-obstetric genitourinary fistulae. The subject
of prevention of urinary incontinence has not been addressed. A systematic review on nocturnal incontinence
found no studies on the topic. The Panel are of the opinion that nocturnal incontinence should be considered in
future research studies.
2.2 Review
This document was subjected to peer review prior to publication in 2015. The decision for re-review is
made based on the extent of the revision. A major revision resulting in significant changes to the clinical
recommendations presented in the text will warrant re-review.
2.3 Terminology
Evidence summaries provide a succinct summary of what the currently available evidence tells us about
an individual clinical question. They are presented according to the levels of evidence used by the EAU.
Recommendations have been deliberately written as ‘action-based’ sentences. The following words or phrases
are used consistently throughout the Guidelines;
• Consider an action. This word is used when there is not enough evidence to say whether the action
causes benefit or risk to the patient. However, in the opinion of the Panel, the action may be justified in
some circumstances. Action is optional.
Future goals:
• An extended literature search revisiting the topic of female nocturia will be undertaken in collaboration
with the Non-neurogenic male LUTS Guidelines Panel.
• An Algorithm for the management of nocturia in both males and females will be presented in the 2018
Urinary Incontinence Guidelines publication.
3. DIAGNOSTIC EVALUATION
3.1 History and physical examination
Taking a careful clinical history is fundamental to the clinical process. Despite the lack of formal evidence,
there is universal agreement that taking a history should be the first step in the assessment of anyone with UI.
The history should include details of the type, timing and severity of UI, associated voiding and other urinary
symptoms. The history should allow UI to be categorised into stress urinary incontinence (SUI), urgency
urinary incontinence (UUI) or mixed urinary incontinence (MUI). It should also identify patients who need rapid
referral to an appropriate specialist. These include patients with associated pain, haematuria, a history of
recurrent urinary tract infection (UTI), pelvic surgery (particularly prostate surgery) or radiotherapy, constant
leakage suggesting a fistula, voiding difficulty or suspected neurological disease. In women, an obstetric and
gynaecological history may help to understand the underlying cause and identify factors that may impact
on treatment decisions. The patient should also be asked about other ill health and for the details of current
medications, as these may impact on symptoms of UI.
Similarly, there is little evidence from clinical trials that carrying out a clinical examination improves care,
but wide consensus suggests that it remains an essential part of assessment of people with UI. It should
include abdominal examination, to detect an enlarged bladder or other abdominal mass, and perineal and
digital examination of the rectum (prostate) and/or vagina. Examination of the perineum in women includes an
assessment of oestrogen status and a careful assessment of any associated pelvic organ prolapse (POP). A
cough test may reveal SUI if the bladder is sufficiently full while pelvic floor contraction together with urethral
mobility can be assessed digitally.
3.2.1 Questions
• In patients with UI, can the use of Questionnaires/PROMS differentiate between stress, urgency and
mixed incontinence, and does this differentiation impact on quality of life (QoL) after treatment?
• In adults with UI, does assessment using either urinary symptom or QoL questionnaires improve
treatment outcome for UI?
• In adults with UI, does assessment of the patient perspective (concerns or expectations) improve patient
outcomes, regarding either urinary symptoms or QoL, compared to no patient-reported assessment?
3.2.2 Evidence
Although many studies have investigated the validity and reliability of urinary symptom questionnaires and
PROMs most of these studies did not include adult patients diagnosed with UI. This limits the extent to which
results and conclusions from these studies can be applied in adults with UI. Some questionnaires (QUID, 3IQ)
have potential to discriminate UI types in women [9, 10]. In men ICIQ-UI-SF score does not differentiate UI
Table 1 shows a summary of the ICUD review (2012) with recent additions. Criteria on which questionnaires are
assessed include validity, reliability and responsiveness to change.
To date, there is no one questionnaire that fulfils all requirements for assessment of people with UI. Clinicians
must evaluate the tools which exist, for use alone or in combination, for assessment and monitoring of
treatment outcome [15].
Summary of evidence LE
Validated condition specific symptom scores assist in the screening for, and categorisation of, urinary 3
incontinence.
Validated symptom scores measure the severity of urinary incontinence. 3
Both condition specific and general health status questionnaires measure current health status, and 3
change following treatment.
3.3.1 Question
• In adults with UI, what is the reliability, diagnostic accuracy and predictive value of a voiding diary
compared to patient history or symptom score?
3.3.2 Evidence
Two articles have suggested a consensus has been reached in the terminology used in voiding
[16, 17]. However, the terms micturition diary, frequency voiding chart and voiding diary, have been used
interchangeably for many years and include information on fluid intake, times of voiding, voided volumes,
incontinence episodes, pad usage, degree of urgency and degree of UI recorded for at least 24 hours. When
reviewing the evidence all possible terminology has been included.
Two studies have demonstrated the reproducibility of voiding diaries in both men and women [18, 19]. Further
studies have demonstrated variability of diary data within a 24-hour period and compared voided volumes
recorded in diaries with those recorded by uroflowmetry [20, 21]. Another study found that keeping a voiding
diary had a therapeutic benefit [22].
A number of observational studies have demonstrated a close correlation between data obtained from voiding
diaries and standard symptom evaluation [23-26].
Summary of evidence LE
Voiding diaries of three to seven days duration are a reliable tool for the objective measurement of 2b
mean voided volume, day time and night time frequency, and incontinence episode frequency.
Voiding diaries are sensitive to change and are a reliable measure of outcome. 2b
Recommendations GR
Ask patients with urinary incontinence to complete a voiding diary. A
Use a diary duration of between three and seven days. B
3.4.1 Question
• In adults with UI, what is the diagnostic accuracy of urinalysis to detect UTI?
• In adults with UI does treatment of UTI or asymptomatic bacteriuria cure or improve UI compared to no
treatment?
3.4.2 Evidence
Urinalysis negative for nitrite and leucocyte esterase reliably excludes UTI in people with UI [28] and should be
included, with urine culture when necessary, in the evaluation of all patients with UI. Urinary incontinence may
Summary of evidence LE
Urinalysis negative for nitrite and leucocyte esterase reliably excludes urinary tract infection. 1
Urinary incontinence may be a symptom during urinary tract infection. 3
The presence of a symptomatic urinary tract infection worsens symptoms of urinary incontinence. 3
Elderly nursing home patients with urinary incontinence do not benefit from treatment of asymptomatic 2
bacteriuria.
Recommendations GR
Perform urinalysis as a part of the initial assessment of a patient with urinary incontinence. A*
If a symptomatic urinary tract infection is present with urinary incontinence, reassess the patient after A*
treatment.
Do not routinely treat asymptomatic bacteriuria in elderly patients to improve urinary incontinence. B
* Recommendation based on expert opinion.
3.5.1 Question
In adults with UI, what is the value of measuring PVR?
3.5.2 Evidence
Most studies investigating PVR have not included patients with UI. Although some studies have included
women with UI and men and women with LUTS, they have also included children and adults with neurogenic
UI. In general, the data on PVR can be applied with caution to adults with non-neurogenic UI. The results
of studies investigating the best method of measuring PVR [32-37] have led to the consensus that US
measurement of PVR is preferable to catheterisation.
In peri- and post-menopausal women without significant LUTS or pelvic organ symptoms, 95% of women had
a PVR < 100 mL [38]. In women with UUI, a PVR > 100 mL was found in 10% of cases [39]. Other research has
found that a high PVR is associated with POP, voiding symptoms and an absence of SUI [38, 40-42].
In women with SUI, the mean PVR was 39 mL measured by catheterisation and 63 mL measured by US, with
16% of women having a PVR > 100 mL [39].
Summary of evidence LE
Lower urinary tract symptoms coexisting with Urinary incontinence are associated with a higher rate of 2
post-void residual compared to asymptomatic subjects.
Recommendations GR
When measuring post-void residual urine volume, use ultrasound. A
Measure post-void residual in patients with urinary incontinence who have voiding symptoms. B
Measure post-void residual when assessing patients with complicated urinary incontinence. C
Post-void residual should be monitored in patients receiving treatments that may cause or worsen A*
voiding dysfunction, including surgery for stress urinary incontinence.
* Recommendation based on expert opinion.
3.6.1 Question
In adults with UI, what is the reproducibility, diagnostic accuracy and predictive value of urodynamic testing?
3.6.2 Evidence
3.6.2.1 Variability
In common with most physiological tests there is variability in urodynamics results. A number of small
studies, assessing same-session repeatability of urodynamic testing, present contradictory findings [43, 44].
Measurement of urethral closure pressure (MUCP) correlates poorly with incontinence severity [45] and there
is conflicting evidence about its reproducibility [46, 47]. One method of recording MUCP cannot be compared
meaningfully to another [48].
Valsalva leak point pressures are not standardised and there is minimal evidence about reproducibility. Valsalva
leak point pressure did not reliably assess incontinence severity in a cohort of women selected for surgical
treatment of SUI [49]. The predictive value of the tests, regarding the outcome of treatment, remains unclear.
No studies on the reproducibility of ambulatory monitoring were found.
The diagnostic accuracy of urethral pressure profilometry [45] and ‘urethral retro-resistance’ is generally poor
[52]. Urethral reflectometry may have greater diagnostic accuracy but its clinical role remains unclear [53].
Ambulatory urodynamics may detect unexpected physiological variance from normal more often than
conventional cystometry, but the clinical relevance of this is uncertain [54, 55].
3.6.2.3 Question
Does urodynamics influence the outcome of conservative therapy?
3.6.2.4 Evidence
A Cochrane review of seven RCTs showed that use of urodynamic tests increased the likelihood of prescribing
drugs or avoiding surgery. However, there was no evidence that this influence on decision making altered the
clinical outcome of treatment [56]. Subanalysis of an RCT comparing fesoterodine to placebo [57, 58] showed
no predictive value for treatment response, by the urodynamic diagnosis of detrusor overactivity (DO).
3.6.2.5 Question
Does urodynamics influence the outcome of surgery for urinary incontinence?
3.6.2.6 Evidence
A high-quality RCT (n = 630) compared office evaluation alone to office evaluation and urodynamics in
women with clinical demonstrable SUI about to undergo surgery for SUI. Whilst urodynamics changed the
clinical diagnosis in 56% of women [59], there was no difference in levels of UI or any secondary outcome at
twelve months follow-up after surgery [60]. Another similar study closed with only 59 women included due
to recruitment problems, found that the omission of urodynamics was not inferior in the pre-operative work
up of SUI [61]. This study was then redesigned so that patients in whom urodynamics were discordant with
clinical assessment (n = 109) were randomly allocated to receive either immediate surgery or individually
tailored therapy based on urodynamics. In this trial, performing immediate surgery, irrespective of the result of
urodynamics, did not result in inferior outcomes [62].
In observational studies there is no consistent correlation between the result of urethral function tests and
subsequent success or failure of SUI surgery [24-27]. The same is true for a secondary analysis of an RCT [63].
The Panel recognise that it may be valuable to use urodynamic test results to select the optimum surgical
procedure but, at the time of this review, there is inconsistent evidence regarding any predictive value that
would support this approach.
3.6.2.7 Question
Does urodynamics help to predict complications of surgery for UI?
3.6.2.8 Evidence
There have been no RCTs designed to answer this question.
The presence of pre-operative DO has been associated with post-operative UUI, but did not predict overall
treatment failure following mid-urethral sling [63] or following sling surgery or colposuspension.
Whilst low pre-operative flow rate has been shown to correlate with post-operative voiding dysfunction [64,
65], post hoc analysis of two high-quality surgical trials showed that no pre-operative urodynamic parameter
had the ability to predict post-operative voiding dysfunction in a selected population of women with low pre-
operative PVR [66, 67].
3.6.2.9 Question
Does urodynamics influence the outcome of treatment for post-prostatectomy urinary
incontinence in men?
3.6.2.10 Evidence
There are no RCTs examining the clinical usefulness of urodynamics in post-prostatectomy UI. Whilst
urodynamics will distinguish causes of incontinence, its ability to predict outcome of surgery for incontinence
for these men is uncertain [68, 69].
Summary of evidence LE
Most urodynamic parameters show variability within the same session and over time, and this limits 3
their clinical usefulness.
Different techniques of measuring urethral function may have good test-retest reliability, but do not 3
consistently correlate to other urodynamic tests or to the severity of urinary incontinence.
There is limited evidence that ambulatory urodynamics is more sensitive than conventional 2
urodynamics for diagnosing stress urinary incontinence or detrusor overactivity.
There may be inconsistency between history and urodynamic results. 3
Preliminary urodynamics can influence the choice of treatment for urinary incontinence, but does not 1a
affect the outcome of conservative therapy or drug therapy for stress urinary incontinence.
Pre-operative urodynamics in women with uncomplicated, clinically demonstrable stress urinary 1b
incontinence does not improve the outcome of surgery for stress urinary incontinence.
There is no consistent correlation between the result of urethral function tests and subsequent 3
success or failure of stress urinary incontinence surgery.
There is no consistent evidence that pre-operative detrusor overactivity is associated with surgical 3
failure of mid-urethral sling in women.
The presence of pre-operative detrusor overactivity may be associated with persistence of urgency 3
post-operatively.
There is no evidence that urodynamics predicts the outcomes of treatment for post-prostatectomy 4
incontinence in men.
3.7.1 Questions
• In adults with UI, what is the reliability, diagnostic accuracy and predictive value of pad testing?
• In adults with UI, is one type of pad test better than another?
3.7.2 Evidence
The clinical usefulness of pad tests for people with UI has been assessed in two systematic reviews [70, 71].
A one-hour pad test using a standardised exercise protocol and a diagnostic threshold of 1.4 g shows good
specificity but lower sensitivity for symptoms of SUI and MUI. A 24-hour pad test using a threshold of 4.4 g
is more reproducible but is difficult to standardise with variation according to activity level [72]. Pad test with
a specific short graded exercise protocol also has diagnostic value but a negative test should be repeated or
the degree of provocation increased [73]. The usefulness of pad tests in quantifying severity and predicting
outcome of treatment is uncertain [70, 74] although early post-operative testing may predict future continence
in men after prostatectomy [75]. Pad test is responsive to change following successful treatment [76]. There is
no evidence that one type of pad test is superior to another.
Summary of evidence LE
A pad test can diagnose urinary incontinence accurately. 2
Standardisation of bladder volume and degree of provocation improves reproducibility. 2
Twenty-four hours is sufficient duration for home-based testing balancing diagnostic accuracy and 2
adherence.
Change in leaked urine volume on pad tests can be used to measure treatment outcome. 2
Recommendations GR
Have a standardised duration and activity protocol for pad test. B
Use a pad test when quantification of urinary incontinence is required. C
Use repeat pad test after treatment if an objective outcome measure is required. C
Ultrasound and magnetic resonance imaging (MRI) have largely replaced X-ray imaging. Ultrasound is preferred
to MRI because of its ability to produce three-dimensional and four-dimensional (dynamic) images at lower
cost and wider availability. Studies on LUT imaging in patients with UI often include an evaluation of surgical
outcomes, making design and conduct of these trials challenging.
3.8.1 Questions
In adults with UI:
• What is the reliability and accuracy of imaging in the diagnosis of UI?
• Do the results of imaging influence the choice of treatment for UI?
• Do the results of imaging help predict outcome of treatment for UI?
• Do the results of imaging help evaluate outcome of treatments for UI?
3.8.2 Evidence
Many studies have evaluated the imaging of bladder neck mobility by US and MRI, and concluded that UI
cannot be identified by a particular pattern of urethrovesical movements [77]. In addition, the generalised
increase in urethral mobility after childbirth does not appear to be associated with de novo SUI [78].
There is a general consensus that MRI provides good global pelvic floor assessment, including POP, defecatory
function and integrity of the pelvic floor support [79]. However, there is a large variation in MRI interpretation
between observers [80] and little evidence to support its clinical usefulness in the management of UI.
Studies have assessed the use of imaging to assess the mechanism of mid-urethral sling insertion
for SUI. One study suggested that mid-urethral sling placement decreased mobility of the mid-urethra but
not mobility of the bladder neck [81]. Following mid-urethral sling, a wider gap between symphysis and sling
(assessed by imaging) has been shown to correlate with a lower chance of cure of SUI [82].
Several imaging studies have investigated the relationship between sphincter volume and function in women
[83] and between sphincter volume and surgery outcome, in men and women [84, 85]. In patients undergoing
radical prostatectomy, longer membranous urethra before and after surgery was associated with a higher
rate of continence [86]. However, no imaging test has been shown to predict the outcome of treatment for UI.
Imaging of the pelvic floor can identify levator ani detachment and hiatus size, although there is little evidence
of a relationship to clinical benefit after treatment of UI.
Summary of evidence LE
Imaging can reliably be used to measure bladder neck and urethral mobility, although there is no 2b
evidence of clinical benefit for patients with urinary incontinence.
There is no consistent evidence that bladder (detrusor) wall thickness measurement is useful in the 3
management of urinary incontinence.
Recommendation GR
Do not routinely carry out imaging of the upper or lower urinary tract as part of the assessment of A
urinary incontinence.
It is possible that improvement of associated disease may reduce the severity of urinary symptoms. However,
this is often difficult to assess as patients frequently suffer from more than one condition. In addition,
interventions may be combined and individualised, making it impossible to decide which alteration in an
underlying disease has affected a patient’s UI.
4.1.1.1.1 Question
In adults with UI, does improving an associated condition improve UI compared to no correction of that
condition?
4.1.1.1.2 Evidence
There is compelling evidence that there is a higher prevalence of UI in women with type 2 diabetes. One study
showed no correlation between earlier intensive treatment of type 1 diabetes mellitus and the prevalence of UI
in later life vs. conventional treatment [88].
Summary of evidence LE
There is a lack of evidence that improving any associated condition improves urinary incontinence, 3
with the exception of weight loss (see section 4.1.2.4 Obesity and weight loss).
Recommendation GR
Patients with urinary incontinence who have associated conditions, should have appropriate treatment A*
for those conditions in line with good medical practice.
* Recommendation based on expert opinion.
In patients with existing UI, particularly the elderly, it may be difficult or impossible to distinguish between the
effects of medication, comorbidity or ageing on UI. Although changing drug regimens for underlying disease
may be considered as a possible early intervention for UI, there is very little evidence of benefit [50]. There is
also a risk that stopping or altering medication may result in more harm than benefit.
4.1.1.2.1 Question
In adults with UI, does adjustment of other (non-incontinence) medication improve UI compared to no change
in treatment?
Summary of evidence LE
There is very little evidence that alteration of non-incontinence medication can cure or improve 3
symptoms of urinary incontinence.
Recommendations GR
Take a drug history from all patients with urinary incontinence. A
Review any new medication associated with the development or worsening of urinary incontinence. C
4.1.1.3 Constipation
Several studies have shown strong associations between constipation and UI. Constipation can be improved
by behavioural, physical and medical treatments.
4.1.1.3.1 Question
Does treatment for constipation improve UI?
4.1.1.3.2 Evidence
Two, large, cross-sectional population-based studies [89, 90] and two longitudinal studies [91, 92] showed that
constipation was a risk factor for LUTS. An observational study comparing women with UI and women with
pelvic organ prolapse (POP) to controls found that a history of constipation was associated with both prolapse
and UI [93]. One RCT found that a multimodal intervention in elderly patients, involving assisted toileting, fluid
intake, etc., reduced the occurrence of UI and constipation, while behavioural therapy appeared to improve
both [94].
In conclusion, constipation appears to be associated with UI. However, there is no evidence to show whether
or not treating constipation improves UI, although both constipation and UI appear to be improved by certain
behavioural interventions.
Summary of evidence LE
There is a consistent association between a history of constipation and the development of urinary 3
incontinence and pelvic organ prolapse.
There is no consistent evidence in adults that treatment of constipation alone improves urinary 4
incontinence.
Recommendation GR
Adults with urinary incontinence who also suffer from constipation should be given advice about C
bowel management in line with good medical practice.
4.1.1.4 Containment
Containment is important for people with UI when active treatment does not cure the problem, or when it is not
available or not possible. Some individuals may prefer containment rather than undergo active treatment with
its associated risks. This includes the use of absorbent pads, urinary catheters, external collection devices,
penile clamps for men and intravaginal devices for women. Studies of catheter use are not specific to patients
with non-neurogenic UI. Detailed literature summaries can be found in the current ICUD monograph [1] and
in European Association of Urological Nurses guidance documents [95-97]. A useful resource for health care
professionals and patients can be found at: www.continenceproductadvisor.org.
4.1.1.4.1 Question
For adults with UI, is one type of containment device better than another?
4.1.1.4.2 Evidence
20 URINARY INCONTINENCE IN ADULTS - LIMITED UPDATE MARCH 2017
One RCT involving elderly women in care comparing management with pads to indwelling urethral catheter
found no difference in dependency level or skin integrity score at six months [98]. Use of an external sheath
was compared with indwelling catheterisation over 30 days in an RCT involving elderly men resident in hospital
[99]; there were no differences in bacteriuria or symptomatic UTI but the sheath was more comfortable. A
short-term (two weeks) crossover RCT in men with UI found that disease specific QoL was better when using
an external sheath and more men preferred it, compared to pads [100].
4.1.1.4.3 Question
For men or women with UI, is one type of pad better than another?
4.1.1.4.4 Evidence
A systematic review of six RCTs comparing different types of pads found that pads filled with superabsorbent
material were better than standard pads, whilst evidence that disposable pads were better than washable pads
was inconsistent [101]. For men with light UI, a randomised crossover trial found that a leaf-shaped type of pad
was preferred to rectangular pads [102]. A series of three crossover RCTs examined performance of different
pad designs for differing populations [103]. For women with light UI, disposable insert pads (within washable
pouch pants) were most effective. In adults with moderate/severe incontinence, disposable pull-up pants were
more effective for women, whilst for men disposable diapers were more effective during the day and washable
diapers at night.
4.1.1.4.5 Question
For men or women with UI, is one type of catheter or external collection device better than another?
4.1.1.4.6 Evidence
A Cochrane review summarised three RCTs comparing different types of long-term indwelling catheters and
found no evidence that one catheter material or type of catheter was superior to another [104]. A systematic
review of non-randomised studies found no differences in UTI outcome or UUT changes between use of
suprapubic or urethral catheter drainage; however, patients with suprapubic catheters were less likely to
have urethral complications [105]. For people using intermittent catheterisation, a Cochrane review found no
evidence that one type of catheter or regimen of catheterisation was better than another [106]. However, there
is recent evidence from a narrative review suggesting that in certain populations using single-use catheters
may reduce urethral trauma and UTI [107]. A Cochrane review summarising five trials comparing washout
policies in adults with indwelling urinary catheters found inconsistent evidence of benefit [108].
A further Cochrane review summarising eight trials testing whether antibiotic prophylaxis was beneficial for
adults using intermittent or indwelling catheterisation found it reduced incidence of symptomatic UTI but
possible harms were not assessed [109].
4.1.1.4.7 Question
For men and women with UI, are external pressure devices more effective than standard treatment and is one
device better than another?
4.1.1.4.8 Evidence
A crossover RCT in twelve men with post-prostatectomy incontinence found a hinge-type penile clamp to be
more effective than circular clamps for control of UI and that the hinge-type penile clamp was preferred by
participants, although it reduced penile blood flow [110].
A Cochrane review summarised seven trials comparing mechanical devices in women with UI finding limited
evidence that SUI was reduced by intravaginal devices, no evidence on the effectiveness of intra-urethral
devices, and that there was no difference in control of UIns between intravaginal and intra-urethral devices
[111]. There was no difference in outcome at twelve months in women with SUI between vaginal pessary alone;
pelvic floor muscle training (PFMT) alone; and vaginal pessary + PFMT, although vaginal pessary was inferior to
PFMT at three months for bother from UI.
Summary of evidence LE
Pads are effective in containing urine. 1b
Hinge-type penile clamps are more effective than circular clamps to control stress urinary incontinence 2a
in men.
Vaginal devices may improve stress urinary incontinence in women in selective groups. 2a
4.1.2.1.1 Question
In adults with UI, does caffeine reduction improve UI or QoL compared to no caffeine reduction?
4.1.2.1.2 Evidence
Four studies were found on the effect of caffeine reduction on UI [113-116]. They were of moderate quality and
the results were inconsistent. The studies were mainly in women, so results can only be cautiously generalised
to men [114, 115]. One RCT showed that reducing caffeine intake as an adjunct to behavioural therapy resulted
in reduced urgency but not reduced UI compared to behavioural therapy alone [114]. Another RCT found that
reducing caffeine had no benefit for UI [115]. A further interventional study in the elderly showed borderline
significance for the benefit of reducing caffeine intake on UI [116]. In a large prospective cohort study there was
no evidence that caffeine reduction reduced the risk of progression of UI over two years [117].
Summary of evidence LE
Reduction of caffeine intake does not improve urinary incontinence. 2
Reduction in caffeine intake may improve symptoms of urgency and frequency. 2
4.1.2.2.1 Question
Does physical exercise cause, improve or exacerbate UI in adults?
4.1.2.2.2 Evidence
The association between exercise and UI is unclear. Four studies [112, 118-120] in differing populations
concluded that strenuous physical exercise increases the risk of SUI during periods of physical activity. There
is also consistent evidence that physically active females and elite athletes experience higher levels of SUI than
control populations [121-126]. On the other hand, the presence of UI may prevent women from taking exercise
[127]. There is no evidence that strenuous exercise predisposes athletes to the development of SUI later in life
[128]. Lower levels of UI have been observed in cohorts of women who undertake moderate exercise, but it
remains unclear whether taking exercise can prevent development of UI [129, 130].
The elderly
Summary of evidence LE
Female athletes may experience urinary incontinence during intense physical activity but not during 3
common activities.
Strenuous physical activity does not predispose for women to urinary incontinence later in life. 3
Moderate exercise is associated with lower rates of urinary incontinence in middle-aged or older 2b
women.
4.1.2.3.1 Question
In adults with UI, what is the effect of modifying fluid intake compared to not modifying fluid intake on
symptoms and QoL?
4.1.2.3.2 Evidence
The few RCTs [115, 133, 134] provide inconsistent evidence. In most studies, the instructions for fluid intake
were individualised and it is difficult to assess participant adherence to protocol. All available studies were in
women. An RCT [134] showed that a reduction in fluid intake by 25% improved symptoms in patients with OAB
but not UI. Personalised fluid advice compared to generic advice made no difference to continence outcomes
in people receiving antimuscarinics for OAB, according to an RCT comparing drug therapy alone to drug
therapy with behavioural advice [135].
Summary of evidence LE
There is conflicting evidence on whether fluid modification improves urinary incontinence. 2
4.1.2.4.1 Question
In adults with UI, does weight loss lead to an improvement in symptoms of UI or QoL?
4.1.2.4.2 Evidence
All the available evidence relates to women. Three systematic reviews plus two large RCTs concluded that
weight loss was beneficial in improving UI [136, 137, 140]. Five further RCTs reported a similar beneficial effect
on incontinence following surgical weight reduction programmes [141-144]. Two large studies in women with
diabetes, for whom weight loss was the main lifestyle intervention, showed UI did not improve but there was
a lower subsequent incidence of UI among those who lost weight [141, 145]. There have been other cohort
studies and case-control studies suggesting similar effects, including surgery for the morbidly obese [146-150].
Summary of evidence LE
Obesity is a risk factor for urinary incontinence in women. 1b
Non-surgical weight loss in overweight and obese women improves urinary incontinence. 1a
Surgical weight loss improves urinary incontinence in obese women. 1b
Weight loss in obese women improves urinary incontinence. 1b
Weight loss in obese adults with diabetes mellitus reduces the risk of developing urinary incontinence. 1b
4.1.2.5.1 Question
In adults with UI, does smoking cessation improve patient outcomes regarding either urinary symptoms or QoL
compared to continued smoking?
4.1.2.5.2 Evidence
The effect of smoking cessation on UI was described as uncertain in a NIHR review [152].
Summary of evidence LE
There is no evidence that smoking cessation will improve the symptoms of urinary incontinence. 4
Recommendations GR
Encourage obese women with urinary incontinence to lose weight and maintain weight loss. A
Advise adults with urinary incontinence that reducing caffeine intake may improve symptoms of B
urgency and frequency but not incontinence.
Patients with abnormally high or abnormally low fluid intake should be advised to modify their fluid C
intake appropriately in line with good medical practice.
Counsel female athletes experiencing urinary incontinence with intense physical activity that it will not C
predispose them to urinary incontinence in later life.
Patients with urinary incontinence who smoke should be given smoking cessation advice in line with A
good medical practice.
Approaches include bladder training (BT) and pelvic floor muscle training (PFMT), but terms such as bladder
drill, bladder discipline and bladder re-education and behaviour modification are also used. Almost always
in clinical practice, these will be introduced as part of a package of care including lifestyle changes, patient
education and possibly some cognitive therapy as well. The extent to which individual therapists motivate,
supervise and monitor these interventions is likely to vary but it is recognised that these influences are
important components of the whole treatment package.
Two systematic reviews (nine RCTs) [154, 155] confirmed a positive effect on continence outcomes for
prompted voiding in comparison to standard care [155]. Timed voiding is defined as fixed, pre-determined,
time intervals between toileting, applicable for those with or without cognitive impairment. A Cochrane review
of timed voiding reviewed two RCTs, finding inconsistent improvement in continence compared with standard
care in cognitively impaired adults [156].
4.1.3.2.1 Questions
In adults with UI:
• Is BT better than no treatment for cure or improvement of UI?
• Is BT better than other conservative treatments for cure or improvement of UI?
• Does BT, as an adjunct to other conservative treatments, cure or improve UI?
• Are the benefits of BT durable in the longer term?
• Are there any patient groups for whom BT is more effective?
4.1.3.2.2 Evidence
There have been three systematic reviews on the effect of BT compared to standard care [50, 152, 157]
confirming that BT is more effective than no treatment in improving UUI. The addition of BT to anticholinergic
therapy did not improve UI compared to antimuscarinics alone but it did improve frequency and nocturia [158].
This review identified seven RCTs in which BT was compared to drug therapy alone and showed only a benefit
for oxybutynin in cure and improvement of UI [158].
Bladder training alone is inferior to a high-intensity programme of PFMT to improve SUI in elderly women
[159]. Bladder training is better than intravaginal pessaries to control SUI, although the improvement may only
be short term. Whatever the method of training used, any benefit of BT on UI is likely to be of short duration
unless the BT programme is practised repeatedly. No adverse events have been reported with BT. Biofeedback
combined with BT increased continence rates and improved MUI in two RCTs [157].
Summary of evidence LE
Bladder training is effective for improvement of urinary incontinence in women. 1b
The effectiveness of bladder training diminishes after the treatment has ceased. 2
The comparative benefit of bladder training and drugs for the improvement of urgency urinary 2
incontinence remains uncertain.
The combination of bladder training with antimuscarinic drugs does not result in greater improvement 1b
of urinary incontinence but may improve frequency and nocturia.
Bladder training is better than pessary alone. 1b
Prompted voiding, either alone or as part of a behavioural modification programme, improves 1b
continence in elderly, care-dependent people.
For recommendations see section 4.1.3.5.
4.1.3.3.1 Question
In adult men and women suffering from UI, does treatment with PFMT, given either alone or augmented with
biofeedback, electrical stimulation or vaginal cones, improve or cure UI or improve QoL, compared to no
treatment, sham treatment or other conservative treatments, e.g. bladder training, electrical stimulation or
vaginal cones?
4.1.3.3.2 Evidence
In a recent UK Health Technology Appraisal (HTA), the role of PFMT in the care of women with SUI was
analysed in a direct comparison of treatments using a mixed treatment comparison model, which compared
different ‘packages’ of care [152]. This extensive meta-analysis reviewed data from 37 interventions and 68
direct comparisons, while the mixed treatment comparisons examined combinations of fourteen different
types of intervention from 55 separate trials. The mixed treatment comparison used both indirect and direct
comparisons and may provide more accurate estimates of effect. Where relevant, the Health Technology
Appraisal has influenced the evidence and recommendations in these Guidelines. The Agency for Healthcare
With regard to the durability of PFMT, another RCT reported fifteen-year follow-up outcomes of an earlier
RCT, showing that long-term adherence to treatment was poor and half of patients had progressed to surgery
[163]. Numerous systematic reviews have addressed the question of whether the effects of PFMT and BT are
additive [152, 157, 164]. These reviews are confounded by differences in patient selection and have arrived at
conflicting conclusions leaving uncertainty about the extent to which one treatment may augment the other.
Similarly, there remains uncertainty about the additional value of biofeedback with systematic reviews reaching
differing conclusions [157, 164].
Comparison of PFMT to other treatments was extensively reviewed by both AHRQ and the 2010 UK HTA [152,
157], which considered additional non-randomised data as part of a mixed treatment comparison. The UK
HTA resulted in a number of different findings from those based solely on direct comparisons. In conclusion,
the HTA, using a revised methodology, supporting the general principle that greater efficacy was achieved by
adding together different types of treatment and by increasing intensity.
Two additional RCTs have shown that written instructions alone offer similar levels of improvement to
supervised PFMT [170, 171]. One RCT found that PFMT was helpful in men who had been incontinent for at
least one year after prostatectomy, and who had had no previous therapy [172].
One RCT compared PFMT to no treatment in men undergoing TURP. There was no demonstrable difference in
the incidence of post-operative incontinence up to twelve months [173].
Summary of evidence LE
Pelvic floor muscle training (PFMT) for women with urinary incontinence
Pelvic floor muscle training is better than no treatment for improving urinary incontinence and QoL in 1
women with stress urinary incontinence and mixed urinary incontinence.
Higher-intensity, supervised treatment regimes, and the addition of biofeedback, confer greater benefit 1
in women receiving PFMT.
Short-term benefits of intensive PFMT are not maintained at fifteen-year follow-up. 2
Pelvic floor muscle training commencing in the early postpartum period improves urinary incontinence 1
in women for up to twelve months.
4.1.3.3.7 Question
In adults with UI, does treatment with ES improve or cure symptoms of UI or QoL compared to no/sham
treatment or antimuscarinics?
4.1.3.3.8 Evidence
Most evidence on ES refers to women with SUI. The topic has been included in two HTAs [152, 157] and three
systematic reviews [50, 174, 175]. The reviews include analysis of fifteen trials and use different comparison
methods, but differ in their assessment of whether ES is more effective than sham stimulation and whether
ES adds to the benefit of PFMT alone. Studies were considered to be of generally low quality, with a variety of
stimulation parameters, treatment regimens and outcome parameters [168].
A subanalysis in a systematic review on one small low quality RCT in which ES had been compared to
oxybutynin and PFMT in patients with UI, showed no difference in incontinence outcomes [176].
A Cochrane review of ES in men with UI (six RCTs) concluded that there was some evidence that electrical
stimulation enhanced the effect of PFMT in the short-term but not after six months. Electrical Stimulation was
also more effective than sham stimulation at six, but not twelve months. There were, however, more adverse
effects (pain or discomfort) with ES [177].
Electromagnetic stimulation has been promoted as treatment for UI but weak evidence of the short-term and
long-term effects has been found in systematic reviews [178, 179].
Summary of evidence LE
In adults with urinary incontinence, electrical stimulation may improve urinary incontinence compared 2
to sham treatment and antimuscarinics.
Electrical stimulation may add benefit to pelvic floor muscle training in the short-term. 2
For recommendations see section 4.1.3.5.
4.1.3.4.1 Question
In adults suffering from UUI, what is the clinical effectiveness of PTNS compared to sham treatment or
alternative treatment such as antimuscarinic drugs?
4.1.3.4.2 Evidence
P-PTNS
The reviewed studies included two twelve-week RCTs of PTNS against sham treatment [180, 181], one
T-PTNS
A small RCT compared transcutaneous PTNS plus standard treatment (PFMT and BT) with PFMT and BT alone
in older women [184]. Women in the T-TPNS group were more likely to achieve improvement at the end of
therapy.
Summary of evidence LE
Percutaneous posterior tibial nerve stimulation (P-PTNS) appears effective for improvement of urgency 2b
urinary incontinence in women who have had no benefit from antimuscarinic medication.
A maintenance programme of P-PTNS has been shown to be effective up to three years. 1b
Percutaneous Posterior tibial nerve stimulation has comparable effectiveness to tolterodine for 1b
improvement of urgency urinary incontinence in women.
No serious adverse events have been reported for P-PTNS in urgency urinary incontinence. 3
There is limited evidence for effectiveness of transcutaneous posterior tibial nerve stimulation (PTNS). 2a
There is no evidence that P-PTNS cures urinary incontinence. 2b
Recommendations GR
Offer bladder training as a first-line therapy to adults with urgency urinary incontinence or mixed A
urinary incontinence.
Offer prompted voiding for adults with incontinence who are cognitively impaired. A
Offer supervised intensive pelvic floor muscle training (PFMT), lasting at least three months, as a first- A
line therapy to women with stress urinary incontinence or mixed urinary incontinence.
Pelvic floor muscle training programmes should be as intensive as possible. B
Offer PFMT to elderly women with urinary incontinence. A
Offer PFMT to post-natal women with urinary incontinence. A
Consider using biofeedback as an adjunct in women with stress urinary incontinence. B
Offer PFMT to men undergoing radical prostatectomy to speed recovery of incontinence. A
Do not offer electrical stimulation with surface electrodes (skin, vaginal, anal) alone for the treatment of A
stress urinary incontinence.
Consider offering electrical stimulation as an adjunct to behavioural therapy in patients with urgency B
urinary incontinence.
Do not offer magnetic stimulation for the treatment of incontinence or overactive bladder in adult B
women.
Offer, if available, PTNS as an option for improvement of urgency urinary incontinence in women who B
have not benefitted from antimuscarinic medication.
Support other healthcare professionals in use of rehabilitation programmes including prompted A
voiding for elderly care-dependent people with urinary incontinence.
4.1.4.1 Question
In adults with MUI, is the outcome of conservative therapy different to that obtained with the same treatment in
patients with either pure SUI or pure UUI?
4.1.4.2 Evidence
No specific systematic reviews were found that addressed the above question. However, a Cochrane report on
A small RCT (n = 71) compared delivery of PFMT, with or without an instructive audiotape. It showed equal
efficacy for different types of UI [185].
Following a RCT of PFMT, a review of 88 women available for follow-up at five years found that outcomes were
less satisfactory in women with MUI than in women with pure SUI [186].
Summary of evidence LE
Pelvic floor muscle training appears less effective for mixed urinary incontinence than for stress urinary 2
incontinence alone.
Electrical stimulation is equally effective for mixed urinary incontinence and stress urinary 1b
incontinence.
Recommendations GR
Treat the most bothersome symptom first in patients with mixed urinary incontinence. C
Warn patients with mixed urinary incontinence that the chance of success of pelvic floor muscle B
training is lower than for stress urinary incontinence alone.
Dry mouth is the commonest side effect, though constipation, blurred vision, fatigue and cognitive dysfunction
may occur [157].
The immediate release (IR) formulation of oxybutynin is the archetype drug in the treatment of UUI. Oxybutynin
IR provides maximum dosage flexibility, including an off-label ‘on-demand’ use. Immediate-release drugs have
a greater risk of side effects than extended release (ER) formulations because of differing pharmacokinetics. A
transdermal delivery system (TDS) and gel developed for oxybutynin gives a further alternative formulation.
4.2.1.1 Question
In adults with UUI, are antimuscarinic drugs better than placebo for improvement or cure of UUI and for the risk
of adverse effects?
4.2.1.2 Evidence
Seven systematic reviews of individual antimuscarinic drugs vs. placebo were reviewed for this section
[157, 187-192] as well as studies published since these reviews up until April 2016. Most studies included
patients with a mean age of 55-60 years. Both female and male subjects were included in different studies but
results cannot be generalised across sexes. Only short-term rates for improvement or cure of UUI are reported.
The evidence reviewed was consistent, indicating that ER and IR formulations of antimuscarinics offer clinically
significant short-term cure and improvement rates for UUI compared to placebo. On balance, IR formulations
tend to be associated with more side effects compared to ER formulations [191].
Cure of UI was deemed to be the most important outcome measure. Risk of adverse events was best
represented by withdrawal from a trial because of adverse events, although this does not reflect practice. Table
2 shows a summary of the findings from a systematic review [157]. In summary, every drug where cure of UI
was available shows superiority compared to placebo in achieving UI, but the absolute size of effect is small.
4.2.1.2.1 Darifenacin
The cure rates for darifenacin were not included in the AHRQ review. Continence rates were 29-33% for
darifenacin compared to 17-18% for placebo [157].
There is limited evidence that patients who do not respond to a first-line antimuscarinic treatment may respond
to a higher dose or a different antimuscarinic agent [194, 195].
4.2.2.1 Question
In adults with UUI, does one type of antimuscarinic drug result in a greater likelihood of cure or improvement
in UUI, and/or a greater improvement in QoL, and/or a lesser likelihood of adverse effects compared to an
alternative antimuscarinic drug?
4.2.2.2 Evidence
There are over 40 RCTs and eight systematic reviews [157, 176, 187, 189, 192, 196-198]. Nearly all the primary
studies were industry sponsored. Upward dose titration is often included in the protocol for the experimental
arm, but not for the comparator arm.
In general, these studies have been designed for regulatory approval. They have short treatment durations
(twelve weeks) and a primary outcome of a change in OAB symptoms rather than a cure of, or an improvement
in, UUI, which were generally analysed as secondary outcomes. The clinical utility of these trials in real life
practice is questionable. Most trials were of low or moderate quality [189]. The 2012 Agency for Healthcare
Research and Quality (AHRQ) review included a specific section addressing comparisons of antimuscarinic
drugs (Table 2).
No antimuscarinic agent improved QoL more than another agent [189]. Dry mouth is the most prevalent
adverse effect. Good evidence indicates that, in general, higher doses of any drug are likely to be associated
with higher rates of adverse events. Also, ER formulations of short-acting drugs and longer-acting drugs are
generally associated with lower rates of dry mouth than IR preparations [189, 196]. Oxybutynin IR showed
higher rates of dry mouth than tolterodine IR and trospium IR, but lower rates of dry mouth than darifenacin,
15 mg daily [189, 196]. Overall, oxybutynin ER has higher rates of dry mouth than tolterodine ER, although
the incidence of moderate or severe dry mouth were similar. Transdermal oxybutynin had a lower rate of
dry mouth than oxybutynin IR and tolterodine ER, but had an overall higher rate of withdrawal due to an
adverse skin reaction [189]. Solifenacin, 10 mg daily, had higher rates of dry mouth than tolterodine ER [189].
Fesoterodine, 8 mg daily, had a higher rate of dry mouth than tolterodine, 4 mg daily [199-201]. In general,
similar discontinuation rates were observed, irrespective of differences in the occurrence of dry mouth (doses
have been given were the evidence relates to a specific dose level typically from trials with a dose escalation
element).
Summary of evidence LE
There is limited evidence that one antimuscarinic drug is superior to an alternative antimuscarinic drug 1b
for cure or improvement of urgency urinary incontinence.
Higher doses of antimuscarinic drugs are more effective to cure or improve urgency urinary 1b
incontinence, but with a higher risk of side effects.
Once daily (extended release) formulations are associated with lower rates of adverse events 1b
compared to immediate release ones, although similar discontinuation rates are reported in clinical
trials.
Dose escalation of antimuscarinic drugs may be appropriate in selected patients to improve treatment 1b
effect although higher rates of adverse events can be expected.
Transdermal oxybutynin (patch) is associated with lower rates of dry mouth than oral antimuscarinic 1b
drugs, but has a high rate of withdrawal due to skin reaction.
4.2.3.1 Question
In adults with UUI, does one type of antimuscarinic drug result in a greater likelihood of cure or improvement in
UUI and/or greater improvement in QoL, and/or lesser likelihood of adverse effects compared to conservative
treatment?
4.2.3.2 Evidence
More than 100 RCTs and high-quality reviews are available [158, 176, 189, 190, 202, 203]. Most of these
studies were independent. A US HTA [176] found that trials were of a low- or moderate-quality. The main focus
of the review was to compare the different drugs used to treat UUI. In one study, multicomponent behavioural
modification produced significantly greater reductions in incontinence episodes compared to oxybutynin
and higher patient satisfaction for behavioural vs. drug treatment. In men with storage LUTS no difference in
efficacy was found between oxybutynin and behavioural therapy [204].
The combination of BT and solifenacin in women with OAB conferred no additional benefit in terms of
continence [205]. A recent Cochrane review on the benefit of adding PFMT to other active treatments of UI in
women showed insufficient evidence of any benefit in adding PFMT to drug treatment [206].
One RCT [207] reported a similar improvement in subjective parameters with either transcutaneous electrical
nerve stimulation (T-PTNS) or oxybutynin. One study compared tolterodine ER to transvaginal/anal electrical
stimulation without differences in UI outcomes [208].
Recommendations GR
Offer antimuscarinic drugs for adults with urgency urinary incontinence who failed conservative A
treatment.
Consider extended release formulations in patients who do not tolerate immediate release A
antimuscarinics.
If antimuscarinic treatment proves ineffective, consider dose escalation or offering an alternative B
treatment.
Consider using transdermal oxybutynin if oral antimuscarinic agents cannot be tolerated due to dry B
mouth.
Offer and encourage early review (of efficacy and side effects) of patients on antimuscarinic C
medication for urgency urinary incontinence.
4.2.4.1 Question
Do patients with UUI adhere to antimuscarinic drug treatment and persist with prescribed treatment in clinical
practice?
4.2.4.2 Evidence
This topic has been reviewed for the development of these Guidelines [210]. Two open-label extensions of
RCTs of fesoterodine 8 mg showed adherence rates at two years of 49-84% [211, 212]. The main drugs
studied were oxybutynin and tolterodine IR and ER. Non-persistence rates were high for tolterodine at twelve
months, and particularly high (68-95%) for oxybutynin.
Five articles reported ‘median days to discontinuation’ as between < 30 days and 50 days [213-217]. In a
military health system where free medication was provided, the median time to discontinuation extended to
273 days [214].
Data on adherence/persistence from open-label extension populations are questionable as these patients are
self-selected to be compliant. A Longitudinal Disease Analyser database study has indicated an increasing
discontinuation rate from 74.8% at one year to 87% at three years [218].
Several of the RCT trials tried to identify the factors associated with low/lower, adherence or persistence of
antimuscarinics. These were identified as:
• low level of efficacy (41.3%);
• adverse events (22.4%);
• cost (18.7%), higher adherence rates were observed when drugs were provided at no cost to the patient
[214].
4.2.5 Antimuscarinic and beta3 agonist agents, the elderly and cognition
Trials have been conducted in elderly people with UI. Considerations in this patient group include the
multifactorial aetiology of UI in the elderly, comorbidities such as cognitive impairment, the effect of
co-medications and the risk of adverse events.
The effects of antimuscarinic agents on cognition have been studied in more detail.
4.2.5.1 Question
What is the comparative efficacy, and risk of adverse effects, particularly the cognitive impact, of treatment with
antimuscarinic medication in elderly men and women with UUI?
4.2.5.2 Evidence
Two systematic reviews focusing on elderly patients are available [219, 220]. A community-based cohort study
found a high incidence of cognitive dysfunction [221]. Other systematic reviews have included sections on
the efficacy and safety of antimuscarinics in elderly patients [157, 189]. A systematic review in 2012 found
inconclusive evidence as to the impact of antimuscarinics on cognition [222].
Two recent longitudinal cohort studies in patients using drugs with antimuscarinic effect showed a deterioration
in cognitive function, alteration in CNS metabolism and an association with brain atrophy [223, 224]. In general,
the long-term impact of antimuscarinic agents specifically approved for OAB treatment on specific patient
cohorts is poorly understood [225-228].
4.2.5.2.1 Oxybutynin
There is evidence that oxybutynin IR may cause/worsen cognitive dysfunction in adults [225, 227, 229-233].
Recent evidence has emerged from a prospective cohort study showing cumulative cognitive deterioration
associated with prolonged use of antimuscarinic medication including oxybutynin [223].
More rapid functional deterioration might result from the combined use of cholinesterase inhibitors with
antimuscarinic agents in elderly patients with cognitive dysfunction [234].
4.2.5.2.2 Solifenacin
One pooled analysis [235] has shown that solifenacin does not increase cognitive impairment in the elderly. No
age-related differences in the pharmacokinetics of solifenacin in different age groups was found, although more
frequent adverse events in subjects over 80 years of age were observed. No cognitive effect on healthy elderly
volunteers was shown [233]. In a subanalysis of a large trial, solifenacin 5-10 mg improved symptoms and QoL
in people ≥ 75 years who had not responded to tolterodine [236]. In patients with mild cognitive impairment,
≥ 65 years, solifenacin showed no difference in efficacy between age groups and a lower incidence of most
side effects compared to oxybutynin IR [232, 237].
4.2.5.2.3 Tolterodine
No change in efficacy or side effects related to age have been reported, although a higher discontinuation rate
was found for both tolterodine and placebo in elderly patients [225]. Two RCTs in the elderly found a similar
efficacy and side effect profile to younger patients [238-241]. Post-hoc analysis has shown little effect on
cognition. One non-randomised comparison showed lower rates of depression in elderly participants treated
with tolterodine ER compared to oxybutynin IR [242].
4.2.5.2.4 Darifenacin
Two RCTs in the elderly population (one in patients with UUI and the other in volunteers) concluded that
darifenacin was effective with no risk of cognitive change, measured as memory scanning tests, compared
to placebo [243, 244]. Another study on darifenacin and oxybutynin ER in elderly subjects concluded that the
two agents had a similar efficacy, but that cognitive function was more often affected in the oxybutynin ER arm
[227].
4.2.5.2.6 Fesoterodine
Pooled analyses of the RCTs of fesoterodine confirmed the efficacy of the 8 mg but not the 4 mg dose in over-
75-year olds [211]. Adherence was lower in the over-75 year-old group but the effect on mental status was not
reported [201, 211, 249]. A more recent RCT showed efficacy of fesoterodine in the vulnerable elderly with no
differences in cognitive function at twelve weeks [250].
4.2.5.2.8 Mirabegron
Analysis of pooled data from three RCTs showed efficacy and safety of mirabegron in elderly patients [253].
4.2.5.2.11 Question
In older people suffering from UI, what is the effect of anticholinergic burden (defined by anticholinergic
cognitive burden scale) on cognitive function?
4.2.5.2.12 Evidence
No studies were identified specifically in older people with UI, but evidence was available from observational
cohort studies relating to the risk in a general population of older people. Lists of drugs with anticholinergic
properties are available from two sources [256, 257].
Two systematic reviews of largely retrospective cohort studies showed a consistent association between long-
term anticholinergic use and cognitive dysfunction [258, 259].
Longitudinal studies in older people over two to four years have found increased rate of decline in cognitive
function for patients on anticholinergics or drugs with anticholinergic effects [223, 224, 260, 261].
Summary of evidence LE
Antimuscarinic drugs are effective in elderly patients. 1b
Mirabegron has been shown to be efficacious and safe in elderly patients. 1b
In older people, the cognitive impact of drugs which have anticholinergic effects is cumulative and 2
increases with length of exposure.
Oxybutynin may worsen cognitive function in elderly patients. 2
Solifenacin, darifenacin, fesoterodine and trospium have been shown not to cause cognitive 1b
dysfunction in elderly people in short-term studies.
Recommendations GR
In older people being treated for urinary incontinence, every effort should be made to employ C
nonpharmacological treatments first.
Long-term antimuscarinic treatment should be used with caution in elderly patients especially those B*
who are at risk of, or have, cognitive dysfunction.
When prescribing antimuscarinic for urgency urinary incontinence, consider the total antimuscarinic C
load in older people on multiple drugs.
Consider the use of mirabegron in elderly patients if additional antimuscarinic load is to be avoided. C
*Recommendation based on expert opinion.
4.2.6 Mirabegron
Mirabegron is the first clinically available beta3 agonist, available from 2013. Beta3 adrenoceptors are the
predominant beta receptors expressed in the smooth muscle cells of the detrusor and their stimulation is
thought to induce detrusor relaxation.
Mirabegron has undergone evaluation in industry-sponsored phase 2 and phase 3 trials [262-265]. Three
systematic reviews assessing the clinical effectiveness of mirabegron [262, 263, 266] reported that mirabegron
at doses of 25, 50 and 100 mg, results in significantly greater reduction in incontinence episodes, urgency
episodes and micturition frequency/24 hours than placebo, with no difference in the rate of common
adverse events [262]. The placebo dry rates in most of these trials are between 35-40%, and 43 and 50% for
mirabegron. In all trials the statistically significant difference is consistent only for improvement but not for
cure of UI. Similar improvement in frequency of incontinence episodes and micturitions/24 hours was found in
people who had previously tried and those who had not previously tried antimuscarinic agents. One systematic
review showed that mirabegron is similarly efficacious as most antimuscarinics in reducing UUI episodes [267].
The most common treatment adverse events in the mirabegron groups were hypertension (7.3%),
nasopharyngitis (3.4%) and UTI (3%), with the overall rate similar to placebo [262, 265, 268].
In a twelve-month, active-controlled RCT of mirabegron 50/100 mg vs. tolterodine ER 4 mg, the improvement
in efficacy seen at twelve weeks was sustained at twelve-month evaluation in all groups. The reported dry rates
at twelve months were 43%, 45% and 45% for mirabegron 50 mg, 100 mg and tolterodine 4 mg respectively
[268]. Post hoc analyses of RCTs showed that clinical improvement observed in parameters of OAB severity
translates to an improvement in HRQoL and efficacy is maintained in patients with more severe degree of UI
[269, 270].
No risk of QTc prolongation on electrocardiogram [271] and raised intraocular pressure [272] were observed up
to 100 mg dose; however, patients with uncontrolled hypertension or cardiac arrhythmia were excluded from
these trials. There is no significant difference in rate of side effects at different doses of mirabegron [268]. Data
from a large Canadian Private Drug Plan database suggest a higher adherence rate for mirabegron compared
to antimuscarinics [273]. Patients on certain concurrent medications (i.e. metroprolol) should be counselled
that, due to common metabolism pathways, their medication dosage may need to be adjusted. In the case of
patients taking metoprolol, blood pressure should be monitored after starting mirabegron and, if necessary,
metoprolol dosing changed.
Evaluation of urodynamic parameters in men with combined BOO and OAB concluded that mirabegron (50 or
100 mg) did not adversely affect voiding urodynamic parameters compared to placebo [274].
Equivalent adherence was observed for tolterodine and mirabegron at twelve months (5.5% and 3.6%),
although the incidence of dry mouth was significantly higher in the tolterodine group [268]. In mirabegron
treated patients, improvement in objective outcome measures correlates directly with clinically relevant PROMs
(OAB-q and PPBC) [269, 275].
An RCT in patients who had inadequate response to solifenacin monotherapy 5 mg, demonstrated that
Summary of evidence LE
Mirabegron is better than placebo and as efficacious as antimuscarinics for improvement of urgency 1a
urinary incontinence symptoms.
Adverse event rates with mirabegron are similar to placebo. 1a
Patients inadequately treated with solifenacin 5 mg may benefit more from the addition of mirabegron 1b
than dose escalation of solifenacin.
Recommendation GR
In patients with UUI and an inadequate response to conservative treatments offer mirabegron, unless A
they have uncontrolled hypertension.
4.2.7.1 Questions
• In adults with SUI, does duloxetine cure or improve UI and/or improve QoL compared to no treatment?
• In adults with SUI, does duloxetine result in a greater cure or improvement of UI, or a greater
improvement in QoL, or a lesser likelihood of adverse effects, compared to any other intervention?
4.2.7.2 Evidence
Duloxetine was evaluated as a treatment for female SUI or MUI in three systematic reviews [190, 251, 252].
Improvement in UI compared to placebo was observed with no clear differences between SUI and
MUI. One study reported cure for UI in about 10% of patients. An improvement in I-QoL was not found in the
study using I-QoL as a primary endpoint. In a further study comparing duloxetine, 80 mg daily, with PFMT
alone, PFMT + duloxetine, and placebo [277], duloxetine reduced leakage compared to PFMT or no treatment.
Global improvement and QoL were better for combined therapy than no treatment. There was no significant
difference between PFMT and no treatment.
Two open-label studies with a follow-up of one year or more evaluated the long-term effect of duloxetine in
controlling SUI; however, both had high discontinuation rates [278, 279].
All studies had a high patient withdrawal rate, which was caused by a lack of efficacy and high incidence of
adverse events, including nausea and vomiting (40% or more of patients), dry mouth, constipation, dizziness,
insomnia, somnolence and fatigue, amongst other causes [278, 279].
A systematic review showed significant efficacy for duloxetine compared to placebo in women with UI but with
increased risk of adverse events [252].
Summary of evidence LE
Duloxetine, 40 mg twice daily improves stress urinary incontinence in women. 1a
Duloxetine causes significant gastrointestinal and central nervous system side effects leading to a high 1a
rate of treatment discontinuation, although these symptoms are limited to the first weeks of treatment.
Recommendations GR
Duloxetine can be used with caution to treat women with symptoms of stress urinary incontinence. A
Duloxetine should be initiated using dose titration because of high adverse event rates. A
4.2.8 Oestrogen
Oestrogenic drugs including conjugated equine oestrogens, oestradiol, tibolone and raloxifene, are used as
hormone replacement therapy (HRT) for women with natural or therapeutic menopause.
4.2.8.1 Questions
• In women with UI, does vaginal (local) oestrogen cure or improve UI compared to no treatment or other
active treatment?
• In women with UI, does oral (systemic) oestrogen cure or improve UI compared to no treatment?
4.2.8.2 Evidence
Vaginal oestrogens
A Cochrane systematic review looked at the use of oestrogen therapy in postmenopausal women [280]
given local oestrogen therapy. There is also a more recent narrative review of oestrogen therapy in urogenital
diseases [283].The Cochrane review (search date cut off June 2012) found that vaginal oestrogen treatment
improved symptoms of UI in the short term [280]. The review found small, low quality trials comparing vaginal
oestrogen treatment with phenylpropanolamine, PFMT, electrical stimulation and its use as an adjunct to
surgery for SUI. Local oestrogen was less likely to improve UI than PFMT but no differences in UI outcomes
were observed for the other comparisons. A single trial of local oestrogen therapy comparing a ring device
to pessaries found no difference in UI outcomes although more women preferred the ring device. No adverse
effects of vaginal administration of oestradiol for vulvovaginal atrophy over two years was seen in one trial
[284].
Vaginal oestrogen therapy can be given as conjugated equine oestrogen, oestriol or oestradiol in vaginal
pessaries, vaginal rings or creams. The ideal treatment duration and the long-term effects are uncertain. A
standardised review of local oestrogen showed improvement of UI over placebo with vaginal rings favoured
subjectively over pessaries; no significant difference between vaginal and oral oestrogen treatments was found
[285].
One RCT in postmenopausal women showed benefit in adding intravaginal oestriol to vaginal ES
and PFMT [286].
Systemic oestrogens
Studies of HRT with non-urogenital primary outcomes have looked for change in urinary continence in
secondary analyses. Large trials using conjugated equine oestrogens showed a higher rate of development
or worsening of UI compared to placebo [287-290]. In a single RCT, use of raloxifene was not associated
with development or worsening of UI [291]. Three small RCTs using oral oestriol or oestradiol as HRT for
vulvovaginal atrophy suggested that UI symptoms were improved although the evidence was unclear [50, 292,
293].
Summary of evidence LE
Vaginal oestrogen therapy improves urinary incontinence for post-menopausal women in the short 1a
term.
Neoadjuvant or adjuvant use of local oestrogens are ineffective as an adjunct to surgery for urinary 2
incontinence.
Systemic hormone replacement therapy using conjugate equine oestrogens in previously continent 1a
women increases the risk of developing urinary incontinence and worsens pre-existing urinary
incontinence.
Recommendations GR
Offer post-menopausal women with urinary incontinence vaginal oestrogen therapy, particularly if A
other symptoms of vulvovaginal atrophy are present.
Vaginal oestrogen therapy for vulvovaginal atrophy should be prescribed long-term. In women with a C
history of breast cancer, the treating oncologist needs to be consulted.
For women taking oral conjugated equine oestrogen as hormone replacement therapy who develop or A
experience worsening urinary incontinence, discuss alternative hormone replacement therapies.
Advise women who are taking systemic oestradiol who suffer from urinary incontinence that stopping A
the oestradiol is unlikely to improve their incontinence.
4.2.9.1 Questions
• In adults with UI, does desmopressin cure or improve UI and/or improve QoL compared to no treatment?
• In adults with UI, does desmopressin result in a lesser likelihood of adverse effects, compared to any
other intervention?
4.2.9.2 Evidence
4.2.9.2.1 Improvement of incontinence
Few studies have examined the use of desmopressin exclusively for the treatment of UI. No evidence was
found that demonstrated any effect of desmopressin on nocturnal incontinence, though evidence does exist for
it reducing nocturnal polyuria, particularly in children [294]. One RCT compared desmopressin to placebo with
daytime UI as an outcome measure, with improved continence shown during the first four hours after taking
desmopressin in women [295].There is no evidence reporting desmopressin cure rates for UI and no evidence
that compares desmopressin with other non-drug treatments for UI.
Summary of evidence LE
The risk of urinary incontinence is reduced within four hours of taking oral desmopressin, but not after 1b
four hours.
Continuous use of desmopressin does not improve or cure urinary incontinence. 1b
Regular use of desmopressin may lead to hyponatraemia. 3
Recommendations GR
Consider offering desmopressin to patients requiring occasional short-term relief from daytime urinary A
incontinence and inform them that this drug is not licensed for this indication.
Monitor plasma sodium levels in patients on desmopressin. A*
Do not use desmopressin for long-term control of urinary incontinence. A
*Recommendation based on expert opinion.
4.2.10.2 Evidence
Many RCTs include patients with MUI with predominant symptoms of either SUI or UUI but few report
outcomes separately for those with MUI compared to pure SUI or UUI groups.
Tolterodine
In an RCT of 854 women with MUI, tolterodine ER was effective for improvement of UUI, but not SUI
suggesting that the efficacy of tolterodine for UUI was not altered by the presence of SUI [296]. In another
study (n = 1380) tolterodine was equally effective in reducing urgency and UUI symptoms, regardless of
whether there was associated SUI [297]. Similar results were found for solifenacin [298, 299].
Duloxetine
In one RCT of duloxetine vs. placebo in 588 women, subjects were stratified into either stress-predominant,
urgency-predominant or balanced MUI groups. Duloxetine was effective for improvement of incontinence and
QoL in all subgroups [300].
Duloxetine was found to have equal efficacy for SUI and MUI in an RCT (n = 553) following secondary analysis
of respective subpopulations [301].
Recommendations GR
Treat the most bothersome symptom first in patients with mixed urinary incontinence. C
Offer antimuscarinic drugs or beta3 agonists to patients with urgency-predominant mixed urinary A*
incontinence.
Consider duloxetine for patients with mixed urinary incontinence unresponsive to other conservative B
treatments and who are not seeking cure.
*Recommendation based on expert opinion.
Although the outcome of surgical procedures should be considered in absolute terms, it is also important to
consider any associated complications, adverse events and costs. The outcome parameters used to evaluate
surgery for SUI have included:
• continence rate and number of incontinence episodes;
• general and procedure-specific complications;
• generic, specific (UI) and correlated (sexual and bowel) QoL.
The Panel has tried to acknowledge emerging techniques as they considered appropriate and have made a
strong recommendation (section 4.3.1.5.2) that new devices are only used as part of a structured research
programme.
4.3.1.1.1 Questions
In women with SUI, what is the effectiveness in curing SUI and adverse effects at one year for:
• mid-urethral synthetic sling insertion compared to Burch colposuspension?
• one method of insertion of a mid-urethral synthetic sling compared to another method?
• one direction of insertion of a mid-urethral synthetic sling compared to another direction of insertion?
4.3.1.2 Adjustability
4.3.1.2.1 Questions
• In women with SUI, does an adjustable sling cure SUI and improve QoL or does it cause adverse
outcome(s)?
• How does an adjustable sling compare to other surgical treatments for SUI?
4.3.1.2.2 Evidence
There are no RCTs investigating outcome of adjustable sling insertion for women with SUI. There are limited
data from cohort studies on adjustable tension slings with variable selection criteria and outcome definitions.
Few studies include sufficient numbers of patients or have a long enough follow-up to provide useful evidence.
The available devices have differing designs, making it difficult to draw general conclusions about adjustable
slings as a class of procedure.
4.3.1.3.2 Evidence
Although there have been many studies published on single-incision devices, it should be noted that there
are significant differences in technical design between devices and it may be misleading to make general
statements about them as a class of operations. It should also be noted that some devices have been
withdrawn from the market (e.g. TVT Secur®, Minitape), and yet evidence relating to these may be included in
current meta-analyses. There was evidence to suggest single-incision slings are quicker to perform and cause
less post-operative thigh pain, but there was no difference in the rate of chronic pain. There was not enough
evidence to conclude any difference between single-incision slings in direct comparisons.
A RCT of 537 women comparing retropubic to transobturator tape, showed that increasing age was an
independent risk factor for failure of surgery over the age of 50 [323]. An RCT assessing risk factors for the
failure of TVT vs. transobturator tension-free vaginal tape (TVT-O) in 162 women found that age is a specific risk
factor (adjusted OR 1.7 per decade) for recurrence at one year [324]. In a subanalysis of a trial cohort of 655
women at 2 years’ follow-up, it was shown that elderly women were more likely to have a positive stress test
at follow-up (OR 3.7, 95% CI 1.7-7.97), are less likely to report objective or subjective improvement in stress
and urgency UI, and are more likely to undergo retreatment for SUI (OR 3.9, 95% CI 1.3-11.48). There was no
difference in time to post-operative normal voiding [325].
Another RCT comparing immediate TVT vs. no surgery (delayed TVT) in older women, confirmed efficacy of
surgery in terms of QOL and satisfaction, but with higher complication rates [326].
A cohort study of 256 women undergoing inside-out transobturator tape reported similar efficacy in older vs.
younger women, but found a higher risk of de novo urgency in older patients [327].
Summary of evidence LE
Compared to colposuspension, the retropubic insertion of a mid-urethral synthetic sling provides 1a
equivalent patient-reported cure of stress urinary incontinence at five years.
Mid-urethral synthetic sling inserted by either the transobturator or retropubic route provides 1a
equivalent patient-reported outcome at twelve months.
Mid-urethral sling insertion is associated with a lower rate of a new symptom of urgency, and voiding 1a
dysfunction, compared to colposuspension.
The retropubic route of insertion is associated with a higher intra-operative risk of bladder perforation 1a
and a higher rate of voiding dysfunction than the transobturator route.
The transobturator route of insertion is associated with a higher risk of chronic pain and vaginal 1a
erosion and extrusion at twelve months, than that found with the retropubic route.
The skin-to-vagina direction of both retropubic and transobturator insertion is associated with a higher 1b
risk of post-operative voiding dysfunction.
Adjustable mid-urethral synthetic sling devices may be effective for cure or improvement of stress 3
urinary incontinence in women.
There is no evidence that adjustable slings are superior to standard mid-urethral slings. 4
The comparative efficacy of single-incision slings against conventional mid-urethral slings is uncertain. 1b
4.3.1.4.1 Question
In women with SUI, what is the effectiveness of open and laparoscopic surgery, compared to other surgical
procedures, measured in terms of cure or improvement of incontinence or QoL, or the risk of adverse events?
4.3.1.4.2 Evidence
Four systematic reviews were found, which covered the subject of open surgery for SUI, including 46 RCTs
[2, 328-330], but no RCTs comparing any operation to a sham procedure were identified.
Open colposuspension
The Cochrane review [330] included 46 trials in which 4,738 women had open colposuspension. In most of
these trials, open colposuspension was used as the comparator to an experimental procedure. Consequently,
for this review we have only considered the absolute effect of colposuspension, but have not reviewed all of
these comparisons. No additional trials have been reported since this review.
Within the first year, complete continence rates of approximately 85-90% were achieved for open
colposuspension, while failure rates for UI were 17% up to five years and 21% over five years. The re-operation
rate for UI was 2%. Colposuspension was associated with a higher rate of development, at five years, of
enterocoele/vault/cervical prolapse (42%) and rectocele (49%) compared to tension-free vaginal tape (TVT)
(23% and 32%, respectively). The rate of cystocoele was similar in colposuspension (37%) and with TVT (41%).
Four trials compared Burch colposuspension to the Marshall Marchetti Krantz procedure and one trial
evaluated Burch colposuspension with paravaginal repair. All showed fewer surgical failures up to five years
with colposuspension but otherwise reported similar outcomes.
Anterior colporrhaphy
Anterior colporrhaphy is now considered an obsolete operation for UI. In a Cochrane review [329], ten trials
compared anterior colporrhaphy (n = 385) with colposuspension (n = 627). The failure rate for UI at follow-
up of up to five years was worse for anterior colporrhaphy with a higher requirement for re-operation for
incontinence.
In twelve trials of autologous fascial sling vs. mid-urethral synthetic slings, the procedures showed
similar efficacy. However, use of the synthetic sling resulted in shorter operating times and lower rates of
complications, including voiding difficulty. Six trials compared autologous fascial slings with other materials
of different origins, with results favouring traditional autologous fascial slings. Post-hoc analysis of an RCT
comparing the autologous fascial sling to Burch colposuspension showed inferior outcomes for women who
suffered pre-operative urgency [325].
Laparoscopic colposuspension
The Cochrane review [328] identified 22 RCTs, of which ten trials compared laparoscopic colposuspension to
open colposuspension. No other trials have been identified. Although these procedures had a similar subjective
cure rate, there was limited evidence suggesting the objective outcomes were less good for laparoscopic
colposuspension. However, laparoscopic colposuspension had a lower risk of complications and shorter
duration of hospital stay.
In eight RCTs comparing laparoscopic colposuspension to mid-urethral slings, the subjective cure rates were
similar, while the objective cure rate favoured the mid-urethral sling at eighteen months. Complication rates
were similar for the two procedures and operating times were shorter for the mid-urethral sling. Comparisons of
colposuspension to mid-urethral sling are covered in section 4.3.1.1.
Summary of evidence LE
Autologous fascial sling is more effective than colposuspension for improvement of stress urinary 1b
incontinence.
Laparoscopic colposuspension has similar efficacy to open colposuspension for cure of stress urinary 1a
incontinence and a similar risk of voiding difficulty or de novo urgency.
Laparoscopic colposuspension has a lower risk of other complications and shorter hospital stay than 1a
open colposuspension.
Autologous fascial sling has a higher risk of operative complications than open colposuspension, 1b
particularly voiding dysfunction and post-operative urinary tract infection.
4.3.1.5.2 Evidence
There have been two Cochrane systematic reviews [332, 333] and one independent systematic review [334],
which reported on twelve RCTs or quasi-RCTs of injectable agents. In general, the trials were only of moderate
quality and small, with many of them only being reported in abstract form. Wide confidence intervals meant a
meta-analysis was not possible. Since the Cochrane review, two further RCTs have been reported [335, 336].
Each injectable product has been the subject of many case series. Short-term efficacy in reducing the
symptoms of SUI has been demonstrated for all materials used. In 2006, NICE published an extensive review
of these case series [50]. These case series have added very little to the evidence provided by RCTs. There has
been only one placebo-controlled RCT, in which an autologous fat injection was compared with the placebo of
a saline injection.
Summary of evidence LE
Peri-urethral injection of bulking agent may provide short-term improvement in symptoms (three 2a
months), but not cure, in women with stress urinary incontinence.
Repeat injections to achieve therapeutic effect are often required. 2a
Bulking agents are less effective than colposuspension or autologous sling for cure of stress urinary 2a
incontinence.
Adverse effect rates are lower compared to open surgery. 2a
There is no evidence that one type of bulking agent is better than another type. 1b
Transperineal route of injection may be associated with a higher risk of urinary retention compared to 2b
the transurethral route.
Recommendations GR
Offer the mid-urethral sling to women with uncomplicated stress urinary incontinence as the preferred A
surgical intervention whenever available.
Warn women who are being offered a retropubic insertion of mid-urethral sling about the relatively A
higher risk of peri-operative complications compared to transobturator insertion.
Warn women who are being offered transobturator insertion of mid-urethral sling about the higher risk A
of pain and dyspareunia in the longer term.
Warn women who are being offered a single-incision sling that long-term efficacy remains uncertain. A
Do a cystourethroscopy as part of the insertion of a mid-urethral sling. C
Offer colposuspension (open or laparoscopic) or autologous fascial sling for women with stress urinary A
incontinence if mid-urethral sling cannot be considered.
Warn women undergoing autologous fascial sling that there is a high risk of voiding difficulty and the C
need to perform clean intermittent self-catheterisation; ensure they are willing and able to do so.
Inform older women with stress urinary incontinence about the increased risks associated with B
surgery, including the lower probability of success.
Inform women that any vaginal surgery may have an impact on sexual function. B
Only offer new devices, for which there is no level 1 evidence base, as part of a structured research A*
programme.
Only offer adjustable mid-urethral sling as a primary surgical treatment for stress urinary incontinence A*
as part of a structured research programme.
Do not offer bulking agents to women who are seeking a permanent cure for stress urinary A*
incontinence.
* Recommendation based on expert opinion.
4.3.2.1.1 Question
In women who have had failed surgery for SUI, what is the effectiveness of any second-line operation,
compared to any other second-line operation, in terms of cure or improvement of UI, QoL or adverse events?
4.3.2.1.2 Evidence
Most of the data on surgery for SUI refer to primary operations. Even when secondary procedures have been
included, it is unusual for the outcomes in this subgroup to be separately reported. When they are, the numbers
of patients is usually too small to allow meaningful comparisons.
Cochrane reviews of individual operative techniques have not included separate evaluation of outcomes in
women undergoing second-line surgery. However, there is a current protocol to address this issue [341]. Only
one RCT was found (abstract only) comparing TVT to laparoscopic colposuspension in women with recurrent
SUI. This small study found similar cure rates and adverse events in the short term for both procedures [315].
Post-hoc subgroup analysis of high-quality RCTs comparing one procedure to another have shown conflicting
evidence of relative effectiveness [74, 325, 342, 343]. One large non-randomised comparative series suggested
that cure rates after more than two previous operations were 0% for open colposuspension and 38% for fascial
sling [344].
Several cohort studies have reported outcomes for TVT specifically for primary and secondary cases. Evidence
on the effectiveness of second-line retropubic tapes conflicts with some series showing equivalent outcomes
for primary and secondary cases [345, 346], whilst other research has shown inferior outcomes for secondary
surgery [347, 348]. Other confounding variables make meaningful conclusions difficult.
Systematic review of older trials of open surgery for SUI suggest that the longer-term outcomes of redo open
colposuspension may be poor compared to autologous fascial slings [349]. Successful results have been
reported from mid-urethral slings after various types of primary surgery, while good outcomes are reported for
both repeat TVT and for ‘tightening’ of TVT, but data are limited to small case series only.
Summary of evidence LE
There is conflicting evidence whether prior surgery for stress incontinence or prolapse results in 2
inferior outcomes from repeat operations for stress urinary incontinence.
Most procedures will be less effective when used as a second-line procedure than when used for 2
primary surgery.
In women who have had more than two procedures for stress urinary incontinence, the results of open 2
colposuspension are inferior to autologous fascial sling.
The two intracorporeal external urethral compression devices available are the adjustable compression therapy
(ACT) device and the artificial urinary sphincter (AUS). Using ultrasound or fluoroscopic guidance, the ACT
device is inserted by placement of two inflatable spherical balloons on either side of the bladder neck. The
volume of each balloon can be adjusted through a subcutaneous port placed within the labia majora. More
recently, an adjustable artificial urinary sphincter (FlowsecureTM) has been introduced. It has the added benefit
of ‘conditional occlusion’, enabling it to respond to rapid changes in intra-abdominal pressure.
4.3.2.2.1 Questions
• In women with SUI, does insertion of an external compressive device cure SUI, improve QoL or cause
adverse outcomes?
• How do external compression devices compare to other surgical treatments for SUI?
4.3.2.2.2 Evidence
The major advantage of AUS over other anti-incontinence procedures is the perceived ability to be able to
void normally [111]. However, voiding dysfunction is a known side effect, with a lack of data making it difficult
to assess its importance. Because of significant differences in design between devices and in selection
criteria between case series, results obtained with specific devices cannot be extrapolated generally to the
use of adjustable devices. A recent consensus report has standardised the terminology used for reporting
complications arising from implantation of materials into the pelvic floor region [17].
There are a few case series in women, including four series (n = 611), with study populations ranging from 45 to
215 patients and follow-up ranging from one month to 25 years [351-354]. Case series have been confounded
by varying selection criteria, especially the proportion of women who have neurological dysfunction or who
have had previous surgery. Most patients achieved an improvement in SUI, with reported subjective cures
in 59-88%. Common side effects included mechanical failure requiring revision (up to 42% at ten years) and
explantation (5.9-15%). In a retrospective series of 215 women followed up for a mean of six years, the risk
factors for failure were older age, previous Burch colposuspension and pelvic radiotherapy [354]. Peri-operative
injury to the urethra, bladder or rectum was also a high-risk factor for explantation [352].
A newly introduced artificial sphincter using an adjustable balloon capacity through a self-sealing port,
and stress responsive design, has been introduced to clinical use. A series of 100 patients reported 28%
explantation at four years but the device has undergone redesign and more up-to-date evidence is awaited
[355]. Early reports of laparoscopically implanted AUS do not have sufficient patient populations and/or
sufficient follow-up to be able to draw any conclusions [356, 357].
Summary of evidence LE
Implantation of an artificial sphincter can improve or cure incontinence in women with stress urinary 3
incontinence caused by sphincter insufficiency.
Implantation of the adjustable compression therapy (ACT) device may improve complicated urinary 3
incontinence.
Complications, mechanical failure and device explantation often occur with both the artificial sphincter 3
and the adjustable compression device.
Explantation is more frequent in older women and among those who have had previous Burch 3
colposuspension or pelvic radiotherapy.
Recommendations GR
Management of complicated stress urinary incontinence should only be offered in expert** centres. A*
The choice of surgery for recurrent stress urinary incontinence should be based on careful evaluation C
of the individual patient including multichannel urodynamics and imaging as appropriate.
Warn women with recurrent stress urinary incontinence that the outcome of a surgical procedure, C
when used as a second-line treatment, is generally inferior to its use as a first-line treatment, both in
terms of reduced efficacy and increased risk of complications.
Consider secondary synthetic sling, colposuspension or autologous sling as first options for women C
with complicated stress urinary incontinence.
Warn women receiving artificial urinary sphincter or ACT device that, even in expert centres, there is a C
high risk of complications, mechanical failure or a need for explantation.
* Recommendation based on expert opinion.
** Expert centres refers to the comments on surgeon volume in the introduction to the surgical chapter.
4.3.3 Women with both stress urinary incontinence and pelvic organ prolapse
There is a clear association between the presence of POP and SUI. Although the subject of prolapse is not part
of the remit of these Guidelines, the extent to which it impacts on the management of SUI will be addressed.
The aim is to assess the options available to women who require surgery for POP and who have associated UI
(either symptomatic or after reduction of prolapse), and to assess the value of prophylactic anti-incontinence
surgery in women with no evidence of UI.
4.3.3.1 Questions
1. In women with POP and UI, does combined surgery for POP and SUI reduce the incidence
of post-operative UI compared to POP surgery alone?
4.3.3.2 Evidence
A Cochrane review in 2013 included sixteen trials concerning bladder function after surgery for pelvic organ
prolapse [362]. After prolapse surgery 434 of 2125 women (20.4%) reported new subjective SUI, in sixteen
trials. New voiding dysfunction was reported in 109 of 1,209 (9%) women, in twelve trials.
1. In women with POP does combined surgery for POP and SUI reduce the incidence of post-
operative UI compared to POP surgery alone?
There are two well-designed RCTs relating to the prevalence of post-operative SUI in women who underwent
prolapse surgery with and without an anti-incontinence procedure. Both of these trials involved women with
POP who did not complain of symptoms of stress incontinence regardless of objective findings.
One trial compared abdominal sacrocolpopexy with and without Burch colposuspension [363], the other
compared vaginal repair with and without a mid-urethral sling [364]. In both trials addition of an anti-
incontinence surgery reduced the risk of SUI at twelve months. In one trial there was a higher rate of adverse
events reported in the combined surgery group [364]. This was also the finding of the Cochrane review and
meta-analysis.
Two trials addressed post-operative SUI in patients who had had SUI pre-operatively. Borstad et al., in a
multicentre trial, randomised women with POP and SUI to have a tension-free vaginal tape (TVT) at the time
of prolapse repair or three months later, if they still had SUI. (n = 53). One year after surgery there was no
difference between the groups regarding continence; however, 44% of the women without initial TVT never
required surgery and 29% were dry [365].
In contrast, Costantini et al. followed-up women with POP and SUI randomised to abdominal POP repair with
or without Burch colposuspension (after a median of 97 months), finding that additional SUI surgery did not
improve outcome [366]. On the contrary, a higher number of patients had de novo storage symptoms when a
Burch colposuspension was performed.
In summary, it is difficult to generalise the results of trials using very different procedures to treat both POP and
UI. It seems that with a combined procedure the rate of SUI post-operatively is lower. Studies using midurethral
slings have generally shown more significant differences in UI outcomes with combined procedures than when
other types of anti-incontinence procedure have been used. Individual patient characteristics may play the
most important role in shaping treatment decisions. It must be taken into account that, although more women
may be dry after combined surgery, the risks of repeat surgery, should it become necessary, may outweigh the
potential benefits.
Summary of evidence LE
Women with prolapse + urinary incontinence
Surgery for pelvic organ prolapse (POP) + stress urinary incontinence shows a higher rate of cure of 1a
urinary incontinence in the short term than POP surgery alone.
There is conflicting evidence on the relative long-term benefit of surgery for POP + stress urinary 1b
incontinence vs. POP surgery alone.
Combined surgery for POP + stress urinary incontinence carries a higher risk of adverse events. 1b
Continent women with pelvic organ prolapse
Are at risk of developing urinary incontinence post-operatively. 1a
The addition of a prophylactic anti-incontinence procedure reduces the risk of post-operative urinary 1b
incontinence.
The addition of a prophylactic anti-incontinence procedure increases the risk of adverse events. 1b
Women with pelvic organ prolapse and overactive bladder
There is some low-level inconsistent evidence to suggest that surgical repair of POP can improve 3
symptoms of overactive bladder.
Surgery for POP + occult stress urinary incontinence shows a higher rate of cure of occult stress 1a
urinary incontinence in the short term than POP surgery alone.
Combined surgery for POP + stress urinary incontinence carries a higher risk of adverse events than 1b
POP surgery alone.
Recommendations for women requiring surgery for bothersome pelvic organ prolapse who GR
have symptomatic or unmasked stress urinary incontinence
Offer simultaneous surgery for pelvic organ prolapse and stress urinary incontinence. A
Warn women of the increased risk of adverse events with combined surgery compared to prolapse A
surgery alone.
Recommendations for women requiring surgery for bothersome pelvic organ prolapse without
symptomatic or unmasked stress urinary incontinence.
Warn women that there is a risk of developing de novo stress urinary incontinence after prolapse A
surgery.
Inform women that the benefit of prophylactic stress urinary incontinence surgery is uncertain. C
Warn women that the benefit of surgery for stress urinary incontinence may be outweighed by the A
increased risk of adverse events with combined surgery compared to prolapse surgery alone.
4.3.4.2 Evidence
No robust diagnostic accuracy studies address this question. However, a case series of 27 patients concluded
that endoluminal (vaginal or rectal) MRI has better diagnostic accuracy than voiding cystourethrography
(VCUG) [373]. In a case series of 60 subjects Pathi, et al. reported that the sensitivity, specificity, positive
predictive value and negative predictive value of MRI is 100%, 83%, 92% and 100%, respectively [374].
Dwarkasing et al. also reports 100% specificity and sensitivity of MRI in a case series of 60 patients [375].
However, in a case series of 41 patients, a study reported 25% discrepancy between MRI and surgical findings
[376].
4.3.4.3 Question
In a woman who has a bothersome urethral diverticulum, what is the relative effectiveness of available surgical
treatments?
Diverticula may undergo neoplastic alterations (6%) including invasive adenocarcinomas [383].
Summary of evidence LE
Magnetic resonance imaging has good sensitivity and specificity for the diagnosis of urethral 3
diverticula; however, there is a risk of misdiagnosis and missing potential intraluminal neoplastic
change.
Surgical removal of symptomatic urethral diverticula provides good long-term results; however, 3
women should be counselled of the risk of recurrence and de novo stress urinary incontinence.
Recommendation GR
Symptomatic urethral diverticula should be completely surgically removed. A*
* Recommendation based on expert opinion.
Summary of evidence LE
Duloxetine, either alone or combined with conservative treatment, can hasten recovery of continence 1b
but does not improve continence rate following prostate surgery.
4.3.5.2.2 Evidence
Most studies are case series with small sample sizes. Small cohort studies showed a lack of benefit using a
number of different materials [389, 390]. However, polyacrylamide hydrogel resulted in limited improvement
in QoL without curing the UI [389]. A Cochrane review on the surgical treatment of post-prostatectomy
incontinence found only one study that fulfilled the inclusion criteria [391]. A prospective, randomised study
compared the AUS to silicon particles (Macroplastique™) in 45 patients. Eighty-two per cent of patients
receiving an AUS were continent compared to 46% receiving silicone particles. In patients with severe
incontinence, outcome was significantly worse after silicon bulking injection.
Summary of evidence LE
There is no evidence that bulking agents cure post-prostatectomy incontinence. 2a
There is weak evidence that bulking agents can offer temporary, short-term, improvement in QoL in 3
men with post-prostatectomy incontinence.
There is no evidence that one bulking agent is superior to another. 3
For the restoration of continence by these male slings, two concepts are now being proposed:
• continence restoration by urethral compression (InVance®, Istop TOMS, Argus®);
• continence restoration by repositioning the bulb of urethra (AdVanceTM) [392].
In principle, the AUS can be used for all degrees of post-prostatectomy incontinence, while male slings
are advocated for mild-to-moderate UI. However, the definitions of mild and moderate UI are not clear. The
definition of cure, used in most studies, was no pad use or one security pad per 24 hours. Some authors used
a stricter criterion of less than 2 g urine loss in a 24-hour pad test [393].
4.3.5.3.1 Question
In men with post-prostatectomy SUI, does insertion of a fixed suburethral sling cure SUI, improve QoL, or
cause adverse outcomes?
4.3.5.3.2 Evidence
Concerning the surgical treatment of post-prostatectomy incontinence, three recent literature reviews are
available [394-396]. There are a large number of uncontrolled case series concerning men implanted with
several types of slings [397, 398].
For the repositioning sling (AdVanceTM), the benefit after a mean follow-up of three years has been published
on 136 patients [399]. Earlier data were available from other cohort studies, totalling at least 614 patients
with a mean follow-up of between three months and three years. Subjective cure rates for the device vary
between 8.6% and 73.7%, with a mean of 49.5%. Radiotherapy was a negative prognostic factor [397]. Post-
operative voiding dysfunction occurred in 5.7-1.3%, while erosions and chronic pain were uncommon (0-0.4%)
[393, 399-401]. The overall failure rate was about 20%.
The previously available ‘InVance®’ device has now been removed from the market in some countries.
Summary of evidence LE
There is limited short-term evidence that fixed male slings cure or improve post-prostatectomy 3
incontinence in patients with mild-to-moderate incontinence.
Men with severe incontinence, previous radiotherapy or urethral stricture surgery may have less 3
benefit from fixed male slings.
There is no evidence that one type of male sling is better than another. 3
4.3.5.4.1 Question
In men with post-prostatectomy incontinence or SUI, does insertion of an adjustable suburethral sling cure or
improve SUI, improve QoL, or cause adverse outcomes?
4.3.5.4.2 Evidence
There are no RCTs. Most studies consist of prospective or retrospective case series, with variable follow-up
and different definitions of success. Some have been published only as conference abstracts.
For the Remeex® system, only two abstracts, with conflicting findings, have been published. One
study followed nineteen patients for nearly seven years and reported 70% success, with no explants, infections
or erosions. The second study followed fourteen patients for 25 months. Only 36% of patients were satisfied
and multiple re-adjustments were needed. Mechanical failure was reported in 21% [402].
Argus® system
Data on the Argus® system has been reported for 404 men, but only four series have reported on more than
50 patients [403, 404], with the longest follow-up being 2.4 years. Success rates varied between 17% and
91.6%, with a mean of 57.6% predominantly reporting a subjective cure. The number of implants requiring
re-adjustment was reported as between 22.9% and 41.5% [404]. Infection of the device occurred in 5.4-8%
[403]. Erosions were reported in 5-10% [405]. Urethral perforations occurred in 2.7-16% [403]. Pain at the
implant site was usually only temporary, but chronic pain has been reported [403, 405]. These complications
resulted in explantation rates of 10-15% [404].
The ATOMS® system consists of a mesh implant with an integrated adjustable cushion, which uses a titanium
port left in the subcutaneous tissue of the lower abdomen or scrotum for adjustment of cushion volume. Initial
reports show objective cure rates of 60.5% and improvement rates of 23.7% but with the need for up to nine
post-operative adjustments [406, 407].
Summary of evidence LE
There is limited evidence that adjustable male slings can cure or improve stress urinary incontinence in 3
men.
There is limited evidence that early explantation rates are high. 3
There is no evidence that adjustability of the male sling offers additional benefit over other types of 3
sling.
4.3.5.5.1 Question
In men with post-prostatectomy SUI, does insertion of an external compression device cure SUI, improve QoL,
or cause adverse outcomes?
4.3.5.5.2 Evidence
Artificial urinary sphincter
Although the AUS is considered to be the standard treatment for men with SUI, there are two systematic
reviews [391, 396] presenting limited evidence, of generally poor quality, except for one RCT comparing AUS
with bulking agents [387]. A continence rate of about 80% can be expected, while this may be lower in men
Trigo Rocha et al. published a prospective cohort study on 40 patients with a mean follow-up of 53 months,
showing that from all urodynamic parameters only low bladder compliance had a negative impact on the
outcome [408]. Another retrospective study showed that no urodynamic factors adversely altered the outcome
of AUS implantation [409].
The transcorporeal technique of placement can be used for repeat surgery but evidence of effectiveness
is lacking [410]. The dual-cuff placement was introduced to treat patients who remained incontinent with a
single 4 cm cuff in place. However, it has not improved control of UI, while the availability of a 3.5 cm cuff may
have eliminated the need for a dual cuff [411, 412]. Patients who experienced complete continence after AUS
implantation had a higher erosion risk [413]. One small series reported results of AUS implantation after failure
of previous AdVanceTM sling, showing no difference in efficacy between secondary and primary implantation
[414].
Summary of evidence LE
There is evidence that primary artificial urinary sphincter (AUS) implantation is effective for cure of 2b
stress urinary incontinence in men.
Long-term failure rate for AUS is high although device replacement can be performed. 3
There are conflicting data on whether previous pelvic radiotherapy affects the outcome of AUS 3
implantation.
The usefulness of tandem-cuff placement is uncertain. 3
There is insufficient evidence to state whether one surgical approach for cuff placement is superior to 3
another.
Very limited short-term evidence suggests that the non-circumferential compression device (ProACT®) 3
is effective for treatment of post-prostatectomy stress urinary incontinence.
The non-circumferential compression device (ProACT®) is associated with a high failure and 3
complication rate leading to frequent explantation.
The rate of explantation of the AUS because of infection or erosion remains high (up to 24% in some 3
series).
Mechanical failure is common with the AUS. 3
Revision and re-implantation of AUS is possible after previous explantation or for mechanical failure. 3
Recommendations GR
Consider offering duloxetine to hasten recovery of continence after prostate surgery but inform the B
patient about the possible adverse events.
Only offer bulking agents to men with mild post-prostatectomy incontinence who desire temporary C
relief of incontinence symptoms.
Do not offer bulking agents to men with severe post-prostatectomy incontinence. C
Offer fixed slings to men with mild-to-moderate* post-prostatectomy incontinence. B
Warn men that severe incontinence, prior pelvic radiotherapy or urethral stricture surgery, may worsen C
the outcome of fixed male sling surgery.
Offer AUS to men with moderate-to-severe post-prostatectomy incontinence. B
Implantation of AUS or artificial compression device (ACT) for men should only be offered in expert C
centres.
4.3.6.1.1 Question
In adults with UUI, is bladder wall injection of onabotA better than no treatment for cure or improvement?
4.3.6.1.2 Evidence
Following a dose ranging study in which the 100 U of onabotA was established as the ideal dose, two phase
III trials randomised (1:1) 1,105 OAB incontinent patients whose symptoms were not adequately managed with
anticholinergics to receive bladder wall injections of onabotA (100 U) or saline. At baseline the population had
on average more than five episodes of UUI, around twelve micturitions per day and small PVR. At week twelve,
in patients treated with onabotA UUI episodes/day were halved and number of micturitions/day reduced by
more than two. A total of 22.9% of the patients in the onabotA arm were fully dry, against 6.5% in the saline
arm [425].
Quality of life was substantially improved in the onabotA arm, as shown by the more than 60% of positive
responses in the TBS questionnaire at week twelve, which was double the positive responses in the saline arm.
Cohort studies have shown the effectiveness of bladder wall injections of onabotA in the elderly and frail elderly
[426], though the success rate might be lower and the PVR (> 150 mL) higher in this group.
The median time to request retreatment in the pooled analysis of the two RCTs was 24 weeks [424, 425].
A recent RCT compared onabotA injection 100 U to solifenacin (with dose escalation or switch to trospium
possible in the solifenacin group) and showed similar rates of improvement in UUI over the course of six
months [427]. However, patients receiving onabotA were not only more likely to have cure of UUI (27% vs.
13%, p = 0.003), but also had higher rates of urinary retention during the initial two months (5% vs. 0%) and of
UTIs (33% vs. 13%). Patients taking antimuscarinics were more likely to have dry mouth.
Identification of DO in urodynamics does not influence the outcome of onabotulinum toxin A injections in
patients with UUI [58].
Summary of evidence LE
A single treatment session of onabotulinum toxin A (100 U) injected in the bladder wall is more 1a
effective than placebo at curing and improving urgency urinary incontinence and QoL.
There is no evidence that repeated injections of onabotulinum toxin A have reduced efficacy. 3
There is a high risk of increased post-void residual when injecting elderly frail patients. 3
The risk of bacteriuria after onabotulinum toxin A (100 U) injection is high but the clinical significance 1b
of this remains uncertain.
Onabotulinum toxin A (100 U) is superior to solifenacin for cure of urgency urinary incontinence, but 1b
rates of improvement were equivalent.
4.3.6.2.1 Question
In adults suffering from refractory UUI, what is the clinical effectiveness of sacral nerve neuromodulation
compared to alternative treatments?
4.3.6.2.2 Evidence
All randomised studies suffer from the limitation that assessors and patients were not blind to the treatment
allocation since all recruited subjects had to respond to a test phase before randomisation. A Cochrane
review of the literature until March 2008 [428] identified three RCTs that investigated sacral nerve stimulation in
patients with refractory UUI.
One study compared implantation to controls who stayed on medical treatment and received delayed
implantation at six months. Fifty percent of the immediately implanted group had > 90% improvement in UUI
at six months compared to 1.6% of the control group [429]. The other RCT [430] achieved similar results,
although these patients had already been included in the first report [429]. However, Weil et al.[430] showed
that the effect on generic QoL measured by the SF-36, was unclear as it differed between the groups in only
one of the eight dimensions.
The results of seventeen case series of patients with UUI, who were treated early in the experience with
sacral nerve stimulation, were reviewed [431]. After a follow-up duration of between one and three years,
approximately 50% of patients with UUI demonstrated > 90% reduction in UI, 25% demonstrated 50-90%
improvement, and another 25% demonstrated < 50% improvement. Two case series describing the outcome
of sacral nerve neuromodulation, with a mean or median follow-up of at least four years [432, 433] reported
continued success (> 50% improvement on original symptoms) in patients available for follow-up. Cure rates
for UUI were 15% [433].
Adverse events occurred in 50% of implanted cases, with surgical revision necessary in 33-41% [432, 433].
In a subanalysis of the RCT, the outcomes of UUI patients, with or without pre-implant DO, were compared.
Similar success rates were found in patients with and without urodynamic DO [434].
Summary of evidence LE
Sacral nerve neuromodulation is more effective than continuation of failed conservative treatment for 1b
cure of urgency urinary incontinence, but no sham controls have been used.
In those patients who have been implanted, at long-term, 50% improvement of urgency urinary 3
incontinence is maintained in at least 50% of patients and 15% may remain cured.
The use of tined, permanent electrodes in a staged approach results in more patients receiving the 4
final implant than occurs with temporary test stimulation.
Recommendation GR
Offer sacral nerve modulation to patients who have urgency urinary incontinence refractory to A
antimuscarinic therapy.
There are no RCTs comparing bladder augmentation to other treatments for patients with UUI. Most often,
bladder augmentation is used to correct neurogenic DO or small-capacity, low-compliant, bladders caused by
fibrosis, tuberculosis, radiation or chronic infection.
The largest case series of bladder augmentation in a mixed population of idiopathic and neurogenic UUI
included 51 women [437]. At an average follow-up of 74.5 months, only 53% were continent and satisfied with
the surgery, whereas 25% had occasional leaks and 18% continued to have disabling UUI. It seems that the
results for patients with idiopathic DO (58%) appeared to be less satisfactory than for patients with neurogenic
UUI (90%).
Adverse effects were common and have been summarised in a review over five to seventeen years of more
than 267 cases, 61 of whom had non-neurogenic UUI [438]. In addition, many patients may require clean
intermittent self-catheterisation to obtain adequate bladder emptying (Table 3).
Summary of evidence LE
There is limited evidence on the effectiveness of augmentation cystoplasty and urinary diversion in 3
treatment of idiopathic detrusor overactivity.
Augmentation cystoplasty and urinary diversion are associated with high risks of short-term and long- 3
term severe complications.
Recommendations GR
Only offer augmentation cystoplasty to patients with detrusor overactivity incontinence who have C
failed conservative therapy, in whom the possibility of botulinum toxin and sacral nerve stimulation has
been discussed.
Warn patients undergoing augmentation cystoplasty of the high risk of having to perform clean C
intermittent self-catheterisation; ensure they are willing and able to do so.
Do not offer detrusor myectomy as a treatment for urinary incontinence. C
Only offer urinary diversion to patients who have failed less invasive therapies for the treatment of C
urinary incontinence and who will accept a stoma.
Warn patients undergoing augmentation cystoplasty or urinary diversion of the high risk of short-term C
and long-term complications, and the possible small risk of malignancy.
Lifelong follow-up is mandatory in patients who have undergone augmentation cystoplasty or urinary C
diversion.
4.3.7.2 Evidence
Many RCTs include both patients with pure SUI or pure UUI and patients with MUI. However, very few RCTs
report separate outcomes for MUI and pure UI groups.
Post-hoc analysis of the SISTER trial showed that in women undergoing either autologous fascial sling or
Burch colposuspension, the outcomes were poorer for women with a concomitant complaint of pre-operative
urgency [325]. A similar post-hoc review of another RCT comparing transobturator and retropubic mid-urethral
slings showed that the greater the severity of pre-operative urgency the more likely that treatment would fail
[74]. However, an earlier study had found that surgery provided similar outcomes, whether or not urgency was
present prior to surgery (this study included only a few patients with urodynamic DO).
Case series tend to show poorer results in patients with MUI compared with those with pure SUI. In a case
series of 192 women undergoing mid-urethral sling insertion, overall satisfaction rates were lower for women
with mixed symptoms and detrusor overactivity on pre-operative urodynamics compared to those with pure
SUI and normal urodynamics (75% vs. 98%, respectively) [443]. A comparison of two parallel cohorts of
patients undergoing surgery for SUI, with and without DO, found inferior outcomes in women with MUI [444].
One cohort of 450 women, showed that in urgency-predominant MUI, the success rate fell to 52% compared
to 80% in stress-predominant MUI [445]. In a study with 1,113 women treated with transvaginal obturator
tape, SUI was cured equally in stress-predominant MUI or urgency-predominant MUI. However, women with
stress-predominant MUI were found to have significantly better overall outcomes than women with urgency
predominant MUI [446].
Overall, the outcome for women with pre-existing urgency incontinence remains uncertain.
Recommendations GR
Treat the most bothersome symptom first in patients with mixed urinary incontinence. C
Warn patients with mixed urinary incontinence that surgery is less likely to be successful than surgery A
in patients with stress urinary incontinence alone.
Warn patients with mixed urinary incontinence that one single treatment may not cure urinary A*
incontinence; it may be necessary to treat other components of the incontinence problem as well as
the most bothersome symptom.
* Upgraded following panel consensus.
An RCT of 537 women comparing retropubic to transobturator tape, showed that cure rates decreased and
failure increased with each decade over the age of 50 [447]. An RCT assessing risk factors for failure of
tension free vaginal tape (TVT) vs. transobturator tension-free vaginal tape (TVT-O) in 162 women found that
age is a specific risk factor (adjusted OR 1.7 per decade) for recurrence at one year [324]. In a subanalysis
of the SISTER trial cohort of 655 women at 2 years of follow-up, it was shown that elderly women were more
likely to have a positive stress test at follow-up (OR 3.7, 95% CI 1.7-7.97), are less likely to report objective or
subjective improvement in stress and urgency UI, and are more likely to undergo retreatment for SUI (OR 3.9,
95% CI 1.3-11.48). There was no difference in time to normal post-operative voiding [325].
Another RCT compared immediate TVT vs. delayed TVT in older women, confirming significant efficacy for
the women operated upon, but the cohort as a whole suffered higher complication rates, particularly bladder
perforation (22%) and urinary retention (13%) [326].
A cohort study of 256 women undergoing inside-out TVT-O reported similar efficacy in older vs. younger
women, but there was a higher risk of de novo urgency in older patients [327].
Cohort studies have shown the effectiveness of onabotulinum toxin A injections in the elderly and frail elderly
[426, 448], although a comparison of cohort groups suggests that there is a lower success rate in the frail
elderly and also a higher rate of increased PVR (> 150 mL) in this group.
Summary of evidence LE
Older women benefit from surgical treatment for incontinence. 1
The risk of failure from surgical repair of stress urinary incontinence, or of suffering adverse events, 2
appears to increase with age.
There is no evidence that any surgical procedure has greater efficacy or safety in older women than 4
another procedure.
Recommendation GR
Inform older women with urinary incontinence about the increased risks associated with surgery B
(including onabotA injection), together with the lower probability of benefit.
Further
assessment
Discuss management
Individualised behavioural and physical therapies including pelvic floor muscle training A
Anti-muscarinics
A
or mirabegron
B
No response
Consider P-PTNS
B
Urgency
Stress predominant
predominant
Offer MUS
A
Advise onabotulinumtoxin A
or
sacral nerve stimulation
A
Failure
Further
assessment
Individualised behavioural and physical therapies including pelvic floor muscle training
Anti-muscarinics
A
or mirabegron
B
No response
Consider P-PTNS
B
Urgency
Stress predominant
predominant
The diagnosis of vesicovaginal fistula (VVF) usually requires clinical assessment often in combination with
appropriate imaging or laboratory studies. Direct visual inspection, cystoscopy, retrograde bladder filling with
a coloured fluid or placement of a tampon into the vagina to identify staining may facilitate the diagnosis of a
VVF. A double-dye test to differentiate between a ureterovaginal and VVF may be useful in some cases [452].
Testing the creatinine level in either the extravasated fluid or the accumulated ascites and comparing this to the
serum creatinine level will confirm urinary leakage.
Contrast-enhanced CT with late excretory phase reliably diagnoses urinary fistulae and provides information
about ureteric integrity and the presence of associated urinoma. Magnetic resonance imaging, in particular with
T2 weighting, also provides optimal diagnostic information regarding fistulae and may be preferred for urinary -
intestinal fistulae [453].
Abdominal procedures
Repair by the abdominal route is indicated when high fistulae are fixed in the vault and are inaccessible through
the vagina. A transvesical repair has the advantage of being entirely extraperitoneal. A simple transperitoneal
repair is used less often although it is favoured by some using the laparoscopic approach. A combined
transperitoneal and transvesical procedure is favoured by many urologists and is particularly useful for fistula
repair following Caesarean section. There are no randomised studies comparing abdominal and vaginal
approaches. Results of secondary and subsequent repairs are not as good as primary repair [456].
A single RCT compared trimming of the fistula edge with no trimming [457]. There was no difference in success
rates but failed repairs in trimmed cases ended up with larger recurrences than untrimmed cases, which were
smaller.
Tissue Interposition
Tissue flaps are often added as an additional layer of repair during VVF surgery. Most commonly, such flaps
are utilised in the setting of recurrence after a prior attempt at repair, for VVF related to previous radiotherapy
(described later), ischemic or obstetrical fistulae, large fistulae, and finally those associated with a difficult or
tenuous closure due to poor tissue quality. However, there is no high-level evidence that the use of such flaps
improves outcomes for either complicated or uncomplicated VVF.
Post-operative management
There is no high-level evidence to support any particular practice in post-operative management but most
reported series used catheter drainage for at least ten days and longer periods in radiation-associated fistulae
(up to three weeks).
Ureterovaginal fistula
Ureterovaginal fistula occurring in the early post-operative phase predominantly after hysterectomy is the most
frequent presentation of upper urinary tract fistulae in urological practice. An RCT in 3,141 women undergoing
open or laparoscopic gynaecological surgery found that prophylactic insertion of ureteric stents made no
difference to the low risk (1%) of ureteric injury [463].
Endoscopic management is sometimes possible [464] by retrograde stenting, percutaneous nephrostomy and
antegrade stenting if there is pelvicalyceal dilatation, or ureteroscopic realignment [465].
If endoluminal techniques fail or result in secondary stricture, the abdominal approach to repair is standard
and may require end-to-end anastomosis, re-implantation into the bladder using psoas hitch or Boari flap, or
replacement with bowel segments with or without reconfiguration.
Most authors describe surgical principles that are identical to those of vesicovaginal fistula repair: primary
closure rates of 53-95.4% have been described. Pushkar et al. described a series of 71 women, treated for
urethrovaginal fistula. 90.1% of fistulae were closed at the first vaginal intervention. Additionally, 7.4% were
closed during a second vaginal intervention. Despite successful closure, stress incontinence developed in
52%. The stress incontinent patients were treated with synthetic or autologous slings and nearly 60% became
dry and an additional 32% improved. Urethral obstruction occurred in 5.6% and was managed by urethral
dilation or urethrotomy [468].
Martius flap
While in obstetrical fistula repair it was not found to have any benefit, in a large retrospective study in 440
women the labial bulbocavernosus muscle/fat flap by Martius is still considered by some to be an important
adjunctive measure in the treatment of genitourinary fistulae where additional bulking with well vascularised
tissue is needed [474]. The series of non-obstetrical aetiology are small and all of them are retrospective. There
are no prospective data, nor randomised studies [475]. The indications for Martius flap in the repair of all types
of fistulae remain unclear.
Recommendations GR
General
Surgeons undertaking complex pelvic surgery should be competent at identifying, preserving and C
repairing the ureter.
Do not routinely use ureteric stents as prophylaxis against injury during routine gynaecological surgery. B
Suspect ureteric injury or fistula in patients following pelvic surgery if a fluid leak or pelvicalyceal C
dilatation occurs post-operatively or if drainage fluid contains high levels of creatinine.
Suspect uretero-arterial fistula in patients presenting with haematuria with a history of relevant surgery. C
Use three dimensional imaging techniques to diagnose and localise urinary fistulae. C
Manage upper urinary tract fistulae by conservative or endoluminal technique where such expertise B
and facilities exists.
Surgical principles
Surgeons involved in fistula surgery should have appropriate training, skills, and experience to select C
an appropriate procedure for each patient.
Attention should be given as appropriate to skin care, nutrition, rehabilitation, counselling and support C
prior to and following fistula repair.
If a vesicovaginal fistula is diagnosed within six weeks of surgery, consider indwelling catheterisation C
for a period of up to twelve weeks after the causative event.
Tailor the timing of fistula repair to the individual patient and surgeon requirements once any oedema, B
inflammation, tissue necrosis, or infection, are resolved.
Where concurrent ureteric re-implantation or augmentation cystoplasty are required, the abdominal C
approach is necessary.
Ensure that the bladder is continuously drained following fistula repair until healing is confirmed C
(expert opinion suggests: 10-14 days for simple and/or postsurgical fistulae; 14-21 days for complex
and/or post-radiation fistulae).
Where urinary and/or faecal diversions are required, avoid using irradiated tissue for repair. C
Use interposition grafts when repair of radiation associated fistulae is undertaken. C
In patients with intractable urinary incontinence from radiation-associated fistula, where life C
expectancy is very short, consider performing ureteric occlusion.
Repair persistent ureterovaginal fistula by an abdominal approach using open, laparoscopic or robotic C
techniques according to availability and competence.
Consider palliation by nephrostomy tube diversion and endoluminal distal ureteric occlusion for C
patients with ureteric fistula associated with advanced pelvic cancer and poor performance status.
Urethrovaginal fistulae should preferably be repaired by a vaginal approach. C
6. CONFLICT OF INTEREST
All members of the Urinary Incontinence Guidelines Panel have provided disclosure statements on all
relationships that they have and that might be perceived to be a potential source of conflict of interest. This
information is publically accessible through the European Association of Urology website: http://uroweb.org/
guideline/. This document was developed with the financial support of the European Association of Urology. No
external sources of funding and support have been involved. The EAU is a non-profit organisation and funding
is limited to administrative assistance and travel and meeting expenses. No honoraria or other reimbursements
have been provided.
2. METHODS 4
2.1 Introduction 4
2.2 Review 5
3. THE GUIDELINE 5
3.1 Epidemiology, aetiology and pathophysiology 5
3.1.1 Introduction 5
3.2 Classification systems 7
3.2.1 Introduction 7
3.2.2 Definitions 7
3.3 Diagnostic evaluation 11
3.3.1 Introduction 11
3.3.2 Classification systems 12
3.3.3 Timing of diagnosis and treatment 12
3.3.4 Patient history 12
3.3.4.1 Bladder diaries 13
3.3.5 Patient quality of life questionnaires 14
3.3.5.1 Questions 14
3.3.5.2 Evidence 14
3.3.6 Physical examination 15
3.3.6.1 Autonomic dysreflexia 15
3.3.6.2 Recommendations for history taking and physical examination 16
3.3.7 Urodynamics 16
3.3.7.1 Introduction 16
3.3.7.2 Urodynamic tests 16
3.3.7.3 Specialist uro-neurophysiological tests 17
3.3.7.4 Recommendations for urodynamics and uro-neurophysiology 18
3.3.8 Renal function 18
3.4 Disease management 18
3.4.1 Introduction 18
3.4.2 Non-invasive conservative treatment 18
3.4.2.1 Assisted bladder emptying - Credé manoeuvre, Valsalva manoeuvre,
triggered reflex voiding 18
3.4.2.2 Neuro-urological rehabilitation 19
3.4.2.2.1 Bladder rehabilitation including electrical stimulation 19
3.4.2.3 Drug treatment 19
3.4.2.3.1 Drugs for storage symptoms 19
3.4.2.3.2 Drugs for voiding symptoms 20
3.4.2.4 Recommendations for drug treatments 20
3.4.2.5 Minimally invasive treatment 21
3.4.2.5.1 Catheterisation 21
3.4.2.5.2 Recommendations for catheterisation 21
3.4.2.5.3 Intravesical drug treatment 21
3.4.2.5.4 Botulinum toxin injections in the bladder 21
3.4.2.5.5 Bladder neck and urethral procedures 21
3.4.2.5.6 Recommendations for minimal invasive treatment* 22
3.4.3 Surgical treatment 22
3.4.3.1 Bladder neck and urethral procedures 22
3.4.3.2 Denervation, deafferentation, sacral neuromodulation 23
3.4.3.3 Bladder covering by striated muscle 23
3.4.3.4 Bladder augmentation 23
4. REFERENCES 29
5. CONFLICT OF INTEREST 52
1.5 Background
The function of the LUT is mainly storage and voiding of urine, which is regulated by the nervous system
that co-ordinates the activity of the urinary bladder and bladder outlet. The part of the nervous system that
regulates LUT function is disseminated from the peripheral nerves in the pelvis to highly specialised cortical
areas. Any disturbance of the nervous system involved, can result in neuro-urological symptoms. The extent
and location of the disturbance will determine the type of LUT dysfunction, which can be symptomatic
or asymptomatic. Neuro-urological symptoms can cause a variety of long-term complications; the most
significant being deterioration of renal function. Since symptoms and long-term complications do not correlate
[5], it is important to identify patients with neuro-urological symptoms, and establish if they have a low or high
risk of subsequent complications. The risk of developing upper urinary tract (UUT) damage and renal failure is
much lower in patients with slowly progressive non-traumatic neurological disorders than in those with spinal
cord injury or spina bifida [6]. In summary, treatment and intensity of follow-up examinations are based on the
type of neuro-urological disorder and the underlying cause.
2. METHODS
2.1 Introduction
For the 2017 Neuro-Urology Guidelines, new and relevant evidence has been identified, collated and appraised
through a structured assessment of the literature. A broad and comprehensive literature search, covering all
sections of the Neuro-Urology Guidelines was performed. Databases searched included Medline, EMBASE,
and the Cochrane Libraries, covering a time frame between January 1st 2013 and June 30th 2016. A total
of 2,221 unique records were identified, retrieved and screened for relevance. A detailed search strategy is
available online: http://uroweb.org/guideline/neuro-urology/?type=appendices-publications
Specific sections were updated by way of systematic reviews based on topics or questions
prioritised by the Guideline Panel. These reviews were performed using standard Cochrane systematic review
methodology; http://www.cochranelibrary.com/about/about-cochrane-systematicreviews.html.
References used in this text are graded according to their level of evidence (LE) and Guidelines are given
a grade of recommendation (GR), according to a classification system modified from the Oxford Centre
for Evidence-Based Medicine Levels of Evidence [9]. Additional information can be found in the general
Methodology section of this print, and online at the EAU website; http://www.uroweb.org/guideline/. A list of
associations endorsing the EAU Guidelines can also be viewed online at the above address.
2.2 Review
Publications ensuing from the systematic reviews have all been peer-reviewed. The 2015 Neuro-Urology
Guidelines were subject to peer review prior to publication.
3. THE GUIDELINE
3.1 Epidemiology, aetiology and pathophysiology
3.1.1 Introduction
Neuro-urological symptoms may be caused by a variety of diseases and events affecting the nervous system
controlling the LUT. The resulting neuro-urological symptoms depend predominantly on the location and the
extent of the neurological lesion. There are no exact figures on the overall prevalence of neuro-urological
disorders in the general population, but data are available on the prevalence of the underlying conditions and
the relative risk of these for the development of neuro-urological symptoms. It is important to note that the
majority of the data shows a very wide range of prevalence/incidence. This reflects the variability in the cohort
(e.g. early or late stage disease) and the frequently small sample sizes, resulting in a low level of evidence in
most published data (summarised in Table 1).
Non-IPD: Parkinson’s-plus (18%): MSA is the most frequent non-IPD OAB and DO at the initial phase,
- Multiple system atrophy (MSA); PS. intrinsic sphincter deficiency and
- Progressive supranuclear palsy; impaired contractility appear as the
- Corticobasal degeneration; disease progress. Complications
- Dementia with Lewy bodies. of neuro-urological symptoms
Secondary Parkinson’s (2%) (infections) account for a major
cause of mortality in MSA [19].
3.2.2 Definitions
Autonomic dysreflexia (AD) Autonomic dysreflexia is a sudden and exaggerated autonomic response
to various stimuli in patients with SCI or spinal dysfunction at or above
level Th 6. It is defined as an increase in SBP > 20 mmHg from baseline
[38]. Autonomic dysreflexia may be symptomatic (headache, blurred
vision, stuffy nose, piloerection, flushing, sweating above the lesion level
(vasodilatation), pale and cold skin (vasoconstriction) below the lesion
level or asymptomatic (silent).
Bladder expression Various manoeuvres aimed at increasing intravesical pressure in order to
facilitate bladder emptying (abdominal straining, Valsalva’s manoeuvre
and Crede´s manoeuvre) [3].
Bladder reflex triggering Various manoeuvres performed by the patient or the therapist in order
to elicit reflex detrusor contraction by exteroceptive stimuli (suprapubic
tapping, thigh scratching and anal/rectal manipulation) [3].
Bladder sensation, absent During history taking, the patient reports no sensation of bladder filling or
desire to void [3].
During filling cystometry, the patient has no bladder sensation [3].
Bladder sensation, normal During history taking, the patient is aware of bladder filling and increasing
sensation up to a strong desire to void [3].
First sensation of bladder filling The feeling, during filling cystometry, when the patient first becomes
aware of the bladder filling [3].
During filling cystometry, can further be judged by the two following
defined points and evaluated in relation to the bladder volume at that
moment and in relation to the patient’s symptomatic complaints [3].
First desire to void The feeling, during filling cystometry, that would lead the patient to pass
urine at the next convenient moment, but voiding can be delayed if
necessary [3].
Strong desire to void Persistent desire to void, during filling cystometry, without the fear of
leakage [3].
Bladder sensation, increased During history taking, the patient feels an early and persistent desire to
void [3].
During filling cystometry, an early first sensation of bladder filling (or an
early desire to void) and/or an early strong desire to void, which occurs at
low bladder volume and which persists. It is a subjective assessment, not
possible to quantify [3].
(C)
The pattern of LUT dysfunction following neurological disease is determined by the site and nature of the lesion.
Panel (A) denotes the region above the pons, panel (B) the region between the pons and the sacral cord and
panel (C) the sacral cord and infrasacral region. Figures on the right show the expected dysfunctional states of
the detrusor-sphincter system. Figure adapted from Panicker et al. [6] with permission from Elsevier.
PVR = post-void residual.
• In non-traumatic neuro-urological patients with an insidious onset, a detailed history may find that the
condition started in childhood or adolescence [49].
Past history
Childhood through to adolescence and into adulthood
Hereditary or familial risk factors
Specific female: Menarche (age); this may suggest a metabolic disorder
Obstetric history
History of diabetes
Diseases, e.g. multiple sclerosis,
(C) parkinsonism, encephalitis, syphilis
Accidents and operations, especially those involving the spine and central nervous system
Present history
Present medication
Lifestyle (smoking, alcohol and drugs); may influence urinary, sexual and bowel function
Quality of life
Specific urinary history
Onset of urological history
Relief after voiding; to detect the extent of a neurological lesion in the absence of obstructive uropathy
Bladder sensation
Initiation of micturition (normal, precipitate, reflex, strain, Credé)
Interruption of micturition (normal, paradoxical, passive)
Enuresis
Mode and type of voiding (catheterisation)
Frequency, voided volume, incontinence, urgency episodes
Sexual history
Genital or sexual dysfunction symptoms
Sensation in genital area
Specific male: erection, (lack of) orgasm, ejaculation
Specific female: dyspareunia, (lack of) orgasm
Bowel history
Frequency and faecal incontinence
Desire to defecate
Defecation pattern
Rectal sensation
Initiation of defecation (digitation)
Neurological history
Acquired or congenital neurological condition
Mental status and comprehension
Neurological symptoms (somatic and sensory), with onset, evolution and any treatment
Spasticity or autonomic dysreflexia (especially in lesions at or above level Th 6)
Mobility and hand function
3.3.5.1 Questions
• Which validated patient questionnaires are available for neuro-urological patients?
• Which questionnaires are the most appropriate for use in neuro-urological patients?
3.3.5.2 Evidence
Three condition-specific questionnaires for urinary or bowel dysfunction and QoL have been developed
specifically for adult neuro-urological patients [61]. In MS and SCI patients the Qualiveen [62, 63] is validated
and can be used for urinary symptoms. A short form of the Qualiveen is available [62, 63] and it has been
translated into various languages [64-67]. The Neurogenic Bladder Symptom Score (NBSS) has been validated
in neurological patients to measure urinary symptoms and their consequences [68]. The QoL scoring tool
related to Bowel Management (QoL-BM) [69] can be used to assess bowel dysfunction in MS and SCI patients.
In addition, sixteen validated questionnaires that evaluate QoL and asses urinary symptoms as a
subscale or question in neuro-urological patients have been identified [70] (Table 5). The condition-specific
Incontinence-Quality of Life (I-QoL) questionnaire which was initially developed for the non-neurological
population has now also been validated for neuro-urological patients [71].
A patient’s overall QoL can be assessed by generic HRQoL questionnaires, the most commonly used being
the Incontinence Quality of Life Instrument (I-QOL), King’s Health Questionnaire (KHQ), or the Short Form
36-item and 12-item Health Survey Questionnaires (SF-36, SF-12) [61]. In addition, the quality-adjusted life year
(QALY), quantifies outcomes, by weighing years of life spent in a specified health state, adjusted by a factor
representing the value placed by society or patients on their specific health state [72].
No evidence was found for which validated questionnaires are the most appropriate for use, since
no quality criteria for validated questionnaires have been assessed [73].
The physical examination includes testing sensations and reflexes mediated through the lower spinal cord.
Abnormal findings would suggest a lesion affecting the lumbosacral segments; mapping out distinct areas of
sensory impairment helps to further localise the site of the lesion. Distribution of dermatomes (areas of skin
mainly supplied by a single spinal nerve) and cutaneous nerves over the perianal region and back of the upper
thigh (A), the perineum [89] (B), male external genitalia [90] (C) and root values of lower spinal cord reflexes (D).
Figure adapted from Panicker et al. [6] with parts A-C adapted from Standring [91], both with permission from
Elsevier.
3.3.7 Urodynamics
3.3.7.1 Introduction
Urodynamic investigation is the only method that can objectively assess the function and dysfunction of the
LUT. In neuro-urological patients, invasive urodynamic investigation is even more challenging than in general
patients. Any technical source of artefacts must be critically considered. It is essential to maintain the quality of
the urodynamic recording and its interpretation [1]. Same session repeat urodynamic investigations are crucial
in clinical decision making, since repeat measurements may yield completely different results [92].
In patients at risk for AD, it is advisable to measure blood pressure during the urodynamic study
[93]. The rectal ampulla should be empty of stool before the start of the investigation. All urodynamic findings
must be reported in detail and performed, according to the ICS technical recommendations and standards [1,
94].
Detrusor leak point pressure (DLPP) [95]: Appears to have no use as a diagnostic tool. Some positive findings
have been reported [96, 97], but sensitivity is too low to estimate the risk to the UUT or for secondary bladder
damage [98, 99].
Pressure flow study: Reflects the co-ordination between detrusor and urethra or pelvic floor during the voiding
phase. It is even more powerful if combined with filling cystometry and video-urodynamics. Lower urinary
tract function must be recorded during the voiding phase. Possible pathological findings include detrusor
underactivity, bladder outlet obstruction (BOO), DSD, a high urethral resistance, and residual urine.
Most types of obstruction caused by neuro-urological disorders are due to DSD [100, 101], non-
relaxing urethra, or non-relaxing bladder neck [102, 103]. Pressure-flow analysis mainly assesses the amount of
mechanical obstruction caused by the urethra’s inherent mechanical and anatomical properties and has limited
value in patients with neuro-urological disorders.
Electromyography (EMG): Reflects the activity of the external urethral sphincter, the peri-urethral striated
musculature, the anal sphincter and the striated pelvic floor muscles. Correct interpretation may be difficult due
to artefacts introduced by other equipment. In the urodynamic setting, an EMG is useful as a gross indication
of the patient’s ability to control the pelvic floor. Possible pathological findings include inadequate recruitment
upon specific stimuli (e.g. bladder filling, involuntary detrusor contractions, onset of voiding, coughing, Valsalva
manoeuvre) suggesting a diagnosis of DSD [104].
Urethral pressure measurement: Has a very limited role in neuro-urological disorders. There is no
consensus on parameters indicating pathological findings [105].
Video-urodynamics: Is the combination of filling cystometry and pressure flow studys with imaging. It is the
optimum procedure for urodynamic investigation in neuro-urological disorders. Possible pathological findings
include all those described in the cystometry and the pressure flow study sections, and any morphological
pathology of the LUT and reflux to the UUT [106].
Ambulatory urodynamics: This is the functional investigation of the urinary tract, which predominantly uses the
natural filling of the urinary tract to reproduce the patient’s normal activity. Although this type of study might be
considered when conventional urodynamics does not reproduce the patient’s symptoms, its role in the neuro-
urological patient still needs to be determined [107, 108].
Triggered tests during urodynamics: Lower urinary tract function can be provoked by coughing, triggered
voiding, or anal stretch. Fast-filling cystometry with cooled saline (the ‘ice water test’) will discriminate between
upper and lower motor neuron lesions [109, 110]. Patients with UMNL develop a detrusor contraction if the
detrusor is intact, while patients with LMNL do not. However, the test does not seem to be fully discriminative
in other types of patients [111].
Previously, a positive bethanechol test [112] (detrusor contraction > 25 cm H2O) was thought to indicate
detrusor denervation hypersensitivity and the muscular integrity of an acontractile detrusor. However, in
practice, the test has given equivocal results. A variation of this method was reported using intravesical
electromotive administration of the bethanechol [113], but there was no published follow-up. Currently, there is
no indication for this test.
Recommendations LE GR
Record a bladder diary. 3 A
Non-invasive testing is mandatory before invasive urodynamics is planned. 4 A*
Perform a urodynamic investigation to detect and specify lower urinary tract (dys-)function, use 1b A
same session repeat measurement as it is crucial in clinical decision making.
Use video-urodynamics for invasive urodynamics in neuro-urological patients. If this is not 4 A*
available, then perform a filling cystometry continuing into a pressure flow study.
Use a physiological filling rate and body-warm saline. 4 A*
Specific uro-neurophysiological tests are elective procedures and should only be carried out in 4 C
specialised settings.
*Upgraded based on panel consensus.
Further considerations are the patient’s disability, cost-effectiveness, technical complexity and possible
complications [119].
Renal failure is the main mortality factor in SCI patients who survive the trauma [120, 121]. Keeping the
detrusor pressure during both the filling and voiding phases within safe limits significantly reduces the mortality
from urological causes in these patients [122-124] and has consequently become the top priority in the
treatment of patients with neuro-urological symptoms [118, 119].
In patients with high detrusor pressure during the filling phase (DO, low bladder compliance),
treatment is aimed primarily at conversion of an overactive, high-pressure bladder into a low-pressure reservoir
despite the resulting residual urine [118]. Reduction of the detrusor pressure contributes to urinary continence,
and consequently to social rehabilitation and QoL. It is also pivotal in preventing UTIs [125, 126]. Complete
continence, however, cannot always be obtained.
Bladder expression (Credé manoeuvre) and voiding by abdominal straining (Valsalva manoeuvre): The
downwards movement of the lower abdomen by suprapubic compression (Credé) or by abdominal straining
(Valsalva) leads to an increase in intravesical pressure, and generally also causes a reflex sphincter contraction
[127, 128]. The latter may increase bladder outlet resistance and lead to inefficient emptying. The high
pressures created during these procedures are hazardous for the urinary tract [129, 130]. Therefore, their use
should be discouraged unless urodynamics show that the intravesical pressure remains within safe limits [119].
Triggered reflex voiding: Stimulation of the sacral or lumbar dermatomes in patients with UMNL can elicit a
reflex detrusor contraction [130]. The risk of high pressure voiding is present and interventions to decrease
outlet resistance may be necessary [131]. Triggering can induce AD, especially in patients with high level SCI
(at or above Th 6) [132]. All assisted bladder emptying techniques require low outlet resistance. Even then, high
detrusor pressures may still be present. Hence, patients need dedicated education and close urodynamic and
urological surveillance [130, 133-135].
Note: In the literature, including some of the references cited here, the concept “reflex voiding” is sometimes
used to cover all three assisted voiding techniques described in this section.
External appliances: Social continence may be achieved by collecting urine during incontinence, for instance
using pads [119]. Condom catheters with urine collection devices are a practical method for men [119]. The
infection risk must be closely observed [119]. The penile clamp is absolutely contraindicated in case of DO
or low bladder compliance because of the risk of developing high intravesical pressure and pressure sores/
necrosis in cases of altered/absent sensations.
Peripheral temporary electrostimulation: Tibial nerve stimulation and transcutaneous electrical nerve stimulation
might be effective and safe for treating neurogenic lower urinary tract dysfunction, but more reliable evidence
from well-designed RCTs is required to reach definitive conclusions [138, 139].
Peripheral temporary electrostimulation combined with pelvic floor muscle training and biofeedback: In
MS patients, combining active neuromuscular electrical stimulation with pelvic floor muscle training and
EMG biofeedback can achieve a substantial reduction of neuro-urological symptoms [140]. This treatment
combination seems to be more effective than either therapy alone [141, 142].
Intravesical electrostimulation: Intravesical electrostimulation can increase bladder capacity and improve
bladder compliance and bladder filling sensation in patients with incomplete SCI or myelomeningocele (MMC)
[143]. In patients with neurogenic detrusor underactivity, intravesical electrostimulation may also improve
voiding and reduce residual volume [144, 145].
Repetitive transcranial magnetic stimulation: Although improvement of neuro-urological symptoms has been
described in PD and MS patients, this technique is still under investigation [146, 147].
Summary: To date, bladder rehabilitation techniques are mainly based on electrical or magnetic stimulation.
However, there is a lack of well-designed studies.
Choice of antimuscarinic agent: Oxybutynin [119, 154-157, 164], trospium [155, 162, 165], tolterodine [166]
and propiverine [155, 167] are established, effective and well tolerated treatments even in long-term use [154,
155, 168, 169]. Darifenacin [170, 171] and solifenacin [169, 172] have been evaluated in NDO secondary to SCI
and MS [155, 170, 171, 173] with results similar to other antimuscarinic drugs. A pilot study using solifenacin in
NDO due to PD showed an improvement in UI [174]. The relatively new drug, fesoterodine, an active metabolite
of tolterodine, has also been introduced, even though to date there has been no published clinical evidence of
its use in the treatment of neuro-urological disorders. Favourable results with the new drug imidafenacin have
been reported [175].
Side effects: Controlled-release antimuscarinics have some minor side effects, e.g. dry mouth [176, 177]. It has
been suggested that different ways of administration may help to reduce side effects. Moreover, imidafenacine
has been safely used in neurological patients with no worsening of cognitive function [175].
Other agents
Beta-3-adrenergic receptor agonists have recently been introduced and evaluated in OAB, but clinical
experience in neuro-urological patients is limited [178]. Studies on safety and effectiveness in NDO are ongoing
[179]. Depending on the results of these studies, combined therapy with antimuscarinics may be an attractive
option [180].
Decreasing bladder outlet resistance: α-blockers (e.g. tamsulosin, naftopidil and silodosin) seem to be effective
for decreasing bladder outlet resistance, post-void residual and AD [185-187].
Increasing bladder outlet resistance: Several drugs have shown efficacy in selected cases of mild SUI, but there
are no high-level evidence studies in neurological patients [119].
Recommendations LE GR
Use antimuscarinic therapy as the first-line medical treatment for neurogenic detrusor 1a A
overactivity.
Alternative routes of administration (i.e., transdermal or intravesical) of antimuscarinic agents 2 A
may be used.
Maximise outcomes for neurogenic detrusor overactivity by considering a combination of 3 B
antimuscarinic agents.
Prescribe α-blockers to decrease bladder outlet resistance. 1b A
Do not prescribe parasympathomimetics for underactive detrusor. 1a A
Do not prescribe drug treatment in neurogenic stress urinary incontinence. 4 A*
*Upgraded based on panel consensus.
Sterile IC cannot be considered a routine procedure [119, 191]. Aseptic IC is an alternative to sterile IC [192].
Contributing factors to contamination are insufficient patient education and the inherently greater risk of UTI in
neuro-urological patients [119, 193-197]. The average frequency of catheterisations per day is four to six times
[198] and the catheter size most often used is between 12-16 Fr. In aseptic IC, an optimum frequency of five
times showed a reduction of UTI [198]. Ideally, bladder volume at catheterisation should, as a rule, not exceed
400-500 mL.
Indwelling transurethral catheterisation and, to a lesser extent, suprapubic cystostomy are
associated with a range of complications as well as an enhanced risk for UTI [119, 199-207]. Therefore, both
procedures should be avoided, when possible. Silicone catheters are preferred as they are less susceptible to
encrustation and because of the high incidence of latex allergy in the neuro-urological patient population [208].
Recommendations LE GR
Use intermittent catheterisation, whenever possible aseptic technique, as a standard treatment 3 A
for patients who are unable to empty their bladder.
Thoroughly instruct patients in the technique and risks of intermittent catheterisation. 3 A
Use a catheter size between 12-16 Fr. 4 B*
Avoid indwelling transurethral and suprapubic catheterisation whenever possible. 3 A
*Upgraded based on panel consensus.
The vanilloids, capsaicin and resiniferatoxin, desensitise the C-fibres and thereby decrease DO, for a period
of a few months, until the sensation of these fibres has been restored [214-216]. The dosage is 1-2 mMol
capsaicin in 100 mL 30% alcohol, or 10-100 nMol resiniferatoxin in 100 mL 10% alcohol for 30 minutes.
Resiniferatoxin has about a 1,000-fold potency compared to capsaicin, with less pain during the instillation,
and is effective in a patient refractory to capsaicin. Clinical studies have shown that resiniferatoxin has limited
clinical efficacy compared to botulinum toxin A (BTX-A) injections in the detrusor [215]. Currently, there is no
indication for the use of these substances, which are not licensed for intravesical treatment.
Balloon dilatation: Favourable immediate results were reported [229], but there have been no further reports
since 1994 therefore, this method is no longer recommended.
Sphincterotomy: By staged incision, bladder outlet resistance can be reduced without completely losing the
closure function of the urethra [118, 119, 219]. Different techniques are used, and laser treatment appears to be
advantageous [230, 231]. Sphincterotomy needs to be repeated at regular intervals in many patients [232], but
it is efficient and does not cause severe adverse effects [118, 229]. Secondary narrowing of the bladder neck
may occur, for which combined bladder neck incision might be considered [233].
Bladder neck incision: This is indicated only for secondary changes at the bladder neck (fibrosis) [118, 230].
This procedure is not recommended in patients with detrusor hypertrophy, which causes thickening of the
bladder neck [118].
Stents: Implantation of urethral stents results in continence being dependent on adequate closure of the
bladder neck [119]. The results are comparable with sphincterotomy and the stenting procedure has a
shorter duration of surgery and hospital stay [234, 235]. However, the costs [118], possible complications and
re-interventions [236, 237] are limiting factors in their use [238-241].
Increasing bladder outlet resistance: This can improve the continence condition. Despite early positive results
with urethral bulking agents, a relative early loss of continence is reported in patients with neuro-urological
disorders [119, 242, 243].
Urethral inserts: Urethral plugs or valves for the management of (female) stress incontinence have not been
applied in neuro-urological patients. The experience with active pumping urethral prosthesis for treatment of
the underactive or acontractile detrusor were disappointing [244].
Recommendations LE GR
Use botulinum toxin injection in the detrusor to reduce neurogenic detrusor overactivity in 1a A
multiple sclerosis or spinal cord injury patients if antimuscarinic therapy is ineffective.
Bladder neck incision is effective in a fibrotic bladder neck. 4 B
*Recommendations for catheterisation are listed separately under Section 3.4.2.5.2.
Urethral sling: Various materials have been used for this procedure with enduring positive results. The
procedure is established in women with the ability to self-catheterise [119, 245-250]. There is growing evidence
that synthetic slings can be used effectively with acceptable medium to long-term results and minimal
morbidity in neurological patients [251, 252]. Besides the pubovaginal sling, which has been considered the
procedure of choice in this subgroup of patients, recent reports suggest that both the transobturator and the
retropubic approaches may also be considered, with similar failure rates and a reduction in the need for IC.
However, for both approaches a higher incidence of de novo urgency was reported [252, 253]. In men, both
autologous and synthetic slings may also be an alternative [251, 252, 254-256].
Artificial urinary sphincter: This device was introduced by Light and Scott [257] for patients with neuro-
urological disorders [119]. It has stood the test of time and acceptable long-term outcomes can be obtained
[258-263].
Bladder neck and urethra reconstruction: The classical Young-Dees-Leadbetter procedure [267] for bladder
neck reconstruction in children with bladder exstrophy, and Kropp urethra lengthening [268] improved by Salle
[269], are established methods to restore continence provided that IC is practiced and/or bladder augmentation
is performed [119, 270].
Continent diversion: This should be the first choice for urinary diversion. Patients with limited dexterity may
prefer a stoma instead of using the urethra for catheterisation. A continent stoma can be created using various
techniques. However, all of them have frequent complications, including leakage or stenosis. The short-term
continence rates are > 80% and good protection of the UUT is achieved [119, 319-331]. For cosmetic reasons,
the umbilicus is often used for the stoma site [326, 329, 330, 332-334].
Recommendations LE GR
Perform bladder augmentation in order to treat refractory neurogenic detrusor overactivity. 3 A
Place an autologous urethral sling in female patients with neurogenic stress urinary 4 B*
incontinence who are able to self-catheterise.
Insert an artificial urinary sphincter in male patients with neurogenic stress urinary 3 A
incontinence.
*Upgraded bases on panel consensus.
The pathogenesis of UTI in neuro-urological patients is multifactorial. Male gender seems to be a risk factor
for febrile UTI [341]. Several etiological factors have been described: altered intrinsic defence mechanisms,
impaired washout and catheterisation [342]. The exact working mechanisms, however, still remain unknown.
The presence of asymptomatic bacteriuria in SCI patients is higher than in the general population, and varies
depending on bladder management. Prevalence of bacteriuria in those performing clean IC varies from 23-89%
[343]. Sphincterotomy and condom catheter drainage has a 57% prevalence [344]. Asymptomatic bacteria
should not be routinely screened for in this population [345].
Individuals with neuro-urological symptoms, especially those with SCI, may have other signs and symptoms in
addition to or instead of traditional signs and symptoms of a UTI in able-bodied individuals. Other problems,
such as AD, may develop or worsen due to a UTI [346]. The most common signs and symptoms suspicious
of a UTI in those with neuro-urological disorders are fever, new onset or increase in incontinence, including
leaking around an indwelling catheter, increased spasticity, malaise, lethargy or sense of unease, cloudy urine
with increased urine odour, discomfort or pain over the kidney or bladder, dysuria, or AD [346, 347].
3.5.3.2 Prevention
If the improvement of bladder function and removal of foreign bodies/stones is not successful, additional UTI
prevention strategies should be utilised. The use of hydrophilic catheters was associated with a lower rate of
UTI in a recent meta-analysis [354]. Bladder irrigation has not been proven effective [355].
Various medical approaches have been tested for UTI prophylaxis in patients with neuro-urological disorders.
The benefit of cranberry juice for the prevention of UTI could not be demonstrated in RCTs [356]. Methenamine
hippurate is not effective in individuals with neuro-urological symptoms [357]. There is no sufficient evidence
to support the use of L-methionine for urine acidification to prevent recurrent UTI [358]. There is only weak
evidence that oral immunotherapy reduces bacteriuria in patients with SCI, and no evidence that recurrent UTIs
are reduced [359]. Low-dose, long-term, antibiotic prophylaxis cannot reduce UTI frequency, but increases
bacterial resistance and is therefore not recommended [351].
An application scheme of antibiotic substances for antibiotic prophylaxis provided long-term
positive results, but the results of this trial need to be confirmed in further studies [360]. Another possible future
option, the inoculation of apathogenic Escherichia coli strains into the bladder, has provided positive results in
initial studies, but because of the paucity of data [361], cannot be recommended as a treatment option.
In summary, based on the criteria of evidence-based medicine, there is currently no preventive measure
for recurrent UTI in patients with neuro-urological disorders that can be recommended without limitations.
Therefore, individualised concepts should be taken into consideration, including immunostimulation,
phytotherapy and complementary medicine [362]. Prophylaxis in patients with neuro-urological disorders is
important to pursue, but since there are no data favouring one approach over another, prophylaxis is essentially
a trial and error approach.
Recommendations LE GR
Do not screen for or treat asymptomatic bacteriuria in patients with neuro-urological disorders. 4 A*
Avoid the use of long-term antibiotics for recurrent urinary tract infections (UTIs). 2a A
In patients with recurrent UTI, optimise treatment of neuro-urological symptoms and remove 3 A
foreign bodies (e.g. stones, indwelling catheters) from the urinary tract.
In patients with neuro-urological disorders, UTI prophylaxis must be individualised since there 4 C
is no optimal prophylactic measure available.
*Upgraded based on panel consensus.
Evidence:
Phosphodiesterase type 5 inhibitors (PDE5Is) are recommended as first-line treatment in neurogenic erectile
dysfunction (ED) [363, 372]. In SCI patients, tadalafil, vardenafil and sildenafil have all improved retrograde
ejaculation and improved erectile function and satisfaction on IIEF-15. Tadalafil 10 mg was shown to be more
effective than sildenafil 50 mg. All currently available PDE5Is appear to be effective and safe, although there
are no high level evidence studies in neuro-urological patients investigating the efficacy and side effects across
different PDE5Is, dosages and formulations [373].
For MS patients two studies reported significant improvement in ED when using sildenafil and tadalafil. One
study, however, showed no improvement in ED with sildenafil.
In PD normal erectile function was described in over half of the patients using sildenafil 100 mg
and a significant improvement in IIEF-15 score was found compared to placebo. While most neuro-urological
patients require long-term therapy for ED some have a low compliance rate or stop therapy because of side
effects [374, 375], most commonly headache and flushing [372]. In addition, PDE5Is may induce relevant
hypotension in patients with tetraplegia/high-level paraplegia and multiple system atrophy [374, 375]. As a
prerequisite for successful PDE5I-therapy, some residual nerve function is required to induce erection. Since
many patients with SCI use on-demand nitrates for the treatment of AD, they must be counselled that PDE5Is
are contraindicated when using nitrate medication.
Recommendations LE GR
Prescribe oral phosphodiesterase type 5 inhibitors as first-line medical treatment in neurogenic 1b A
erectile dysfunction.
Give intracavernous injections of vasoactive drugs (alone or in combination) as second-line 3 A
medical treatment in neurogenic erectile dysfunction.
Offer mechanical devices such as vacuum devices and rings to patients with neurogenic 3 B
erectile dysfunction.
Reserve penile prostheses for selected patients with neurogenic erectile dysfunction. 4 B*
*Upgraded based on panel consensus.
Prostatic massage is safe and easy to use for obtaining semen in men with lesions above Th 10 [398]. In
several patients, vibrostimulation or transrectal electroejaculation are needed for sperm retrieval [390, 395, 399,
400]. Semen retrieval is more likely with vibrostimulation in men with lesions above Th 10 [401-403]. In men
with SCI, especially at or above Th 6, AD might occur during sexual activity and ejaculation [404, 405]; patients
at risk and fertility clinics must be informed and aware of this potentially life-threatening condition. In SCI
patients the use of oral midodrine can improve sperm retrieval at vibrostimulation [406].
In men with MS, use of disease modifying drugs during the conception phase, has not been associated with
altered pregnancy outcomes [407]. Surgical procedures, such as, microsurgical epididymal sperm aspiration
(MESA) or testicular sperm extraction (TESE), may be used if vibrostimulation and electroejaculation are not
successful [408, 409]. Pregnancy rates in patients with SCI are lower than in the general population, but since
the introduction of intracytoplasmic sperm injection (ICSI), men with SCI now have a good chance of becoming
biological fathers [410-412].
Recommendations LE GR
Perform vibrostimulation and transrectal electroejaculation for sperm retrieval in men with 3 B
spinal cord injury.
Perform microsurgical epididymal sperm aspiration, testicular sperm extraction and 3 B
intracytoplasmic sperm injection after failed vibrostimulation and/or transrectal
electroejaculation in men with spinal cord injury.
Counsel men with spinal cord injury at or above Th 6 and fertility clinics about the potentially 3 A*
life-threatening condition of autonomic dysreflexia.
*Upgraded based on panel consensus.
The use of specific drugs for sexual dysfunction is indicated to treat inadequate lubrication. Data on sildenafil
for treating female sexual dysfunction are poor and controversial [427]. Although good evidence exists that
psychological interventions are effective in the treatment of female hypoactive sexual desire disorder and
female orgasmic disorder [428], there is a lack of high-evidence level studies in the neurological population.
Neurophysiological studies have shown that women with the ability to perceive Th 11-L2 pin-prick sensations
may have psychogenic genital vasocongestion. Reflex lubrication and orgasm is more prevalent in women with
SCI who have preserved the sacral reflex arc (S2-S5), even when it has not been shown in an individual woman
that a specific level and degree of lesion is the cause of a particular sexual dysfunction. In SCI women with a
complete lesion of the sacral reflex, arousal and orgasm may be evoked through stimulation of other erogenous
zones above the level of lesions [429-431].
Sacral neuromodulation for LUT dysfunction may improve sexual function but high-evidence studies
are lacking [427].
Women with SCI reported dissatisfaction with the quality and quantity of sexuality-related
rehabilitation services and were less likely to receive sexual information than men [429, 432, 433].
Recommendation LE GR
Do not offer medical therapy for the treatment of neurogenic sexual dysfunction in women. 4 A*
*Upgraded based on panel consensus.
Although it seems that the reproductive capacity of women with SCI is only temporarily affected by SCI with
cessation of menstruation for approximately six months after SCI [435], there are no high-evidence level
studies. About 70% of sexually active women use some form of contraception after injury, but fewer women
use the birth control pill compared to before their injury [436].
Women with SCI are more likely to suffer complications during pregnancy, labour and delivery
compared to able-bodied women. Complications of labour and delivery include bladder problems, spasticity,
pressure sores, anaemia, and AD [437, 438]. Obstetric outcomes include higher rates of Caesarean sections
and an increased incidence of low birth-weight babies [436].
Epidural anaesthesia is chosen and effective for most patients with AD during labour and delivery [439, 440].
There is very little published data on women’s experience of the menopause following SCI [441]. Women with
MS who plan a pregnancy should evaluate their current drug treatment with their treating physician [442].
Clinical management should be individualised to optimise both the mother’s reproductive outcomes and MS
course [443].
Recommendation LE GR
Take a multidisciplinary approach, tailored to individual patient’s needs and preferences, in the 4 A*
management of fertility, pregnancy and delivery in women with neurological diseases.
*Upgraded based on panel consensus.
3.7 Follow-up
3.7.1 Introduction
Neuro-urological disorders are often unstable and the symptoms may vary considerably, even within a relatively
short period. Regular follow-up is therefore necessary [117].
Depending on the type of the underlying neurological pathology and the current stability of the neuro-urological
symptoms, the interval between initial investigations and control diagnostics may vary and in many cases
should not exceed one to two years. In high-risk neuro-urological patients this interval should be much shorter.
Urinalysis should be performed regularly; the frequency to be guided by patient symptoms. The UUT should
be checked by ultrasonography at regular intervals in high-risk patients; about once every six months. In these
patients, physical examination and urine laboratory should take place every year. Any significant clinical change
warrants further, specialised, investigation. However, there is a complete lack of high level evidence studies on
this topic and every recommendation must be viewed critically in each individual neuro-urological patient [117].
In addition, bladder wall thickness can be measured on ultrasonography as an additional risk assessment for
upper tract damage [444], although a ‘safe’ cut-off threshold for this has not been agreed [445]. The utility of
DMSA for follow-up of neuro-urological patients has not been fully evaluated [446].
Recommendations LE GR
Assess the upper urinary tract at regular intervals in high risk patients. 4 A*
Preform a physical examination and urine laboratory every year in high risk patients. 4 A*
Any significant clinical changes should instigate further, specialised, investigation. 4 A*
Preform urodynamic investigation as a mandatory baseline diagnostic intervention in high-risk 3 A
patients at regular intervals.
*Upgraded based on panel consensus.
3.8 Conclusions
Neuro-urological disorders have a multi-faceted pathology. They require an extensive and specific diagnosis
before one can embark on an individualised therapy, which takes into account the medical and physical
condition of the patient and the patient’s expectations about their future. The urologist can select from a
wealth of therapeutic options, each with its own pros and cons. Notwithstanding the success of any therapy
embarked upon, close surveillance is necessary for the patient’s entire life.
These Guidelines offer you expert advice on how to define the patient’s neuro-urological symptoms
as precisely as possible and how to select, together with the patient, the appropriate therapy. This last choice,
as always, is governed by the golden rule: as effective as needed, as non-invasive as possible.
4. REFERENCES
1. Schafer, W., et al. Good urodynamic practices: uroflowmetry, filling cystometry, and pressure-flow
studies. Neurourol Urodyn, 2002. 21: 261.
https://www.ncbi.nlm.nih.gov/pubmed/11948720
2. Abrams, P., et al. Reviewing the ICS 2002 terminology report: the ongoing debate. Neurourol
Urodyn, 2009. 28: 287.
https://www.ncbi.nlm.nih.gov/pubmed/19350662
5. CONFLICT OF INTEREST
All members of the EAU Neuro-urology Guidelines Panel have provided disclosure statements on all
relationships that they have that might be perceived to be a potential source of a conflict of interest. This
information is publically accessible through the EAU website: http://www.uroweb.org/guidelines/. These
Guidelines were developed with the financial support of the EAU. No external sources of funding and support
have been involved. The EAU is a non-profit organisation, and funding is limited to administrative assistance
and travel and meeting expenses. No honoraria or other reimbursements have been provided.
2. METHODS 7
2.1 Introduction 7
2.2 Review 7
2.3 Future goals 7
4. REFERENCES 58
5. CONFLICT OF INTEREST 89
The aim of the third section is to provide the practicing urologist with the most recent evidence on the
diagnosis and management of penile curvature in order to assist in their decision-making. Penile curvature is
a common urological disorder which can be congenital or acquired. Congenital curvature is briefly discussed
in these guidelines as a distinct pathology in the adult population without any other concomitant abnormality
present (such as urethral abnormalities). For paediatric congenital penile curvature, please refer to the EAU
Guidelines on Paediatric Urology, Chapter on Congenital Penile Curvature [3]. Acquired curvature is mainly due
to Peyronie’s disease but can also be due to the development of fibrosis following penile fracture.
The aim of the fourth section is to present the current evidence for the diagnosis and treatment of patients
suffering from priapism. Priapism is a pathological condition representing a true disorder of penile erection
that persists for more than four hours and beyond, or is unrelated to, sexual interest or stimulation [4]. Overall,
erections lasting up to four hours are by consensus defined as ‘prolonged’. Priapism may occur at all ages. The
incidence rate of priapism in the general population is low (0.5-0.9 cases per 100,000 person-years) [5, 6]. In
men with sickle cell disease, the prevalence of priapism is up to 3.6% in men less than eighteen years of age
[7] increasing up to 42% in men more than eighteen years of age [8-11].
The Guidelines Office of the European Association of Urology (EAU) has appointed an Expert Panel to update
previously published EAU guidelines for ED, PE, penile curvature and priapism.
It must be emphasised that clinical guidelines present the best evidence available to the experts. However,
following guidelines recommendations will not necessarily result in the best outcome. Guidelines can never
replace clinical expertise when making treatment decisions for individual patients, but rather help to focus
decisions - also taking personal values and preferences/individual circumstances of patients into account.
Guidelines are not mandates and do not and should not purport to be a legal standard of care.
The 2016 edition merged the previous EAU guidelines for ED, PE, penile curvature and priapism into one
guideline [15].
For the 2016 print, a scoping search was performed covering all areas of the guideline covering the period May
2015 to June 2016. Embase, Medline and the Cochrane Central Register of Controlled Trials (RCTs) databases
were searched, with a limitation to systematic reviews, meta-analyses or randomised controlled trials. A total
of 2,783 unique records were identified, retrieved and screened for relevance, of which 56 were selected
for inclusion. A detailed search strategy is available online: http://www.uroweb.org/guideline/male-sexual-
dysfunction/.
2.2 Review
This document was subject to peer review prior to publication in 2015.
3.1.1.1 Epidemiology
Epidemiological data have shown a high prevalence and incidence of ED worldwide. Among others, the
Massachusetts Male Aging Study (MMAS) [25] reported an overall prevalence of 52% ED in non-institutionalised
men aged 40-70 years in the Boston area; specific prevalence for minimal, moderate, and complete ED was
17.2%, 25.2%, and 9.6%, respectively. In the Cologne study of men aged 30-80 years, the prevalence of ED
was 19.2%, with a steep age-related increase from 2.3% to 53.4% [31]. The incidence rate of ED (new cases
per 1,000 men annually) was 26 in the long-term data from the MMAS study [32] and 19.2 (mean follow-up of 4.2
years) in a Dutch study [33]. In a cross-sectional real-life study among men seeking first medical help for new-
onset ED, one in four patients was younger than 40 years, with almost 50% of the young men complaining of
severe ED [34]. Differences between these studies can be explained by differences in methodology, in the ages,
and socio-economic and cultural status of the populations studied.
Epidemiological studies have also demonstrated consistent evidence for an association between lower urinary
tract symptoms (LUTS)/benign prostatic hyperplasia (BPH) and sexual dysfunction, regardless of age, other
comorbidities and various lifestyle factors [41]. The Multinational Survey on the Aging Male (MSAM-7) study -
performed in the US, France, Germany, Italy, Netherlands, Spain, and the UK - systematically investigated the
relationship between LUTS and sexual dysfunction in > 12,000 men aged 50-80 years. From the 83% of men
who self-reported to be sexually active, the overall prevalence of LUTS was 90%, with the overall prevalence
of ED being 49%, and a reported complete absence of erection in 10% of patients. Moreover, the overall
prevalence of ejaculatory disorders was 46% [42].
The most recent epidemiological data collection have also highlighted other unexpected risk factors potentially
associated with ED including psoriasis [43], ankylosing spondylitis [44], non-alcoholic fatty liver [45], and
transrectal ultrasound (TRUS)-guided prostate biopsy [46].
3.1.1.3 Pathophysiology
The pathophysiology of ED may be vasculogenic, neurogenic, anatomical, hormonal, drug-induced and/or
psychogenic (Table 1) [23].
Table 1: Pathophysiology of ED
Vasculogenic
Cardiovascular disease (hypertension, coronary artery disease, peripheral vasculopathy, etc.)
Diabetes mellitus
Hyperlipidaemia
Smoking
Major pelvic surgery (radical prostatectomy (RP)) or radiotherapy (pelvis or retroperitoneum)
Neurogenic
Central causes
Degenerative disorders (multiple sclerosis, Parkinson’s disease, multiple atrophy, etc.)
Spinal cord trauma or diseases
Stroke
Central nervous system tumours
Peripheral causes
Type 1 and 2 diabetes mellitus
Chronic renal failure
Polyneuropathy
Surgery (major surgery of pelvis/retroperitoneum)
Surgery of the urethra (urethral stricture, urethroplasty, etc.)
Anatomical or structural
Hypospadias, epispadias
Micropenis
Peyronie’s disease
Penile cancer
Phimosis
Hormonal
Hypogonadism
Hyperprolactinaemia
Hyper- and hypothyroidism
Hyper- and hypocortisolism (Cushing’s disease, etc.)
Panhypopituitarism and multiple endocrine disorders
Drug-induced
Antihypertensives (thiazide diuretics, etc.)
Antidepressants (selective serotonin reuptake inhibitors, tricyclics)
Pre-operative potency is a major factor associated with the recovery of EF after surgery [49]. Patients being
considered for nerve-sparing RP (NSRP) should ideally be potent pre-operatively [48, 49]. Overall, the
chronological aspects are of major clinical importance in terms of post-operative recovery of erectile function.
Available data confirm that post-operative erectile function recovery can also occur years following RP (up to
48 months) [57]. Likewise, it is shared opinion that the timing of post-operative therapy (any type) should be
commenced as close as possible to the surgical procedure [48, 50].
Erectile Dysfunction is also a common sequela after external beam radiotherapy and brachytherapy for PCa
[58, 59]. The mechanisms contributing to ED after prostate irradiation involve injury to the neurovascular
bundles, penile vasculature, and cavernosal structural tissue [58]. Alternative treatments for PCa including
cryotherapy and high-intensity focused ultrasound (HIFU) are also associated with equivalent or higher rates of
ED compared to surgery or radiation therapy [60, 61].
Summary of evidence LE
ED is common worldwide. 2b
ED shares common risk factors with cardiovascular disease. 2b
Lifestyle modification (regular exercise and decrease in body mass index) can improve erectile 1b
function.
ED is a symptom, not a disease. Some patients may not be properly evaluated or receive treatment for 4
an underlying disease or condition that may be causing ED.
ED is common after RP, irrespective of the surgical technique used. 2b
ED is common after external radiotherapy and brachytherapy. 2b
ED is common after cryotherapy and high-intensity focused US. 2b
A detailed description should be made of the rigidity and duration of both sexually-stimulated and morning
erections and of problems with sexual desire, arousal, ejaculation, and orgasm [63, 64]. Validated psychometric
questionnaires, such as the International Index for Erectile Function (IIEF) [65] or its short version the Sexual
Health Inventory for Men (SHIM) [66], help to assess the different sexual function domains (i.e. sexual desire,
erectile function, orgasmic function, intercourse, and overall satisfaction), as well as the potential impact of a
specific treatment modality.
Psychometric analyses also support the use of the erectile hardness score for the assessment of penile
rigidity in practice and in clinical trials research [67]. In cases of clinical depression, the use of a 2-question
scale for depression is recommended in everyday clinical practice: “During the past month have you often
been bothered by feeling down, depressed or hopeless? During the past month have you often been
bothered by little interest or pleasure, doing things?” [68]. Patients should always be screened for symptoms
of possible hypogonadism (= testosterone deficiency), including decreased energy, libido, fatigue and
cognitive impairment, as well as for LUTS. In this regard, although LUTS/BPH in itself does not represent a
contraindication to treat a patient for late onset hypogonadism, screening for LUTS severity is clinically relevant
[69].
Laboratory tests
The EAU Guidelines for diagnosing and treating men with ED have been adapted from previously published
recommendations from the Princeton Consensus conferences on sexual dysfunction and cardiac risk [83].
The Princeton Consensus (Expert Panel) Conference is dedicated to optimising sexual function and preserving
cardiovascular health [83-85]. Accordingly, patients with ED can be stratified into three cardiovascular risk
categories (Table 2), which can be used as the basis for a treatment algorithm for initiating or resuming sexual
activity (Figure 2). It is also possible for the clinician to estimate the risk of sexual activity in most patients from
their level of exercise tolerance, which can be determined when taking the patient’s history [40].
Figure 2: T
reatment algorithm for determining level of sexual activity according to cardiac risk in Erectile
Dysfunction (based on 3rd Princeton Consensus) [83]
ED confirmed
Exercise abilitya
Stress testb
Pass Fail
Advice,
Cardiologist
treat ED
a exual activity is equivalent to walking 1 mile on the flat in 20 minutes or briskly climbing two flights of stairs in
S
10 seconds.
b Sexual activity is equivalent to four minutes of the Bruce treadmill protocol.
Recommendations LE GR
Take a comprehensive medical and sexual history in every patient. 3 B
Use a validated questionnaire related to erectile dysfunction to assess all sexual function 3 B
domains and the effect of a specific treatment modality.
Include a physical examination in the initial assessment of men with erectile dysfunction (ED) to 4 B
identify underlying medical conditions that may be associated with ED.
Assess routine laboratory tests, including glucose-lipid profile and total testosterone, to identify 4 B
and treat any reversible risk factors and lifestyle factors that can be modified.
Include specific diagnostic tests in the initial evaluation only in the presence of the conditions 4 B
presented in Table 3.
The management of post-RP ED has been revolutionised by the advent of phosphodiesterase 5 inhibitors
(PDE5Is), with their demonstrated efficacy, ease of use, good tolerability, excellent safety, and positive
impact on QoL. It must be emphasised that post-RP, ED patients are poor responders to PDE5Is. However,
PDE5Is are considered as the first-line therapy in patients who have undergone nerve-sparing (NS) surgery
regardless of the surgical technique used [48, 49]. A number of clinical parameters have been identified as
potential predictors of PDE5Is in men undergoing RP. Patient age and quality of NS technique are key factors
in preserving post-RP erectile function [48, 49, 52]. The response rate to sildenafil treatment for ED after RP in
different trials has ranged from 35% to 75% among those who underwent NSRP and from 0% to 15% among
those who underwent non-NSRP [48, 94]. Early use of high-dose sildenafil after RP has been suggested to be
associated with preservation of smooth muscle within the corpora cavernosa [95]. Daily sildenafil also results in
a greater return of spontaneous normal erectile function after RP compared to placebo following bilateral NSRP
in patients who were fully potent before surgery [96]. Conversely, a recent prospective, randomised, placebo-
controlled study, which assessed the effects of nightly sildenafil citrate therapy during penile rehabilitation
using nocturnal penile rigidity in addition to the IIEF-EF, showed no therapeutic benefit for nightly sildenafil
when compared to on-demand dosing in determining recovery of erectile function post-prostatectomy [97].
The effectiveness of tadalafil and vardenafil as on-demand treatment has been evaluated in post-RP ED. A
large multicentre trial in Europe and the USA has studied tadalafil in patients with ED following bilateral NS
surgery. Erectile function was improved in 71% of patients treated with 20 mg tadalafil vs. 24% of those
treated with placebo, while the rate of successful intercourse attempts was 52% with 20 mg tadalafil vs. 26%
with placebo [98]. Similarly, vardenafil has been tested in patients with ED following NSRP in a randomised,
multicentre, prospective, placebo-controlled study in North America [99]. Following bilateral NSRP, erectile
function improved by 71% and 60% with 10 and 20 mg vardenafil, respectively. An extended analysis of
the same cohort of patients showed the benefit of vardenafil compared to placebo in terms of intercourse
satisfaction, hardness of erection, orgasmic function, and overall satisfaction with sexual experience [100].
Moreover, a randomised, double-blind, double-dummy trial in men < 68 years of age and normal pre-operative
erectile function who underwent NSRP at 50 centres from nine European countries and Canada, compared
tadalafil once daily with placebo [101]. Tadalafil was most effective for drug-assisted erectile function in men
with ED following NSRP, and data suggested a potential role for tadalafil once daily - provided early after
surgery - in contributing to the recovery of post-operative erectile function and possibly protecting penile
structural changes [101]. Unassisted erectile function was not improved after cessation of active therapy
for nine months [101]. Moreover, taking tadalafil once daily significantly shortened time to erectile function
recovery versus placebo over the nine month double/blind treatment period. Conversely tadalafil on demand
did not [102]. Likewise, tadalafil once daily improved QoL post-operatively, both at double-blind treatment and
open label treatment period [103].
Historically, the treatment options for post-RP ED have included intracavernous injections [108], urethral
microsuppository [48, 109], vacuum device therapy [48, 110], and penile implants [48, 111, 112].
Intracavernous injections
PDE5 Vacuum devices
inhibitors Intraurethral/topical
alprostadil
Testosterone supplementation is contraindicated in patients with unstable cardiac disease [69, 119].
Conversely, the role of testosterone in the cardiovascular health of men is controversial. Clinical trials
examining TS have been insufficiently powered to provide definitive and unequivocal evidence of adverse
events in terms of cardiovascular outcomes [120-125]. Current guidelines from the Endocrine Society make
no recommendations on whether patients with heart disease should be screened for hypogonadism and
do not recommend supplementing testosterone in patients with heart disease to improve survival [72].
However, a recent comprehensive SR and meta-analysis of all placebo-controlled RCTs on the effect of TS on
cardiovascular-related problems did not support a causal role between TS and adverse cardiovascular events
[119].
Sildenafil
Sildenafil was launched in 1998 and was the first PDE5I available on the market [131]. It is administered in
doses of 25, 50 and 100 mg. The recommended starting dose is 50 mg and should be adapted according to the
patient’s response and side-effects [131]. Sildenafil is effective from 30-60 minutes after administration [131].
Its efficacy is reduced after a heavy, fatty meal due to delayed absorption. Efficacy may be maintained for up
to twelve hours [132]. The pharmacokinetic data of sildenafil are presented in Table 5. Adverse events (Table 6)
are generally mild in nature and self-limited by continuous use [133, 134]. After 24 weeks in a dose-response
study, improved erections were reported by 56%, 77% and 84% of a general ED population taking 25, 50 and
100 mg sildenafil, respectively, compared to 25% of men taking placebo [135]. Sildenafil significantly improved
patient scores for IIEF, SEP2, SEP3, and General Assessment Questionnaire (GAQ) and treatment satisfaction.
The efficacy of sildenafil in almost every subgroup of patients with ED has been successfully established. (LE:
1). Recently, an orally disintegrating tablet (ODT) of sildenafil citrate at the dosage of 50 mg has been developed
mainly for the benefit of patients who have difficulty swallowing solid dosage forms.
Efficacy has been confirmed in post-marketing studies [130, 138]. The efficacy of tadalafil in almost every
subgroup of patients with ED, including difficult-to-treat subgroups (e.g. diabetes mellitus), has been
successfully established [139]. Daily tadalafil has also been licensed for the treatment of LUTS secondary to
BPH. Therefore, it is useful in patients with concomitant ED and LUTS [140].
Vardenafil
Vardenafil became commercially available in March 2003 and is effective from 30 minutes after administration
[139]. Its effect is reduced by a heavy, fatty meal (> 57% fat). 5, 10 and 20 mg doses have been approved for
on-demand treatment of ED. The recommended starting dose is 10 mg and should be adapted according to the
patient’s response and side-effects [141]. Pharmacokinetic data of vardenafil are presented in Table 5. Adverse
events (Table 6) are generally mild in nature and self-limited by continuous use [141]. After twelve weeks in a
dose-response study, improved erections were reported by 66%, 76% and 80% of a general ED population
taking 5, 10 and 20 mg vardenafil, respectively, compared with 30% of men taking placebo [141, 142]. Vardenafil
significantly improved patient scores for IIEF, SEP2, SEP3, and GAQ and treatment satisfaction. Efficacy has been
confirmed in post-marketing studies [141, 142]. The efficacy of vardenafil in almost every subgroup of patients
with ED, including difficult-to-treat subgroups (e.g. diabetes mellitus), has been successfully established. More
recently, an ODT form of vardenafil has been released [142]. Orodispersable tablet formulations offer improved
convenience over film-coated formulations and may be preferred by patients. Absorption is unrelated to food
intake and they exhibit better bio-availability compared to film-coated tablets [143]. The efficacy of vardenafil ODT
has been demonstrated in several RCTs and did not seem to differ from the regular formulation [143-145].
Avanafil
Avanafil is a highly-selective PDE5I that became commercially available in 2013 [146]. Avanafil has a high
ratio of inhibiting PDE5 as compared with other PDE subtypes allowing for the drug to be used for ED while
minimising adverse effects [147]. 50 mg, 100 mg, and 200 mg doses have been approved for on-demand
treatment of ED [146]. The recommended starting dose is 100 mg taken as needed approximately 15 to 30
minutes before sexual activity and the dosage may be adapted according to efficacy and tolerability [146, 148,
149]. In the general population with ED, the mean percentage of attempts resulting in successful intercourse
was approximately 47%, 58%, and 59% for the 50 mg, 100 mg, and 200 mg avanafil groups, respectively,
as compared with approximately 28% for placebo [146, 148]. Data from sexual attempts made within fifteen
minutes of dosing showed successful attempts in 64%, 67%, and 71% of cases, with avanafil 50, 100, and 200
mg, respectively. The maximum recommended dosing frequency is once per day. Dosage adjustments are not
warranted based on renal function, hepatic function, age or gender [148]. Pharmacokinetic data of avanafil are
presented in Table 5 [146, 148]. Adverse events are generally mild in nature (Table 6) [146, 148]. Pairwise meta-
analytic data from available studies suggested that avanafil significantly improved patient scores for IIEF, SEP2,
SEP3, and GAQ, with an evident dose-response relationship [146, 150]. Administration with food may delay the
onset of effect compared with administration in the fasting state but avanafil can be taken with or without food.
The efficacy of avanafil in many groups of patients with ED, including difficult-to-treat subgroups (e.g diabetes
mellitus), has been successfully established.
Table 5: S
ummary of the key pharmacokinetic data for the four PDE5Is currently EMA-approved to treat
ED*
Table 6: Common adverse events of the four PDE5Is currently EMA-approved to treat ED*
α-Blocker interactions
All PDE5Is show some interaction with α-blockers, which under some conditions may result in orthostatic
hypotension.
• Sildenafil labelling advises that 50 or 100 mg sildenafil should be used with caution in patients taking an
α-blocker (especially doxazosin). Hypotension is more likely to occur within four hours following treatment
with an α-blocker. A starting dose of 25 mg is recommended [133].
• Concomitant treatment with vardenafil should only be initiated if the patient has been stabilised on
his α-blocker therapy. Co-administration of vardenafil with tamsulosin is not associated with clinically
significant hypotension [139, 141, 142].
• Tadalafil is not recommended in patients taking doxazosin, but this is not the case for tamsulosin [136,
164].
• Avanafil labelling currently reports that patients should be stable on α-blocker therapy prior to initiating
avanafil. In these patients, avanafil should be initiated at the lowest dose of 50 mg. Conversely, in those
patients already taking an optimised dose of avanafil, α-blocker therapy should be initiated at the lowest
dose.
Dosage adjustment
Drugs that inhibit the CYP34A pathway will inhibit the metabolic breakdown of PDE5Is, thus increasing
PDE5Is blood levels (e.g. ketoconazole, ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone,
nelfinavir, saquinavir and telithromycin). Therefore, lower doses of PDE5Is are necessary. However, other
agents, such as rifampin, phenobarbital, phenytoin and carbamazepine, may induce CYP3A4 and enhance the
breakdown of PDE5Is, so that higher doses of PDE5Is are required. Severe kidney or hepatic dysfunction may
require dose adjustments or warnings.
Very recently, data suggested that response to sildenafil treatment was also dependent on polymorphism in the
PDE5A gene, which encodes the principal cGMP-catalyzing enzyme in the penis, regulating cGMP clearance,
and it is the primary target of sildenafil [177]. Overall, the findings of a meta-regression aimed at evaluating the
effectiveness and prognostic factors of PDE5I to treat ED showed that PDE5Is are more effective in Caucasians
than Asians, and in patients with more severe ED [178].
The combination of long-acting injectable testosterone undecanoate and tadalafil 5 mg once daily produced a
significant improvement in terms of EF of combined treatment [184]. Moreover, the improvement in EF was well
maintained, even after the cessation of treatment.
The most common adverse events are local pain (29-41%) and dizziness with possible hypotension (1.9-14%).
Penile fibrosis and priapism are very rare (< 1%). Urethral bleeding (5%) and urinary tract infections (0.2%) are
adverse events related to the mode of administration. Efficacy rates are significantly lower than intracavernous
pharmacotherapy [195]. Intraurethral pharmacotherapy is a second-line therapy and provides an alternative to
intracavernous injections in patients who prefer a less-invasive, although less-efficacious treatment.
Topical alprostadil is another way of administering alprostadil. It is a cream that includes a permeation
enhancer in order to facilitate absorption of alprostadil (200 and 300μg) through the urethral meatus [211].
Clinical data are limited. Significant improvement compared to placebo was recorded for IIEF, SEP2 and SEP3
in a broad range of patients with mild-to-severe ED [212]. Side-effects include penile erythema, penile burning
and pain. Systemic side-effects are very rare. Topical alprostadil is approved and it is only available in some
European countries.
There are two main surgical approaches for penile prosthesis implantation: penoscrotal and infrapubic
[214-217]. The penoscrotal approach provides an excellent exposure, it affords proximal crural exposure if
necessary, avoids dorsal nerve injury and permits direct visualisation of pump placement. However, with this
approach, the reservoir is blindly placed into the retropubic space, which can be a problem in patients with
a history of major pelvic surgery (mainly radical cystectomy). The infrapubic approach has the advantage
of reservoir placement under direct vision, but the implantation of the pump may be more challenging, and
patients are at a slightly increased risk of penile dorsal nerve injury. Revision surgery is associated with
decreased outcomes and may be more challenging. Regardless of the indication, prosthesis implantation
has one of the highest satisfaction rates (92-100% in patients and 91-95% in partners) among the treatment
options for ED based on appropriate consultation [48, 111, 214, 218-224]. In patients with favourable oncologic
prognosis after RP for PCa, combination surgery for treatment of ED, with the implant of a penile prosthesis,
and stress urinary incontinence (male sling or artificial urinary sphincter) is effective and durable and has an
established, definitive role to address this problem [48, 111, 225-227]. A structured psychosexual counselling
may improve sexual activities and erotic functions in both patients and their partners after penile implants [228].
3.1.4.4.1 Complications
The two main complications of penile prosthesis implantation are mechanical failure and infection. Several
technical modifications of the most commonly used 3-piece prosthesis (AMS 700CX/CXRTM and Coloplast
Alpha ITM) resulted in mechanical failure rates of < 5% after five years of follow-up [111, 229, 230]. Careful
surgical techniques with proper antibiotic prophylaxis against Gram-positive and Gram-negative bacteria
reduces infection rates to 2-3% with primary implantation in low-risk patients and in high volume centres
[231-233]. The infection rate may be further reduced to 1-2% by implanting an antibiotic-impregnated
prosthesis (AMS Inhibizone™) or hydrophilic-coated prosthesis (Coloplast Titan™) [111, 231, 234-237].
Higher-risk populations include patients undergoing revision surgery, those with impaired host defenses
Recommendations LE GR
Enact lifestyle changes and risk factor modification prior to or accompanying erectile 1a A
dysfunction (ED) treatment.
Start pro-erectile treatments at the earliest opportunity after radical prostatectomy. 1b A
Treat a curable cause of ED first, when found. 1b B
Use phosphodiesterase type 5 inhibitors (PDE5Is) as first-line therapy. 1a A
Assess all patients for inadequate/incorrect prescriptions and poor patient education, since 3 B
they are the main causes of a lack of response to PDE5Is.
Use vacuum erection devices as a first-line therapy in well-informed older patients with 4 C
infrequent sexual intercourse and comorbidity requiring non-invasive, drug-free management
of ED.
Use intracavernous injections as second-line therapy. 1b B
Use implantation of a penile prosthesis as third-line therapy. 4 C
3.1.4.6 Follow-up
Follow-up is important in order to assess efficacy and safety of the treatment provided. It is also essential to
assess patient satisfaction since successful treatment for ED goes beyond efficacy and safety. Physicians
must be aware that there is no single treatment that fits all patients or all situations as described in detail in the
previous section.
3.2.1.1 Epidemiology
The major problem in assessing the prevalence of PE is the lack of an accurate (validated) definition at the
time the surveys were conducted [243]. The highest prevalence rate of 31% (men aged 18-59 years) was
found by the USA National Health and Social Life Survey (NHSLS) study [244]. Prevalence rates were 30%
(18-29 years), 32% (30-39 years), 28% (40-49 years) and 55% (50-59 years). It is, however, unlikely that the
PE prevalence is as high as 20-30% based on the relatively low number of men who present for treatment of
PE. These high prevalence rates may be a result of the dichotomous scale (yes/no) in a single question asking
if ejaculation occurred too early, as the prevalence rates in European studies have been significantly lower
[245]. According to the four PE subtypes proposed by Waldinger et al. [246], the prevalence rates were 2.3%
(lifelong PE), 3.9% (acquired PE), 8.5% (natural variable PE) and 5.1% (premature-like ejaculatory dysfunction)
[247]. An approximately 5% prevalence of acquired PE and lifelong PE in general populations is consistent with
epidemiological data indicating that around 5% of the population have an ejaculation latency of less than 2
minutes [248].
3.2.2 Classification
There have previously been two official definitions of PE, neither of which have been universally accepted:
In the Diagnostic and Statistical Manual of Mental Disorders IV-Text Revision (DSM-IV-TR), PE is defined as a
‘persistent or recurrent ejaculation with minimal sexual stimulation before, on, or shortly after penetration and
before the person wishes it. The clinician must take into account factors that affect duration of the excitement
phase, such as age, novelty of the sexual partner or situation, and recent frequency of sexual activity’ [270]. This
DSM definition has been recently updated in the DSM V edition [271].
The International Society for Sexual Medicine (ISSM) has adopted a completely new definition of PE which
is the first evidence-based definition [272]. Premature ejaculation (lifelong and acquired) is a male sexual
dysfunction characterised by the following:
1. Ejaculation that always or nearly always occurs prior to or within about 1 minute of vaginal
penetration (lifelong PE) or a clinically significant and bothersome reduction in latency time, often to
about three minutes or less (acquired PE).
2. The inability to delay ejaculation on all or nearly all vaginal penetrations.
3. Negative personal consequences, such as distress, bother, frustration, and/or the avoidance of
sexual intimacy.
The addition of these new types may aid patient stratification, diagnosis and treatment, but their exact role
remains to be defined [274].
The most widely used tool is the PEDT. However, there is a low correlation between a diagnosis provided by
PEDT and a self-reported diagnosis. A recent study reported that only 40% of men with PEDT-diagnosed PE
and 19% of men with probable PE self-reported the condition [290]. Questionnaires are a significant step in
simplifying the methodology of PE drug studies, although further cross-cultural validation is needed [291].
Other questionnaires used to characterise PE and determine treatment effects include the PEP [281], Index of
Premature Ejaculation (IPE) [292] and Male Sexual Health Questionnaire Ejaculatory Dysfunction (MSHQ-EjD)
[293]. Currently, their role is optional in everyday clinical practice.
Recommendations LE GR
Perform the diagnosis and classification of premature ejaculation (PE) based on medical and 1a A
sexual history, which should include assessment of intravaginal ejaculatory latency time (IELT)
(self-estimated), perceived control, distress and interpersonal difficulty due to the ejaculatory
dysfunction.
Do not use stopwatch-measured IELT in clinical practice. 2a B
Do not use patient-reported outcomes in clinical practice. 3 C
Include physical examination in the initial assessment of PE to identify anatomical 3 C
abnormalities that may be associated with PE or other sexual dysfunctions, particularly erectile
dysfunction.
Do not perform routine laboratory or neurophysiological tests. They should only be directed by 3 C
specific findings from history or physical examination.
Masturbation before anticipation of sexual intercourse is a technique used by younger men. Following
masturbation, the penis is desensitised resulting in greater ejaculatory delay after the refractory period is over.
In a different approach, the man learns to recognise the signs of increased sexual arousal and how to keep his
level of sexual excitement below the intensity that elicits the ejaculatory reflex. Efficacy is similar to the ‘stop-
start’ programme [296].
Psychological factors may be associated with PE and should be addressed in treatment. These factors
mainly relate to anxiety, but could also include relationship factors [264]. The limited studies available suggest
that behavioural therapy, as well as functional sexological treatment, lead to improvement in the duration of
intercourse and sexual satisfaction [297, 298].
Overall, short-term success rates of 50-60% have been reported [297, 298], with limited evidence on the
efficacy of these behavioural therapies on IELT improvement [299]. A double-blind, randomised, crossover
3.2.4.2 Pharmacotherapy
3.2.4.2.1 Dapoxetine
Dapoxetine hydrochloride is a short-acting SSRI, with a pharmacokinetic profile suitable for on-demand
treatment for PE. It has a rapid Tmax (1.3 hours) and a short half-life (95% clearance rate after 24 hours) [304].
Dapoxetine has been investigated in 6,081 subjects to date [305]. It is approved for on-demand treatment
of PE in European countries and elsewhere, but not in the USA. Both available doses of dapoxetine (30 mg
and 60 mg) have shown 2.5- and 3.0-fold increases, respectively, in IELT overall, rising to 3.4- and 4.3-fold in
patients with baseline average IELT < 0.5 minutes [306, 307]. In RCTs, dapoxetine, 30 mg or 60 mg one to two
hours before intercourse, was effective from the first dose on IELT and increased ejaculatory control, decreased
distress, and increased satisfaction. Dapoxetine has shown a similar efficacy profile in men with lifelong and
acquired PE [307-309]. Treatment-related side-effects were dose-dependent and included nausea, diarrhoea,
headache and dizziness. Side-effects were responsible for study discontinuation in 4% (30 mg) and 10% (60
mg) of subjects [283]. There was no indication of an increased risk of suicidal ideation or suicide attempts and
little indication of withdrawal symptoms with abrupt dapoxetine cessation [310]. Moreover, dapoxetine is found
to be safer compared with other anti-depressants which are used for the treatment of PE [311].
Regarding a combination of PDE5Is with dapoxetine, the addition of dapoxetine to a given regimen of PDE5Is
may increase the risk of possible prodromal symptoms that may progress to syncope compared to both
PDE5Is inhibitors and SSRIs administered alone. Generally, when dapoxetine is co-administered with PDE5Is,
it is well tolerated, with a safety profile consistent with previous phase 3 studies of dapoxetine alone [312].
A low rate of vasovagal syncope was reported in phase 3 studies. According to the summary of product
characteristics, orthostatic vital signs (blood pressure and heart rate) must be measured prior to starting
dapoxetine. No cases of syncope were observed in a post-marketing observational study, which had identified
patients at risk for orthostatic reaction using the patient’s medical history and orthostatic testing [313].
The mechanism of action of short-acting SSRIs in PE is still speculative. Dapoxetine resembles the
antidepressant SSRIs in the following ways: the drug binds specifically to the 5-HT re-uptake transporter
at subnanomolar levels, has only a limited affinity for 5-HT receptors and is a weak antagonist of the
1A-adrenoceptors, dopamine D1 and 5-HT2B receptors. The rapid absorption of dapoxetine might lead to
an abrupt increase in extracellular 5-HT following administration that might be sufficient to overwhelm the
compensating autoregulation processes. Does the mechanism of action of short-acting SSRIs differ from that
of the conventional chronic SSRI mechanism of action? Either such agents do not cause the auto-receptor
activation and compensation reported using chronic SSRIs, or these effects occur, but they simply cannot
prevent the action of short-acting SSRIs [314].
Selective serotonin re-uptake inhibitors are used to treat mood disorders, but can delay ejaculation and are
therefore widely used ‘off-label’ for PE. As for depression, SSRIs must be given for one to two weeks to be
effective in PE [314]. Administration of chronic SSRIs causes prolonged increases in synaptic cleft serotonin,
which desensitises the 5-HT1A and 5-HT1B receptors [317]. Clomipramine, the most serotoninergic tricyclic
antidepressant, was first reported in 1973 as an effective PE treatment [318]. Selective serotonin re-uptake
inhibitors have revolutionised treatment of PE, but they have also changed our understanding of PE since
the first publication on paroxetine in 1970 [319]. Before dapoxetine, daily treatment with SSRIs was the first
choice of treatment in PE. Commonly used SSRIs include citalopram, fluoxetine, fluvoxamine, paroxetine and
sertraline, all of which have a similar pharmacological mechanism of action.
Ejaculation delay may start a few days after drug intake, but it is more evident after one to two weeks since
receptor de-sensitisation requires time to occur. Although efficacy may be maintained for several years,
tachyphylaxis (decreasing response to a drug following chronic administration) may occur after six to twelve
months [318]. Common side-effects of SSRIs include fatigue, drowsiness, yawning, nausea, vomiting, dry
mouth, diarrhoea and perspiration; which are usually mild and gradually improve after two to three weeks [274,
306]. Decreased libido, anorgasmia, anejaculation and ED have also been reported.
Because of a theoretical risk of suicidal ideation or suicide attempts, caution is suggested in prescribing SSRIs
to young adolescents with PE aged eighteen years or less, and to men with PE and a comorbid depressive
disorder, particularly when associated with suicidal ideation. Patients should be advised to avoid sudden
cessation or rapid dose reduction of daily dosed SSRIs which may be associated with a SSRI withdrawal
syndrome [283].
In one controlled trial, on-demand use of clomipramine (but not paroxetine), three to five hours before
intercourse, was reported to be efficacious, though IELT improvement was inferior compared to daily
treatment with the same drug [324]. However, on-demand treatment may be combined with an initial trial
of daily treatment or concomitant low-dose daily treatment reducing adverse effects [325, 326]. Individual
countries’ regulatory authorities strongly advise against prescribing medication for indications if the medication
in question is not licensed/approved and prescription of off-label medication may present difficulties for
physicians.
Alternatively, the condom may be removed prior to sexual intercourse and the penis washed clean of any
residual active compound. Although no significant side-effects have been reported, topical anaesthetics are
contraindicated in patients or partners with an allergy to any ingredient in the product.
An experimental aerosol formulation of lidocaine, 7.5 mg, plus prilocaine, 2.5 mg (Topical Eutectic Mixture for
Premature Ejaculation [TEMPE]), was applied five minutes before sexual intercourse in 539 males. There was
an increase in the geometric mean IELT from a baseline of 0.58 minutes to 3.17 minutes during three months of
double-blind treatment; a 3.3-fold delay in ejaculation compared with placebo (p < 0.001) [333].
3.2.4.2.3.2 Tramadol
Tramadol is a centrally acting analgesic agent that combines opioid receptor activation and re-uptake inhibition
A large, randomised, double-blind, placebo-controlled, multi-centre twelve week study was carried out to
evaluate the efficacy and safety of two doses of tramadol (62 and 89 mg) by ODT in the treatment of PE [336].
A bioequivalence study had previously been performed that demonstrated equivalence between tramadol ODT
and tramadol HCI. In patients with a history of lifelong PE and an IELT < 2 minutes, increases in the median
IELT of 0.6 minutes (1.6-fold), 1.2 minutes (2.4-fold) and 1.5 minutes (2.5-fold) were reported for placebo,
62 mg of tramadol ODT, and 89 mg of tramadol ODT, respectively. It should be noted that there was no dose-
response effect with tramadol. The tolerability during the twelve-week study period was acceptable. Several
other studies also reported that tramadol exhibits a significant dose-related efficacy and side-effects over
placebo for treatment of PE [337]. Moreover, the efficacy and safety of tramadol have been confirmed in SRs
and meta-analyses [338, 339].
Tramadol has shown a moderate beneficial effect with a similar efficacy as dapoxetine. From what is known
about the neuropharmacology of ejaculation and the mechanism of action of tramadol, the delaying effect
on ejaculation could be explained by combined CNS μ-opioid receptor stimulation and increased brain 5-HT
availability. However, efficacy and tolerability of tramadol would have to be confirmed in more patients and
longer-term.
Several open-label studies showed that PDE5Is combined with an SSRI is superior to SSRI monotherapy:
• Sildenafil combined with paroxetine improved IELT significantly and satisfaction vs. paroxetine alone
[341];
• Sildenafil combined with sertraline improved IELT and satisfaction significantly vs. sertraline alone [342];
• Sildenafil combined with paroxetine and psychological and behavioural counselling significantly improved
IELT and satisfaction in patients in whom other treatments failed [343];
• Tadalafil combined with paroxetine significantly improved IELT and satisfaction vs. paroxetine and
tadalafil alone [344];
• Finally, sildenafil combined with behavioural therapy significantly improved IELT and satisfaction vs.
behavioural therapy alone [345].
There are very limited data on the efficacy of other PDE5Is (tadalafil and vardenafil) [346, 347]. However, recent
meta-analyses demonstrated that the combined use of SSRIs and PDE5Is may be more effective compared
with SSRIs or PDE5Is monotherapy [348-350].
Summary of evidence LE
Pharmacotherapy includes either dapoxetine on demand (a short-acting SSRI that is the only 1a
approved pharmacological treatment for premature ejaculation) or other off-label antidepressants, i.e.
daily SSRIs and clomipramine, that are not amenable to on-demand dosing. With all antidepressant
treatment for premature ejaculation, recurrence is likely after treatment cessation.
Recommendations LE GR
Treat erectile dysfunction, other sexual dysfunction or genitourinary infection (e.g. prostatitis 2a B
first).
Use pharmacotherapy as first-line treatment of lifelong premature ejaculation (PE). 1a A
Use off-label topical anaesthetic agents as a viable alternative to oral treatment with selective 1b A
serotonin re-uptake inhibitor (SSRI’s).
Use tramadol on demand as a weak alternative to SSRI’s. 2a B
Do not use PDE5Is in patients with premature ejaculation without erectile dysfunction. 3 C
Use psychological/behavioural therapies in combination with pharmacological treatment in the 3 C
management of acquired PE.
Congenital penile curvature results from disproportionate development of the tunica albuginea of the corporal
bodies and is not associated with urethral malformation. In the majority of cases the curvature is ventral but it
can also be lateral and rarely dorsal.
Summary of evidence LE
Medical and sexual history are usually sufficient to establish the diagnosis of congenital penile 3
curvature. Physical examination during erection is useful for documentation of the curvature and
exclusion of other pathologies.
Surgery is the only treatment option which is deferred until after puberty and can be performed at any 3
time in adult life.
Recommendation LE GR
Use Nesbit and other plication techniques for the treatment of congenital penile curvature in 3 B
patients who undergo surgery.
3.3.2.1.2 Aetiology
The aetiology of PD is unknown. However, an insult (repetitive microvascular injury or trauma) to the tunica
albuginea is the most widely accepted hypothesis on the aetiology of the disease [370]. A prolonged
inflammatory response will result in the remodelling of connective tissue into a fibrotic plaque [370-372]. Penile
plaque formation can result in curvature which, if severe, may prevent penetrative sexual intercourse.
In addition to the physiological and functional alteration of the penis, affected men also suffer significant
distress. Validated mental health questionnaires have shown that 48% of men with Peyronie’s disease have
mild or moderate depression, sufficient to warrant medical evaluation [382].
Summary of evidence LE
Peyronie’s disease is a connective tissue disorder, characterised by the formation of a fibrotic lesion or 2b
plaque in the tunica albuginea, which leads to penile deformity.
The contribution of associated comorbidities or risk factors (e.g. diabetes, hypertension, lipid 3
abnormalities and Dupuytren’s contracture) to the pathophysiology of Peyronie’s disease is still
unclear.
Two phases of the disease can be distinguished. The first phase is the acute inflammatory phase 2b
(painful erections, ‘soft’ nodule/plaque), and the second phase is the fibrotic/calcifying phase with
formation of hard palpable plaques (disease stabilisation).
Spontaneous resolution is uncommon (3-13%) and most patients experience disease progression (30- 2a
50%) or stabilisation (47-67%). Pain is usually present during the early stages of the disease but tends
to resolve with time in 90% of men.
Major attention should be given to whether the disease is still active, as this will influence medical treatment
or the timing of surgery. Patients who are still likely to have an active disease are those with a short symptom
duration, pain during erection, or a recent change in penile curvature. Resolution of pain and stability of the
curvature for at least three months are well-accepted criteria of disease stabilisation and patients’ referral for
surgical intervention when indicated [379].
The examination should start with a routine genitourinary assessment, which is then extended to the hands and
feet for detecting possible Dupuytren’s contracture or Ledderhose scarring of the plantar fascia [380]. Penile
examination is performed to assess the presence of a palpable node or plaque. There is no correlation between
plaque size and the degree of curvature [385]. Measurement of penile length during erection is important
because it may have impact on the subsequent treatment decisions [386].
An objective assessment of penile curvature with an erection is mandatory. This can be obtained by a
home (self) photograph of a natural erection (preferably) or using a vacuum-assisted erection test or an
intracavernous injection using vasoactive agents [387]. Erectile function can be assessed using validated
instruments such as the IIEF although this has not been validated in PD patients [65]. Erectile dysfunction
is common in patients with PD (> 50%) but it is important to define whether it pre- or post-dates the onset
of Peyronie’s disease. It is mainly due to penile vascular disease [373], [385]. The presence of ED and
psychological factors may impact on the treatment strategy [388].
Ultrasound measurement of the plaque’s size is inaccurate and it is not recommended in everyday clinical
practice [389]. Doppler US may be required for the assessment of vascular parameters [388].
Summary of evidence LE
Ultrasound (US) measurement of the plaque’s size is inaccurate and operator dependent. 3
Doppler US is required to ascertain vascular parameters associated with ED. 2a
Recommendations LE GR
In the medical and sexual history of patients with Peyronie’s disease, include duration of 2b B
the disease, penile pain, change of penile deformity, difficulty in vaginal intromission due to
deformity, and erectile dysfunction.
In the physical examination, include assessment of palpable plaques, penile length, extent 2a B
of curvature (self-photograph, vacuum-assisted erection test or pharmacological-induced
erection) and any other possibly related diseases (Dupuytren’s contracture, Ledderhose
disease).
Do not use Peyronie’s disease specific questionnaire in everyday clinical practice. 2a B
Do not use ultrasound (US) measurement of plaque size in everyday clinical practice. 3 C
Use Doppler US only in the case of diagnostic evaluation of erectile dysfunction, to ascertain 2a B
vascular parameters associated with erectile dysfunction.
Oral treatments
Vitamin E
Potassium para-aminobenzoate (Potaba)
Tamoxifen
Colchicine
Acetyl esters of carnitine
Pentoxifylline
Phosphodiesterase type 5 inhibitors
Intralesional treatments
Steroids
Verapamil
Clostridium collagenase
Interferon
Topical treatments
Verapamil
Iontophoresis
Extracorporeal shockwave treatment
Traction devices
Tamoxifen
Tamoxifen is a non-steroidal oestrogen receptor antagonist modulating transforming growth factor β1 (TGF
β1) secretion by fibroblasts. Preliminary studies reported that tamoxifen (20 mg twice daily for three months)
improved penile pain, penile curvature, and reduced the size of penile plaque [400]. However, a placebo-
controlled, randomised study (in only 25 patients, at a late stage of the disease with a mean duration of twenty
months) using the same treatment protocol, failed to show any significant improvement in pain, curvature, or
plaque size in patients with PD [401].
Colchicine
Colchicine has been introduced into the treatment of PD on the basis of its anti-inflammatory effect [402].
Clinical data should be interpreted with caution since they come from only uncontrolled studies. Preliminary
results showed that half of the men given colchicine (0.6-1.2 mg daily for three to five months) found that
painful erections and penile curvature improved, while penile plaque decreased or disappeared in 50% of 24
men [403]. In another study in 60 men (colchicine 0.5-1 mg daily for three to five months with escalation to
2 mg twice daily), penile pain resolved in 95% and penile curvature improved in 30% [402]. Similar results have
been reported in another uncontrolled retrospective study in 118 patients [404]. Reported treatment-related
adverse events with colchicine are gastrointestinal effects (nausea, vomiting, diarrhoea) that can be improved
with dose escalation [402].
The combination of vitamin E and colchicine (600 mg/day and 1 mg every twelve hours, respectively for six
months) in patients with early-stage PD resulted in significant improvement in plaque size and curvature, but
not in pain compared to ibuprofen 400 mg/day for six months [405].
Finally, the combination of intralesional verapamil (10 mg weekly for ten weeks) with propionyl-l-carnitine (2 g/
day for three months) significantly reduced penile curvature, plaque size, and disease progression compared to
intralesional verapamil combined with tamoxifen (40 mg/day) for three months [407].
Pentoxifylline
Pentoxifylline is a non-specific phosphodiesterase inhibitor which down-regulates TGF β1 and increases
fibrinolytic activity [408]. Moreover, an increase of NO levels may be effective in preventing progression of PD
Steroids
Intralesional steroids are thought to act by opposing the inflammatory milieu responsible for Peyronie’s plaque
progression via inhibition of phospholipase A2, suppression of the immune response and by decreasing
collagen synthesis [413]. In small, non-randomised studies, a decrease in penile plaque size and pain resolution
was reported [414, 415]. In the only single-blind, placebo-controlled study with intralesional administration
of betamethasone, no statistically significant changes in penile deformity, penile plaque size, and penile
pain during erection were reported [416]. Adverse effects include tissue atrophy, thinning of the skin and
immunosuppression [414].
Verapamil
The rationale for intralesional use of verapamil (a calcium channel antagonist) in patients with Peyronie’s
disease is based on in-vitro research [417, 418]. A number of studies have reported that intralesional verapamil
injection may induce a significant reduction in penile curvature and plaque volume [419-423]. These findings
suggested that intralesional verapamil injections could be advocated for the treatment of non-calcified acute
phase or chronic plaques to stabilise disease progression or possibly reduce penile deformity, although
large scale, placebo-controlled trials have not yet been conducted [422]. Side-effects are uncommon (4%).
Minor side-effects include nausea, light-headedness, penile pain, and ecchymosis [422]. However, in the only
randomised, placebo-controlled study, no statistically significant differences on plaque size, penile curvature,
penile pain during erection or plaque ‘softening’ were reported [424]. Younger age and larger baseline penile
curvature were found to be predictive of favourable curvature outcomes in a case-series study [425].
Clostridium collagenase
Clostridium collagenase (CCH) is a chromatographically purified bacterial enzyme that selectively attacks
collagen, which is known to be the primary component of the PD plaque [426-428]. Clostridium collagenase
is now approved by the FDA for PD in adult men with a palpable plaque and a curvature deformity of at least
30° at the start of therapy. Findings from two independent, double-blind, placebo controlled studies, reveal the
efficacy and tolerability of CCH for improving the co-primary outcomes of physical penile curvature and the
psychological subject reported PD symptom bother domain of the PDQ in adults with PD. Participants were
given up to four treatment cycles of CCH or placebo and were then followed for 52 weeks. Overall, of the 551
treated men with CCH 60.8% were global responders compared with 29.5% of the 281 patients who received
the placebo. The most commonly reported side-effects were penile pain, penile swelling, and ecchymosis at
the site of injection [427]. The data from these two large RCTs were analysed by subgroups including: baseline
penile curvature deformity, PD duration, degree of penile calcification, and baseline erectile function severity
with better results in patients with less than 60º of curvature, more than two years of evolution, no calcification
in the plaque and good erectile function [429].
Clostridium collagenase was approved by the EMA in 2014 specifying that CCH should be
administered by a healthcare professional who is experienced in the treatment of male urological diseases.
The Risk Management Plan (RMP) requires participating healthcare professionals to be certified within the
programme by enrolling and completing training in the administration of CCH treatment for PD [430].
Interferon
Interferon α-2b has been shown to decrease fibroblast proliferation, extracellular matrix production and
collagen production from fibroblasts and improve the wound healing process from PD plaques in-vitro [432].
Intralesional injections (5 x 106 units of interferon α-2b in 10 mL saline, two times per week for twelve weeks)
significantly improved penile curvature, plaque size and density, and pain compared to placebo [433, 434].
Side-effects include myalgias, arthralgia, sinusitis, fever and flu-like symptoms. They can be effectively treated
with non-steroidal anti-inflammatory drugs before interferon injection.
Hyaluronic Acid
In a prospective, single-arm, multicentre pilot study, 65 patients underwent a ten week cycle of weekly
intraplaque injections with hyaluronic acid. Plaque size significantly decreased, penile curvature decreased in
37%, as well as overall sexual satisfaction and seems preferably indicated in the early (active) phase of the
disease [435].
H-100 Gel
H-100 Gel is composed of nicardipine, superoxide dismutase and emu oil. Twenty-two patients (PD twelve
months duration) were studied in a prospective randomised, double-blind, placebo-controlled study. H-100
showed significant improvement in all PD parameters at six months: mean stretched penile length increase
(22.6%, P = 0.0002), mean curvature reduction (40.8%, P = 0.0014), and mean pain level reduction (85.7%,
P = 0.004). Placebo group showed no significant improvement except for mean stretched penile length
increase (6.8%, P = 0.009). Crossover patients from placebo to H-100 showed significant improvement in all
parameters: mean stretched penile length increase (17.5%, P = 0.000007), mean curvature reduction (37.1%,
P = 0.006), and mean pain level reduction (40%, P = 0.17). Treatment was well tolerated. A self-limited rash
was the only side-effect in three patients. Statistically significant improvements in flaccid-stretched penile
length, curvature and pain suggest that H-100 is a safe and possibly effective non-invasive, topically applied
treatment for acute phase PD [439].
Traction devices
The application of continuous traction in Dupuytren’s contracture increases the activity of degradative enzymes
[445]. This initially leads to a loss of tensile strength and ultimately to solubilisation. It is followed by an increase
in newly synthesised collagen [445]. This concept has been applied in an uncontrolled study, including ten
patients with Peyronie’s disease. The FastSize Penile Extender was applied as the only treatment for two to
eight hours per day for six months [111]. Reduced penile curvature of 10-40° was found in all men with an
In another prospective study, there was a significant reduction in penile curvature (mean 20° reduction). Erectile
function and erection hardness also improved significantly. The percentage of patients who were not able to
achieve penetration decreased from 62% to 20% (p < 0.03). Importantly, the need for surgery was reduced in
40% of patients who would otherwise have been candidates for surgery and simplified the complexity of the
surgical procedure (from grafting to plication) in one in three patients [446].
3.3.2.3.1.4 Summary of evidence and recommendations for non-operative treatment of Peyronie’s disease
Summary of evidence LE
Conservative treatment for PD is primarily aimed at treating patients in the early stage of the disease. 3
Oral treatment with potassium para-aminobenzoate may result in a significant reduction in penile 1b
plaque size and penile pain as well as penile curvature stabilisation.
Intralesional treatment with verapamil may induce a significant reduction in penile curvature and 1b
plaque volume.
Intralesional treatment with CCH showed significant decreases in the deviation angle, plaque width 1b
and plaque length.
Intralesional treatment with interferon may improve penile curvature, plaque size and density, and pain. 1b
Topical verapamil gel 15% may improve penile curvature and plaque size. 1b
Iontophoresis with verapamil 5 mg and dexamethasone 8 mg may improve penile curvature and 1b
plaque size.
Extracorporeal shockwave treatment does not improve penile curvature and plaque size, but it may be 1b
offered for penile pain.
Intralesional treatment with steroids is not associated with significant reduction in penile curvature, 2b
plaque size or penile pain.
Recommendations LE GR
Use conservative treatment in patients not fit for surgery or when surgery is not acceptable to 3 C
the patient.
Do not use extracorporeal shockwave treatment to improve penile curvature and reduce 1b C
plaque size.
Use penile traction devices and vacuum devices to reduce penile deformity and increase penile 2b C
length.
Do not use intralesional treatment with steroids to reduce penile curvature, plaque size or pain. 1b B
Do not use oral treatment with vitamin E and tamoxifen for significant reduction in penile 2b B
curvature or plaque size.
Do not offer other oral treatments (acetyl esters of carnitine, pentoxifylline, colchicine). 3 C
The potential aims and risks of surgery should be discussed with the patient so that he can make an informed
decision. Specific issues that should be mentioned during this discussion are the risks of penile shortening, ED,
penile numbness, the risk of recurrent curvature, the potential for palpation of knots and stitches underneath
the skin, and the potential need for circumcision at the time of surgery [378]. Two major types of repair may be
considered for both congenital penile curvature and PD: penile shortening and penile lengthening procedures
[448].
Selection of the most appropriate surgical intervention is based on penile length assessment, curvature severity
and erectile function status, including response to pharmacotherapy in cases of ED [378]. Patient expectations
from surgery must also be included in the pre-operative assessment. There are no standardised questionnaires
for the evaluation of surgical outcomes [90]. Data from well-designed prospective studies are scarce, with a low
level of evidence. Most data are mainly based on retrospective studies, typically non-comparative and non-
randomised, or on expert opinion [378, 451].
Plication procedures are based on the same principle as the Nesbit operation but are simpler to perform.
Many of them have been described as Nesbit modifications in the older literature. They are based on single or
multiple longitudinal incisions on the convex side of the penis closed in a horizontal way, applying the Heineke-
Miculicz principle, or plication is performed without making an incision [458-463]. Another modification has
been described as the ‘16 dot’ technique with minimal tension under local anaesthesia [464]. The use of non-
absorbable sutures reduced recurrence of the curvature. Results and satisfaction rates are similar to the Nesbit
procedure [448]. However, numerous different modifications have been described and the level of evidence is
not sufficient to recommend one method over the other.
Devine and Horton introduced dermal grafting in 1974 [466]. Since then, a variety of grafting materials and
techniques have been reported (Table 10) [467-481]. Unfortunately, the ideal material for grafting has yet to be
identified. In addition, grafting procedures are associated with ED rates as high as 25%. Despite excellent initial
surgical results, graft contracture and long-term failures resulted in a 17% re-operation rate [482].
Vein grafts have the theoretical advantage of endothelial-to-endothelial contact when grafted to underlying
cavernosal tissue. The Saphenous vein is the most common vein draft used, followed by dorsal penile vein
[448]. In the first case, a secondary incision for graft harvesting is avoided. Post-operative curvature (20%),
penile shortening (17%) and graft herniation (5%) have been reported after vein graft surgery [472, 477,
480]. Tunica vaginalis is relatively avascular, easy to harvest and has little tendency to contract due to its low
metabolic requirements [470].
Dermal grafts are commonly associated with contracture resulting in recurrent penile curvature (35%),
progressive shortening (40%), and a 17% re-operation rate at ten years [483]. Cadaveric pericardium
(Tutoplast®) offers good results by coupling excellent tensile strength and multi-directional elasticity/expansion
Small intestinal submucosa (SIS, a collagen-based xenogenic graft derived from the submucosal layer of the
porcine small intestine) has been shown to promote tissue-specific regeneration, and supports the growth of
endothelial cells. Small intestinal submucosa acts as a scaffold to promote angiogenesis, host cell migration
and differentiation, resulting in tissue structurally and functionally similar to the original. It has been used
successfully to repair severe chordee and Peyronie’s disease, without significant contraction or histological
alterations, but data are limited [478].
More recently the use of buccal mucosa grafts (BMG) has been advocated. Buccal mucosa grafts provided
excellent short-term results, suggested by the fast return of spontaneous erections and prevented shrinkage,
which is the main cause of graft failure. It also proved to be safe and reproducible, thus representing a valuable
treatment option for PD [469].
Grafting by collagen fleece (TachoSil®) in PD is feasible and promising. Major advantages are decreased
operative times and easy application. Moreover, an additional haemostatic effect is provided [484].
Tunical incision, preferably with grafting, offers an excellent surgical option for men with curvatures over 60o
as well as patients with an hour-glass deformity and good erectile function that are willing to risk a higher
rate of post-operative ED [485]. The presence of pre-operative ED, the use of larger grafts, age more than
60 years, and ventral curvature are considered poor prognostic factors for functional outcome after grafting
surgery [450]. Although the risk for penile shortening is significantly less compared to the Nesbit or plication
procedures, it is still an issue and patients must be informed accordingly [448]. The use of geometric principles
introduced by Egydio helps to determine the exact site of the incision, and the shape and size of the defect to
be grafted [471].
The use of a penile extender device on an eight to twelve hour daily regimen has been advocated as an
effective and safe treatment for loss of penile length in patients operated on for PD [486].
Autologous grafts
Dermis
Vein grafts
Tunica albuginea
Tunica vaginalis
Temporalis fascia
Buccal mucosa
Allografts
Cadaveric pericardium
Cadaveric fascia lata
Cadaveric dura matter
Cadaveric dermis
Xenografts
Porcine small intestinal submucosa
Bovine pericardium
Porcine dermis
Synthetic grafts
Gore-Tex®
Dacron®
Collagen fleece (TachoSil®)
Most patients with mild-to-moderate curvature can expect an excellent outcome simply by cylinder insertion.
In cases of severe deformity, intra-operative ‘modelling’ of the penis over the inflated cylinders (manually
bent on the opposite side of the curvature for 90 seconds, often accompanied by an audible crack) has
been introduced as an effective treatment [487, 488]. If there is a residual curvature of less than 30o, no
further treatment is recommended, as the prosthesis will act as a tissue expander and will result in complete
correction of curvature after a few months of cycling the prosthesis [487]. While this technique is effective in
most patients, a Nesbit/plication procedure or plaque excision/incision and grafting may be required in order to
achieve adequate straightening [489-491].
The risk of complications (infection, malformation, etc.) is not increased compared to the general population.
However, a small risk of urethral perforation (3%) has been reported in patients with ‘modelling’ over the
inflated prosthesis [488].
In selected cases of end-stage PD with ED and significant penile shortening, a lengthening procedure, which
involves simultaneous PP implantation and penile length restoration, such as the ‘sliding’ technique, can be
considered but only in the hands of experienced high-volume surgeons [492].
Table 10: R
esults of surgical treatments for Peyronie’s disease (data from different, non-comparable
studies) [453, 455-481, 483, 485]
Treatment algorithm
The decision on the most appropriate surgical procedure to correct penile curvature is based on pre-operative
assessment of penile length, the degree of the curvature and erectile function status. If the degree of curvature
is less than 60o, penile shortening is acceptable and the Nesbit or plication procedures are usually the method
of choice. This is typically the case for congenital penile curvature. If the degree of curvature is over 60o
or is a complex curvature, or if the penis is significantly shortened in patients with a good erectile function
(with or without pharmacological treatment), then a grafting procedure is feasible. If there is ED, which is
not responding to pharmacological treatment, the best option is the implantation of an inflatable PP, with or
without an associated procedure over the penis (modelling, plication or even grafting plus the prosthesis). The
treatment algorithm is presented in Figure 5.
The results of the different surgical approaches are presented in Table 10. It must be emphasised that there
are no RCTs available addressing surgery in PD. The risk of ED seems to be greater for penile lengthening
procedures [378, 448]. Recurrent curvature implies either failure to wait until the disease has stabilised, a
re-activation of the condition following the development of stable disease, or the use of re-absorbable sutures
that lose their strength before fibrosis has resulted in acceptable strength of the repair [120]. Accordingly, it is
recommended that only non-absorbable sutures or slowly re-absorbed absorbable sutures be used. Although
with non-absorbable sutures, the knot should be buried to avoid troublesome irritation of the penile skin but
this issue may be alleviated by the use of slowly re-absorbed absorbable sutures [455]. Penile numbness is
a potential risk of any surgical procedure involving mobilisation of the dorsal neurovascular bundle. This will
usually be a neuropraxia, due to bruising of the dorsal sensory nerves. Given that the usual deformity is a
dorsal deformity, the procedure most likely to induce this complication is a lengthening (grafting) procedure
[448].
Recommendations LE GR
Perform surgery only when Peyronie’s disease has been stable for at least three months 3 C
(without pain or deformity deterioration), which is usually the case after twelve months from the
onset of symptoms, and intercourse is compromised due to deformity.
Prior to surgery, assess penile length, curvature severity, erectile function (including response 3 C
to pharmacotherapy in case of erectile dysfunction) and patient expectations.
Use tunical shortening procedures, especially plication techniques as the first treatment 2b B
option for congenital penile curvature and for Peyronie’s disease with adequate penile length,
curvature < 60° and absence of special deformities (hour-glass, hinge).
Use grafting techniques for patients with Peyronie’s disease and normal erectile function, with 2b B
no adequate penile length, curvature > 60º and presence of special deformities (hour-glass,
hinge).
Use penile prosthesis implantation, with or without any additional procedure (modelling, 2b B
plication or grafting), in Peyronie’s disease patients with erectile dysfunction not responding to
pharmacotherapy.
3.4 Priapism
3.4.1 Ischaemic (Low-Flow or Veno-Occlusive) Priapism
3.4.1.1 Epidemiology/aetiology/pathophysiology
Ischaemic priapism is the most common form of priapism, accounting for more than 95% of all priapism
episodes [493, 494]. It is usually painful, with a rigid erection characterised clinically by absent or reduced
intracavernous arterial inflow (often proximally there is a compensated high velocity picture with little flow
distally). In ischaemic priapism, there are time-dependent alterations in the corporal metabolic environment,
progressively leading to hypoxia, hypercapnia, glucopenia and acidosis [495].
Ischaemic priapism beyond four hours is considered the same as a compartment syndrome, characterised by
supraphysiological pressure within the closed space of the corpora cavernosa, which severely compromises
cavernous circulation. Emergency medical intervention is required to minimise potential irreversible
consequences, such as smooth muscle necrosis, corporal fibrosis and permanent ED [496, 497]. The duration
of priapism represents the most significant predictor for the development of ED. In this context, interventions
beyond 48-72 hours of onset may help to relieve the erection and pain, but have little benefit in preventing
long-term ED.
Histologically, by twelve hours, corporal smooth muscle biopsies show interstitial oedema, progressing to
destruction of the sinusoidal endothelium, exposure of the basement membrane and thrombocyte adherence
at 24 hours. At 48 hours, thrombi can be found in the sinusoidal spaces and smooth muscle necrosis with
fibroblast-like cell transformation is evident [422]. In terms of the pathophysiology (Table 11), no specific
cause can be identified in the majority of cases [494, 498]. However, ischaemic priapism can be associated
with sickle cell disease, haematological dyscrasias, neoplastic syndromes, and with the use of a number
of pharmacological agents. Ischaemic priapism may occur (0.4-35%) after intracavernous injections of
erectogenic agents [194, 494, 496, 499, 500]. The risk is highest with papaverine-based combinations, while
the risk of priapism is < 1% following prostaglandin E1 injection [501].
Since their introduction on the market, a few cases of priapism have been described in men who have taken
PDE5Is [494]. Most of these men however, had other risk factors for priapism, and it is unclear whether PDE5Is
alone can cause ischaemic priapism [494]. Since most men who experienced priapism following PDE5I use had
additional risk factors for ischaemic priapism, PDE5I use is usually not regarded a risk factor in itself. Sickle cell
disease is the most common cause in childhood, accounting for 63% of the cases. It is the primary aetiology
in 23% of adult cases [501], with a lifetime probability of developing ischaemic priapism of 29-42% in men
with sickle cell disease [501-503] (LE: 4). Mechanisms of sickle cell disease associated priapism may involve
dysfunctional NO synthase and Rho-associated protein kinase (ROCK) signaling, and increased oxidative
stress associated with nicotinamide adenine dinucleotide phosphate (NADPH) oxidase mediated signaling
[504].
Priapism in children is extremely rare and is most commonly related to malignancy, haematological or
otherwise. The investigative focus should be on identifying any underlying causes.
Partial priapism, or idiopathic partial segmental thrombosis of the corpus cavemosum, is a very rare condition.
It is an often classified as subtype of priapism limited to a single crura but ischaemia does not develop, rather
it is a thrombus within the corpus. Its aetiology is unknown, but bicycle riding, trauma, drug usage, sexual
intercourse, haematological diseases and a-blockers have been associated with partial priapism [506]. There
may be a congenital web in the corpora which poses a risk factor [507].
Idiopathic
Haematological dyscrasias (sickle cell disease, thalassemia, leukaemia; multiple myeloma, Hb Olmsted
variant, fat emboli during hyperalimentation, haemodialysis, glucose-6-phosphate dehydrogenase deficiency,
Factor V Leiden mutation)
Infections (toxin-mediated) (i.e. scorpion sting, spider bite, rabies, malaria)
Metabolic disorders (i.e. amyloidosis, Fabry’s disease, gout)
Neurogenic disorders (i.e. syphilis, spinal cord injury, cauda equina syndrome, autonomic neuropathy, lumbar
disc herniation, spinal stenosis, cerebrovascular accident, brain tumour, spinal anaesthesia)
Neoplasms (metastatic or regional infiltration) (i.e. prostate, urethra, testis, bladder, rectal, lung, kidney)
Medications
- Vasoactive erectile agents (i.e. papaverine, phentolamine, prostaglandin E1/alprostadil, combination of
intracavernous therapies)
- α-adrenergic receptor antagonists (i.e. prazosin, terazosin, doxazosin, tamsulosin)
- Anti-anxiety agents (hydroxyzine)
- Anticoagulants (heparin, warfarin)
- Antidepressants and antipsychotics (i.e. trazodone, bupropion, fluoxetine, sertraline, lithium, clozapine,
risperidone, olanzapine, chlorpromazine, thiorizadine, phenothiazines)
- Antihypertensives (i.e. hydralazine, guanethidine, propranolol)
- Hormones (i.e. gonadotropin-releasing hormone, testosterone)
- Recreational drugs (i.e. alcohol, marijuana, cocaine [intranasal and topical], crack, cocaine)
3.4.1.1.1 Summary of evidence on the epidemiology, aetiology and pathophysiology of ischaemic priapism
Summary of evidence LE
Ischaemic priapism is most common, accounting for more than 95% of all cases. 1b
Ischaemic priapism is identified as idiopathic in the vast majority of patients, while sickle cell anaemia 1b
is the most common cause in childhood.
Ischaemic priapism occurs relatively often (up to 35%) after intracavernous injections of papaverine 2a
based combinations, while it is rare (< 1%) after prostaglandin E1 monotherapy.
Priapism is rare in men who have taken PDE5Is with only sporadic cases reported. 1a
3.4.1.2 Classification
Ischaemic priapism is a persistent erection marked by rigidity of the corpora cavernosa and by little or no
cavernous arterial inflow [494]. The patient typically complains of penile pain and examination reveals a rigid
erection. Resolution of ischaemic priapism is characterised by return to a flaccid non-painful state. However, in
many cases, persistent penile oedema, ecchymosis and partial erections can occur and may mimic unresolved
priapism. The partial erections may reflect reactive hyperaemia and are sometimes misdiagnosed as persistent
priapism. When left untreated, resolution may take days and ED invariably results.
Prolonged erection
For > 4 hours
Ischaemic High-flow
priapism priapism
Penile Penile
Penile Penile
History blood gas History blood gas
Doppler US Doppler US
analysis analysis
Normal arterial
Perineal or
Dark blood; Bright red flow and
Sluggish or penile trauma;
Painful, rigid hypoxia, blood; may show
non-existent painless,
erection hypercapnia arterial blood turbulent flow
blood flow fluctuating
and acidosis gas values at the site of
erection
a fistula
3.4.1.3.1 History
Taking a comprehensive history is the mainstay in priapism diagnosis [494, 508]. The medical history must
include asking about a history of sickle cell disease or any other haematological abnormality [9, 509] and a
history of pelvic, genital or perineal trauma. The sexual history must include complete details of the duration
of the erection, the presence and degree of pain, prior medical drug use, any previous history of priapism and
erectile function prior to the last priapism episode (Table 12). The history can help to determine the underlying
subtype of priapism (Table 13). Ischaemic priapism is classically associated with progressive penile pain and
the erection is rigid.
Table 12: Key points in taking the history of priapism (adapted from Broderick et al. [494])
Duration of erection
Presence and degree of pain
Previous episodes of priapism and method of treatment
Current erectile function, especially the use of any erectogenic therapies prescription or nutritional supplements
Medications and recreational drugs
Sickle cell disease, haemoglobinopathies, hypercoagulable states
Trauma to the pelvis, perineum, or penis
Blood aspiration from the corpora cavernosa shows dark ischaemic blood (Table 13) (LE: 2b). Blood gas
analysis is essential to differentiate between ischaemic and arterial priapism (Table 14). Further laboratory
Examination of the penile shaft and perineum is recommended. In ischaemic priapism there will be an absence
of blood flow in the cavernous arteries. The return of the cavernous artery waveform will result in successful
detumescence [494, 512, 513]. After aspiration, a reactive hyperaemia may develop with a high arterial flow
proximally that may mislead the diagnosis as arterial priapism.
The role of MRI in the diagnostic evaluation of priapism is controversial. It may be helpful in cases of ischaemic
priapism to assess the viability of the corpora cavernosa and the presence of penile fibrosis. In a prospective
study in 38 patients with ischaemic priapism, the sensitivity of MRI in predicting non-viable smooth muscle
was 100%, as confirmed by corporal biopsy [514]. In this study, all patients with viable smooth muscle on MRI
maintained erectile function on clinical follow-up (LE: 3).
Table 13: Key findings in priapism (adapted from Broderick et al. [494])
Table 14: Typical blood gas values (adapted from Broderick et al. [494])
Recommendations GR
Take a comprehensive history for diagnosis which can help to determine the underlying type of B
priapism.
Include physical examination of the genitalia, the perineum and the abdomen in the diagnostic B
evaluation.
For laboratory testing, include complete blood count, white blood count with blood cell differential, B
platelet count and coagulation profile. Direct further laboratory testing by history, clinical and
laboratory findings. In children with priapism, perform a complete evaluation of all possible causes.
Analyse blood gas of blood aspirated from the penis for the differentiation between ischaemic and B
arterial priapism.
Perform colour duplex ultrasound of the penis and perineum for the differentiation between ischaemic B
and arterial priapism as an alternative or adjunct to blood gas analysis.
In cases of prolonged ischaemic priapism, use magnetic resonance imaging of the penis to predict B
smooth muscle viability and confirm erectile function restoration.
Perform selected pudendal arteriogram when embolisation is planned for the management of arterial B
priapism.
The treatment is sequential and the physician should move on to the next stage if the treatment fails.
Cavernosal irrigation
• Irrigate with 0.90% w/v saline solution
Intracavernosal therapy
• Inject intracavernosal adrenoceptor agonist
• Current first-line therapy is phenylephrine* with aliquots of 200 µg being injected every
3-5 minutes until detumescence is achieved (Maximum dose of phenylephrine is 1mg
within 1 hour)*
Surgical therapy
• Surgical shunting
• Consider primary penile implantation if priapism has been present for more than 36 hours
(*) T
he dose of phenylephrine should be reduced in children. It can result in significant hypertension and should
be used with caution in men with cardiovascular disease and monitoring of pulse, blood pressure and
electrocardiogram (ECG) is advisable in all patients during administration and for 60 minutes afterwards. Its
use is contraindicated in men with a history of cerebro-vascular disease and significant hypertension.
Some clinicians use two angiocatheters or butterfly needles at the same time to accelerate drainage, as well as
aspirating and irrigating simultaneously with a saline solution [502] (LE: 4). Aspiration should be continued until
fresh red, oxygenated, blood is aspirated (LE: 4).
This approach has up to a 30% chance of resolving the priapism. There are insufficient data to determine
whether aspiration followed by saline intracorporeal irrigation is more effective than aspiration alone (LE: 4).
3.4.1.4.1.3 Aspiration ± irrigation with 0.90% w/v saline solution in combination with intracavernous injection of
pharmacological agents.
This combination is currently considered the standard of care in the treatment of ischaemic priapism [4, 494,
516] (LE: 4). Pharmacological agents include sympathomimetic drugs or α-adrenergic agonists. Options
for intracavernous sympathomimetic agents include phenylephrine, etilephrine, ephedrine, epinephrine,
norepinephrine and metaraminol with a resolution rate of up to 80%. [494, 516-524] (LE: 2b). The use of
intracavernous adrenaline injection alone has also been sporadically reported [525].
Phenylephrine
Phenylephrine is currently the drug of choice due to its high selectivity for the α-1-adrenergic receptor, without
concomitant β-mediated inotropic and chronotropic cardiac effects [517, 521, 522] (LE: 4).
Phenylephrine is diluted in normal saline to a concentration of 100-500 μg/mL. Usually 200 μg are given every
three to five minutes directly into the corpus cavernosum. Maximum dosage is 1 mg within one hour (LE: 4). A
lower concentration or volume is applicable for children and patients with severe cardiovascular disease (LE: 4).
Phenylephrine use has potential cardiovascular side-effects [494, 516-518, 521, 522] and it is recommended
that blood pressure and pulse are monitored every fifteen minutes for an hour after the injection. This is
particularly important in older men with existing cardiovascular diseases. After injection, the puncture site
should be compressed and the corpora cavernosa massaged to facilitate drug distribution.
Etilephrine
Etilephrine is the second most widely used sympathomimetic agent, administered by intracavernous injection
at a concentration of 2.5 mg in 1-2 mL normal saline [518] (LE: 3).
Methylene blue
Methylene blue is a guanylate cyclase inhibitor, which may be a potential inhibitor of endothelial-mediated
cavernous relaxation. It has therefore been suggested for treating short-term pharmacologically induced
priapism [526, 527] (LE: 3). Methylene blue, 50-100 mg [526], should be injected intracavernously and left for
five minutes. It is then aspirated and the penis compressed for an additional five minutes [527]. Treatment-
related side-effects include a transient burning sensation and blue discolouration of the penis.
Oral terbutaline
Oral terbutaline is a β-2-agonist with minor β-1 effects and some α-agonist activity. A dose of 5 mg has been
suggested to treat prolonged erections lasting more than 2.5 hours, after intracavernous injection of vasoactive
agents, although the mechanism of action is not yet fully understood [528-530] (LE: 1b). Its main use is in the
prevention of recurrent episodes of prolonged erection. Terbutaline should be given cautiously in patients with
coronary artery disease, increased intravascular fluid volume, oedema and hypokalaemia [530].
However, as with other haematological disorders, other therapeutic practices may also need to be implemented
[531, 533, 534]. Specific measures for sickle cell disease related priapism include intravenous hydration and
parental narcotic analgesia while preparing the patient for aspiration and irrigation. In addition, supplemental
oxygen administration and alkalinisation with bicarbonate can be helpful [503, 532].
Exchange blood transfusion has also been proposed, with the aim of increasing the tissue delivery of oxygen
[535]. The transfused blood should be HbS negative, Rh and Kell antigen matched [536]. However, the
evidence is inconclusive as to whether exchange transfusion itself helps to resolve the priapism in these men.
It should also be noted that several reports suggest that this treatment may result in serious neurological
sequelae [537]. Because of these considerations, the routine use of this therapy is not recommended (LE: 4).
It is important to assess the success of surgery by either direct observation or by investigation (e.g. cavernous
blood gas testing, penile colour duplex US) (LE: 4) [494, 516].
The recovery rates of erectile function in men undergoing shunt surgery for prolonged erections are low and
directly relate to the duration of the priapism [539, 540]. Priapism for more than 36 hours appears to irreversibly
impair erectile tissue both structurally and functionally [539]. In general, shunt procedures undertaken after this
time period may only serve to limit pain without any benefit for erectile function (LE: 4) [541, 542].
Four categories of shunt procedures have been reported [4, 494, 538, 542]. The limited available data preclude
any recommendation for one procedure over another based on outcome (LE: 4).
Ebbehoj’s technique: this technique involves making multiple tunical incision windows between the glans and
each tip of the corpus cavernosum by means of a size 11 blade scalpel passed several times percutaneously
[4, 494, 543, 546, 547] (LE: 3).
T-Shunt: this technique involves performing a bilateral procedure using a size 10 blade scalpel placed vertically
through the glans just lateral to the meatus until fully within the corpus cavernosum. The blade is then rotated
90° away from the urethra and pulled out [4, 494, 543, 548] (LE: 3). This is followed by a tunneling procedure
using a size 8 dilator inserted through the glans and into the corpora which can be performed using US for
guidance, mainly in order to avoid urethral injury [548].
Burnett’s technique (Snake manoeuvre): a modification of the Al-Ghorab corpora-glanular shunt surgery
involves the retrograde insertion of a 7/8 Hegar dilator into the distal end of each corpus cavernosum through
the original Al-Ghorab glanular excision. After removal of the dilator from the corpus cavernosum, blood
evacuation is facilitated by manual compression of the penis sequentially from a proximal to distal direction.
After detumescence, the glans penis skin is closed as in the Al-Ghorab procedure [4, 494, 543, 551, 552]
(LE: 3). Reported complications include wound infection, penile skin necrosis and a urethrocutaneous fistula
[552].
Vein anastomoses/shunts
Grayhack’s procedure: this mobilises the saphenous vein below the junction of the femoral vein and
anastomoses the vein end-to-side onto the corpus cavernosum. Venous shunts may be complicated by
saphenofemoral thrombus formation and by pulmonary embolism [4, 494, 554-556] (LE: 3).
Currently, there are no clear indications for immediately implanting a penile prosthesis in a man with acute
ischaemic priapism [516]. Relative indications include [494] (LE: 4):
• ischaemia that has been presented for more than 36 hours [560];
• failure of aspiration and sympathomimetic intracavernous injections;
• failure of distal and proximal shunting (although in delayed cases, implantation might be considered
ahead of shunt surgery);
• Magnetic resonance imaging or corporal biopsy evidence of corporal smooth muscle necrosis [494, 557]
(LE: 4).
Prosthesis implantation is occasionally indicated in sickle cell patients with severe ED since other therapeutic
options such as PDE5Is and intracavernous injections are avoided as they may provoke a further priapism
event [494, 516]. In severe corporal fibrosis, semi-rigid prosthetic devices are preferable to inflatable implants
[557, 565] (LE: 3). Following severe priapism that has resulted in penile destruction with complicated
deformities or even loss of penile tissue, penile reconstruction and concomitant prosthesis implant may be
considered [566] (LE: 3).
3.4.1.5 Summary of evidence and recommendations for the treatment of ischaemic priapism
Summary of evidence LE
Intervene rapidly for ischaemic priapism, which is an emergency condition. 2b
Treatment aims to restore painless penile flaccidity, in order to prevent chronic damage to the corpora 3
cavernosa.
Erectile function preservation is directly related to the duration of ischaemic priapism. 2b
Phenylephrine is the recommended drug due to its favourable safety profile on the cardiovascular 2b
system compared to other drugs. Phenylephrine is usually diluted in normal saline with a
concentration of 100-500 μg/mL and given in 200 μg doses every three to five minutes directly into the
corpus cavernosum. Maximum dosage is 1 mg within one hour. Patients at high cardiovascular risk
should be given lower doses. Patient monitoring is highly recommended.
The efficacy of shunt procedures for ischaemic priapism is questionable. Diagnose smooth muscle 3
necrosis when needed with cavernous biopsy. No clear recommendation on one type of shunt over
another can be given.
Erectile dysfunction is inevitable in prolonged cases or priapism. Implantation of penile prosthesis at a 2b
later stage can be difficult due to severe corporal fibrosis.
3.4.1.6 Follow-up
Follow-up of ischaemic priapism after successful treatment should include modification of risk factors (if any)
in order to avoid a new event and assessment of erectile function since it may be severely compromised
especially after surgical treatment with a shunt. Penile fibrosis is usually easily identified with clinical
examination of the penis.
There is often a delay between the injury and the development of the priapism that may be up to two to three
weeks [571]. This has been suggested to reflect either spasm or ischaemic necrosis of the injured artery, with
the fistula only developing as the spasm resolves or when the ischaemic segment blows out.
Occasional cases are associated with metastatic malignancy to the penis [572, 573], with acute spinal cord
injury [574] and occasionally following intracavernous injections or aspiration due to a lacerated cavernous
artery or branch [575, 576]. Under these circumstances, it may complicate low-flow priapism. It has also
been reported to occur following internal urethrotomy [577] and a Nesbit procedure [578]. Although sickle
cell disease is usually associated with low-flow priapism, occasional cases of high-flow priapism have been
reported [579].
3.4.2.1.1 Summary of Evidence on the epidemiology, aetiology and pathophysiology of arterial priapism
Summary of evidence LE
Arterial priapism usually occurs after blunt perineal or penile trauma. 2
3.4.2.2 Classification
Arterial priapism is a persistent erection caused by unregulated cavernous arterial inflow [494]. The patient
typically reports an erection that is not fully rigid and is not associated with pain although fully rigid erections
may occur with sexual stimulation.
A selective pudendal arteriogram can reveal a characteristic blush at the site of the injury to the cavernosal
artery in arterial priapism [580, 581]. However, due to its invasiveness it should be reserved for the
management of arterial priapism, when embolisation is being considered [494, 508] (LE: 3).
The role of MRI in the diagnostic evaluation of priapism is controversial. In arterial priapism, its role is limited
since the small penile vessels and arteriovenous fistulae cannot be easily demonstrated [582].
Blood aspiration is not helpful for the treatment of arterial priapism and the use of α-adrenergic antagonists
is not recommended due to potential severe adverse effects, e.g. transfer of the drug into the systemic
circulation.
Embolisation in children, although reportedly successful, is technically challenging and requires treatment
within a specialist paediatric vascular radiology department [520, 598].
3.4.2.4.3 Summary of evidence and recommendations for the treatment of arterial priapism
Summary of evidence LE
Because high-flow priapism is not an emergency, perform definitive management at the discretion of 2b
the treating physician.
Conservative management with the use of ice applied to the perineum or site-specific perineal 3
compression may be successful particularly in children. The use of androgen deprivation therapy may
enable closure of the fistula reducing spontaneous and sleep-related erections.
Artery embolisation, using temporary or permanent substances, has high success rates. No 3
definitive statement can be made on the best substance for embolisation in terms of sexual function
preservation.
Repeat the procedure for the recurrence of arterial priapism following selective artery embolisation. 2b
Reserve selective surgical ligation of the fistula as a last treatment option when embolisation has 3
failed.
Recommendations GR
Because high-flow priapism is not an emergency, perform definitive management at the discretion of B
the treating physician.
Manage conservatively with the use of ice applied to the perineum or site-specific perineal C
compression as the first step, especially in children. Use androgen deprivation therapy only in adults.
Perform selective artery embolisation, using temporary or permanent substances. B
Repeat the procedure for the recurrence of arterial priapism following selective artery embolisation. B
Reserve selective surgical ligation of the fistula as a final treatment option when embolisation has C
failed.
3.4.2.4.4 Follow-up
Follow-up after successful treatment of arterial priapism should include assessment of erectile function and
clinical examination to identify signs of recurrence especially after embolisation.
The aetiology of stuttering priapism is similar to that of ischaemic priapism. While sickle cell disease is the most
common cause, idiopathic cases and cases due to a neurological disorder have been reported. Moreover, men
who have suffered from an acute ischaemic priapic event, especially one which has been prolonged (more than
four hours) are at risk for developing stuttering priapism [564].
3.4.3.1.1 Summary of evidence on the epidemiology, aetiology and pathophysiology of stuttering priapism
Summary of evidence LE
Stuttering priapism is similar to ischaemic priapism in that it is low-flow, ischaemic and, if left 3
untreated would result in significant penile damage, with sickle cell disease being the most common
cause. But the cause can also be idiopathic and in rare cases may be due to a neurological disorder.
3.4.3.2 Classification
Stuttering priapism, also termed intermittent or recurrent priapism, is a distinct condition that is characterised
by repetitive and painful episodes of prolonged erections. Erections are self-limited with intervening periods
of detumescence [532, 603]. These are analogous to repeated episodes of low-flow (or ischaemic) priapism.
The duration of the erectile episodes is generally shorter than in ischaemic priapism [4]. The frequency and/
or duration of these episodes is variable and a single episode can sometimes progress into a major ischaemic
priapic episode.
Of the hormonal agents suggested for preventing priapism, GnRH agonists and anti-androgens appear to be
the most efficacious and safe. They are recommended as primary treatments for the management of stuttering
priapism in adult men (LE: 4).
The duration of hormonal treatment for effective suppression of recurrent priapic events is problematic. It is
not possible to make any conclusions on the efficacy, dose and the duration of treatment. Moreover, hormonal
agents have a contraceptive effect and interfere with normal sexual maturation. Caution is therefore strongly
advised when prescribing hormonal treatments to pre-pubertal boys, adolescents or men who are trying with
their female partner to conceive. Castrate levels of testosterone, which have a contraceptive effect, interfere
with growth, and significantly affect sexual function.
3.4.3.4.3 Digoxin
Digoxin (a cardiac glycoside and a positive inotrope) is used to treat patients with congestive heart failure.
Digoxin regulates smooth muscle tone through a number of different pathways leading to penile detumescence
[503, 532, 612]. The use of maintenance digoxin doses (0.25-0.5 mg daily) in idiopathic stuttering priapism
has been proven to reduce the number of hospital visits and to improve QoL [532]. A small, clinical, double-
blind, placebo-controlled study, using digoxin, produced a decrease in sexual desire and excitement with a
concomitant reduction in penile rigidity, regardless of any significant change in plasma levels of testosterone,
oestrogens and luteinising hormone [612] (LE: 2b). Side-effects may include a decreased libido, anorexia,
nausea, vomiting, confusion, blurred vision, headache, gynaecomastia, rash and arrhythmia.
3.4.3.4.4 Terbutaline
Terbutaline is a β-agonist that causes vasodilation, resulting in smooth muscle relaxation of the vasculature
[503, 532] and has been used to prevent stuttering priapism with detumescence rates of 36% in patients
with alprostadil-induced priapism [529] (LE: 3). The only randomised, placebo-controlled study (n = 68) in
patients with pharmacologically-induced priapism, showed detumescence in 42% of the terbutaline-treated
group compared to only 15% in the placebo-treated group [530] (LE: 1b). Side-effects include nervousness,
shakiness, drowsiness, heart palpitations, headache, dizziness, hot flashes, nausea and weakness.
3.4.3.4.5 Gabapentin
Gabapentin has anticonvulsant, antinociceptive and anxiolytic properties and is widely used as an analgesic
and antiepileptic agent. Its proposed mechanism of action is to inhibit voltage-gated calcium channels, which
attenuates synaptic transmission [608], and reduces testosterone- and FSH levels [613]. It is given at a dose of
400 mg, four times a day, up to 2,400 mg daily, until complete penile detumescence occurs, with subsequent
maintenance administration of gabapentin, 300 mg daily [614] (LE: 4). Side-effects include anorgasmia and
impaired erectile function.
3.4.3.4.6 Baclofen
Baclofen is a gamma-aminobutyric acid (GABA) derivative that acts as a muscle relaxant and anti-muscle
spasm agent. It can inhibit penile erection and ejaculation through GABA activity and prevents recurrent
reflexogenic erections or prolonged erections from neurological diseases [503]. Oral baclofen has little efficacy
and it is not usually used in stuttering priapism but intrathecal baclofen dosing is more effective [532, 615-617]
(LE: 4). Side-effects include drowsiness, confusion, dizziness, weakness, fatigue, headache, hypotension and
nausea.
3.4.3.4.7 Hydroxyurea
Hydroxyurea blocks the synthesis of deoxyribonucleic acid (DNA) by inhibiting ribonucleotide reductase,
which has the effect of arresting cells in the S-phase [608, 618]. It is an established treatment for ameliorating
sickle cell disease and improving patient life expectancy [531, 619]. For such patients with recurrent priapism
there is limited evidence to suggest a medical prophylactic role (LE: 3), [608, 618, 620]. Side-effects include
oligozoospermia and leg ulcers.
Tissue plasminogen activator (TPA) is a secreted serine protease that converts the pro-enzyme plasminogen to
plasmin, which acts as a fibrinolytic enzyme. Limited clinical data have suggested that a single intracavernous
injection of TPA can successfully treat patients with recalcitrant priapism [608, 626] (LE: 3). Mild bleeding is the
most commonly observed side-effect.
3.4.3.4.10 Summary of evidence and recommendations for the treatment of stuttering priapism
Summary of evidence LE
The primary goal in the management of patients with stuttering priapism is the prevention of future 2b
episodes, which can generally be achieved pharmacologically.
PDE5Is have a paradoxical effect in alleviating and preventing stuttering priapism, mainly in patients 3
with idiopathic and sickle cell disease associated priapism.
The evidence with other systemic drugs (digoxin, α-adrenergic agonists, baclofen, gabapentin, 3
terbutaline) is very limited.
Recommendations GR
Manage each acute episode similar to that for ischaemic priapism. B
Use hormonal therapies (mainly gonadotropin-receptor hormone agonists or antagonists) and/or C
antiandrogens for the prevention of future episodes in patients with frequent relapses. Do not use
them before sexual maturation is reached.
Initiate treatment with phosphodiesterase type 5 inhibitors (PDE5Is) only when the penis is in its flaccid C
state.
Use digoxin, α-adrenergic agonists, baclofen, gabapentin or terbutaline only in patients with very C
frequent and uncontrolled relapses.
Use intracavernous self-injections at home of sympathomimetic drugs for the treatment of acute C
episodes on an interim basis until ischaemic priapism has been alleviated.
3.4.3.5 Follow-up
Follow-up for stuttering priapism include history and clinical examination to assess the efficacy of treatments in
preventing or alleviating erectile events as well as assessing erectile function and penile fibrosis.
5. CONFLICT OF INTEREST
All members of the EAU Male Sexual Dysfunction Guidelines Panel have provided disclosure statements of all
relationships which they have and which may be perceived as a potential source of conflict of interest. This
information is publically accessible through the EAU website https://uroweb.org/guideline/. This document was
developed with the financial support of the European Association of Urology. No external sources of funding
and support have been involved. The EAU is a non-profit organisation and funding is limited to administrative
assistance and travel and meeting expenses. No honoraria or other reimbursements have been provided.
2. METHODS 5
2.1 Introduction 5
2.2 Review 6
2.3 Future goals 6
6. REFERENCES 33
7. CONFLICT OF INTEREST 46
It must be emphasised that clinical guidelines present the best evidence available to the experts. However
following guideline recommendations will not necessarily result in the best outcome. Guidelines can never
replace clinical expertise when making treatment decisions for individual patients, but rather help to focus
decisions - also taking personal values and preferences/individual circumstances of patients into account.
Guidelines are not mandates and do not and should not purport to be a legal standard of care.
2. METHODS
2.1 Introduction
References used in this text are graded according to their Level of Evidence (LE) and Guidelines are given a
Grade of Recommendation (GR), according to a classification system modified from the Oxford Centre for
Evidence-based Medicine Levels of Evidence [4]. Additional methodology information can be found in the
general Methodology section of this print, and online at the EAU website: http://www.uroweb.org/guideline/.
A list of Associations endorsing the EAU Guidelines can also be viewed online at the above address. In
particular, the Male Infertility Guidelines have been endorsed by the Hellenic Society of Reproductive Medicine.
The recommendations provided in these guidelines are based on a systematic literature search performed
by the panel members. The controlled vocabulary of the MeSH database was used alongside a free
text protocol, combining “male infertility” with the terms “diagnosis”, “epidemiology”, “investigations”,
“treatment”, “spermatogenic failure”, “genetic abnormalities”, “obstruction”, “hypogonadism”, “varicocele”,
“cryptorchidism”, “testicular cancer”, “male accessory gland infection”, “idiopathic”, “contraception”,
“ejaculatory dysfunction”, and “cryopreservation”.
For the 2017 print a scoping search was performed, covering all areas of the guideline, starting from the last
cut-off date April 2015 with a cut-off date of April 2016. Embase, Medline and the Cochrane Central Register
of Controlled Trials databases were searched, with a limitation to reviews, meta-analyses or meta-analysis
of randomised controlled trials. A total of 409 unique records were identified, retrieved and screened for
relevance, of which nine publications were selected for inclusion. A detailed search strategy is available online:
http://www.uroweb.org/guideline/male-infertility/.
About 15% of couples do not achieve pregnancy within one year and seek medical treatment for infertility. One
in eight couples encounter problems when attempting to conceive a first child and one in six when attempting
to conceive a subsequent child. Three percent of women remain involuntarily childless, while 6% of parous
women are not able to have as many children as they would wish [7]. Infertility affects both men and women.
In 50% of voluntarily childless couples, a male-infertility-associated factor is found together with with abnormal
semen parameters. A fertile partner may compensate for the fertility problem of the man and thus infertility
usually manifests if both partners have reduced fertility [6]. Male fertility can be reduced as a result of [6]:
• congenital or acquired urogenital abnormalities;
• malignancies;
• urogenital tract infections;
• increased scrotal temperature (e.g. as a consequence of varicocele);
• endocrine disturbances;
• genetic abnormalities;
• immunological factors.
In 30-40% of cases, no male-infertility-associated factor is found (idiopathic male infertility). These men present
with no previous history of diseases affecting fertility and have normal findings on physical examination and
endocrine, genetic and biochemical laboratory testing. However, semen analysis might reveal pathological
findings in the spermiogram (see 4.2.1). Table 1 summarises the main male-infertility-associated factors.
Idiopathic male infertility is assumed to be caused by several factors, including endocrine disruption as a result
of environmental pollution, reactive oxygen species, or genetic and epigenetic abnormalities.
Recommendations GR
Investigate both partners simultaneously, to categorise infertility. C
Include the fertility status of the female partner in the diagnosis and management of male subfertility B
because this might determine the final outcome.
Examine all men diagnosed with fertility problems, including men with abnormal semen parameters for C
urogenital abnormalities.
The cumulative pregnancy rate is 27% in infertile couples with two years of follow-up and oligozoospermia
as the primary cause of infertility [9]. Female age is the most important single variable influencing outcome in
assisted reproduction [10]. Compared to a woman aged 25 years, the fertility potential of a woman aged 35
years is reduced to 50%, to 25% at 38 years, and less than 5% at over 40 years. In many Western countries,
women postpone their first pregnancy until after their education and starting a career.
Table 2: Lower reference limits (5th centiles and their 95% CIs) for semen characteristics
Recommendations GR
Perform semen analyses according to the guidelines of the WHO Laboratory Manual for the A*
Examination and Processing of Human Semen (5th edn).
Perform further andrological assessment when semen analysis is abnormal in at least two tests. A*
Adhere to the 2010 WHO Manual for the standardised investigation, diagnosis and management of the C
infertile male for diagnosis and evaluation of male subfertility.
*Upgraded following panel consensus.
5.1.1 Aetiology
The causes of testicular deficiency are summarised in Table 3.
Factors Causes
Congenital Anorchia
Testicular dysgenesis/cryptorchidism
Genetic abnormalities (karyotype, Y-chromosome deletions)
Acquired Trauma
Testicular torsion
Post-inflammatory forms, particularly mumps orchitis
Exogenous factors (medications, cytotoxic or anabolic drugs, irradiation, heat)
Systemic diseases (liver cirrhosis, renal failure)
Testicular tumour
Varicocele
Surgery that may compromise vascularisation of the testes and lead to testicular atrophy
Idiopathic Unknown aetiology
Unknown pathogenesis
5.1.2.3 Ultrasonography
In addition to physical examination, a scrotal US may be helpful in finding signs of obstruction (e.g., dilatation
of rete testis, enlarged epididymis with cystic lesions, or absent vas deferens) and may demonstrate signs
of testicular dysgenesis (e.g., non-homogeneous testicular architecture and microcalcifications) and testis
tumours. For patients with a low seminal volume and in whom distal obstruction is suspected, transrectal
ultrasound (TRUS) is essential [11].
The results of ICSI are worse when using sperm retrieved from men with NOA compared to sperm from
ejaculated semen and from men with obstructive azoospermia (OA) [23-27]. Birth rates are lower in NOA vs.
OA (19% vs 28%) [28, 29]. ICSI results in significantly lower fertilisation and implantation rates. In longitudinal
studies including patients with NOA as defined by testicular histopathology, only one out of seven NOA
patients embarking for TESE and eventually ICSI will father their genetically-own child [30]. Neonatal health
in terms of birth parameters, major anomalies and chromosomal aberrations in a large cohort of children born
after use of non-ejaculated sperm are comparable to the outcome of children born after use of ejaculated
sperm [31].
Summary of evidence LE
The WHO laboratory manual proposes reference values based on fertility therefore these reference 2a
values do not allow classification of men as infertile.
Impaired spermatogenesis is often associated with elevated FSH concentration. 3
For patients with NOA who have spermatozoa in their testicular biopsy, intracytoplasmic sperm 2a
injection (ICSI) with fresh or cryopreserved spermatozoa is the only therapeutic option. Spermatozoa
are found by a TESE procedure in about 50% of patients with NOA.
Pregnancies and live births are eventually obtained in 30-50% of couples with NOA, when 3
spermatozoa have been found in the testicular biopsy.
Based on the frequencies of chromosomal aberrations in patients with different sperm concentration, karyotype
analysis is indicated in men with azoospermia or oligozoospermia (spermatozoa < 10 million/mL) [35]. A recent
study proposes to restrict karyotype to NOA men with the purpose to prevent adverse pregnancy outcomes
[36]. If there is a family history of recurrent spontaneous abortions, malformations or mental retardation,
karyotype analysis should be requested, regardless of the sperm concentration.
5.2.1.1 Sex chromosome abnormalities (Klinefelter’s syndrome and variants [47,XXY; 46,XY/47, XXY
mosaicism])
Klinefelter’s syndrome is the most common sex chromosome abnormality [37]. Adult men with Klinefelter’s
syndrome have small firm testicles, devoid of germ cells. The phenotype varies from a normally virilised man to
one with the stigmata of androgen deficiency, including female hair distribution, scant body hair, and long arms
and legs due to late epiphyseal closure. Leydig cell function is commonly impaired in men with Klinefelter’s
syndrome [38]. Testosterone levels may be normal or low, oestradiol levels normal or elevated, and FSH levels
increased. Libido is often normal despite low testosterone levels, but androgen replacement may be needed as
the patient ages.
Germ cell presence and sperm production are variable in men with Klinefelter’s mosaicism, 46,XY/47,XXY.
Based on sperm fluorescence in situ hybridisation (FISH) studies showing an increased frequency of sex
chromosomal abnormalities and increased incidence of autosomal aneuploidy (disomy for chromosomes 13,
18 and 21), concerns have been raised about the chromosomal normality of the embryos generated through
ICSI [39].
The production of 24,XY sperm has been reported in 0.9% and 7.0% of men with Klinefelter’s mosaicism [40,
41] and in 1.36-25% of men with somatic karyotype 47,XXY [42-45]. In patients with azoospermia, TESE (42%)
or micro-TESE (57%) can be proposed as a therapeutic option since spermatozoa can be recovered in about
50% of cases [46]. There is growing evidence that TESE or micro TESE yields higher sperm recovery rates
when done at younger age. Numerous healthy children have been born using ICSI without pre-implantation
genetic diagnosis (PGD) and the conception of one 47,XXY foetus has been reported [37]. However, a study of
ICSI combined with PGD in 113 embryos reported a significant fall in the rate of normal embryos for couples
with Klinefelter’s syndrome with respect to controls (54% vs. 77.2%) [45]. Due to the significant increase of
sex chromosomal and autosomal abnormalities in the embryos of Klinefelter’s patients, PGD or amniocentesis
analysis should be considered.
Spermatogenesis can be relatively easily induced by hormonal treatment [54], therefore, genetic screening
prior to therapy is advisable although it is limited by the rarity of specialised genetic laboratories that can
offer this genetic test. Treatment with gonadotropins allows natural conception in most cases, even for men
with a relatively low sperm count. Thus, identification of the involved gene (X-linked, autosomal dominant or
recessive) can help to provide more accurate genetic counselling, that is, risk estimation for transmission to the
offspring.
The specificity and genotype/phenotype correlation reported above means that Y-deletion analysis has both a
diagnostic and prognostic value for testicular sperm retrieval [66].
According to four meta-analyses, gr/gr deletion is a significant risk factor for impaired sperm production [77,
78]. It is worth noting that both the frequency of gr/gr deletion and its phenotypic expression vary between
different ethnic groups, depending on the Y-chromosome background. For example, in some Y haplogroups,
the deletion is fixed and appears to have no negative effect on spermatogenesis. Consequently, the routine
screening for gr/gr deletion is still a debated issue, especially in those laboratories serving diverse ethnic
Congenital bilateral absence of the vas deferens (CBAVD) is associated with CFTR gene mutations and was
found in ~2% of men with OA attending a clinic in Edinburgh, UK [82]. The incidence in men with OA varies
between different countries. The clinical diagnosis of absent vasa is easy to miss and all men with azoospermia
should be very carefully examined to exclude CBAVD, particularly those with a semen volume < 1.5 mL and pH
< 7.0. Approximately 1,500 mutations are listed on the CFTR database http://www.genetsickkids.on.ca/cftr/.
The most frequently found mutations are the F508, R117H and W1282X, but their frequency and the presence
of other mutations largely depend on the ethnicity of the patient [83, 84]. Given the functional relevance of a
DNA variant (the 5T allele) in a non-coding region of CFTR [79], it is now considered a mild CFTR mutation
rather than a polymorphism and it should be analysed in each CBAVD patient. As more mutations are defined
and tested for, almost all men with CBAVD will probably be found to have mutations. It is not practical to test
for all known mutations, because many have a very low prevalence in a particular population. Routine testing is
usually restricted to the most common mutations in a particular community through the analysis of a mutation
panel. Given that this is a recessive disease if a second mutation is not found with the routine panel, a second
step analysis is advised which comprises the direct sequencing of the entire gene. Men with CBAVD often have
mild clinical stigmata of CF (e.g., history of chest infections). When a man has CBAVD, it is important to test
also his partner for CF mutations. If the female partner is found to be a carrier of CFTR mutations, the couple
must consider very carefully whether to proceed with ICSI using the male’s sperm, as the risk of having a child
with CF or CBAVD will be 50%, depending on the type of mutations carried by the parents. If the female
partner is negative for known mutations, the risk of being a carrier of unknown mutations is ~0.4% [85].
5.2.5 Summary of evidence and recommendations for genetic disorders in male infertility
Summary of evidence LE
In men with spermatogenic damage there is a higher prevalence of chromosome abnormalities, 1b
reaching the highest frequency in NOA men.
AZF deletions are clear-cut causes of spermatogenic impairments with diagnostic and prognostic 1a
value for TESE.
AZF deletions will be transmitted to the son. 1a
gr/gr deletion has been confirmed as a significant risk factor for impaired sperm production, whereas 2b
further evidence of the prognostic significance of gr/gr and development of a testicular germ cell
tumour is needed.
Recommendations GR
Obtain standard karyotype analysis in all men with damaged spermatogenesis (spermatozoa B
< 10 million/mL) who are seeking fertility treatment by in vitro fertilisation (IVF).
Provide genetic counselling in all couples with a genetic abnormality found in clinical or genetic A
investigation and in patients who carry a (potential) inheritable disease.
For all men with Klinefelter’s syndrome, provide long-term endocrine follow-up and androgen A
replacement therapy, if necessary.
Do not test for microdeletions in men with obstructive azoospermia (OA) when intracytoplasmic sperm A
injection (ICSI) is used because spermatogenesis should be normal.
Inform men with Yq microdeletion and their partners who wish to proceed with intracytoplasmic sperm A
injection (ICSI) that microdeletions will be passed to sons, but not to daughters.
In men with structural abnormalities of the vas deferens (unilateral or bilateral absence), test the man A
and his partner for cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations.
5.3.1 Classification
5.3.1.1 Intratesticular obstruction
Intratesticular obstruction occurs in 15% of men with OA [93]. Congenital forms are less common than
acquired forms (post-inflammatory or post-traumatic).
Summary of evidence LE
Obstructive lesions of the seminal tract are frequent in azoospermic or severely oligozoospermic 3
patients with normal-sized testes and normal reproductive hormones.
Recommendations GR
Perform microsurgical vasovasostomy or tubulovasostomy for azoospermia caused by vasal or B
epididymal obstruction.
Use sperm retrieval techniques, such as microsurgical epididymal sperm aspiration (MESA), testicular B
sperm extraction (TESE) and percutaneous epididymal sperm aspiration (PESA) only when cryostorage
of the material obtained is available.
5.4.1 Classification
The following classification of varicocele [121] is useful in clinical practice:
• Subclinical: not palpable or visible at rest or during Valsava manoeuvre, but can be shown by special
tests (Doppler ultrasound studies),
• Grade 1: palpable during Valsava manoeuvre, but not otherwise,
• Grade 2: palpable at rest, but not visible,
• Grade 3: visible and palpable at rest.
5.4.3.2 Varicocelectomy
Varicocele repair has been a subject of debate for several decades. A meta-analysis of randomised
controlled trials (RCTs) and observational studies in men with only clinical varicoceles showed that surgical
varicocelctomy significantly improves semen parameters in men with abnormal semen parameters including
men with non-obstructive azoospermia [123, 125, 126].
In randomised controlled studies, varicocele repair in men with a subclinical varicocele was found to be
ineffective in increasing the chance of spontaneous pregnancies [127]. Also, in randomised studies that
included mainly men with normal semen parameters no benefit was found in favour of treatment over
observation [128]. A Cochrane review from 2013 concluded that there is evidence to suggest that treatment
of a varicocele in men from couples with otherwise unexplained subfertility may improve a couple’s chance
of pregnancy [129]. In a subgroup analyses of five RCTs comparing treatment to observation in men with a
clinical varicocele, oligospermia and otherwise unexplained infertility, the analyses favoured treatment, with a
combined odds ratio (OR) of 2.39 (95% CI 1.56 to 3.66) [129].
Summary of evidence LE
The presence of varicocele in some men is associated with progressive testicular damage from 2a
adolescence onwards and a consequent reduction in fertility.
Although the treatment of varicocele in adolescents may be effective, there is a significant risk of over- 3
treatment: the majority of boys with a varicocele will have no fertility problems later in life.
Varicocele repair was shown to be effective in men with oligospermia, a clinical varicocele and 1a
otherwise unexplained infertility.
Recommendations GR
Treat varicoceles in adolescents with progressive failure of testicular development documented by B
serial clinical examination.
Do not treat varicoceles in infertile men who have normal semen analysis and in men with a subclinical A
varicocele.
Treat varicoceles in men with a clinical varicocele, oligospermia and otherwise unexplained infertility in A
the couple.
5.5 Hypogonadism
Hypogonadism is characterised by impaired testicular function, which may affect spermatogenesis and/or
testosterone synthesis. The symptoms of hypogonadism depend on the degree of androgen deficiency and if
the condition develops before or after pubertal development of the secondary sex characteristics.
The most common conditions within these three categories are given in Table 5 (see also Chapter 3.3).
A suspected tumour requires imaging [computed tomography (CT) or magnetic resonance imaging (MRI)] of
the sella region and a complete endocrine work-up. Normal androgen levels and subsequent development of
secondary sex characteristics (in cases of onset of hypogonadism before puberty) and a eugonadal state can
be achieved by androgen replacement alone. However, stimulation of sperm production requires treatment with
human chorionic gonadotropin (hCG) combined with recombinant FSH, urinary FSH or human menopausal
gonadotropins (HMGs) [143]. If hypogonadotropic hypogonadism is hypothalamic in origin, an alternative to
hCG treatment is pulsatile GnRH [144]. In patients who have developed hypogonadism before puberty and
have not been treated with gonadotropins or GnRH, one to two years of therapy may be needed to achieve
sperm production.
Generally, androgen replacement should not be given to men who are considering parenthood or in case of
male infertility. Testosterone suppresses pituitary production of LH and FSH, therefore, replacement therapy
should not be given for infertility . In obese men, low levels of testosterone may exist due to the conversion of
testosterone to oestradiol by the enzyme aromatase [148]. Anti-oestrogens and aromatase inhibitors may help
in these patients elevating FSH and LH and potentially increase sperm quality, next to weight reduction. See
also EAU Guidelines on Male Hypogonadism [149].
Recommendations GR
Provide testosterone replacement therapy for symptomatic patients with primary and secondary A
hypogonadism who are not considering parenthood.
In men with hypogonadotropic hypogonadism, induce spermatogenesis by an effective drug therapy A*
(human chorionic gonadotropin( hCG), human menopausal gonadotropins (hMG), recombinant follicle-
stimulating hormone (rFSH)).
Do not use testosterone replacement for the treatment of male infertility. A*
*Upgraded following panel consensus.
5.6 Cryptorchidism
Cryptorchidism is the most common congenital abnormality of the male genitalia, at one year of age nearly
1% of all full-term male infants have cryptorchidism [150]. Approximately 30% of undescended testes are
nonpalpable and may be located within the abdominal cavity. This guideline only deals with the management in
adults.
Summary of evidence LE
Cryptorchidism is multifactorial in origin and can be caused by genetic factors and endocrine 2a
disruption early in pregnancy.
Cryptorchidism is often associated with testicular dysgenesis and is a risk factor for infertility and 2b
germ cell tumours.
Paternity in men with unilateral cryptorchidism is almost equal to that in men without cryptorchidism. 3
Bilateral cryptorchidism significantly reduces the likelihood of paternity. 3
Recommendations GR
Do not use hormonal treatment of cryptorchidism in adults. A
If undescended testes are corrected in adulthood, perform simultaneous testicular biopsy for B
detection of intratubular germ cell neoplasia of unclassified type (ITGCNU) (formerly carcinoma in situ
(CIS)).
Recommendations GR
Medically treat male infertility only for cases of hypogonadotropic hypogonadism. A
No clear recommendation can be made for treatment with gonadotropins, anti-oestrogens and B
antioxidants even for a subset of patients.
5.8.1 Vasectomy
Vasectomy is an effective method of permanent male surgical sterilisation [168]. Extensive guidelines on
vasectomy were published by the EAU in 2012 [2]. Before vasectomy, the couple should be fully informed
about the benefits and risks, especially as an Australian telephone survey found that 9.2% of respondents
regretted having a vasectomy [176].
5.8.1.1.1 Complications
Vasectomy does not significantly alter spermatogenesis and Leydig cell function. The volume of ejaculate
remains unchanged. Potential systemic effects of vasectomy, including atherosclerosis, have not been proven,
and there is no evidence of a significant increase in any systemic disease after vasectomy. An increased rate of
prostate cancer in men who underwent vasectomy has not been detected [182, 183]. Acute local complications
associated with vasectomy include haematoma, wound infection, and epididymitis in up to 5% of cases [182].
The potential long-term complications (e.g., chronic testicular pain) [184] must be discussed with the patient
before the procedure.
5.8.2 Counselling
Counselling with regard to vasectomy must address the following aspects:
• Vasectomy should be considered irreversible,
• Vasectomy is associated with a low complication rate; however, because it is an elective operation, even
small risks must be explained, because men (and their partners) might wish to consider these before
giving consent,
5.8.3.2 Tubulovasostomy
The chance of secondary epididymal obstruction after vasectomy increases with time. After an interval of
ten years, 25% of men appear to have epididymal blockage. If secondary epididymal obstruction occurs,
tubulovasostomy is needed to reverse the vasectomy (see Chapter 5.3) [192].
5.8.3.3 Microsurgical vasectomy reversal vs. epididymal or testicular sperm retrieval and ICSI
According to the calculations of cost per delivery for vasectomy reversal vs. sperm retrieval/ICSI, under a
wide variety of initial assumptions, it is clear that vasectomy reversal is associated with a considerably lower
cost per delivery and higher delivery rates [80, 113, 193, 194]. Sperm retrieval and ICSI must yield an 81%
pregnancy rate per cycle to achieve equal costs to vasectomy reversal.
Summary of evidence LE
Vasectomy meets best the criteria for male contribution to permanent contraception, with regard to 1a
efficacy, safety and side effects.
All available data indicate that vasectomy is not associated with any serious, long-term side-effects. 1b
Microsurgical vasectomy reversal is a low-risk and cost-effective method of restoring fertility. 1a
Methods of male contraception other than vasectomy are associated with high failure rates or are still 3
experimental (e.g., hormonal approach).
Recommendations GR
Cauterisation and fascial interposition are the most effective techniques for the prevention of early A
recanalisation.
Inform patients seeking vasectomy about the surgical method, risk of failure, potential irreversibility, A*
the need for post-procedure contraception until clearance, and the risk of complications.
To achieve pregnancy, microsurgical epididymal sperm aspiration (MESA)/ percutaneous epididymal B
sperm aspiration (PESA)/testicular sperm extraction (TESE) - together with intracytoplasmic sperm
injection (ICSI) is a second-line option for men who decline a vasectomy reversal and those with failed
vasectomy reversal surgery.
*Upgraded following panel consensus
Only antibiotic therapy of chronic bacterial prostatitis (NIH II according to the classification) has provided
symptomatic relief, eradication of microorganisms, and a decrease in cellular and humoral inflammatory
parameters in urogenital secretions. Although antibiotics might improve sperm quality [219], there is no
evidence that treatment of chronic prostatitis increases the probability of conception [196, 220].
Patients with epididymitis known or suspected to be caused by N. gonorrhoeae or C. trachomatis must be told
to refer their sexual partners for evaluation and treatment [226].
5.9.4 Summary of evidence and recommendation for male accessory gland infections
Summary of evidence LE
Urethritis and prostatitis are not clearly associated with male infertility. 3
Antibiotic treatment often only eradicates microorganisms; it has no positive effect on inflammatory 2a
alterations and cannot reverse functional deficits and anatomical dysfunction.
Although antibiotic treatment for MAGI might provide improvement in sperm quality, it does not 2a
necessarily enhance the probability of conception.
Recommendation GR
Instruct patients with epididymitis that is known or suspected to be caused by N. gonorrhoeae or C. B
trachomatis to refer their sexual partners for evaluation and treatment.
Recommendations GR
As for all men, encourage patients with testicular microlithiasis (TM) and without special risk factors B
(see below) to perform self-examination because this might result in early detection of testicular germ
cell tumour (TGCT).
Do not perform testicular biopsy, follow-up scrotal ultrasound, routine use of biochemical tumour B
markers, or abdominal or pelvic computed tomography (CT), in men with isolated TM without
associated risk factors (e.g. infertility, cryptorchidism, testicular cancer, and atrophic testis).
Perform testicular biopsy for men with TM, who belong to one of the following high-risk groups: B
infertile and bilateral TM, atrophic testes, undescended testes, a history of TGCT.
If there are suspicious findings on physical examination or ultrasound in patients with TM and B
associated lesions, perform surgical exploration with testicular biopsy or orchidectomy.
Follow men with TGCT because they are at increased risk of developing hypogonadism and sexual B
dysfunction.
Neurogenic Pharmacological
Spinal cord injury Antihypertensives
Cauda equina lesions α1-adrenoceptor antagonists
Multiple sclerosis Antipsychotics and antidepressants
Autonomic neuropathy (diabetes mellitus) Alcohol
Retroperitoneal lymphadenectomy
Sympathectomy or aortoiliac surgery
Colorectal and anal surgery
Parkinson´s disease
Urethral Bladder neck incompetence
Ectopic ureterocele Congenital defects/dysfunction of hemitrigone
Urethral stricture Bladder extrophy
Urethral valves or verumontaneum hyperplasia Bladder neck resection (transurethral resection of the
prostate)
Congenital dopamine β-hydroxylase deficiency Prostatectomy
Sperm collection from post-orgasmic urine for use in ART is recommended if:
• drug treatment is ineffective or intolerable as a result of side-effects;
• the patient has a spinal cord injury;
• drug therapy inducing retrograde ejaculation cannot be interrupted.
If the biological sperm preparation is not of sufficient quality for intrauterine insemination, the couple must
undergo in vitro reproductive procedures (e.g. ICSI). In the case of insufficient drug therapy, testicular (TESE or
PESA) or epididymal (MESA) sperm retrieval techniques can be used for assisted reproduction.
5.11.3.2.3 Anejaculation
Drug treatment for anejaculation caused by lymphadenectomy and neuropathy, or psychosexual therapy for
anorgasmia is not very effective. In all these cases, and in men who have a spinal cord injury, vibrostimulation
(i.e., application of a vibrator to the penis) is first-line therapy. In anejaculation, vibrostimulation evokes the
ejaculation reflex [260], which requires an intact lumbosacral spinal cord segment. If the quality of semen
is poor, or ejaculation is retrograde, the couple may enter an IVF programme. If vibrostimulation has failed,
electro-ejaculation can be the therapy of choice [261]. When electro-ejaculation fails or cannot be carried
out, sperm can be retrieved from the seminal ducts by aspiration from the vas deferens [262] (see Chapter
5.3) or seminal tract washout [263]. TESE can then be used [252, 264]. Anejaculation following either surgery
for testicular cancer or total mesorectal excision can be prevented using monolateral lymphadenectomy or
autonomic nerve preservation [264], respectively.
Summary of evidence LE
Ejaculation disorders can be treated using a wide range of drugs and physical stimulation (eg vibratory 3
stimulation), with a high level of efficacy.
Pharmacotherapy includes either dapoxetine on demand (a short-acting SSRI that is the only 1a
approved pharmacological treatment for PE) or other off-label antidepressants, i.e. daily SSRIs and
clomipramine, that are not amenable to on-demand dosing. Alternatively use topical anesthetics (LE:
1b) or tramadol (LE: 2a).
In men with spinal cord injury, vibrostimulation and/or electro-ejaculation are effective methods of 2
sperm retrieval.
Recommendations GR
Offer aetiological treatments for ejaculatory disorders before performing sperm collection and assisted B
reproduction technique (ART).
To treat disorders of ejaculation, offer pharmacological treatment of either dapoxetine on demand (a A
short-acting selective serotonin reuptake inhibitors (SSRI) that is the only approved pharmacological
treatment for premature ejaculation), or other off-label antidepressants, i.e. daily SSRIs and
clomipramine, that are not amenable to on-demand dosing.
Alternatively offer topical anaesthetics or tramadol. A
Cryopreservation can be used for sperm collected through TESE, avoiding repeated sperm retrieval procedures
and unnecessary hyperstimulation of the female partner:
• in any situation in which sperm have been obtained by a sperm retrieval procedure (e.g., after failed
vasectomy reversal, or in some cases of epididymal obstruction not amenable to surgery);
• for storage of donor sperm, because cryopreservation reduces the risk of transmission of infection from
sperm donors. According to the European directives 2004/23 EC and 2006/17 EC fresh sperm are no
longer to be used for non-partner donations.
Several techniques have been developed to try to reduce damage caused by freezing and thawing, including:
• one-step freezing method [272, 273]: sample is held in the vapour phase for ten minutes before being
plunged into liquid nitrogen;
• slow or multi-step method [274]: sample is gradually cooled in the vapour phase for approximately 40
minutes. A programmable automatic freezing machine, which is preset to cool at a rate of 1-10°C per
minute is used.
The method available depends on the resources of the laboratory. Whichever freezing technique is used, it
should be tested using donor sperm and post-thaw examination, and should regularly undergo a quality-
control programme. The likelihood of sperm survival decreases with repeated freezing and thawing. The
maximum viable storage time for human sperm is not known.
Summary of evidence LE
The purpose of sperm cryopreservation is to enable future assisted reproduction technique 1b
procedures.
Cryopreservation techniques are not optimal, and future efforts are needed to improve the outcome of 3
sperm banking.
Recommendations GR
Offer cryopreservation of semen to all men who are candidates for chemotherapy, radiation or surgical A
interventions that might interfere with spermatogenesis or cause ejaculatory disorders.
Offer simultaneous sperm cryopreservation if testicular biopsies will be performed for fertility A
diagnosis.
If cryopreservation is not available locally, inform patients about the possibility of visiting, or C
transferring to a cryopreservation unit before therapy starts.
Take precautions to prevent transmission of viral, sexually transmitted or any other infection by C
cryostored materials from donor to recipient, and to prevent contamination of stored samples. These
precautions include testing of the patient and the use of rapid testing and quarantine of samples until
test results are known. Do not store samples from men who are positive for hepatitis virus or HIV in the
same container as samples from men who have been tested and are free from infection.
7. CONFLICT OF INTEREST
All members of the EAU Chronic Pelvic Pain Guidelines working panel have provided disclosure statements
on all relationships that they have that might be perceived to be a potential source of conflict of interest. This
information is publically accessible through the European Association of Urology website http://www.uroweb.
org/guidelines/. This document was developed with the financial support of the European Association of
Urology. No external sources of funding and support have been involved. The EAU is a non-profit organisation
and funding is limited to administrative assistance and travel and meeting expenses. No honoraria or other
reimbursements have been provided.
2. METHODS 4
2.1 Introduction 4
2.2 Review 5
2.3 Future goals 5
4. DIAGNOSTIC EVALUATION 10
4.1 Clinical symptoms and laboratory testing 10
4.2 History-taking and questionnaires 12
4.3 Physical examination 12
4.4 Summary of evidence and recommendations for the diagnostic evaluation 12
4.5 Clinical consequences of hypogonadism 12
4.5.1 Prenatal androgen deficiency 12
4.5.2 Prepubertal onset of androgen deficiency 13
4.5.3 Adult-onset hypogonadism 13
4.5.4 Hypogonadism in Type 2 Diabetes 14
4.5.4.1 Recommendations for screening men with adult-onset
hypogonadism 14
5. DISEASE MANAGEMENT 14
5.1 Indications and contraindications for treatment 14
5.2 Benefits of treatment 15
5.3 Choice of treatment 16
5.3.1 Preparations 16
5.3.1.1 Testosterone undecanoate 16
5.3.1.2 Testosterone cypionate and enanthate 16
5.3.1.3 Transdermal testosterone 16
5.3.1.4 Future perspectives 17
5.4 Hypogonadism and fertility issues 17
5.5 Recommendations for testosterone replacement therapy 18
5.6 Risk factors in testosterone treatment 18
5.6.1 Male breast cancer 18
5.6.2 Risk for prostate cancer 18
5.6.3 Cardiovascular diseases 18
5.6.4 Obstructive sleep apnoea 20
5.6.5 Anabolic steroid–induced hypogonadism 20
5.7 Summary of evidence and recommendations on risk factors in testosterone
replacement treatment 20
7. REFERENCES 22
8. CONFLICT OF INTEREST 31
It must be emphasised that clinical guidelines present the best evidence available to the experts. However
following guideline recommendations will not necessarily result in the best outcome. Guidelines can never
replace clinical expertise when making treatment decisions for individual patients, but rather help to focus
decisions - also taking personal values and preferences/individual circumstances of patients into account.
Guidelines are not mandates and do not and should not purport to be a legal standard of care.
2. METHODS
2.1 Introduction
References used in this text are assessed according to their Level of Evidence (LE) and Guidelines are given
a Grade of Recommendation (GR) according to a classification system modified from the Oxford Centre for
Evidence-based Medicine Levels of Evidence [1]. Additional methodology information can be found in the
general Methodology section of this print, and online at the EAU website: http://www.uroweb.org/guideline/.
A list of Associations endorsing the EAU Guidelines can also be viewed online at the above address.
The recommendations provided in these guidelines are based on a systematic literature search and review
performed by the panel members in 2016. MedLine, Embase and Cochrane databases were searched to
identify original articles and review articles. The controlled vocabulary of the Medical Subject Headings
(MeSH) database was used alongside a ‘free-text’ protocol, combining ‘male hypogonadism’ with the terms
‘diagnosis’, ‘epidemiology’, ‘investigations’, ‘treatment’, ‘testosterone’, ‘androgens’ and ‘hypogonadism’.
For the 2017 update, a scoping search was performed, covering all areas of the guideline and the search terms
‘hypogonadism’, ‘eugonadal or hypogonadism or hypogonadal or gonadal’, and ‘low or lower testosterone’,
starting from 2011 with a cut-off date of April 2016. Embase, Medline and the Cochrane Central Register
2.2 Review
This document was subject to peer review prior to publication in 2015.
Androgen deficiency increases slightly with age also in healthy men [5, 6]. In middle-aged men, the incidence
of biochemical hypogonadism varies from 2.1-12.8% [7]. The incidence of low testosterone and symptoms of
hypogonadism in men aged 40-79 varies form 2.1-5.7% [6, 7]. Hypogonadism is more prevalent in older men,
in men with obesity, those with co-morbidities, and in men with a poor health status.
3.2 Physiology
Male sexual development starts between the 7th and 12th week of gestation. The undifferentiated gonads
develop into a foetal testis through expression of multiple genes, including the sex-determining region of
the Y chromosome (SRY gene complex) and the SOX genes [9]. The foetal testis produces three hormones:
testosterone, insulin-like peptide 3 (INSL3) and anti-Müllerian hormone (AMH). Testosterone is needed for
the stabilisation of the Wolffian ducts, resulting in formation of the epididymis, vas deferens and seminal
vesicle. Anti-Müllerian hormone activity results in regression of the Müllerian ducts (Figure 1). INSL3, AMH and
testosterone regulate testicular descent.
Under the influence of intratesticular testosterone, the number of gonocytes per tubule increases threefold
during the foetal period [10]. In addition, testosterone is needed for development of the prostate, penis
and scrotum. However, in these organs testosterone is converted into the more potent metabolite
5α-dihydrotestosterone (DHT) by the enzyme 5α-reductase. Testosterone and DHT are required for penile
growth, both activating the androgen receptor [11].
Intratesticular testosterone is needed to maintain the spermatogenic process and to inhibit germ cell apoptosis
[12]. The seminiferous tubules of the testes are exposed to concentrations of testosterone 25-100 times greater
than circulating levels. Suppression of gonadotropins (e.g. through excessive testosterone abuse) results in
a reduced number of spermatozoa in the ejaculate and hypospermatogenesis [13]. Complete inhibition of
intratesticular testosterone results in full cessation of meiosis up to the level of round spermatids [14, 15].
Testosterone does not appear to act directly on the germ cells, but functions through the Sertoli cells by
expression of the androgen receptor (AR) and influencing the seminiferous tubular microenvironment [15].
Summary of evidence
Testosterone is essential for normal male development.
Foetal pituitary
SRY gene complex
SOX genes
LH FSH
Anti-Müllerian
Testosterone INSL3
hormone (AMH)
Regression of the
5α -reductase
Müllerian ducts
Dihydrotestosterone
(DHT)
Differentiation of the
Testicular descent
Wolffian ducts
Differentiation of the
genital tubercle and
the urogenital sinus
Epididymis
External genitalia
Vas deferens
Prostate
FSH = follicle-stimulating hormone; LH = luteinising hormone; SRY = sex determining region of the Y
chromosome; INSL3= insulin-like peptide 3.
3.3 Aetiology
Hypogonadism results from testicular failure, or is due to the disruption of one or several levels of the
hypothalamic-pituitary-gonadal axis (Figure 2).
Male hypogonadism can be classified in accordance with disturbances at the level of:
• the testes (primary hypogonadism);
• the hypothalamus and pituitary (secondary hypogonadism);
• the hypothalamus/pituitary and gonads (common in adult-onset hypogonadism);
• androgen target organs (androgen insensitivity/resistance).
3.4 Classification
3.4.1 Male hypogonadism of testicular origin (primary hypogonadism)
Primary testicular failure is the most frequent cause of hypogonadism and results in low testosterone levels,
impairment of spermatogenesis and elevated gonadotropins (high LH and FSH). The most common clinical
forms of primary hypogonadism are Klinefelter syndrome and testicular tumours.
• Klinefelter syndrome affects 0.2% of the male population. It is the most frequent form of male
hypogonadism and the most common numerical chromosomal aberration, with 47,XXY in 90% of cases
[21]. It arises due to non-disjunction during paternal or maternal meiotic division of germ cells [22].
• Testicular tumours are the most frequent type of cancer in young males after puberty. Risk factors are
contralateral germ cell cancer, maldescended testes, gonadal dysgenesis, infertility, testicular atrophy
and familial germ cell cancer. Twenty-five per cent of men with testicular tumours develop testosterone
deficiency after treatment [23-25].
These disorders are characterised by disturbed hypothalamic secretion (low LH and FSH) or low levels
of gonadatropin-releasing hormone (GnRH). An inborn error of migration and homing of GnRH-secreting
neurons results in Kallmann’s syndrome [27, 28]. The most important symptom is the constitutional delay of
puberty: it is the most common cause of delayed puberty (pubertas tarda) [29]. Other rare forms of secondary
hypogonadism are listed in Table 2.
The classification of hypogonadism has therapeutic implications. In patients with secondary hypogonadism,
hormonal stimulation with hCG and FSH or alternatively pulsatile GnRH treatment can restore fertility in most
cases [34, 35]. Detailed evaluation may, for example, detect pituitary tumours, systemic disease, or testicular
tumours. Combined forms of primary and secondary hypogonadism can be observed in ageing, mostly obese
men, with a concomitant age-related decline in testosterone levels resulting from defects in testicular as well as
hypothalamic-pituitary function.
Recommendation LE GR
Differentiate the two forms of hypogonadism (primary and secondary hypogonadism) 1b B
by determining luteinising hormone and follicle-stimulating hormone levels, as this has
implications for patient evaluation and treatment and makes it possible to identify patients with
associated health problems and infertility.
Testosterone
Hypothalamus
(-)
(+) GnRH
Inhibin B Testosterone
FSH (+) LH
Testosterone
Leydig
Sertoli cells
cells
Germ cells
Testes
Spermatozoa
4. DIAGNOSTIC EVALUATION
Hypogonadism is diagnosed on the basis of persistent signs and symptoms related to androgen deficiency
and assessment of consistently low testosterone levels (on at least two occasions) with a reliable method
[7, 37-40]. It should be noted that over-time there is a substantial portion of men who recover from secondary
hypogonadism, prompting the importance of re-evaluation if testosterone therapy has been instituted in men
without defined hypothalamic or pituitary disease [41].
The most prevalent symptoms of male hypogonadism in ageing men are reduced sexual desire and sexual
activity, erectile dysfunction, loss of vigour and changes in mood [7, 43]. Other factors found associated
with low testosterone are obesity and a poor general health status [7]. Signs and symptoms of androgen
deficiency vary depending on age of onset, duration and the severity of the deficiency. Reference ranges for
the lower normal level of testosterone (2.5%) have been compiled from three large community-based samples,
suggesting a cut-off of 12.1 nmol/L for total serum testosterone and 243 pmol/L for free testosterone, to
distinguish between normal levels and levels possibly associated with deficiency [44]. Symptoms suggesting
the presence of hypogonadism [7, 43] are summarised in Table 3. It should, however, be noted that these
symptoms are also found in men with normal testosterone levels and may have causes other than androgen
deficiency.
In men aged 40-79 years, the threshold for total testosterone was 8 nmol/L for decreased frequency of sexual
thoughts, 8.5 nmol/L for erectile dysfunction, 11 nmol/L for decreased frequency of morning erections and
13 nmol/L for diminished vigour [45, 46]. The strongest predictor for hypogonadism in this age group was three
sexual symptoms (decreased sexual thoughts, weakened morning erections, erectile dysfunction) and either a
total testosterone level of < 8 nmol/L or serum testosterone in the range of 8-11 nmol/L and free testosterone
< 220 pmol/L. These data are based on serum samples taken in the morning, when mean levels are highest
and most reproducible in younger men [47].
Laboratory testing of testosterone should reflect on the diurnal variation of testosterone. In most cases two
morning (7.00 to 11.00) samples are sufficient, but should trigger further evaluation if the difference is > 20%
[48]. Both immunoassay and mass spectrometry based assays can produce reliable results, as long as they
are well-validated. Evaluation should be based on reference ranges for normal men provided by the laboratory
measuring the samples.
In cases with discrepancy between testosterone levels and symptoms, free testosterone (FT) levels should
be analysed. For determination of FT levels, the calculation of FT with the help of the sex hormone binding
globulin (SHBG) is recommended.
Hypogonadism may be more subtle and not always evident by low testosterone levels. For
example, men with primary testicular damage often have normal testosterone levels but high LH. This could
be considered a sub-clinical or compensated form of hypogonadism. The clinical consequences of an isolated
elevation of LH is not clear yet, but potentially, these men may become hypogonadal in the future.
To differentiate between primary and secondary forms of hypogonadism and to clarify
hypogonadism in adult men, determination of LH serum levels is required. Both LH and testosterone serum
levels should be analysed twice within 30 days, preferably in a fasting state [49].
Summary of evidence
The diagnosis of male hypogonadism is based on signs and symptoms of androgen deficiency, together with
consistently low serum testosterone levels.
Recommendations LE GR
Restrict the diagnosis of testosterone deficiency to men with persistent symptoms suggesting 3 C
hypogonadism (Tables 3 and 4).
Measure testosterone in the morning before 11.00 hours, preferably in the fasting state. 2 A
Repeat total testosterone on at least two occasions with a reliable method. In addition, 1 A
measure the free testosterone level in men with:
-- Total testosterone levels close to the lower normal range (8-12 nmol/L), to strengthen the
laboratory assessment.
-- Suspected or known abnormal sex hormone-binding globulin (SHBG) levels.
Assess testosterone in men with a disease or treatment in which testosterone deficiency is 2 B
common and in whom treatment may be indicated.
This includes men with:
-- Sexual dysfunction.
-- Type 2 diabetes.
-- Metabolic syndrome.
-- Obesity.
-- Pituitary mass, following radiation involving the sellar region and other diseases in the
hypothalamic and sellar region.
-- Treatment with medications that cause suppression of testosterone levels - e.g.
corticosteroids and opiates.
-- Moderate to severe chronic obstructive lung disease.
-- Infertility.
-- Osteoporosis or low-trauma fractures.
-- HIV infection with sarcopenia.
Analyse LH serum levels to differentiate between primary and secondary forms of 2 A
hypogonadism.
In addition, testosterone has explicit psychosexual effects, including increased libido. Delayed puberty is
defined as an absence of testicular enlargement at the age of fourteen [56]. As this is a ‘statistical’ definition,
based on reference ranges for the onset of puberty in the normal population, delayed puberty does not
necessarily indicate the presence of a disease. In cases of severe androgen deficiency, the clinical picture of
prepubertal onset hypogonadism is evident (Table 4) and diagnosis and treatment are fairly straightforward. The
major challenge in younger individuals with presumed isolated (congenital) hypogonadotrophic hypogonadism
is to differentiate the condition from a constitutional delay in puberty and to determine when to start androgen
treatment. In milder cases of androgen deficiency, as seen in patients with Klinefelter syndrome, pubertal
development can be normal, incomplete or delayed, resulting in a more subtle phenotypic picture. In these
patients, several clues may lead to a diagnosis of hypogonadism. These include: small testes, (a history of)
cryptorchidism, gynaecomastia, sparse body hair, eunuchoid habitus, low bone mass and sub-fertility [57].
Delayed puberty
Small testes
Cryptorchidism
Gynaecomastia
High-pitched voice
Unclosed epiphyses
Linear growth into adulthood
Eunuchoid habitus
Sparse body hair/facial hair
Infertility
Low bone mass
Sarcopenia
Reduced sexual desire/activity
Depending on the underlying cause of hypogonadism, the decline in gonadal function may be gradual and
partial. The resulting clinical picture may be variable, and the signs and symptoms may be obscured by the
physiological phenotypic variation. Symptoms that have been associated with adult-onset hypogonadism are
summarised in Table 3. Most of these symptoms have a multi-factorial aetiology, are reminiscent of normal
ageing and can also be found in men with completely normal testosterone levels [5]. As a result, signs and
symptoms of adult-onset hypogonadism may be non-specific, and confirmation of a clinical suspicion by
hormonal testing is mandatory. For many of the symptoms mentioned above, the probability of their presence
increases with lower plasma testosterone levels. Most studies indicate a threshold level below which the
prevalence of symptoms starts to increase [43, 58]. This threshold level is near the lower level of the normal
range for plasma testosterone levels in young men, but there appears to be a wide variation between
individuals and, even within one individual, the threshold level may be different for different target organs.
Androgen receptor activity may also contribute to this variance [59, 60].
Recommendations LE GR
Screen for testosterone deficiency only in adult men with consistent and multiple signs and 3 C
symptoms listed in Table 3.
Young men with testicular dysfunction and men older than 50 years of age with low 2 B
testosterone should additionally be screened for osteoporosis.
5. DISEASE MANAGEMENT
5.1 Indications and contraindications for treatment
Testosterone treatment aims to restore testosterone levels to the physiological range in men with consistently
low levels of serum testosterone and associated symptoms of androgen deficiency. The aim of testosterone
treatment is to restore physiological androgen dependent functions and to improve QoL, e.g. sense of well-
being, sexual function, muscle strength and bone mineral density. Table 5 highlights the main indications for
testosterone treatment. Table 6 lists the main contraindications against testosterone treatment.
In adult-onset hypogonadism testosterone treatment may improve symptoms, but many hypogonadal men are
sick and/or obese, and weight reduction, lifestyle modification and good treatment of comorbidities are more
important than just testosterone treatment [74a, 74b].
Testosterone treatment may present several benefits regarding body composition, metabolic control,
psychological and sexual parameters. Observational trials show a correlation between restored physiological
testosterone levels, muscle mass and strength measured as leg press strength and quadriceps muscle volume
[42, 75-77]. Low testosterone levels are common in men with chronic renal failure on haemodialysis and there is
also a worsening of prognosis associated to lower testosterone levels. There, is however, a lack of interventions
studies evaluating eventual benefits of testosterone therapy in this group of men [78]. Similar positive results
are shown in meta-analysis designed to address the value of the role of exogenous testosterone in bone
mineral density: it is evident how testosterone therapy improves mineral density at the lumbar spine producing
a reduction in bone resorption markers. Available trials failed to demonstrate a similar effect at the femoral
neck. At present though, bone mineral density seems to remain a surrogate marker of bone health and there
are no RCTs detailing actual bone fracture risk [76, 79-81]. Improvement in bone mineral density and bone
structure in men with Klinefelter syndrome has also been reported [82]. Body composition is influenced by
testosterone therapy in hypogonadal men, with a consequent decrease of fat mass and an increase in lean
body mass [76, 83]. Men with hypogonadism are at an increased risk of having osteoporosis and osteopenia.
Young men with testicular dysfunction and men older than 50 years of age with low testosterone should
additionally be screened for osteoporosis [84].
Several studies based on testosterone undecanoate, demonstrate a significant reduction in trunk and waist
fat with an evident decrease in waist size [85-87]. In the same trials, testosterone undecanoate administration
showed an improvement in body weight, body mass index and lipid profile after three months of therapy [85].
A strong correlation between decreased testosterone levels and increased cardiovascular mortality has been
reported in meta-analyses and retrospective studies showing that total-testosterone and free-testosterone
in the normal range are related moreover to reduced all-cause mortality [88-94]. It is suggested that low
testosterone is a biomarker for a poor health condition and as such is a marker for increased risk of
cardiovascular disease [95]. Of interest is also the observation that testosterone treatment (transdermal) over
a three year period compared to placebo did not cause any change in dynamics of atherosclerotic plaque
development in the intima media of the carotids [96].
In a small RCT, testosterone therapy did not improve cognitive functions but had a positive effect on verbal
memory and depressive symptoms [104]. Significant improvement of depressive symptoms in men treated
with testosterone undecanoate were reported in a recent randomised trial [67]. Meta-analysis of data from
randomised placebo-controlled trials has shown a significant positive impact of testosterone on mood [105].
Summary of evidence LE
Testosterone treatment may improve symptoms, but many hypogonadal men have a chronic illness 2
and are obese. Weight reduction, lifestyle modification and good treatment of comorbidities can
increase testosterone and reduce associated risks for diabetes and cardiovascular diseases.
Testosterone treatment can improve body composition, bone mineralisation, signs of the metabolic 3
syndrome, male sexual problems, diabetes regulations, memory and depressive symptoms.
A reduction in BMI and waist size, improved glycaemic control and lipid profile are observed in 2a
hypogonadal men receiving testosterone treatment.
Recommendations LE GR
Improve lifestyle, reduce weight in case of obesity and treat comorbidities before starting 3 C
testosterone therapy.
In hypogonadal men with erectile dysfunction start with a PDE5-inhibitor as first line treatment 2 A
and add testosterone in case of a poor response to PDE5i treatment.
Consider testosterone therapy in hypogonadal men with diabetes. 2 B
5.3.1 Preparations
5.3.1.1 Testosterone undecanoate
Testosterone undecanoate (TU) is the most widely used and safest oral delivery system. It rarely causes a rise
in testosterone levels above the mid-range and it is therefore infrequently associated with side-effects [106].
In oral administration, resorption depends on simultaneous intake of fatty food. Testosterone undecanoate is
also available as a long-acting intramuscular injection (with intervals of up to three months). This long period of
action ensures a normal testosterone serum concentration for the entire period, but the relatively long wash-out
period may cause problems if complications appear [109]. In the recent IPASS study, a total worldwide sample
of 1,438 men was evaluated during nine to twelve months of treatment with injectable TU: TU was effective and
well-tolerated, with marked improvements in several psychosexual functions and waist circumference. Adverse
events and adverse drug reactions (more common: increase in hematocrit, increase in PSA, and injection
site pain) were 12% and 6% respectively, mostly mild to moderate, and with no increase in prostate cancer
observed [87].
Human chorionic gonadotropin treatment has higher costs than testosterone treatment. There is insufficient
information about the therapeutic and adverse effects of long-term hCG treatment. This type of treatment
can therefore not be recommended for long-term treatment of male hypogonadism, except in patients in
whom fertility treatment is indicated. Previous testosterone treatment does not seem to affect the efficacy of
gonadotropin therapy [71, 73]. Anti-oestrogens and aromatase inhibitors are further options for hypogonadal
patients with an active child wish, though evidence is limited [123].
Recommendations LE GR
Fully inform the patient about expected benefits and side-effects of the treatment option. 3 A
Select the preparation with a joint decision by an informed patient and the physician.
Use short-acting preparations rather than long-acting depot administration when starting the 3 B
initial treatment, so that therapy can be adjusted or stopped in case of adverse side-effects.
Do not use testosterone therapy in patients with male infertility and active child wish since it 1b A
may suppress spermatogenensis.
Only use human chorionic gonadotropin treatment for hypogonadotrophic hypogonadal 1b B
patients with simultaneous fertility treatment.
In patients with adult-onset hypogonadism, only prescribe testosterone treatment in men with 2 A
multiple symptoms and if weight loss, lifestyle modification and good treatment balance of
comorbidities have proven unsuccessful.
Testosterone treatment is clearly contraindicated in men with advanced prostate cancer. A topic under debate
is the use of testosterone treatment in hypogonadal men with history of prostate cancer and no evidence of
active disease. So far only studies with a limited number of patients and a relatively short period of follow-up
are available and indicate no increased risk for prostate cancer recurrence [134, 135]. According to a recent
retrospective study on hypogonadal men with previous history of prostate cancer receiving testosterone
following cancer diagnosis, treatment was not associated with increased overall or cancer-specific mortality,
but testosterone treatment was more likely to be prescribed in patients undergoing radical prostatectomy for
well-differentiated tumours [136]. No randomised placebo-controlled trials are available yet to document its
long-term safety in these patients [106]. Symptomatic hypogonadal men who have been surgically treated
for localised prostate cancer and who are currently without evidence of active disease (i.e. measurable
PSA, abnormal rectal examination, evidence of bone/visceral metastasis) can be cautiously considered for
testosterone treatment [137]. In these men, treatment should be restricted to those patients with a low risk for
recurrent prostate cancer (i.e. Gleason score < 8; pathological stage pT1-2; pre-operative PSA < 10 ng/ml). It is
advised that therapy should not start before one year of follow-up after surgery and patients should be without
PSA recurrence [138].
Patients who underwent brachytherapy or external beam radiation (EBRT) for low-risk prostate cancer can
also be cautiously considered for testosterone treatment in case of symptomatic hypogonadism with a close
monitoring of prostate cancer recurrence [136, 138, 139], although no long-term safety data are available in
these patients.
Two studies have reported that men with testosterone levels in the upper quartile of the normal range have a
reduced number of cardiovascular events when compared to the combined data from the lower three quartiles
[141, 142]. The knowledge that hypogonadism and erectile dysfunction are biomarkers of cardiovascular
disease demonstrates that patients should be assessed for cardiovascular risk factors and where appropriate
referred to cardiology. Individual cardiovascular risk factors (e.g. lifestyle, diet, exercise, smoking, hypertension,
diabetes, dyslipidaemia) should be treated in men with pre-existing cardiovascular disease. Their secondary
prevention should be optimised as best possible.
Testosterone treatment has also demonstrated in some studies beneficial effects on certain cardiovascular
risk factors [143]. In men with angiographically proven coronary disease those with low testosterone are at
greater risk of mortality [144, 145]. Over many years since testosterone treatment has been available up until
recently, there have been no clinical studies in the medical literature, which have shown concern in regard to
an increased risk of major cardiovascular events (MACE) apart from heart failure [146]. MACE is defined as the
composite of cardiovascular death, non-fatal acute myocardial infarction, acute coronary syndromes, stroke
and cardiac failure. However, three recent studies (one placebo-controlled trial [147] and two observational
studies [148, 149] have suggested that testosterone treatment may be associated with an increased risk of
cardiovascular events. These studies have recently been reviewed by the FDA who concluded that, ‘each of
the studies had major limitations, precluding the ability to draw definitive conclusions’ [150]. These findings are
supported by letters in response to the paper by Vigen et al. [151]. The controversy was fueled also by a meta-
analysis by Xu et al. [152] of 27 small studies involving 2,994 predominantly older men that demonstrated that
testosterone therapy increased the risk for cardiovascular-related events and that the effect of testosterone
therapy was more dependent on the source of funding of the reported trials than on underlying baseline
testosterone levels [153, 154]. However, other studies demostrated that testosterone treatment is at least not
proatherogenic over a wide range of doses [155]. In order to overcome some of the limitations of the analysis
of Xu et al., Corona et al. performed an updated systematic review and meta-analysis of RCTs on testosterone
treatment, using a more conventional definition of cardiovascular events similar to that used by regulatory
authorities to verify the safety of newly registered drugs (including MACE). The results do not support a causal
role between testosterone treatment and adverse cardiovascular events [89].
Recent studies have provided some clarification in regard to the effect of testosterone treatment on
cardiovascular events. A large (n=83,010, follow up mean > 4.7 years) retrospective study of men with low
testosterone that had testosterone replaced to the normal range was associated with a reduction in myocardial
infarction, whereas men treated with testosterone which did not achieve normalisation had no benefit [156]. A
second retrospective analysis of MACE at three years (n=4,736) in men again treated to normalise testosterone
compared groups with low, normal and high testosterone. The result was that normal testosterone reduced
MACE and death [157]. A third large study (population-based matched cohort 10,311 TRT versus 28,029
controls) followed up for five years and reported that men with the highest tertile of testosterone treatment
exposure decreased mortality and cardiovascular events whereas men in the lowest tertile of testosterone
treatment exposure had increased mortality and cardiovascular events [94]. These studies demonstrate that
when testosterone is used adequate replacement should be administered in order to normalise testosterone
levels and that patients are compliant.
The European Medicines Agency (EMA) has stated ‘The Co-ordination Group for Mutual Recognition and
Decentralised Procedures - Human (CMDh), a regulatory body representing EU Member States, has agreed
by consensus that there is no consistent evidence of an increased risk of heart problems with testosterone
medicines in men who lack the hormone (a condition known as hypogonadism). However, the product
information is to be updated in line with the most current available evidence on safety, and with warnings that
the lack of testosterone should be confirmed by signs and symptoms and laboratory tests before treating men
with these medicines.’
Two large retrospective studies have not shown any evidence that testosterone treatment is associated with an
increased incidence of venous thromboembolism [164, 165]. Venous thromboembolism in one study of men
on testosterone treatment reported 42 (38 men) cases, 40 of which had evidence of underlying thrombophilia
(which included Factor V Leiden deficiency, prothrombin mutations, homocysteinuria) of which 39 had their
condition diagnosed after an event [166]. In addition, high endogenous levels of testosterone and/or oestradiol
are not associated with an increased risk of venous thromboembolism [164, 165, 167]. Testosterone treatment
is contraindicated in men with severe chronic cardiac failure as fluid retention may lead to an exacerbation
of the condition. Some studies including one of twelve months duration have shown that men with moderate
chronic cardiac failure (NYHA class III) may benefit from low doses of testosterone, which achieve mid-normal
range testosterone levels [75, 168, 169]. If a decision is made to treat hypogonadism in men with chronic
cardiac failure it is essential that the patient is followed carefully with clinical assessment and testosterone
and hematocrit measurements, on a regular basis. An interesting observation is that testosterone deficiency
increased the re-admission and mortality rate in men with heart failure [93].
Summary of evidence LE
Case reports and small cohort studies point to a possible correlation between testosterone treatment 3
and the onset of breast cancer, but there is as yet a lack of strong evidence for this relationship.
Randomised controlled trials support the hypothesis that testosterone treatment does not result in 1b
changes in prostatic histology.
Recent studies indicate that testosterone treatment does not increase the risk of prostate cancer, but 3
long-term follow-up data are not yet available.
There is no evidence for a relationship between testosterone treatment and obstructive sleep apnoea. 3
There is no substantive evidence that testosterone treatment, when replaced to the normal 1a
physiological range, is related to the development of major adverse cardiovascular events.
In hypogonadal men testosterone treatment has been demonstrated to have a positive impact on 1b
cardiovascular risks [89].
6. FOLLOW-UP
6.1 Monitoring of patients receiving testosterone replacement therapy
Regular follow-up is needed in patients receiving testosterone treatment, as potentially androgen-dependent
symptoms and conditions may occur. The side-effects of testosterone treatment are limited, but their
incidence and clinical relevance is as yet unclear. The primary aim of testosterone treatment is to alleviate the
clinical symptoms of testosterone deficiency. Careful monitoring of changes in the clinical manifestations of
testosterone deficiency should therefore be an essential part of every follow-up visit. Effects of testosterone
treatment on sexual interest may already appear after three weeks of treatment, and reach a plateau at six
weeks [76]. Changes in erectile function and ejaculation may require up to six months [76]. Effects on QoL, and
also on depressive mood, may become detectable within one month, but the maximum effect may take longer
[76].
6.4 Haematocrit
It is important to use only minimal or no venous occlusion when taking a blood sample for haematocrit
measurements [163]. Elevated haematocrit is the most frequent side-effect of testosterone treatment. The
clinical significance of a high haematocrit level is unclear, but it may be associated with hyperviscosity and
thrombosis [167]. The effect of erythropoiesis may become evident at three months and peaks at twelve
months [76].
Recommendations LE GR
Assess the response to testosterone treatment at three, six and twelve months after the onset 4 C
of treatment, and thereafter annually.
Monitor testosterone, haematocrit at three, six and twelve months and thereafter annually. 4 C
Decrease the testosterone dosage or switch testosterone preparation from parenteral to topical
or venesection, if haematocrit is above 0.54. If haematocrit remains elevated, stop testosterone
and reintroduce at a lower dose once haematocrit has normalised.
Assess prostate health by digital rectal examination and prostate-specific antigen (PSA) before 4 C
the start of testosterone replacement therapy (TRT). Follow-up by PSA tests at three, six and
twelve months and thereafter annually.
Assess men with cardiovascular diseases for cardiovascular symptoms before testosterone 1b A
treatment is initiated and continue close clinical assessment during treatment.
7. REFERENCES
1. Phillips, B., et al. Oxford Centre for Evidence-based Medicine Levels of Evidence. Updated by
Jeremy Howick March 2009.
http://www.cebm.net/oxford-centre-evidence-based-medicine-levels-evidence-march-2009/
2. ‘t Hoen L., et al. What are the risks of major cardiovascular events (MACE) from testosterone
replacement therapy (TRT)? PROSPERO: International prospective register of systematic reviews,
2016.
http://www.crd.york.ac.uk/prospero/display_record.asp?src=trip&ID=CRD42016035584
3. Van den Broeck T., et al. What are the benefits and harms of testosterone treatment for male sexual
dysfunction? PROSPERO: International prospective register of systematic reviews, 2015.
http://www.crd.york.ac.uk/PROSPERO/display_record.asp?ID=CRD42015028029
4. Nieschlag, E., et al., Andrology: male reproductive health and dysfunction. 3rd edn. 2010,
Heidelberg.
http://www.springer.com/us/book/9783540783541
5. Kaufman, J.M., et al. The decline of androgen levels in elderly men and its clinical and therapeutic
implications. Endocr Rev, 2005. 26: 833.
https://www.ncbi.nlm.nih.gov/pubmed/15901667
6. Wu, F.C., et al. Hypothalamic-pituitary-testicular axis disruptions in older men are differentially linked
to age and modifiable risk factors: the European Male Aging Study. J Clin Endocrinol Metab, 2008.
93: 2737.
https://www.ncbi.nlm.nih.gov/pubmed/18270261
7. Hall, S.A., et al. Correlates of low testosterone and symptomatic androgen deficiency in a
population-based sample. J Clin Endocrinol Metab, 2008. 93: 3870.
https://www.ncbi.nlm.nih.gov/pubmed/18664536
8. Nieschlag, E., et al., Testosterone: action, deficiency, substitution. 2004, 3rd ed. Cambridge.
http://www.andrology.org/books/37-isa-library/books/114-testosterone-action-deficiency-
substitution
9. Parker, K.L., et al. Genes essential for early events in gonadal development. Cell Mol Life Sci, 1999.
55: 831.
https://www.ncbi.nlm.nih.gov/pubmed/10412366
8. CONFLICT OF INTEREST
All members of the EAU Male Hypogonadism Guidelines Panel have provided disclosure statements on all
relationships that they have that might be perceived to be a potential source of a conflict of interest. This
information is publically accessible through the European Association of Urology website: http://www.uroweb.
org/guideline/. This guidelines document was developed with the financial support of the European Association
of Urology. No external sources of funding and support have been involved. The EAU is a non-profit
organisation, and funding is limited to administrative assistance and travel and meeting expenses. No honoraria
or other reimbursements have been provided.
2. METHODS 6
2.1 Introduction 6
2.2 Review 6
3. THE GUIDELINE 7
3.1 Classification 7
3.2 Antimicrobial stewardship 7
3.3 Asymptomatic bacteriuria in adults 8
3.3.1 Evidence question 8
3.3.2 Background 8
3.3.3 Epidemiology, aetiology and pathophysiology 8
3.3.4 Diagnostic evaluation 8
3.3.5 Evidence summary 8
3.3.6 Disease management 9
3.3.6.1 Patients without identified risk factors 9
3.3.6.2 Patients with ABU and recurrent UTI, otherwise healthy 9
3.3.6.3 Pregnant women 9
3.3.6.3.1 Is treatment of ABU beneficial in pregnant women? 9
3.3.6.3.2 Which treatment duration should be applied to treat
ABU in pregnancy? 9
3.3.6.3.2.1 Single dose vs. short course treatment 10
3.3.6.4 Patients with identified risk-factors 10
3.3.6.4.1 Diabetes mellitus 10
3.3.6.4.2 ABU in post-menopausal women 10
3.3.6.4.3 Elderly institutionalised patients 10
3.3.6.4.4 Patients with renal transplants 10
3.3.6.4.5 Patients with dysfunctional and/or reconstructed
lower urinary tracts 10
3.3.6.4.6 Patients with catheters in the urinary tract 11
3.3.6.4.7 Patients with ABU subjected to catheter
placements/exchanges 11
3.3.6.4.8 Immuno-comprised and severely diseased patients,
patients with candiduria 11
3.3.6.5 Prior to urological surgery 11
3.3.6.6 Prior to orthopaedic surgery 11
3.3.6.7 Pharmacological management 11
3.3.7 Follow-up 11
3.3.8 Recommendations for the management of ABU 12
3.4 Uncomplicated cystitis 12
3.4.1 Introduction 12
3.4.2 Epidemiology, aetiology and pathophysiology 12
3.4.3 Diagnostic evaluation 12
3.4.3.1 Clinical diagnosis 12
3.4.3.2 Differential diagnosis 12
3.4.3.3 Laboratory diagnosis 12
3.4.3.4 Recommendations for the diagnostic evaluation
of uncomplicated cystitis 13
3.4.4 Disease management 13
3.4.4.1 Cystitis in pregnancy 13
3.4.4.2 Cystitis in men 13
3.4.4.3 Renal insufficiency 14
3.4.4.4 Recommendations for antimicrobial therapy for
uncomplicated cystitis 14
4. REFERENCES 40
5. CONFLICT OF INTEREST 63
2. METHODS
2.1 Introduction
For the 2017 Urological Infections Guidelines, specific chapters were updated based on systematic reviews of
topics or questions prioritised by the Guideline Panel. These reviews were performed using standard Cochrane
systematic review methodology, http://www.cochranelibrary.com/ about/about-cochrane-systematicreviews.
html.
Systematic review results for the following evidence questions are included in the 2017 Urological Infections
Guidelines:
1. What is the most effective management for adults with asymptomatic bacteriuria [3]?
2. What is the best antimicrobial prophylaxis strategy to reduce risk of infectious complication
of prostate biopsy [4]?
References used in this text are graded according to their level of evidence (LE) and Guidelines are given
a grade of recommendation (GR), according to a classification system modified from the Oxford Centre
for Evidence-Based Medicine Levels of Evidence [5]. Additional information can be found in the general
Methodology section of this print, and online at the EAU website: http://www.uroweb.org/guideline/. A list of
associations endorsing the EAU Guidelines can also be viewed online at the above address.
2.2 Review
This document was subject to independent peer review prior to publication in 2015 and 2016.
Cystitis
Recurrent UTI
Catheter-associated UTI
Urosepsis
The following classification of UTIs is adopted in the EAU Urological Infections Guidelines:
Classification of UTI
Uncomplicated UTIs Acute, sporadic or recurrent lower (uncomplicated cystitis) and/or
upper (uncomplicated pyelonephritis) UTI, limited to non-pregnant, pre-
menopausal women with no known anatomical and functional abnormalities
within the urinary tract or comorbidities.
Complicated UTIs All UTIs which are not defined as uncomplicated. Meaning in a narrower
sense UTIs in a patient with an increased chance of a complicated course:
i.e. all men, pregnant women, patients with anatomical or functional
abnormalities of the urinary tract, indwelling urinary catheters, renal
diseases, and/or with other concomitant immunocompromising diseases for
example, diabetes.
Recurrent UTIs Recurrences of uncomplicated and/or complicated UTIs, with a frequency of
at least three UTIs/year or two UTIs in the last six months.
Catheter-associated UTIs Catheter-associated urinary tract infection (CA-UTI) refers to UTIs occurring
in a person whose urinary tract is currently catheterised or has been
catheterised within the past 48 hours.
Urosepsis A systemic, deleterious host response to infection originating from the
urinary tract and/or male genital organs. Urosepsis is accompanied by signs
of systemic inflammation, presence of symptoms of organ dysfunction and
persistent hypotension associated with tissue anoxia.
Several studies in hospital settings have shown that regular ward visits and audit of practice by infectious
disease physicians markedly reduce overall use of antimicrobial agents by promoting shorter duration of
therapy, earlier step-down to oral medication and avoidance of antimicrobial use when patient outcome is
unlikely to be compromised [16, 17]. Studies specific to the urology setting are lacking but a case-control
study showed reduction in antimicrobial usage and bacterial resistance in hospitalised urology patients
when EAU Guidelines on peri-operative prophylaxis were adhered to, without change in the rate of infectious
complications [18].
3.3.2 Background
Urinary growth of bacteria in an asymptomatic individual, asymptomatic bacteriuria (ABU), is common,
and relates to commensal colonisation [19]. Clinical studies have shown that ABU may protect against
superinfecting symptomatic UTI, therefore, treatment of ABU should be performed only in cases of proven
benefit for the patient to avoid the risk of selecting for antimicrobial resistance and eradicating a potentially
protective ABU strain [20, 21]. The aim of this section is to support the clinician in deciding when ABU should
or should not be treated.
Nine studies compared single dose to short course treatment [28, 34, 35, 40, 41, 46, 47, 49, 53], one study
compared single dose to long course treatment [52] and one study compared long course to continuous
treatment [56]. As long term and continuous antibiotic treatment is not used in current practice, only studies
comparing single dose to standard short course treatment are presented.
3.3.7 Follow-up
There are no studies focusing on follow-up after treatment of ABU. However, if the resolution of ABU has
a clinical significance (e.g. in pregnancy), follow-up with subsequent urine culture is needed to secure the
treatment effect.
Recommendations LE GR
Do not screen or treat asymtomatic bacteriuria in the following conditions:
• women without risk factors; 2a A*
• patients with well-regulated diabetes mellitus; 1b A
• post-menopausal women; 1a A
• elderly institutionalised patients; 1a A
• patients with dysfunctional and/or reconstructed lower urinary tracts; 2b B
• patients with catheters in the urinary tract; 4 C
• patients with renal transplants; 1b A
• patients prior to arthoplasty surgeries; 1b A
• patients with recurrent urinary tract infections. 1b A
Screen for and treat asymptomatic bacteriuria prior to urological procedures breaching the 1a A
mucosa.
Screen for and treat asymptomatic bacteriuria in pregnant women with standard short course 1a A
treatment.
Take a urine culture following treatment of asymptomatic bacteriuria to secure treatment effect. 4 C
* Upgraded based on panel consensus
A colony count of 103 cfu/mL of uropathogens is microbiologically diagnostic in women who present
with symptoms of uncomplicated cystitis [112]. Women who present with atypical symptoms of either
uncomplicated cystitis or uncomplicated pyelonephritis, as well as those who fail to respond to appropriate
antimicrobial therapy should be considered for additional diagnostic studies.
Recommendations LE GR
Diagnose uncomplicated cystitis based on: 2a B
• a focused history of lower urinary tract symptoms (dysuria, frequency and urgency);
• the absence of vaginal discharge or irritation, in women who have no other risk factors for
complicated urinary tract infections.
Use urine dipstick testing, as an alternative to culture for diagnosis of acute uncomplicated 2a B
cystitis.
Urine cultures should be done in the following situations: 4 B*
• suspected acute pyelonephritis;
• symptoms that do not resolve or recur within two-four weeks after the completion of
treatment;
• women who present with atypical symptoms;
• pregnant women.
* Upgraded based on panel consensus
According to these principles and the available susceptibility patterns in Europe, fosfomycin trometamol 3 g
single dose, pivmecillinam 400 mg three times a day for three to five days, and nitrofurantoin macrocrystal
100 mg twice daily for 5 days, are considered as drugs of first choice, when available [114-116].
Alternative antimicrobials include trimethoprim alone or combined with a sulphonamide.
Co-trimoxazole (160/800 mg twice daily of three days) or trimethoprim (200 mg twice daily for five days) should
only be considered as drugs of first choice in areas with known resistance rates for E. coli of < 20% [117, 118].
Despite lower resistance rates in certain countries, fluoroquinolones are not considered first choice because of
adverse effects including negative ecological effects and selection for resistance.
Aminopenicillins are no longer suitable for empirical therapy because of worldwide high E. coli
resistance. Aminopenicillins in combination with a beta-lactamase inhibitor such as ampicillin/sulbactam or
amoxicillin/clavulanic acid and oral cephalosporins are in general not effective as short-term therapy and are
not recommended for empirical therapy due to ecological collateral damage, but may be used in selected
cases [119, 120].
Recommendations
Antimicrobial Daily dose Duration of Comments LE GR
therapy
First choice
Fosfomycin trometamol 3 g SD 1 day Recommended in women not men. 1 A
Nitrofurantoin 100 mg b.i.d 5 days
macrocrystal
Pivmecillinam 400 mg t.i.d 3-5 days
Alternatives
Cephalosporins (e.g. 500 mg b.i.d 3 days Or comparable. 1b B
cefadroxil)
If the local resistance pattern for E. coli is < 20%
Trimethoprim 200 mg b.i.d 5 days Not in the first trimenon of 1b B
pregnancy.
Trimethoprim- 160/800 mg b.i.d 3 days Not in the last trimenon of
sulphamethoxazole pregnancy.
Treatment in men
Trimethoprim- 160/800 mg b.i.d 7 days Restricted to men, fluoroquinolones 4 C
sulphamethoxazole can also be prescribed in
accordance with local susceptibility
testing.
SD = single dose; b.i.d = twice daily; t.i.d = three times daily.
3.4.5 Follow-up
Routine post-treatment urinalysis or urine cultures in asymptomatic patients are not indicated [123]. In women
whose symptoms do not resolve by end of treatment, and in those whose symptoms resolve but recur within
two weeks, urine culture and antimicrobial susceptibility testing should be performed [124]. For therapy in
this situation, one should assume that the infecting organism is not susceptible to the agent originally used.
Retreatment with a seven day regimen using another agent should be considered [124].
Recommendations LE GR
Do not perform an extensive routine workup in women with recurrent UTI without risk factors. 1b B
Advise patients on behavioural modifications which might reduce the risk of recurrent UTI. 3 C
Use vaginal oestrogen replacement in post-menopausal women to prevent recurrent UTI. 1b A
Use immunoactive prophylaxis to reduce recurrent UTI in all age groups. 1a A
When non-antimicrobial interventions have failed, continuous or post-coital antimicrobial 2b B
prophylaxis should be used to prevent recurrent UTI, but patients should be counselled
regarding possible side effects.
For patients with good compliance, self-administrated short term antimicrobial therapy should 2b A*
be considered.
* Upgraded based on panel consensus.
Recommendations LE GR
Perform urinalysis (e.g. using a dipstick method), including the assessment of white and red 4 A*
blood cells and nitrite, for routine diagnosis.
Perform urine culture and antimicrobial susceptibility testing in patients with pyelonephritis. 4 A*
Perform ultrasound of the upper urinary tract to exclude obstructive pyelonephritis. 4 A*
Additional imaging investigations, such as an unenhanced helical computed tomography 4 A*
should be done if the patient remains febrile after 72 hours of treatment or in patients with
suspected complications e.g. sepsis.
*Upgraded based on panel consensus.
Recommendations
Antimicrobial Daily dose Duration of LE GR Comments
therapy
Ciprofloxacin 500-750 mg 7-10 days 1b B Fluoroquinolone resistance should be
b.i.d less than 10 percent.
Levofloxacin 750 mg q.d 5 days 1b B
Trimethoprim 160/800 mg b.i.d 7-14 days 1b B If such agents are used empirically,
sulphamethoxazol an initial intravenous dose of a long-
Cefpodoxime 200 mg b.i.d 10 days 4 B* acting parenteral antimicrobial (e.g.
Ceftibuten 400 mg q.d 10 days 4 B* ceftriaxone) should be administered.
*Upgraded based on panel consensus.
b.i.d = twice daily; q.d = every day.
Recommendations
Antimicrobials Daily dose LE GR Comments
Ciprofloxacin 400 mg b.i.d 1b B
Levofloxacin 750 mg q.d 1b B
Cefotaxime 2 g t.i.d 2 A* Not studied as monotherapy in acute
Ceftazidime 1-2 g t.i.d 2 A* uncomplicated pyelonephritis.
Co-amoxiclav 1.5 g t.i.d 2 C Not studied as monotherapy in acute
uncomplicated pyelonephritis. Mainly for Gram-
positive pathogens.
Ceftriaxone 1-2 g q.d 1b A* Lower dose studied, but higher dose
Cefepime 1-2 g b.i.d 1b B recommended. Same protocol for acute
Piperacillin/tazobactam 2.5-4.5 g t.i.d 1b A* uncomplicated pyelonephritis and complicated
UTI (stratification not always possible).
Ceftolozane/tazobactam 1.5 g t.i.d 1b B
Ceftazidime/avibactam 2.5 g t.i.d 1b B
Gentamicin 5 mg/kg q.d 1b B Not studied as monotherapy in acute
Amikacin 15 mg/kg q.d 1b B uncomplicated pyelonephritis.
Ertapenem 1 g q.d 1b B Same protocol for acute uncomplicated
Imipenem/cilastatin 0.5/0.5 g t.i.d 1b B pyelonephritis and complicated UTI (stratification
Meropenem 1 g t.i.d 2 B not always possible).
Doripenem 0.5 g t.i.d 1b B
* Upgraded based on panel consensus.
b.i.d = twice daily; t.i.d = three times daily; q.d = every day.
In pregnant women with pyelonephritis, outpatient management with appropriate antimicrobials may also be
considered, provided symptoms are mild and close follow-up is feasible [151, 152]. In more severe cases of
pyelonephritis, hospitalisation and supportive care are usually required. After clinical improvement parenteral
therapy can also be switched to oral therapy for a total treatment duration of seven to ten days. In men
with febrile UTI, pyelonephritis, or recurrent infection, or whenever a complicating factor is suspected a
minimum treatment duration of two weeks is recommended, preferably with a fluoroquinolone since prostatic
involvement is frequent [153].
3.6.4 Follow-up
Routine post-treatment urinalysis or urine cultures in asymptomatic patients are not indicated, except in
pregnant women, if asymptomatic bacteriuria is an issue (see section 3.3.6.3).
Recommendations LE GR
Do not use amoxicillin, co-amoxiclav, trimethoprim and trimethoprim-sulphamethoxazole for 2 A
empirical treatment of complicated UTI.
Use the combination of: 2 A
• amoxicillin plus an aminoglycoside;
• a second generation cephalosporin plus an aminoglycoside;
• a third generation cephalosporin intravenously as empirical treatment of complicated UTI
with systemic symptoms.
Only use ciprofloxacin provided that the local resistance percentages are < 10% when; 2 A
• the entire treatment is given orally;
• patients do not require hospitalisation;
• patient has an anaphylaxis for beta-lactam antimicrobials.
Do not use ciprofloxacin and other fluoroquinolones for the empirical treatment of complicated 2 A
UTI in patients from the urology department or when patients have used fluoroquinolones in
the last six months.
Use an initial one-time intravenous dose of a long-acting antimicrobial, such as a third 2 A
generation cephalosporin or an aminoglycoside if the prevalence of fluoroquinolone resistance
is thought to be > 10% and resistance data are pending.
If the prevalence of fluoroquinolone resistance is thought to be > 10% and the patient has 2 A
contra indications for third generation cephalosporins or an aminoglycoside, ciprofloxacin can
be prescribed as an empirical treatment in women with uncomplicated pyelonephritis.
In the event of hypersensitivity to penicillin, a third generation cephalosporin can still be 2 A
prescribed, with the exception of systemic anaphylaxis in the past.
In patients with a UTI with systemic symptoms, empirical treatment should cover ESBL in the 2 A
initial treatment only in patients who are colonised with ESBL-producing micro-organisms. The
resistance pattern of the ESBL strain should guide empirical therapy.
ESBL = Extended-spectrum beta-lactamase.
Recommendations LE GR
Do not carry out routine urine culture in an asymptomatic catheterised patients. 1a A
Do not use pyuria as an indicator for catheter-associated UTI. 2 A
Do not use the presence, absence, or degree of pyuria to differentiate catheter-associated 2 A
asymptomatic bacteriuria from catheter-associated UTI.
Do not use the presence or absence of odorous or cloudy urine alone to differentiate catheter- 3 C
associated asymptomatic bacteriuria from catheter-associated UTI.
Recommendations LE GR
Take a urine culture prior to initiating antimicrobial therapy in catheterised patients in whom the 3 A*
catheter has been removed.
Do not treat catheter-associated asymptomatic bacteriuria in general. 1a A
Treat catheter-associated asymptomatic bacteriuria prior to traumatic urinary tract 1a A
interventions (e.g. transurethral resection of the prostate).
Replace or remove the indwelling catheter before starting antimicrobial therapy. 4 B*
Do not apply topical antiseptics or antimicrobials to the catheter, urethra or meatus. 1a A
Do not use prophylactic antimicrobials to prevent catheter-associated UTIs. 1a A
The duration of catheterisation should be minimal. 2a B
Remove an indwelling catheter after non-urological operation within the same day. 1b B
Change long-term indwelling catheters at intervals adapted to the individual patient. 3 C
* Upgraded based on panel consensus.
3.9 Urosepsis
3.9.1 Introduction
Patients with urosepsis should be diagnosed at an early stage, especially in the case of a cUTI. Systemic
inflammatory response syndrome (SIRS), characterised by fever or hypothermia, hyperleukocytosis or
leukopenia, tachycardia and tachypnoea, is recognised as the first event in a cascade leading to multi-organ
failure (Figure 2). Mortality is considerably increased the more severe the sepsis is.
The treatment of urosepsis involves adequate life-supporting care, appropriate and prompt
antimicrobial therapy, adjunctive measures and the optimal management of urinary tract disorders [172]. The
decompression of any obstruction and drainage of larger infectious abscess in the urinary tract is essential as
first-line focus control [172]. Urologists are recommended to treat patients in collaboration with intensive care
and infectious diseases specialists.
Urosepsis is seen in both community-acquired and healthcare associated infections. Nosocomial
urosepsis may be reduced by measures used to prevent nosocomial infection, e.g. reduction of hospital stay,
early removal of indwelling urethral catheters, avoidance of unnecessary urethral catheterisation, correct use of
closed catheter systems, and attention to simple daily aseptic techniques to avoid cross-infection.
Sepsis is diagnosed when clinical evidence of infection is accompanied by signs of systemic
inflammation, presence of symptoms of organ dysfunction and persistent hypotension associated with tissue
anoxia.
Disorder Definition
Systematic inflammatory response Response to a wide variety of clinical insults, which can be infectious,
syndrome (SIRS) as in sepsis but may also be non-infectious in aetiology (e.g. burns, or
pancreatitis). This systemic response is manifested by two or more of
the following criteria:
• temperature > 38°C or < 36°C;
• heart rate > 90 bpm;
• respiratory rate > 20 breaths/min or PaCO2 < 32 mmHg
(< 4.3 kPa);
• white blood cell count > 12,000 cells/mm3 or < 4,000 cells/mm3 or
> 10% immature (band) forms.
Sepsis Life-threatening organ dysfunction caused by a dysregulated host
response to infection. For clinical application, organ dysfunction can
be represented by an increase in the Sequential [Sepsis-related] Organ
Failure Assessment (SOFA) score of 2 points or more.
3.9.5.2 Treatment
During the first six hours of resuscitation, the goals of initial resuscitation of sepsis-induced hypoperfusion
should include all of the following:
• central venous pressure (CVP) 8-12 mmHg;
• mean arterial pressure (MAP) 65-90 mmHg;
• central venous oxygen (CVO2) > 70%;
• haematocrit (HKT) > 30 %;
• urine output > 0.5 mL/kg/hr.
Early goal-directed resuscitation was initially shown to improve survival for emergency department patients
presenting with septic shock in a randomised, controlled, single-centre study [189]. However, recent follow up
studies in an improved emergency medicine background have not achieved positive effects with this strategy
[190-192].
Recommendations
Antimicrobials Daily dose LE GR Comments
Cefotaxime 2 g t.i.d 2 A* Not studied as monotherapy in acute
Ceftazidime 1-2 g t.i.d 2 A* uncomplicated pyelonephritis.
Ceftriaxone 1-2 g q.d 1b A* Lower dose studied, but higher dose
Cefepime 1-2 g b.i.d 1b B recommended. Same protocol for acute
Piperacillin/tazobactam 2.5-4.5 g t.i.d 1b A* uncomplicated pyelonephritis and complicated
UTI (stratification not always possible).
Ceftolozane/tazobactam 1.5 g t.i.d 1b B
Ceftazidime/avibactam 2.5 g t.i.d 1b B
Gentamicin 5 mg/kg q.d 1b B Not studied as monotherapy in acute
Amikacin 15 mg/kg q.d 1b B uncomplicated pyelonephritis.
Ertapenem 1 g q.d 1b B Same protocol for acute uncomplicated
Imipenem/cilastatin 0.5/0.5 g t.i.d 1b B pyelonephritis and complicated UTI (stratification
Meropenem 1 g t.i.d 2 B not always possible).
Doripenem 0.5 g t.i.d 1b B
* Upgraded based on panel consensus.
b.i.d = twice daily; t.i.d = three times daily; q.d = every day.
In conclusion, sepsis syndrome in urology remains a severe situation with an considerable mortality rate. A
recent campaign, ‘Surviving Sepsis Guidelines’, aims to reduce mortality by 25% in the next years [172, 193].
Early recognition of the symptoms may decrease the mortality by timely treatment of urinary tract disorders,
e.g. obstruction, or urolithiasis. Adequate life-support measures and appropriate antimicrobial treatment
provide the best conditions for improving patient survival. The prevention of sepsis syndrome is dependent on
good practice to avoid nosocomial infections and using antimicrobial prophylaxis and therapy in a prudent and
well-accepted manner.
6h 1h
Clinical status indicative of No
Observation
severe sepsis
General ward
Yes
Systematic inflammatory No
response syndrome Observation
criteria positive
Yes
Microbiology investigation
(urine & blood analysis/culture)
3. Transfer to alternative
Yes department
Yes
Source control
3.10 Urethritis
3.10.1 Introduction
Inflammation of the urethra presents usually with symptoms of the LUT and must be distinguished from other
infections of the LUT. The following recommendations are based on a review of several European national
guidelines and are aligned with the CDC’s guidelines on sexual transmitted diseases (STDs) [194-197].
Recommendations LE GR
Use a gram stain of urethral discharge or a urethral smear to preliminarily diagnosis pyogenic 3 B
urethritis.
Use a validated nucleic acid amplification tests to diagnosis chlamydial and gonococcal 3 B
infections.
3.10.5 Follow-up
Patients should be followed-up for control of eradication or if symptoms persist or recur after completion
of therapy. Patients should be instructed to abstain from sexual intercourse for seven days after therapy is
initiated, provided their symptoms have resolved and their sexual partners have been adequately treated.
Reporting and source tracing should be done in accordance with national guidelines and in co-operation with
specialists in venereology, whenever required. Persons who have been diagnosed with a new STD should
receive testing for other STDs, including syphilis and HIV.
Recommendations LE GR
Perform digital rectal examination to assess the condition of the prostate. 4 A*
Take a mid-stream urine culture in patients with acute prostatitis-related symptoms for 3 A*
diagnosis and targeted treatment planning.
Perform the Meares and Stamey four-glass test in patients with chronic bacterial prostatitis. 2b B
Accurate microbiological evaluation for atypical pathogens such as Chlamydia trachomatis or 2b B
Mycoplasmata is recommended in patients with chronic bacterial prostatitis.
Perform transrectal ultrasound only in selected cases to rule out the presence of prostatic 3 B
abscess, calcification in the prostate and dilatation of the seminal vesicles.
Ejaculate analysis and prostate specific antigen measurement should not be performed as 3 B
routine, due to the high number of false positive results.
*Upgraded based on panel consensus.
3.11.7 Follow-up
In asymptomatic post-treatment patients routine urinalysis and/or urine culture is not mandatory. The Meares
and Stamey four-glass test should be repeated in patients representing with persistent symptoms. In patients
with persistent symptoms and repeated positive microbiological results for sexually transmitted infectious
pathogens, microbiological screening of the patients partner(s) is recommended [218, 232].
Empiric antibiotic regimens from existing guidelines [249-251] and panel consensus:
1. For men with acute epididymitis at low risk of gonorrhoea (e.g. no discharge) a single agent
or combination of two agents of sufficient dose and duration to eradicate C. trachomatis and
Enterobacteriaceae should be used. Appropriate options are:
A. A fluoroquinolone active against C. trachomatis orally once daily for ten to fourteen days*
OR
B. Doxycycline 200 mg initial dose by mouth and then 100 mg twice daily for ten to fourteen
days* plus an antibiotic active against Enterobacteriaceae** for ten to fourteen days*
3. or non-sexually active men with acute epididymitis a single agent of sufficient dose and duration
F
to eradicate Enterobacteriaceae should be used. Appropriate option is a fluoroquinolone by mouth
once daily for ten to fourteen days*
Surgical exploration may be required to drain abscesses or debride tissue. A comparative cohort study found
that lack of separation of epididymis and testis on palpation and the presence of abscess on US may predict
requirement for surgery following initial antibiotic treatment [252].
A cohort study found semen parameters may be impaired during epididymitis but recovered
following successful treatment [255]. Comparative clinician cohort studies suggest adherence to guidelines
for assessment and treatment of epididymitis is low, particularly by urologists compared to sexual health
specialists [253] and by primary care physicians [254].
Recommendations LE GR
Obtain a mid-stream urine and first voided urine for pathogen identification. 3 A*
Initially prescribe a single antibiotic or a combination of two antibiotics active against 3 A*
Chlamydia trachomatis and Enterobacteriaceae in young sexually active men; in older men
without sexual risk factors only Enterobacteriaceae have to be considered.
If gonorrhoeal infection is likely, give single dose ceftriaxone 500 mg intramuscularly in addition 3 A*
to a course of an antibiotic active against Chlamydia trachomatis.
Adjust antibiotic agent when pathogen has been identified and adjust duration according to 3 A*
clinical response.
Follow national policies on reporting and tracing/treatment of contacts for sexually transmitted 3 A*
infections.
* Upgraded based on Panel consensus.
Mid-stream urine
Urethral swab/smear
Failure to respond or
abscess present First voided urine for nucleic
acid amplification test (NAAT)
Scrotal
ultrasound Single antibiotic or a combination of Ceftriaxone 500mg IM
examination two antibiotics active against plus a course of an
Clinical Chlamydiat rachomatis and antibiotic active against
Assesment Enterobacteriaceae Chlamydia trachomatis
3.13.2.1 Microbiology
Fournier’s gangrene is typically a type 1 necrotising fasciitis that is polymicrobial in origin, including S.aureus,
Streptococcus sp., Klebsiella sp., E. coli and anerobes; involvement of Clostridium sp. is now less common
[258, 260, 262]. These organisms secrete endotoxins causing tissue necrosis and severe cardiovascular
impairment. Subsequent inflammatory reaction by the host contributes to multi-organ failure and death if
untreated.
Recommendations LE GR
Commence full, repeated, surgical debridement within 24 hours of presentation. 3 B
Start treatment with broad-spectrum antibiotics on presentation, with subsequent refinement 3 A*
according to culture and clinical response.
Do not use adjunctive treatments such as pooled immunoglobulin and hyperbaric oxygen, 3 A*
except in the context of clinical trials.
* Upgraded based on panel consensus.
3.14.2 Background
Identifying bacteriuria prior to diagnostic and therapeutic procedures aims to reduce the risk of infectious
complications by controlling any pre-operative detected bacteriuria and to optimise antimicrobial coverage
in conjunction with the procedure. However, the absence of bacteriuria by itself is not an assurance against
infectious complications and antimicrobial prophylaxis according to section 3.15 is recommended.
The standard method, laboratory culture of an appropriate urine sample, is time consuming and
logistically difficult. Alternative rapid near-patient methods such as reagent strip (dipstick) urinalysis, automated
microscopy, flow cytometry, and dipslide culture have been developed but their diagnostic accuracy is
uncertain.
Recommendation LE GR
Laboratory urine culture is the recommended method to determine the presence or absence of 3 B
clinically significant bacteriuria in patients prior to undergoing urological interventions.
3.15.4.1.2 Cystoscopy
The frequency of infectious complications after cystoscopy, standard urodynamic studies and diagnostic
simple ureteroscopy in otherwise healthy individuals with sterile pre-operative urine is low [301-303]. In view of
the very large number of cystoscopic examinations, the low infectious risk and the potential adverse effect on
bacterial sensitivity, AMP is not recommended. However, bacteriuria, indwelling catheters, neurogenic LUTD
and a history of urogenital infection are risk factors that must be considered [304-317].
3.15.4.2.3 Ureteroscopy
Well-conducted prospective controlled trials on ureteroscopy are lacking. It is reasonable, however, to
distinguish low-risk procedures, such as simple diagnostic and distal stone treatment in otherwise healthy
individuals, from higher-risk procedures, such as treatment of proximal impacted stones with obstruction.
Therefore the present Guidelines recommend clinicians choose the appropriate AMP regime based on the
degree of severity, stone anatomic position and patient related risk factors, all of which are supported by a
large database study [321].
3.15.4.5 Prostatectomy
In open enucleation of prostatic adenoma, the risk of post-operative infection is particularly high and AMP
is recommended [346]. As there are no studies on AMP in radical prostatectomy the use of AMP may be
considered optional.
3.15.4.8 Implantation of prosthetic devices: testis, penile prosthesis and artificial sphincter
Antimicrobial prophylaxis is recommended. When infectious complications occur in implant surgery, they are
usually problematic and often result in removal of the prosthetic device. Diabetes mellitus is considered a
specific risk factor for infection. Skin-related staphylococci are responsible for most infections, AMP used must
be chosen to target these strains [351-354].
Recommendations
Procedure Comments Antimicrobial prophylaxis LE GR
Diagnostic procedures
Cystoscopy Low frequency of infection. No 1b A
Consider individual risk factors for
UTI (i.e. asymptomatic bacteriuria,
history of febrile UTI)
Urodynamic study Low frequency of infections. No 1a A
Consider individual risk factors for
UTI (i.e. asymptomatic bacteriuria,
history of febrile UTI)
Transrectal core biopsy High risk of infection Fluoroquinolones Trimethoprim 1b A
of prostate ± sulphamethoxazole
Targeted alternative
Diagnostic No available studies Optional 4 C
ureteroscopy
Common endourological/endoscopic therapeutic procedures (examples)
Fulguration of small Low frequency of infections. Optional 2b C
bladder tumours
Transurethral resection Poor data. No concern given Trimethoprim ± 2b C
of the bladder to burden of tumour, i.e. size, sulphamethoxazole
multiplicity, necrosis Aminopenicillin/ Beta-lactamase
Transurethral resection High risk of infection inhibitor 1a A
of the prostate Cephalosporin group 2 or 3
Shock-wave lithotripsy Low frequency of infections 1a A
Ureteroscopy for stone Distal stone removal. 2b B
management
Percutaneous and High risk of infection 1b A
retrograde intra-renal
stone management
Common open and/or laparoscopic surgery
Nephrectomy ± Surgical site infection/wound Optional 3 C
ureterectomy infection poorly documented
Adrenalectomy Secondary post-operative catheter-
Radical prostatectomy related asymptomatic bacteriuria/
UTI
Planned scrotal Conflicting data No 3 C
surgery, vasectomy,
surgery for varicocele
Recommendation LE GR
Use rectal cleansing with povidone-iodine in men prior to transrectal prostate biopsy. 1a B*
*Downgraded as highest quality trial in meta-analysis showed no difference [391].
Recommendation LE GR
Use antimicrobial prophylaxis in men prior to transrectal prostate biopsy. 1a A
5. CONFLICT OF INTEREST
All members of the EAU Urological Infections Guidelines Panel have provided disclosure statements on all
relationships that they have that might be perceived to be a potential source of a conflict of interest. This
information is publically accessible through the EAU website: http://www.uroweb.org/guidelines/. These
Guidelines were developed with the financial support of the EAU. No external sources of funding and support
have been involved. The EAU is a non-profit organisation, and funding is limited to administrative assistance
and travel and meeting expenses. No honoraria or other reimbursements have been provided.
2. METHODS 6
2.1 Data identification 6
2.2 Review 7
2.3 Future goals 7
3. GUIDELINES 7
3.1 Prevalence, aetiology, risk of recurrence 7
3.1.1 Introduction 7
3.1.2 Stone composition 7
3.1.3 Risk groups for stone formation 8
3.2 Classification of stones 9
3.2.1 Stone size 9
3.2.2 Stone location 9
3.2.3 X-ray characteristics 9
3.3 Diagnostic evaluation 10
3.3.1 Diagnostic imaging 10
3.3.1.1 Evaluation of patients with acute flank pain/suspected ureteral stones 10
3.3.1.2 Radiological evaluation of patients with renal stones 11
3.3.2 Diagnostics - metabolism-related 11
3.3.2.1 Basic laboratory analysis - non-emergency urolithiasis patients 11
3.3.2.2 Analysis of stone composition 11
3.3.3 Diagnosis in special groups and conditions 12
3.3.3.1 Diagnostic imaging during pregnancy 12
3.3.3.2 Children 12
3.3.3.2.1 Diagnostic imaging 12
3.3.3.2.2 Ultrasound 13
3.3.3.2.3 Plain films (KUB radiography) 13
3.3.3.2.4 Intravenous urography (IVU) 13
3.3.3.2.5 Helical computed tomography (CT) 13
3.3.3.2.6 Magnetic resonance urography (MRU) 13
3.4 Disease management 13
3.4.1 Management of patients with renal or ureteral stones 13
3.4.1.1 Renal colic 13
3.4.1.2 Management of sepsis and/or anuria in obstructed kidney 14
3.4.1.3 General recommendations and precautions for stone removal 15
3.4.1.3.1 Antibiotic therapy 15
3.4.1.3.2 Antithrombotic therapy and stone treatment 15
3.4.1.3.3 Obesity 17
3.4.1.3.4 Stone composition 17
3.4.1.3.5 Steinstrasse 17
3.4.2 Specific stone management in renal stones 17
3.4.2.1 Types of treatments 18
3.4.2.1.1 Conservative treatment (Observation) 18
3.4.2.1.2 Chemolysis 18
3.4.2.1.2.1 Percutaneous irrigation chemolysis 18
3.4.2.1.2.2 Oral chemolysis 18
3.4.2.1.3 Extracorporeal shock wave lithotripsy (SWL) 18
3.4.2.1.3.1 Contraindications of extracorporeal
shock wave lithotripsy 18
3.4.2.1.3.2 Best clinical practice 19
5. REFERENCES 55
6. CONFLICT OF INTEREST 83
Summary of evidence LE
Administration of daily α-blockers seems to reduce colic episodes, although controversy 1b
remains in the published literature.
Summary of evidence - Number of shock waves, energy setting and repeat treatment LE
sessions
Stepwise power ramping prevents renal injury. 1b
Clinical experience has shown that repeat sessions are feasible (within one day for ureteral 4
stones).
Optimal shock wave frequency is 1.0 to 1.5Hz. 1a
Recommendation GR
Offer active treatment for renal stones in case of stone growth, de novo obstruction, C
associated infection, and acute and/or chronic pain.
Summary of evidence LE
Medical expulsion therapy (MET) seems to be efficacious treating patients with ureteric stones 1a
who are amenable to conservative management. The greatest benefit might be among those
with larger (distal) stones.
Recommendations LE GR
Select patients for an attempt at spontaneous passage or MET, based on well- 4 C
controlled pain, no clinical evidence of sepsis, and adequate renal functional reserve.
Offer α-blockers as MET as one of the treatment options, in particular for (distal) 1a A
ureteral stones > 5 mm.
Counsel patients regarding the controversies in the literature, attendant risks of MET, 1b A*
including associated drug side effects. Inform the patient that α-blockers as MET are
administered off-label†**.
† It is not known if tamsulosin harms the human foetus or if it is found in breast milk.
*Upgraded based on panel consensus.
**MET in children cannot be recommended due to the limited data in this specific population.
Summary of evidence LE
In ureterorenoscopy (URS) (in particular for renal stones), pre-stenting has been shown to 1b
improve outcome.
Recommendation GR
In obese patients ureterorenoscopy is a safe and efficient option to remove renal stones. 2b
Ureterorenoscopy in morbidly obese patients have significantly higher complication rates as 1a
compared to normal weight patients.
2. METHODS
2.1 Data identification
For the 2017 Urolithiasis Guidelines, new and relevant evidence has been identified, collated and appraised
through a structured assessment of the literature.
A broad and comprehensive scoping exercise covering all areas of the guideline was performed.
The search was limited to studies representing high levels of evidence only (i.e. systematic reviews with meta-
analysis, randomised controlled trials (RCTs), and prospective non-randomised comparative studies only)
published in the English language. The search was restricted to articles published between September 1st
2015 and October 12th, 2016. Databases covered by the search included Medline, EMBASE and the Cochrane
Libraries. A total of 751 unique records were identified, and screened for relevance. The search strategy is
published online: http://uroweb.org/guideline/urolithiasis/?type=appendices-publications.
In addition to the new literature identified through the electronic searches, the authors included
one additional, more recent, article as of significant relevance for two sections (3.4.1.1 Renal colic & 3.4.3.1.2
Pharmacological treatment, Medical expulsive therapy (MET) [4].
Two sections of the text have been updated based on two systematic reviews (SRs). These SRs were
performed using standard Cochrane SR methodology; http://www.cochranelibrary.com/about/about-
cochranesystematic-reviews.html.
2.2 Review
The 2015 Urolithiasis Guidelines were subjected to peer review prior to publication.
3. GUIDELINES
3.1 Prevalence, aetiology, risk of recurrence
3.1.1 Introduction
Stone incidence depends on geographical, climatic, ethnic, dietary and genetic factors. The recurrence risk is
basically determined by the disease or disorder causing the stone formation. Accordingly, the prevalence rates
for urinary stones vary from 1% to 20% [8]. In countries with a high standard of life such as Sweden, Canada or
the US, renal stone prevalence is notably high (> 10%). For some areas an increase of more than 37% over the
last 20 years has been reported [9-11].
Stones can be classified into those caused by: infection, or non-infectious causes (infection- and non-infection
stones); genetic defects [12]; or adverse drug effects (drug stones) (Table 3.1.1).
Non-infection stones
Calcium oxalate
Calcium phosphate
Uric acid
Infection stones
Magnesium ammonium phosphate
Carbonate apatite
Ammonium urate
Genetic causes
Cystine
Xanthine
2,8-Dihydroxyadenine
Drug stones
*See Section 4.4.2
General factors
Early onset of urolithiasis (especially children and teenagers)
Familial stone formation
Brushite-containing stones (CaHPO4.2H2O)
Uric acid and urate-containing stones
Infection stones
Solitary kidney (the kidney itself does not particularly increase the risk of stone formation, but prevention of
stone recurrence is of more importance)
Diseases associated with stone formation
Hyperparathyroidism
Metabolic syndrome
Nephrocalcinosis
Polycystic kidney disease (PKD)
Gastrointestinal diseases (i.e., jejuno-ileal bypass, intestinal resection, Crohn’s disease, malabsorptive
conditions, enteric hyperoxaluria after urinary diversion) and bariatric surgery [20]
Sarcoidosis
Spinal cord injury, neurogenic bladder
Genetically determined stone formation
Cystinuria (type A, B and AB)
Primary hyperoxaluria (PH)
Renal tubular acidosis (RTA) type I
2,8-Dihydroxyadeninuria
Xanthinuria
Lesch-Nyhan syndrome
Cystic fibrosis
Drug-induced stone formation (see Table 4.11)
Anatomical abnormalities associated with stone formation
Medullary sponge kidney (tubular ectasia)
Ureteropelvic junction (UPJ) obstruction
Calyceal diverticulum, calyceal cyst
Ureteral stricture
Vesico-uretero-renal reflux
Horseshoe kidney
Ureterocele
Environmental factors
Chronic lead exposure
Stratification of stones according to aetiology, composition and risk of recurrence is addressed in Section 3.1.
Recommendation LE GR
With fever or solitary kidney, and when diagnosis is doubtful, immediate imaging is indicated. 4 A*
*Upgraded following panel consensus.
Recommendation LE GR
Following initial ultrasound assessment, use non-contrast-enhanced computed tomography 1a A
to confirm stone diagnosis in patients with acute flank pain, as it is superior to intravenous
urography.
Non-contrast-enhanced computed tomography can detect uric acid and xanthine stones, which are
radiolucent on plain films, but not indinavir stones [35]. Non-contrast-enhanced computed tomography can
determine stone density, inner structure of the stone and skin-to-stone distance and surrounding anatomy; all
of which affect selection of treatment modality [28, 36-38]. The advantage of non-contrast imaging must be
balanced against loss of information on renal function and urinary collecting system anatomy, as well as higher
radiation dose [39-42].
Radiation risk can be reduced by low-dose CT, which may, however, be difficult to introduce in
standard clinical practice [43, 44]. In patients with a body mass index (BMI) < 30, low-dose CT has been shown
to have a sensitivity of 86% for detecting ureteric stones < 3 mm and 100% for calculi > 3 mm [45]. A meta-
analysis of prospective studies [46] has shown that low-dose CT diagnosed urolithiasis with a pooled sensitivity
of 96.6% (95% CI: 95.0-97.8) and specificity of 94.9% (95% CI: 92.0-97.0).
Dual-energy CT can differentiate uric acid containing stones from calcium-containing stones [47].
Recommendations LE GR
Perform a contrast study if stone removal is planned and the anatomy of the renal collecting 3 A*
system needs to be assessed.
Use enhanced computed tomography in complex cases because it enables 3D reconstruction 2a C
of the collecting system, as well as measurement of stone density and skin-to-stone distance.
Intravenous urography may also be used.
*Upgraded based on panel consensus.
Table 3.3.1: R
ecommendations: basic laboratory analysis - emergency urolithiasis patients
[15, 16, 49, 50]
Recommendations GR
Urine
Dipstick test of spot urine sample A*
• red cells A
• white cells
• nitrite
• approximate urine pH
Urine microscopy and/or culture
Blood
Serum blood sample A*
• creatinine
• uric acid
• (ionised) calcium
• sodium
• potassium
Blood cell count
• C-reactive protein (CRP)
Perform a coagulation test (partial thromboplastin time [PTT] and international normalised ratio [INR]) if A*
intervention is likely or planned.
*Upgraded based on panel consensus.
Patients should be instructed to filter their urine to retrieve a concrement for analysis. Stone passage and
restoration of normal renal function should be confirmed.
The preferred analytical procedures are infrared spectroscopy (IRS) or X-ray diffraction (XRD)
[52-54]. Equivalent results can be obtained by polarisation microscopy. Chemical analysis (wet chemistry) is
generally deemed to be obsolete [52].
Recommendations LE GR
Perform stone analysis in first-time formers using a valid procedure (X-ray diffraction or infrared 2 A
spectroscopy).
Repeat stone analysis in patients: 2 B
• presenting with recurrent stones despite drug therapy;
• with early recurrence after complete stone clearance;
• with late recurrence after a long stone-free period because stone composition may
change.
Recommendations LE GR
Use ultrasound as the preferred method of imaging in pregnant women. 1a A*
In pregnant women, use magnetic resonance imaging as a second-line imaging modality. 3 C
In pregnant women, use low-dose computed tomography as a last-line option. 3 C
*Upgraded following panel consensus.
3.3.3.2 Children
Children with urinary stones have a high risk of recurrence; therefore, standard diagnostic procedures for high-
risk patients apply (Section 3.1.3 and Chapter 4). The most common non-metabolic disorders facilitating stone
formation are vesicoureteral reflux (VUR), UPJ obstruction, neurogenic bladder, and other voiding difficulties
[62].
Summary of evidence LE
In children, the most common non-metabolic disorders facilitating stone formation are vesicoureteral 4
reflux, ureteropelvic junction obstruction, neurogenic bladder, and other voiding difficulties [62].
Recommendations GR
In all children, complete a metabolic evaluation based on stone analysis. A
Collect stone material for analysis to classify the stone type. A*
In children, use ultrasound as first-line imaging modality when a stone is suspected; it should include B
the kidney, fluid-filled bladder and the ureter next to the kidney and the (filled) bladder.
If ultrasound will not provide the required information, perform a kidney-ureter-bladder radiography (or B
low-dose non-contrast-enhanced computed tomography).
*Upgraded following panel consensus.
Recommendations GR
Provide immediate pain relief in acute stone episodes. A
Whenever possible, offer a non-steroidal anti-inflammatory as the first drug of choice. e.g. metamizol A
(dipyrone); alternatively, depending on cardio-vascular risk factors, diclofenac*, indomethacin or
ibuprofen**.
Offer hydromorphine, pentazocine or tramadol as a second choice. C
*Affects glomerular filtration rate (GFR) in patients with reduced renal function (LE: 2a).
**Recommended to counteract recurrent pain after ureteral colic.
Summary of evidence LE
Administration of daily α-blockers seems to reduce colic episodes, although controversy remains in 1b
the published literature.
For symptomatic ureteral stones, urgent stone removal as first-line treatment is a feasible option in 1b
selected cases (see text).
Decompression
Currently, there are two options for urgent decompression of obstructed collecting systems:
• placement of an indwelling ureteral stent;
• percutaneous placement of a nephrostomy tube.
There is little evidence to support the superiority of percutaneous nephrostomy over retrograde stenting for
primary treatment of infected hydronephrosis. There is no good quality evidence to suggest that ureteric
stenting has more complications than percutaneous nephrostomy [89, 90].
Only one RCT [91] compared different modalities of decompression of acute infected
hydronephrosis. The complications of percutaneous nephrostomy insertion have been reported consistently,
but those of ureteric stent insertion are less well described [89]. Definitive stone removal should be delayed
until the infection is cleared following a complete course of antimicrobial therapy. A small RCT showed the
feasibility of immediate ureteroscopic stone removal combined with appropriate antibiotic regimen; however, at
the cost of longer hospital stay and higher analgesic requirements [92].
In children, ureteric stents might have some advantage compared to PCN in case of acute anuria
[93].
Summary of evidence LE
For decompression of the renal collecting system, ureteral stents and percutaneous nephrostomy 1b
catheters are equally effective.
Further measures
Following urgent decompression of the obstructed and infected urinary collecting system, both urine- and
blood samples should be sent for culture-antibiogram sensitivity testing, and antibiotics should be initiated
immediately thereafter or continued if initiated prior to testing. The regimen should be re-evaluated in the light
of the culture-antibiogram test. Although clinically well accepted, the impact of a second antibiogram test on
treatment outcome has not yet been evaluated. Intensive care might become necessary [94].
Recommendations GR
Collect (again) urine for antibiogram test following decompression. A*
Start antibiotics immediately (+ intensive care if necessary).
Re-evaluate antibiotic regimen following antibiogram findings.
*Upgraded based on panel consensus.
Recommendation GR
Obtain a urine culture or perform urinary microscopy before any treatment is planned. A*
*Upgraded following panel consensus.
Recommendations LE GR
Exclude or treat urinary tract infections prior to stone removal. 1b A
Offer perioperative antibiotic prophylaxis to all patients undergoing endourological treatment. 1b A*
Shock wave lithotripsy is feasible and safe after correction of the underlying coagulopathy [107-111]. In the
case of an uncorrected bleeding disorder or continued antithrombotic therapy, ureterorenoscopy (URS), in
contrast to SWL and PNL, might offer an alternative approach since it is associated with less morbidity [112-
116]. Only data on flexible ureterorenoscopy are available which support the superiority of URS in the treatment
of proximal ureteric stones [113, 117].
Table 3.4.2: Suggested strategy for antithrombotic therapy in stone removal [101-103]
(In collaboration with cardiologist/internist weigh the risks and benefits of discontinuation of therapy, vs.
delaying elective surgical procedures.)
3.4.1.3.3 Obesity
Obesity can cause a higher risk due to anesthesiological requirements, and a lower success rate after SWL and
PNL.
Recommendations LE GR
Consider the stone composition before deciding on the method of removal, based on patient 2-4 B*
history, former stone analysis of the patient or Hounsfield unit (HU) on unenhanced computed
tomography (CT). Stones with density > 1,000 HU on non-contrast-enhanced CT are less likely
to be disintegrated by shock wave lithotripsy.
Attempt to dissolve radiolucent stones (See Section 3.4.2.1.2.2). 2a B
*Upgraded in parts based on panel consensus.
3.4.1.3.5 Steinstrasse
Steinstrasse is an accumulation of stone fragments or stone gravel in the ureter, may interfere with the passage
of urine [119]. Steinstrasse occurs in 4-7% cases of SWL [120], and the major factor in in the development of
steinstrasse formation is stone size [121].
A major problem of steinstrasse is ureteral obstruction, which may be silent in up to 23% of cases. A meta-
analysis including eight RCTs (n = 876) suggests a benefit of stenting before SWL in terms of steinstrasse
formation, but does not result in a benefit on stone-free rates (SFRs) or less auxiliary treatments [122-124].
When steinstrasse is asymptomatic, conservative treatment is an initial option. Medical expulsion
therapy significantly increases stone expulsion and reduces the need for endoscopic intervention [125, 126].
Summary of evidence LE
Medical expulsion therapy increases the stone expulsion rate of steinstrasse [125]. 1b
When spontaneous passage is unlikely, further treatment of steinstrasse is indicated. 4
Shock wave lithotripsy is indicated in asymptomatic and symptomatic cases, with no evidence of 4
urinary tract infection (UTI), when large stone fragments are present [127].
Ureterenoscopy is effective for the treatment of steinstrasse [128]. 3
Placement of a percutaneous nephrostomy tube or ureteral stent is indicated for symptomatic ureteric 4
obstruction with/without urinary tract infection.
Recommendations LE GR
Treat steinstrasse associated with urinary tract infection/fever preferably with percutaneous 4 C
nephrostomy.
Treat steinstrasse when large stone fragments are present with shock wave lithotripsy or 4 C
ureterorenoscopy.
Summary of evidence LE
It is still debatable whether renal stones should be treated, or whether annual follow-up is sufficient for 4
asymptomatic calyceal stones that have remained stable for six months.
Recommendation GR
Follow-up periodically in cases where renal stones are not treated (initially after six months then yearly, A*
evaluating symptoms and stone status [either by ultrasound, kidney-ureter-bladder radiography or
computed tomography]).
*Upgraded based on panel consensus.
3.4.2.1.2 Chemolysis
3.4.2.1.2.1 Percutaneous irrigation chemolysis
Percutaneous chemolysis is rarely used nowadays. Percutaneous irrigation chemolysis may be an option
for infection- and uric acid stones [130, 131]. For dissolution of struvite stones, Suby’s G solution (10%
hemiacidrin; pH 3.5-4) can be used [132].
Recommendations GR
Inform the patient how to modify the dosage of alkalising medication according to urine pH, which is a A
direct consequence of such medication.
Inform the patient how to monitor urine pH by dipstick three times a day (at regular intervals). A
Morning urine must be included.
Carefully monitor radiolucent stones during/after therapy. A*
Inform the patient of the significance of compliance. A
*Upgraded based on panel consensus.
Pacemaker
Patients with a pacemaker can be treated with SWL, provided that appropriate technical precautions are taken;
patients with implanted cardioverter defibrillators must be managed with special care (firing mode temporarily
reprogrammed during SWL treatment). However, this might not be necessary with new-generation lithotripters
[138].
Summary of evidence LE
Stepwise power ramping prevents renal injury. 1b
Clinical experience has shown that repeat sessions are feasible (within one day for ureteral stones). 4
Optimal shock wave frequency is 1.0 to 1.5Hz. 1a
Recommendation LE GR
Ensure correct use of the coupling agent because this is crucial for effective shock wave 2a B
transportation.
Procedural control
Results of treatment are operator dependent, and better results are obtained by experienced clinicians. During
the procedure, careful imaging control of localisation contributes to outcome quality [159].
Recommendation LE GR
Maintain careful fluoroscopic and/or ultrasonographic monitoring during shock wave lithotripsy. 3 A*
*Upgraded based on panel consensus.
Pain control
Careful control of pain during treatment is necessary to limit pain-induced movements and excessive
respiratory excursions [160-162].
Antibiotic prophylaxis
No standard antibiotic prophylaxis before SWL is recommended. However, prophylaxis is recommended in the
case of internal stent placement ahead of anticipated treatments and in the presence of increased bacterial
burden (e.g., indwelling catheter, nephrostomy tube, or infectious stones) [50, 163, 164].
Recommendation LE GR
In the case of infected stones or bacteriuria, prescribe antibiotics prior to shock wave 4 C
lithotripsy.
Complications % Ref.
Related to stone Steinstrasse 4-7 [120, 175, 176]
fragments Regrowth of residual 21 - 59 [177, 178]
fragments
Renal colic 2-4 [179]
Infectious Bacteriuria in non- 7.7 - 23 [177, 180]
infection stones
Sepsis 1 - 2.7 [177, 180]
Tissue effect Renal Haematoma, symptomatic <1 [181]
Haematoma, asymptomatic 4 - 19 [181]
Cardiovascular Dysrhythmia 11 - 59 [177, 182]
Morbid cardiac events Case reports [177, 182]
Gastrointestinal Bowel perforation Case reports [183-185]
Liver, spleen haematoma Case reports [15-188]
The relationship between SWL and hypertension or diabetes is unclear. Published data are contradictory;
however, no evidence exists supporting the hypothesis that SWL may cause long-term adverse effects [189-
194].
3.4.2.1.4.1.1 Contraindications
Patients receiving anticoagulant therapy must be monitored carefully pre- and post-operatively. Anticoagulant
therapy must be discontinued before PNL [112].
Other important contraindications include:
• untreated UTI;
Recommendation GR
Use ultrasonic, ballistic and holmium: yttrium-aluminium-garnet devices for intracorporeal lithotripsy A*
during percutaneous nephrolithotomy.
*Upgraded based on panel consensus.
Pre-operative imaging
Pre-procedural evaluations are summarised in Section 3.3.1. In particular, PNL, US or CT of the kidney and
the surrounding structures can provide information regarding interpositioned organs within the planned
percutaneous path (e.g., spleen, liver, large bowel, pleura, and lung) [201].
Recommendation GR
Perform pre-procedural imaging, including contrast medium where possible or retrograde study when A*
starting the procedure, to assess stone comprehensiveness and anatomy of the collecting system to
ensure safe access to the renal stone.
*Upgraded based on panel consensus.
For antibiotic therapy - see General recommendations and precautions for stone removal (Section 3.4.1.4.1).
Although the supine position confers some advantages, it depends on appropriate equipment being available
to position the patient correctly, for example, X-ray devices and an operating table. Most studies cannot
demonstrate an advantage of supine PNL in terms of operating room (OR) time. In some series, SFR is lower
than for the prone position despite a longer OR time. Prone position offers more options for puncture and is
therefore preferred for upper pole or multiple access [202-204]. On the other hand, supine position allows
simultaneous retrograde access to the collecting system, using flexible ureteroscope [205]. The Urolithiasis
Guidelines Panel aim to set up a SR to assess this topic.
Puncture
Although fluoroscopy is the most common intra-operative imaging method, the (additional) use of US reduces
the radiation exposure.
Colon interposition in the access tract of PNL can lead to colon injuries. Pre-operative CT or
intra-operative US allows identification of the tissue between the skin and kidney and lowers the incidence
of bowel injury. The calyceal puncture may be done under direct visualisation using simultaneous flexible
ureterenoscopy [206-209].
Dilatation
Dilatation of the percutaneous access tract can be achieved using a metallic telescope, single (serial) dilators,
or a balloon dilatator. Although there are papers demonstrating that single step dilation is equally effective
as other methods, the difference in outcomes is most likely related to surgeon experience rather than to the
technology used [210].
Choice of instruments
The Urolithiasis Panel performed a SR assessing the outcomes of PNL using smaller tract sizes (< 22 Fr,
mini-PNL) for removing renal calculi [5]. Stone-free rates were comparable in miniaturised and standard PNL
Small bore nephrostomies seem to have advantages in terms of post-operative pain [211, 212]. Tubeless PNL
is performed without a nephrostomy tube. When neither a nephrostomy tube nor a ureteral stent is introduced,
the procedure is known as totally tubeless PNL. In uncomplicated cases, the latter procedure results in a
shorter hospital stay, with no disadvantages reported [213-215].
Recommendation LE GR
In uncomplicated cases, perform a tubeless (without nephrostomy tube) or totally tubeless 1b A
(without nephrostomy tube and ureteral stent) percutaneous nephrolithotomy procedure as it is
a safe alternative.
3.4.2.1.4.1.3 Complications
The most common post-operative complications associated with PNL are fever and bleeding, urinary leakage,
and problems due to residual stones (Table 3.4.2).
Peri-operative fever can occur, even with a sterile pre-operative urinary culture and peri-operative antibiotic
prophylaxis, because the renal stones themselves may be a source of infection. Intra-operative renal stone
culture may therefore help to select post-operative antibiotics [217, 218]. Intra-operative irrigation pressure
< 30 mmHg and unobstructed post-operative urinary drainage may be important factors in preventing post-
operative sepsis. Bleeding after PNL may be treated by brief clamping of the nephrostomy tube. Super-
selective embolic occlusion of the arterial branch may become necessary in the case of severe bleeding.
Recommendations LE GR
Offer laparoscopic or open surgical stone removal in rare cases in which shock wave 3 C
lithotripsy, (flexible) ureterorenoscopy and percutaneous nephrolithotomy fail, or are unlikely to
be successful.
When expertise is available, perform surgery laparoscopically before proceeding to open 3 C
surgery, especially when the stone mass is centrally located.
The risk of a symptomatic episode or need for intervention of patients with asymptomatic renal stones seems
to be ~10-25% per year, with a cumulative five-year event probability of 48.5% [129, 241, 242]. A prospective
RCT with > 2 year clinical follow-up reported no significant difference between SWL and observation when
comparing asymptomatic calyceal stones < 15 mm in terms of SFR, symptoms, requirement for additional
treatment, quality of life (QoL), renal function, or hospital admission [243]. Although some have recommended
prophylaxis for these stones to prevent renal colic, haematuria, infection, or stone growth, conflicting data
have been reported [242, 244, 245]. In a follow-up period of almost five years after SWL, two series have
demonstrated that up to 25% of patients with small residual fragments needed treatment [178, 246]. Although
the question of whether calyceal stones should be treated is still unanswered, stone growth, de novo
obstruction, associated infection, and acute and/or chronic pain are indications for treatment [240, 247, 248].
Summary of evidence LE
Although the question of whether calyceal stones should be treated is still unanswered, stone growth, 3
de novo obstruction, associated infection, and acute and/or chronic pain are indications for treatment.
Recommendations GR
Offer active treatment for renal stones in case of stone growth, de novo obstruction, associated C
infection, and acute and/or chronic pain.
Assess comorbidity and patient preference when making treatment decisions. C
The following can impair successful stone treatment by SWL [260, 266-269]:
• steep infundibular-pelvic angle;
• long calyx;
• long skin-to-stone distance;
• narrow infundibulum (Table 3.4.4).
Further anatomical parameters cannot yet be established. Supportive measures such as inversion, vibration or
hydration may facilitate stone clearance [270].
Table 3.4.4: U
nfavourable factors for shock wave lithotripsy success for lower calyceal stones
[260, 266, 271]
If there are negative predictors for SWL, PNL and RIRS might be reasonable alternatives, even for smaller
calculi [258]. Retrograde renal surgery seems to have comparable efficacy to SWL [173, 253]. Recent clinical
experience has suggested a higher SFR of RIRS compared to SWL, but at the expense of greater invasiveness.
Depending on operator skills, stones up to 3 cm can be treated by RIRS [221, 272-274]. However, staged
procedures are frequently required.
In complex stone cases, open or laparoscopic approaches are possible alternatives (see
appropriate chapters).
Recommendations GR
Offer shock wave lithotripsy (SWL) and endourology (percutaneous nephrolithotomy [PNL], retrograde B
renal surgery [RIRS]) as treatment options for stones < 2 cm within the renal pelvis and upper or
middle calices.
Perform PNL as first-line treatment of larger stones > 2 cm. B
In case PNL is not an option, treat larger stones (> 2 cm) with flexible ureterorenoscopy or SWL. B
However, in such instances there is a higher risk that a follow-up procedure and placement of a
ureteral stent may be needed.
For the lower pole, perform PNL or RIRS, even for stones > 1 cm, as the efficacy of SWL is limited B
(depending on favourable and unfavourable factors for SWL).
Kidney stone
(all but lower pole stone 10-20 mm)
1. PNL
> 20 mm
2. RIRS or SWL
1. SWL or RIRS
< 10 mm
2. PNL
No SWL or Endourology*
Unfavourable
10-20 mm factors for SWL
(see Table 3.4.4)
1. Endourology*
Yes 2. SWL
Based on the analysis of available evidence, an exact cut-off size for stones that are likely to pass
spontaneously cannot be provided; < 10 mm may be considered a best estimate [189]. Therefore, the Panel
decided not to include stone size but rather recommend “small”, suggesting < 6 mm. The Panel is aware of
the fact that spontaneous stone expulsion decreases with increasing stone size and that there are differences
between individual patients.
Summary of evidence LE
MET seems to be efficacious treating patients with ureteric stones who are amenable to conservative 1a
management. The greatest benefit might be among those with larger (distal) stones.
Based on studies with a limited number of patients [279, 283, 284] (LE: 1b), no recommendation for the use of
corticosteroids in combination with α-blockers in MET can be made.
Summary of evidence LE
There is no evidence to support the use of corticosteroids as monotherapy for MET. 1b
Insufficient data exist to support the use of corticosteroids in combination with α-blockers as an 2a
accelerating adjunct.
Recommendations LE GR
Select patients for an attempt at spontaneous passage or medical expulsive therapy (MET), 4 C
based on well-controlled pain, no clinical evidence of sepsis, and adequate renal functional
reserve.
Offer α-blockers as MET as one of the treatment options, in particular for (distal) ureteral 1a A
stones > 5 mm.
Counsel patients regarding the controversies in the literature, attendant risks of MET, including 1b A*
associated drug side effects. Inform the patient that α-blockers as MET are administered off-
label†**.
Follow-up patients in short intervals to monitor stone position and assess for hydronephrosis. 4 A*
† It is not known if tamsulosin harms the human foetus or if it is found in breast milk.
*Upgraded based on panel consensus.
**MET in children cannot be recommended due to the limited data in this specific population.
Medical expulsive therapy in special situations is addressed in the particular chapters
Stenting
The stenting is not recommended as part of SWL, since it does not increase SFRs [189, 285]. When a stent is
inserted, patients often suffer from frequency, dysuria, urgency, and suprapubic pain [285].
Recommendation LE GR
Do no routinely use a stent as part of shock wave lithotripsy treatment of ureteral stones. 1b A
3.4.3.1.4.1.1 Contraindications
Apart from general problems, for example, with general anaesthesia or untreated UTIs, URS can be performed
in all patients without any specific contraindications.
Safety aspects
Fluoroscopic equipment must be available in the OR. We recommend placement of a safety wire, even though
some groups have demonstrated that URS can be performed without it [288-290].
Balloon and plastic dilators should be available, if necessary.
Prior rigid ureterenoscopy can be helpful for optical dilatation followed by flexible URS, if necessary.
If ureteral access is not possible, insertion of a JJ stent followed by URS after seven to fourteen days offers an
alternative procedure. Bilateral URS during the same session is feasible resulting in similar SFRs, but slightly
higher overall (mostly minor) complication rates [291].
Stone extraction
The aim of URS is complete stone removal. “Dust and go” strategies should be limited to the treatment of large
(renal) stones.
Stones can be extracted by endoscopic forceps or baskets. Only baskets made of nitinol can be
used for flexible URS [296].
Recommendation LE GR
Do not perform stone extraction using a basket without endoscopic visualisation of the stone 4 A*
(blind basketing).
*Upgraded based on panel consensus.
Recommendation LE GR
Use holmium: yttrium-aluminium-garnet laser lithotripsy for (flexible) ureterorenoscopy. 3 B
Summary of evidence LE
In uncomplicated ureterorenoscopy (URS), a stent need not be inserted. 1a
In URS (in particular for renal stones), pre-stenting has been shown to improve outcome. 1b
An α-blocker can reduce stent-related symptoms and colic episodes. 1b
3.4.3.1.4.1.3 Complications
The overall complication rate after URS is 9-25% [189, 312, 313]. Most are minor and do not require
intervention. Ureteral avulsion and strictures are rare (< 1%). Previous perforations are the most important risk
factor for complications.
Recommendation GR
Use percutaneous antegrade removal of ureteral stones as an alternative when shock wave lithotripsy A
is not indicated or has failed, and when the upper urinary tract is not amenable to retrograde
ureterorenoscopy.
Recommendation LE GR
For ureterolithotomy, perform laparoscopy for large impacted stones when endoscopic 2 B
lithotripsy or shock wave lithotripsy has failed.
Summary of evidence LE
In the case of severe obesity, ureterorenoscopy is a more promising therapeutic option than shock 2b
wave lithotripsy.
The Panel performed an SR to assess the benefits and harms of URS compared to SWL [6]. Compared with
SWL, URS was associated with a significantly greater SFR up to four weeks, but the difference was not
significant at three months in the included studies. Ureterorenoscopy was associated with fewer re-treatments
and need for secondary procedures, but with a higher need for adjunctive procedures, greater complication
rates and longer hospital stay. Counterbalancing for URS’s higher SFRs, SWL is associated with least
morbidity. Clavien-Dindo grade complications were, if reported, less frequent in patients treated with SWL.
Figure 3.4.2: Treatment algorithm for ureteral calculi (if indicated for active stone removal) (GR: A*)
1. URS
> 10 mm
2. SWL
Recommendations GR
Inform patients that ureterorenoscopy (URS) has a better chance of achieving stone-free status with a A
single procedure.
Inform patients that URS has higher complication rate when compared to shock wave lithotripsy. A
Recommendations LE GR
Identify biochemical risk factors and offer appropriate stone prevention to patients with 1b A
residual fragments or stones [178, 325, 326].
Follow-up patients with residual fragments or stones regularly to monitor disease course. 4 C
Recurrence risk in patients with residual fragments after treatment of infection stones is higher than for other
stones [326]. For all stone compositions, 21-59% of patients with residual stones required treatment within
five years. Fragments > 5 mm are more likely than smaller ones to require intervention [178, 324, 327]. There
is evidence that fragments > 2 mm are more likely to grow, although this is not associated with increased
re-intervention rates at one year follow up [328].
3.4.4.1 Therapy
The indications for active removal of residual stones and selection of the procedure are based on the same
criteria as for primary stone treatment (Section 3.4.2.4) and includes repeat SWL [329].
If intervention is not required, medical therapy according to stone analysis, patient risk group, and
metabolic evaluation might help to prevent regrowth of residual fragments [330-332].
Summary of evidence LE
For well-disintegrated stone material in the lower calix, an inversion therapy with simultaneous 1b
mechanical percussion manoeuvre under enforced diuresis may facilitate stone clearance [270].
Recommendation LE GR
After shock wave lithotripsy and ureteronoscopy, and in the presence of residual fragments, 1a A
offer medical expulsive therapy using an α-blocker to improve fragment clearance.
If spontaneous passage does not occur, or if complications develop (e.g., induction of premature labour),
placement of a ureteral stent or a percutaneous nephrostomy tube is necessary [333-335]. Unfortunately, these
Summary of evidence LE
If intervention becomes necessary, placement of a ureteral stent or a percutaneous nephrostomy tube 3
is a readily available primary option.
Ureterenoscopy is a reasonable alternative to avoid long-term stenting/drainage. 1a
Regular follow-up until final stone removal is necessary due to the higher encrustation tendency of
stents during pregnancy.
Recommendation GR
Treat all uncomplicated cases of urolithiasis in pregnancy conservatively (except those that have A
clinical indications for intervention).
3.4.5.2.2 Management
Smaller upper-tract stones can be treated effectively with SWL [316, 345]. In the majority, endourological
techniques are necessary to achieve stone-free status [315]. In individuals with long, tortuous conduits or with
invisible ureter orifices, a retrograde endoscopic approach might be difficult or impossible.
Summary of evidence LE
The choice of access depends on the feasibility of orifice identification in the conduit or bowel 4
reservoir. Whenever a retrograde approach is impossible, percutaneous access with antegrade
ureterorenoscopy is the alternative.
Recommendation GR
Perform percutaneous lithotomy to remove large renal stones in patients with urinary diversion, as well A*
as for ureteral stones that cannot be accessed via a retrograde approach, or that are not amenable to
shock wave lithotripsy.
For stones in the conduit, a trans-stomal approach can be used to remove all stone material (along with the
foreign body) using standard techniques, including intracorporeal lithotripsy and flexible endoscopes. Trans-
stomal manipulations in continent urinary diversion must be performed carefully to avoid disturbance of the
continence mechanism [346].
Before considering any percutaneous approach in these cases, CT should be undertaken to assess
the presence of an overlying bowel, which could make this approach unsafe [347], and if present, an open
surgical approach should be considered.
3.4.5.2.3 Prevention
Recurrence risk is high in these patients [344]. Metabolic evaluation and close follow-up are necessary
to obtain the risk parameters for effective long-term prevention. Preventive measures include medical
management of metabolic abnormalities, appropriate therapy of urinary infections, and hyperdiuresis or regular
irrigation of continent reservoirs [348].
3.4.5.3.2 Management
Management of calculi in patients with neurogenic bladder is similar to that described in Section 3.3.3. In
MMC (myelomeningocele) patients, latex allergy is common, therefore, appropriate measures need to be taken
regardless of the treatment [352]. Any surgery in these patients must be performed under general anaesthesia
because of the impossibility of using spinal anaesthesia. Bone deformities often complicate positioning on
the operating table [353]. The risk of stone formation after augmentation cystoplasty in immobile patients with
sensory impairment can be significantly reduced by irrigation protocols [348].
For efficient long-term stone prevention in patients with neurogenic bladder, correction of the
metabolic disorder, appropriate infection control, and restoration of normal storing/voiding function of the
bladder are needed.
Summary of evidence LE
Patients undergoing urinary diversion and/or suffering from neurogenic bladder dysfunction are at risk 3
for recurrent stone formation.
Recommendation GR
Take appropriate measures regardless of the treatment provided since in myelomeningocele patients B
latex allergy is common.
Recommendation LE GR
Perform ultrasound or non-contrast-enhanced computed tomography to rule out calculi 4 B
in patients with transplanted kidneys, unexplained fever, or unexplained failure to thrive
(particularly in children) [358].
3.4.5.4.2 Management
Selecting the appropriate technique for stone removal in a transplanted kidney is difficult, although
management principles are similar to those applied in other single renal units [359-362]. Additional factors such
as transplant function, coagulative status, and anatomical obstacles due to the iliacal position of the organ,
directly influence the surgical strategy.
For large or ureteral stones, careful percutaneous access and subsequent antegrade endoscopy
are more favourable. The introduction of small flexible ureteroscopes and the holmium laser has made
ureterenoscopy a valid treatment option for transplant calculi. However, one must be aware of potential injury
to adjacent organs [363-365]. Retrograde access to transplanted kidneys is difficult due to the anterior location
of the ureteral anastomosis, and ureteral tortuosity [366-368].
Recommendations GR
Offer patients with transplanted kidneys, any of the contemporary management options, including B
shock wave therapy, flexible ureterenoscopy and percutaneous nephrolithotomy.
Complete metabolic evaluation after stone removal. A*
*Upgraded following panel consensus.
Calyceal diverticulum • Shock wave lithotripsy (SWL), percutaneous nephrolithotomy (PNL) (if
stones possible) or retrograde renal surgery (RIRS).
• Can also be removed using laparoscopic retroperitoneal surgery [371-375].
• Patients may become asymptomatic due to stone disintegration (SWL),
whilst well-disintegrated stone material remains in the original position due
to narrow calyceal neck.
Horseshoe kidneys • Can be treated in line with the options described above [376].
• Passage of fragments after SWL might be poor.
• Acceptable SFRs can be achieved with flexible ureteroscopy [377].
Stones in pelvic kidneys • SWL, RIRS, PNL or laparoscopic surgery.
• In obese patients, the options are RIRS, PNL or open surgery.
Stones formed in a • See Section 3.4.4.
continent reservoir • Each stone must be considered and treated individually.
Patients with obstruction of • When outflow abnormality requires correction, stones can be removed by
the ureteropelvic junction PNL together with percutaneous endopyelotomy or open/laparoscopic
reconstructive surgery.
• Ureterorenoscopy together with endopyelotomy with holmium: yttrium-
aluminium-garnet laser.
• Incision with an Acucise® balloon catheter might be considered, provided
the stones can be prevented from falling into the pelvi-ureteral incision
[378-381].
• Open surgery with correction of the UPJ obstruction (pyeloplasty) and
stone removal is a feasible option [382].
The need for general anaesthesia during SWL depends on patient age and the lithotripter used. General or
dissociative anaesthesia is administered in most children aged < 10 years, to prevent patient and stone motion
and the need for repositioning [396, 398]. With modern lithotripters, intravenous sedation or patient-controlled
analgesia have been used in selected co-operative older children [401] (LE: 2b). There are concerns regarding
the safety and potential biological effects of SWL on immature kidneys and surrounding organs in children.
However, during short- and long-term follow-up, no irreversible functional or morphological side effects of high-
energy shock waves have been demonstrated. In addition, when the potential deterioration of renal function is
taken into account (although transient), restricting the number of shock waves and the energy used during each
treatment session helps protect the kidneys [402-405].
If the stone burden requires a ureteral stent, alternative procedures should be considered. Ureteral
stents are seldom needed following SWL of upper tract stones, ureteral pre-stenting decreases the SFR after
initial treatment [394-396].
Summary of evidence LE
In children, the indications for shock wave lithotripsy are similar to those in adults; however, children 3
pass fragments more easily.
Children with renal stones of a diameter up to 20 mm (~300 mm2) are ideal candidates for shock wave 1b
lithotripsy.
Summary of evidence LE
In children, the indications for percutaneous nephrolithotomy are similar to those in adults. 1a
Recommendation GR
In children, perform percutaneous nephrolithotomy for the treatment of renal pelvic or calyceal stones
with a diameter > 20 mm (~300 mm2). For ureteral stones, ureterorenoscopy may be an alternative, in
case shockwave lithotripsy does not look promising.
Recommendation LE GR
For intracorporeal lithotripsy, use the same devices as in adults (holmium: yttrium-aluminium- 3 C
garnet laser, pneumatic- and ultrasound lithotripters).
Flexible URS
Despite concerns about the potential risks and complications related to endoscopic surgery of children’s
delicate ureter and collecting system, with the development of smaller size endoscopes, flexible
ureterenoscopy (RIRS) has become an efficacious treatment modality for renal and ureteral stones [413,
419-421] and might be a particularly effective treatment option for lower calyx stones in the presence of
unfavourable factors for SWL.
Similar to adults, routine stenting is not necessary before URS. However, leaving a ureteral stent for
the subsequent session must be considered in case of failure of ureterenoscopy. Pre-stenting facilitates URS,
increases SFR and decreases complication rates [422].
For large and complex kidney stones PNL has a higher SFR compared to RIRS, but RIRS is associated with
less radiation exposure, lower complication rates and a shorter hospital stay [423]. The experience of the
surgical team is of the utmost importance for the success of both endourological techniques.
STONE
Specific metabolic
evaluation
Only high-risk stone formers require specific metabolic evaluation. Stone type is the deciding factor for further
diagnostic tests. The different stone types include:
• calcium oxalate;
• calcium phosphate;
• uric acid;
• ammonium urate;
• struvite (and infection stones);
• cystine;
• xanthine;
• 2,8-Dihydroxyadenine;
• drug stones;
• stones of unknown composition.
Follow-up studies are necessary in patients taking medication for recurrence prevention [435]. The first follow-
up 24-hour urine measurement is suggested eight-twelve weeks after starting pharmacological prevention
of stone recurrence. This enables drug dosage to be adjusted if urinary risk factors have not normalised,
with further 24-hour urine measurements if necessary. Once urinary parameters have been normalised, it is
sufficient to perform 24-hour urine evaluation every twelve months. The panel realise that on this issue there is
only very limited published evidence. The Urolithiasis Guidelines Panel aim to set up a SR on the ideal timing of
the 24-hour urine collection.
Table 4.1: Normal laboratory values for blood parameters in adults [436]
Table 4.3: Normal values for spot urine samples: creatinine ratios (solute/creatinine) in adults [441]
4.2.2 Diet
A common sense approach to diet should be taken, that is, a mixed balanced diet with contributions from all
food groups, without any excesses [444, 449, 450].
Fruits, vegetables and fibres: fruit and vegetable intake should be encouraged because of the beneficial effects
of fibre, although the role of the latter in preventing stone recurrences is debatable [451-454]. The alkaline
content of a vegetarian diet also increases urinary pH.
Oxalate: excessive intake of oxalate-rich products should be limited or avoided to prevent high oxalate load
[445], particularly in patients who have high oxalate excretion.
Vitamin C: although vitamin C is a precursor of oxalate, its role as a risk factor in calcium oxalate stone
formation remains controversial [455]. However, it seems wise to advise calcium oxalate stone formers to avoid
excessive intake.
Animal protein: should not be taken in excess [456, 457] and limited to 0.8-1.0 g/kg body weight. Excessive
consumption of animal protein has several effects that favour stone formation, including hypocitraturia, low
urine pH, hyperoxaluria and hyperuricosuria.
Calcium intake: should not be restricted unless there are strong reasons due to the inverse relationship between
dietary calcium and stone formation [452, 458]. The daily requirement for calcium is 1,000 to 1,200 mg [16].
Calcium supplements are not recommended except in enteric hyperoxaluria, when additional calcium should be
taken with meals to bind intestinal oxalate [444, 457, 459]. Older adults, who do not have a history of renal stones
but who take calcium supplements should ensure adequate fluid intake since it may prevent increases in urine
calcium concentration, and thereby reduce or eliminate any increased risk of renal stones formation associated
with calcium supplement use [460].
Calcium stone formation can be reduced by restricting sodium and animal protein [456, 457]. A positive
correlation between sodium consumption and risk of first-time stone formation has been confirmed only
in women [458, 461]. There have been no prospective clinical trials on the role of sodium restriction as an
independent variable in reducing the risk of stone formation.
Urate: intake of purine-rich food should be restricted in patients with hyperuricosuric calcium oxalate [462, 463]
and uric acid stones. Intake should not exceed 500 mg/day [16].
4.2.3 Lifestyle
Lifestyle factors may influence the risk of stone formation, for example, obesity [464] and arterial hypertension
[465, 466].
Recommendations LE GR
Advise patients that a generous fluid intake is to be maintained, allowing for a 24-hour urine 1b A
volume > 2.5 L.
Advise patients with a small urine volume to increase their fluid intake. 1b a
4.4.1 Diagnosis
Blood analysis requires measurement of creatinine, sodium, potassium, chloride, ionised calcium (or total
calcium + albumin), uric acid, and parathyroid hormone (PTH) (and vitamin D) in the case of increased calcium
levels. Urinalysis requires measurement of urine volume, urine pH profile, specific weight, calcium, oxalate, uric
acid, citrate, sodium and magnesium.
The most common metabolic abnormalities associated with calcium stone formation are hypercalciuria, which
affects 30-60% of adult stone formers, and hyperoxaluria (26-67%), followed by hyperuricosuria (15-46%),
hypomagnesiuria (7-23%), and hypocitraturia (5-29%). However, ranges tend to differ based on ethnicity [503].
• Elevated levels of ionised calcium in serum (or total calcium and albumin) require assessment of intact
PTH to confirm or exclude suspected hyperparathyroidism (HPT).
• “Acidic arrest” (urine pH constantly < 5.8) may promote co-crystallisation of uric acid and calcium oxalate.
• Similarly, increased uric acid excretion (> 4 mmol/day in adults or > 12 mg/kg/day in children) can act as a
promoter.
• Urine pH levels constantly > 5.8 in the day profile indicate renal tubular acidosis (RTA), provided UTI has
been excluded. An ammonium chloride loading test confirms RTA and identifies RTA subtype (Section
4.6.5).
• Hypercalciuria may be associated with normocalcemia (idiopathic hypercalciuria, or granulomatous
diseases) or hypercalcaemia (hyperparathyroidism, granulomatous diseases, vitamin D excess, or
malignancy).
• Hypocitraturia (male < 1.7 mmol/d, female < 1.9 mmol/d) may be idiopathic or secondary to metabolic
acidosis or hypokalaemia.
• Oxalate excretion > 0.5 mmol/day in adults (> 0.37 mmol/1.73 m2/day in children) confirms hyperoxaluria.
oo primary hyperoxaluria (oxalate excretion mostly > 1 mmol/day), appears in three genetically
determined forms;
oo secondary hyperoxaluria (oxalate excretion > 0.5 mmol/day, usually < 1 mmol/day), occurs due to
intestinal hyperabsorption of oxalate or extreme dietary oxalate intake;
oo mild hyperoxaluria (oxalate excretion 0.45-0.85 mmol/day), commonly found in idiopathic calcium
oxalate stone formers.
• Hypomagnesuria (< 3.0 mmol/day) may be related to poor dietary intake or to reduced intestinal
absorption (chronic diarrhoea).
Basic evaluation
24 h urine collection
Hyperuricosuria
Male < 1.7 mmol/d > 0.5 mmol/d > 1 mmol/d and
5-8 mmol/d2 8 mmol/d > 4 mmol/d Hyperuricemia < 3 mmol/d
Female < 1.9 mmol/d (Enteric) (Primary)
> 380 µmol/L
alkaline
citrate
alkaline hydrochlorothiazide 9-12 g/d
citrate initially 25 mg/d calcium pyridoxine or alkaline citrate
9-12 g/d up to 50 mg/d alkaline > 1,000 initial 5 sodium 9-12 g/d
or chlorthalidone mg/d1 and mg/kg/d PLUS magnesium
citrate bicarbonate
sodium 25 mg/d magnesium up to allopurinol 200-400 mg/d3
9-12 g/d 1.5 g tid2
bicarbonate indapamide 200-400 mg/d 20 mg/kg/d PLUS/OR 100-300 mg/d4,5
1.5 g tid2,4 2.5 mg/d allopurinol
100 mg/d
4.5.1 Diagnosis
Diagnosis requires blood analysis for: creatinine, sodium, potassium, chloride, ionised calcium (or total calcium
+ albumin), and PTH (in the case of increased calcium levels). Urinalysis includes measurement of: volume,
urine pH profile, specific weight, calcium, phosphate and citrate.
Figure 4.3: Diagnostic and therapeutic algorithm for calcium phosphate stones
Calcium phosphate
stones
Carbonate
apatite Brushite stones
stones
Hydrochlorothiazide Hypercalciuria
initially 25 mg/d Exclude RTA Exclude UTI > 8 mmol/d
up to 50 mg/d
HPT = hyperparathyroidism; RTA = renal tubular acidosis; UTI = urinary tract infection.
Urinary pH
constantly > 5.8
RTA Type I
possible
Ammonium chloride
loading test**
(NH4CI 0.1 g/kg body weight)
Except in patients with
clinically confirmed
metabolic acidosis
** An alternative Ammonium Chloride loading test using NH4Cl load with 0.05 g/kg body weight over three days
might provide similar results and may be better tolerated by the patient. A second alternative in these cases
could be the furosemide acidification test.
Renal tubular acidosis can be acquired or inherited. Reasons for acquired RTA can be obstructive uropathy,
recurrent pyelonephritis, acute tubular necrosis, renal transplantation, analgesic nephropathy, sarcoidosis,
idiopathic hypercalciuria, and primary parathyroidism; it may also be drug-induced (e.g. zonisamide). Table 4.7
shows the inherited causes of RTA.
The main therapeutic aim of RTA treatment is restoring a normal acid-base equilibrium. Despite the alkaline pH
of urine in RTA, alkalinisation using alkaline citrates or sodium bicarbonate is key to normalising the metabolic
changes (intracellular acidosis) responsible for stone formation (Table 4.8). The alkali load reduces tubular
reabsorption of citrate, which in turn normalises citrate excretion and simultaneously reduces calcium turnover.
Therapeutic success can be monitored by venous blood gas analysis (base excess: ± 2.0 mmol/L) in complete
RTA. If excessive calcium excretion (> 8 mmol/day) persists after re-establishing acid-base equilibrium,
thiazides may lower urinary calcium excretion.
4.6.6.1 Diagnosis
Diagnosis requires the following blood analysis: PTH (in the case of increased calcium levels), vitamin D and
metabolites, vitamin A, sodium, potassium, magnesium, chloride, and blood gas analysis. Urinalysis should
investigate: urine pH profile (minimum four times daily), daily urine volume, specific weight of urine, and levels
of calcium, oxalate, phosphate, uric acid, magnesium and citrate.
Ammonium urate stones are extremely rare, comprising < 1% of all types of urinary stones. They are
associated with UTI, malabsorption (inflammatory bowel disease and ileostomy diversion or laxative abuse),
potassium deficiency, hypokalaemia and malnutrition.
Suggestions on uric acid and ammonium urate nephrolithiasis are based on level 3 and 4 evidence.
4.7.1 Diagnosis
Figure 4.5 shows the diagnostic and therapeutic algorithm for uric acid and ammonium urate stones. Blood
analysis requires measurement of creatinine, potassium and uric acid levels. Urinalysis requires measurement
of urine volume, urine pH profile, specific weight of urine, and uric acid level. Urine culture is needed in the
case of ammonium urate stones.
Hyperuricosuria is defined as uric acid excretion > 4 mmol/day in adults or > 0.12 mmol/kg/day in children.
Hyperuricaemia may be present, but there is only weak evidence for its association with stone formation.
Hyperuricosuric calcium oxalate stone formation can be distinguished from uric acid stone
formation by: urinary pH, which is usually > 5.5 in calcium oxalate stone formation and < 5.5 in uric acid
stone formation and occasional absence of hyperuricosuria in patients with pure uric acid stones [517, 518].
Ammonium urate crystals form in urine at pH > 6.5, at high uric acid concentration when ammonium is present
to serve as a cation [519-521].
Ammonium
Urate acid stone
urate stones
allopurinol Correction
100-300 mg/d of factors
Dose depends
predisposing
on targeted
amm.urate stone
urine pH
formation4
Prevention Chemolytholisis
urine pH 6.2-6.8 urine pH 6.5-7.23
1 d: day.
2 tid: three times a day.
3 A higher pH may lead to calcium phosphate stone formation.
4 In patients with high uric acid excretion, allopurinol may be helpful.
4.8.1 Diagnosis
Blood analysis requires measurement of creatinine, and urinalysis requires repeat urine pH measurements and
urine culture.
Interpretation
Infection stones contain the following minerals: struvite and/or carbonate apatite and/or ammonium urate.
Urine culture typically provides evidence for urease-producing bacteria, which increase ammonia ions and
develop alkaline urine (Table 4.10). Carbonate apatite starts to crystallise at a urine pH level of 6.8. Struvite only
precipitates at pH > 7.2 [531, 532]. Proteus mirabilis accounts for more than half of all urease-positive UTIs
[533, 534].
Recommendations LE GR
Surgically remove the stone material as completely as possible. 3-4 A*
Prescribe a short-term antibiotic course. 3 B
Prescribe a long-term antibiotic course in case of recurrent infections. 3 B
Prescribe ammonium chloride, 1 g, two or three times daily to ensure urinary acidification. 3 B
Prescribe methionine, 200-500 mg, one-three times daily, as an alternative, to ensure urinary 3 B
acidification.
Consider prescription of urease inhibitors in case of severe infection (if licensed). 1b A
*Upgraded following panel consensus.
Neurogenic bladder
Spinal cord injury/paralysis
Continent urinary diversion
Ileal conduit
Foreign body
Stone disease
Indwelling urinary catheter
Urethral stricture
Benign prostatic hyperplasia
Bladder diverticulum
Cystocele
Calyceal diverticulum
UPJ obstruction
Infection stones
(Struvite carbon apatite
Ammonium urate1)
Basic evaluation
Urease Urinary pH
producing Treatment (Carbon apatite > 6.8
bacteria Struvite > 7.2)
Complete
surgical Urine Urease
Antibiotics
removal acidification inhibition*
is mandatory
Percutaneous
Ammonium Methionine
chemolysis may Short or AHA2
Chloride 200-500 mg
be a useful long course 15 mg/kg/day
1 g bid or tid 1-3 times/d
adjunct
4.9.1 Diagnosis
Blood analysis includes measurement of creatinine, and urinalysis includes measurement of urine volume, pH
profile, specific weight, and cystine.
Interpretation
• Cystine is poorly soluble in urine and crystallises spontaneously within the physiological urinary pH range.
• Cystine solubility depends strongly on urine pH: at pH 6.0, the limit of solubility is 1.33 mmol/L.
• Routine analysis of cystine is not suitable for therapeutic monitoring.
• Regardless of phenotype or genotype of the cystinuric patient, the clinical manifestations are the same
[540].
• There is no role for genotyping patients in the routine management of cystinuria [541, 542].
• Reductive therapy targets the disulphide binding in the cysteine molecule. For therapy monitoring, it is
essential to differentiate between cystine, cysteine and drug-cysteine complexes. Only high-performance
liquid chromatography (HPLC)-based analysis differentiates between the different complexes formed by
therapy.
• Diagnosis is established by stone analysis. The typical hexagonal crystals are detectable in only 20-25%
of urine specimens from patients with cystinuria [543].
Tiopronin is currently the best choice for cystine reduction. However, side effects often lead to treatment
termination, for example, when nephrotic syndrome develops, or poor compliance, especially with long-term
use.
After carefully considering the risk of early tachyphylaxis, putting into place a dose-escape phenomenon for
long-term use, and recurrence risk, tiopronin is recommended at cystine levels > 3.0 mmol/day or in the case of
recurring stone formation, notwithstanding other preventive measures.
Cystine stones
Basic evaluation
Therapeutic measures LE GR
Urine dilution 3 B
Advise patients to increase their fluid intake so that 24-hour urine volume exceeds 3 L.
Intake should be > 150 mL/h.
Alkalinisation 3 B
For patients with cystine excretion < 3 mmol/day, prescribe potassium citrate 3-10 mmol two
or three times daily, to achieve pH > 7.5.
Complex formation with cystine 3 B
For patients with cystine excretion, > 3 mmol/day, or when other measures are insufficient:
prescribe in addition to other measures tiopronin, 250-2,000 mg/day.
Diagnostic imaging begins with US examination of both kidneys to establish whether the patient is stone free.
Stone detection by US should be followed by KUB and unenhanced multislice CT in adults to differentiate
between calcium-containing and non-calcium stones.
Blood analysis demonstrates severe metabolic and organic disorders, such as renal insufficiency,
HPT or other hypercalcaemic states and hyperuricaemia. In children, hyperoxalaemia is additionally screened
for.
Urinalysis is performed routinely with a dipstick test as described above. Urine culture is required if
there are signs of infection.
Constant urine pH < 5.8 in the daily profile indicates acidic arrest, which may promote uric acid
Following this programme, the most probable stone type can be assumed and specific patient evaluation can
follow. However, if any expulsed stone material is available, it should be analysed by diagnostic confirmation or
correction.
Table 4.12: Recommendations for the assessment of patients with stones of unknown composition
5. REFERENCES
1. Skolarikos, A., et al. Metabolic evaluation and recurrence prevention for urinary stone patients: EAU
guidelines. Eur Urol, 2015. 67: 750.
https://www.ncbi.nlm.nih.gov/pubmed/25454613
2. Turk, C., et al. EAU Guidelines on Diagnosis and Conservative Management of Urolithiasis. Eur Urol,
2016. 69: 468.
https://www.ncbi.nlm.nih.gov/pubmed/26318710
3. Turk, C., et al. EAU Guidelines on Interventional Treatment for Urolithiasis. Eur Urol, 2016. 69: 475.
https://www.ncbi.nlm.nih.gov/pubmed/26344917
4. Hollingsworth, J.M., et al. Alpha blockers for treatment of ureteric stones: systematic review and
meta-analysis. BMJ, 2016. 355: i6112.
https://www.ncbi.nlm.nih.gov/pubmed/27908918
5. Ruhayel, Y., et al. Tract sizes in miniaturized percutaneous nephrolithotomy: A systematic review.
Eur Urol 2017. [No abstract available].
6. Drake, T. What are the benefits and harms of ureteroscopy (URS) compared with shock-wave
lithotripsy (SWL) in the treatment of upper ureteral stones (UUS): A systematic review. Eur Urol 2017.
[No abstract available].
7. Phillips, B., et al. Oxford Centre for Evidence-based Medicine Levels of Evidence. Updated by
Jeremy Howick March 2009.
http://www.cebm.net/oxford-centre-evidence-based-medicine-levels-evidence-march-2009/
6. CONFLICT OF INTEREST
All members of the Urolithiasis Guidelines Panel have provided disclosure statements of all relationships that
they have that might be perceived as a potential source of a conflict of interest. This information is publicly
accessible through the European Association of Urology website: http://www.uroweb.org/guidelines/online-
guidelines/. This guidelines document was developed with the financial support of the European Association of
Urology. No external sources of funding and support have been involved. The EAU is a non-profit organisation
and funding is limited to administrative assistance and travel and meeting expenses. No honoraria or other
reimbursements have been provided.
2. METHODS 10
2.1 Peer review 10
2.2 Future goals 10
3. THE GUIDELINE 10
3.1 Phimosis 10
3.1.1 Epidemiology, aetiology and pathophysiology 10
3.1.2 Classification systems 10
3.1.3 Diagnostic evaluation 10
3.1.4 Management 10
3.1.5 Follow-up 11
3.1.6 Summary of evidence and recommendations for the management
of phimosis 11
3.2 Management of undescended testes 11
3.2.1 Background 11
3.2.2 Classification 12
3.2.2.1 Palpable testes 12
3.2.2.2 Non-palpable testes 13
3.2.3 Diagnostic evaluation 13
3.2.3.1 History 13
3.2.3.2 Physical examination 13
3.2.3.3 Imaging studies 13
3.2.4 Management 13
3.2.4.1 Medical therapy 13
3.2.4.1.1 Medical therapy for testicular descent 14
3.2.4.1.2 Medical therapy for fertility potential 14
3.2.4.2 Surgical therapy 14
3.2.4.2.1 Palpable testes 14
3.2.4.2.1.1 Inguinal orchidopexy 14
3.2.4.2.1.2 Scrotal orchidopexy 15
3.2.4.2.2 Non-palpable testes 15
3.2.4.2.3 Complications of surgical therapy 16
3.2.4.2.4 Surgical therapy for undescended testes after puberty 16
3.2.5 Undescended testes and fertility 16
3.2.6 Undescended testes and malignancy 17
3.2.7 Summary of evidence and recommendations
for the management of undescended testes 17
3.3 Hydrocele 17
3.3.1 Epidemiology, aetiology and pathophysiology 17
3.3.2 Diagnostic evaluation 18
3.3.3 Management 18
3.3.4 Summary of evidence and recommendations for the management of hydrocele 18
3.4 Acute scrotum 19
3.4.1 Epidemiology, aetiology and pathophysiology 19
3.4.2 Diagnostic evaluation 19
3.4.3 Management 20
3.4.3.1 Epididymitis 20
3.4.3.2 Testicular torsion 20
3.4.3.3 Surgical treatment 20
3.4.4 Follow-up 20
4. REFERENCES 92
It must be emphasised that clinical guidelines present the best evidence available to the experts but following
guideline recommendations will not necessarily result in the best outcome. Guidelines can never replace
clinical expertise when making treatment decisions for individual patients, but rather help to focus decisions
- also taking personal values and preferences/individual circumstances of children and their care-givers into
account. Guidelines are not mandates and do not purport to be a legal standard of care.
3.6.4 Summary of evidence and recommendations for the management of congenital penile curvature
Summary of evidence LE
Isolated congenital penile curvature is relatively uncommon. 2a
Congenital penile curvature is often associated with hypospadias. 2a
Diagnosis is usually made late in childhood. 2a
The penis only appears abnormal when erect. 1b
Congenital penile curvature can cause aesthetic as well as functional sexual problems. 1b
Congenital penile curvature is treated with surgery. 1b
The goal of surgery is to achieve corpora of similar size. 1b
Recommendations LE GR
Ensure that a thorough medical history is taken and a full clinical examination done to 1a A
rule out associated anomalies in boys presenting with congenital curvature.
Provide photo documentation of the erect penis from different angles as a prerequisite 1b A
in the pre-operative evaluation.
Perform surgery after weighing aesthetic as well as functional implications of the 2b B
curvature.
At the beginning as well as at the end of surgery perform artificial erection tests. 2a A
Summary of evidence LE
Androgen stimulation therapy results in increased penile length and glans circumference. 1B
The complication rate is about 10% in distal and 25% in proximal hypospadias one-stage 3
repairs. Higher and variable rate (between 28 and 68%) can occur in two-stage repairs.
Recommendations GR
In children diagnosed with proximal hypospadias and a small appearing penis, reduced B
glans circumference or reduced urethral plate, pre-operative hormonal androgen stimulation
treatment is an option and the body of evidence to accentuate its harms and benefits is
inadequate.
Ensure long-term follow-up to detect urethral stricture, voiding dysfunctions and recurrent A
penile curvature.
Use validated objective scoring systems to assist in evaluating the functional and cosmetic A
outcome.
3.12.5 Summary of evidence and recommendations for the management of ureteropelvic junction (UPJ)-,
UVJ-obstruction
Summary of evidence LE
In children diagnosed with antenatal hydronephrosis, a systematic review could not establish 1b
any benefits or harms related to continuous antibiotic prophylaxis.
In children diagnosed with antenatal hydronephrosis, non-circumcised infants (LE: 1a), 2
children diagnosed with high-grade hydronephrosis (LE: 2) and hydroureteronephrosis (LE: 1b)
were shown to be at higher risk of developing UTI.
Recommendation LE GR
Offer continuous antibiotic prophylaxis to the subgroup of children with antenatal 2 A
hydronephrosis who are at high risk of developing urinary tract infection
(uncircumcised infants (LE: 1a), children diagnosed with hydroureteronephrosis
(LE: 1b) and high-grade hydronephrosis (LE: 2).
All other chapters of the Paediatric Urology Guidelines were peer-reviewed in 2015.
• What are the short-term and long-term benefits and harms of varicocoele intervention in children?
3. THE GUIDELINE
3.1 Phimosis
3.1.1 Epidemiology, aetiology and pathophysiology
At the end of the first year of life, retraction of the foreskin behind the glandular sulcus is possible in
approximately 50% of boys; this rises to approximately 89% by the age of three years. The incidence of
phimosis is 8% in six to seven year olds and just 1% in males aged sixteen to eighteen years [6].
3.1.4 Management
Conservative treatment is an option for primary phimosis. A corticoid ointment or cream (0.05-0.1%) can
be administered twice a day over a period of 20-30 days with a success rate of > 90% [9-12] (LE: 1b). A
recurrence rate of up to 17% can be expected [13]. This treatment has no side effects and the mean bloodspot
3.1.5 Follow-up
Any surgery done on the prepuce requires an early follow-up of four to six weeks after surgery.
Summary of evidence LE
Treatment for phimosis usually starts after two years of age or according to parents’ preference. 3
In primary phimosis, conservative treatment with a corticoid ointment or cream is a first line treatment 1b
with a success rate of more than 90%.
Recommendations LE GR
Treat primary phimosis conservatively with a corticoid ointment or cream. Circumcision will 1b A
also solve the problem if being considered.
Do not delay treatment of primary phimosis in recurrent balanoposthitis and recurrent urinary 2b A
tract infection (UTI) in patients with urinary tract abnormalities.
Circumcision is indicated in secondary phimosis. 2b A
Do not delay treatment in case of paraphimosis, this is an emergency situation. Perform a 3 B
dorsal incision of the constrictive ring if manual reposition has failed.
Routine neonatal circumcision is not recommended to prevent penile carcinoma. 2b B
Undescended testis
Palpable Non-palpable
Intra-
Inguinal Inguinal Ectopic Absent
abdominal
Ectopic
Agenesis
Retractile
Vanishing
testis
Ectopic testes
If the position of a testis is outside its normal path of descent and outside the scrotum, the testis is considered
to be ectopic. The most common aberrant position is in the superficial inguinal pouch. Sometimes an ectopic
testis can be identified in a femoral, perineal, pubic, penile or even contralateral position. Usually, there is no
possibility for an ectopic testis to descend spontaneously to the correct position; therefore, it requires surgical
intervention. In addition, an ectopic testis might not be palpable due to its position.
Retractile testes
Retractile testes have completed their descent into a proper scrotal position but can be found again in a
suprascrotal position along the path of their normal descent. This is due to an overactive cremasteric reflex
[39]. Retractile testes can be easily manipulated down to the scrotum and remain there at least temporarily.
They are typically normal in size and consistency. However, they may not be normal and should be monitored
carefully since up to one-third can ascend and become undescended [40].
Intra-abdominal testes
Intra-abdominal testes can be located in different positions, with most of them being found close to the internal
inguinal ring. However, possible locations include the kidney, anterior abdominal wall, and retrovesical space. In
the case of an open internal inguinal ring, the testis may be peeping into the inguinal canal.
Absent testes
Monorchidism can be identified in up to 4% of boys with undescended testes, and anorchidism (bilateral
absence) in < 1%. Possible pathogenic mechanisms include testicular agenesis and atrophy after intrauterine
torsion with the latter one most probably due to an in utero infarction of a normal testis by gonadal vessel
torsion. The term vanishing testis is commonly used for this condition [41].
3.2.3.1 History
Parents should be asked for maternal and paternal risk factors, including hormonal exposure and genetic
or hormonal disorders. If the child has a history of previously descended testes this might be suggestive of
testicular ascent [42]. Prior inguinal surgery is indicative of secondary undescended testes due to entrapment.
3.2.4 Management
Treatment should be started at the age of six months. After that age, undescended testes rarely descend [51].
Any kind of treatment leading to a scrotally positioned testis should be finished by twelve months, or eighteen
months at the latest, because histological examination of undescended testes at that age has already revealed
a progressive loss of germ cells and Leydig cells [52]. The early timing of treatment is also driven by the final
adult results on spermatogenesis and hormone production, as well as on the risk of tumour development [53].
Proximal cutting and transection of the testicular vessels, with conservation of the collateral arterial blood
supply, via the deferential artery and cremasteric vessels comprise the key features of the Fowler-Stephens
procedure. Recently, a modification with low spermatic vessel ligation has gained popularity, allowing blood
supply from the testicular artery to the deferential artery. An additional advantage is the position of the
peritoneal incision, leading to a longer structure, to ease later scrotal placement [86]. Due to the nature of these
approaches the testis is at risk of hypotrophy or atrophy if the collateral blood supply is insufficient [87]. The
testicular survival rate in the one-stage Fowler-Stephens technique varies between 50 and 60%, with success
rates increasing up to 90% for the two-stage procedure [88]. The advantages of two-stage orchidopexy, with
the second part done usually six months after the first, are to allow for development of collateral blood supply
and to create greater testicular mobility [89]. In addition preservation of the gubernaculum may also decrease
the chance of testicular atrophy [90].
An alternative might be microsurgical auto-transplantation, which has a success rate of up to 90%.
However, this approach requires skilled and experienced surgeons and is performed in a limited number of
centres [91].
Unilateral non-palpable
testis
Re-exam under
anaesthesia
Still
Palpable
non-palpable
Inguinal
Diagnostic exploration Standard
laparoscopy with possible orchidopexy
laparoscopy
In summary, regarding preservation of fertility potential, early surgical correction of undescended testes is
highly recommended before twelve months of age, and by eighteen months at the latest [52].
3.2.7 Summary of evidence and recommendations for the management of undescended testes
Summary of evidence LE
An undescended testis justifies treatment early in life to avoid loss of spermatogenic potential. 2a
A failed or delayed orchidopexy may increase the risk of testicular malignancy later in life. 2a
The earlier the treatment, the lower the risk of impaired fertility and testicular cancer. 2a
In unilateral undescended testis, fertility rate is reduced whereas paternity rate is not. 1b
In bilateral undescended testes, fertility and paternity rates are impaired. 1b
The treatment of choice for undescended testis is surgical replacement in the scrotum. 1b
The palpable testis is usually treated surgically using an inguinal approach. 2b
The non-palpable testis is most commonly approached laparoscopically. 2b
There is no consensus on the use of hormonal treatment. 2b
Recommendations LE GR
Boys with retractile testes do not need medical or surgical treatment, but ensure close follow- 2a A
up until puberty.
Perform surgical orchidolysis and orchidopexy before the age of twelve months, and by 2b B
eighteen months at the latest.
Evaluate male neonates with bilateral non-palpable testes for possible disorders of sex 1b A
development (DSD).
In case of non-palpable testes and no evidence of DSDs, laparoscopy is recommended 1a A
because of its excellent sensitivity and specificity in identifying an intra-abdominal testis, as
well as the possibility for subsequent treatment in the same session.
Do not routinely offer hormonal therapy, either in an adjuvant or neo-adjuvant setting. Patients 2a C
have to be evaluated on an individual basis.
In case of bilateral undescended testes, offer endocrine treatment. 4 C
For an undescended testis in a post-pubertal boy or older, with a normal contralateral testis, 3 B
discuss removal with the patient/parents because of the theoretical risk of a later malignancy.
3.3 Hydrocele
3.3.1 Epidemiology, aetiology and pathophysiology
Hydrocele is defined as a collection of fluid between the parietal and visceral layers of the tunica vaginalis
[103]. Pathogenesis of primary hydrocele is based on patency of processus vaginalis in contrast with
secondary hydrocele. Incomplete obliteration of the processus vaginalis peritonei results in formation of
various types of communicating hydrocele; a large open processus vaginalis allowing passage of abdominal
viscera results in clinical hernia [104]. The exact time of spontaneous closure of the processus vaginalis is not
known. It persists in approximately 80-94% of newborns and in 20% of adults [105]. If complete obliteration
3.3.3 Management
In the majority of infants, surgical treatment of hydrocele is not indicated within the first twelve months because
of the tendency for spontaneous resolution [109] (LE: 2). Little risk is taken by initial observation as progression
to hernia is rare and does not result in incarceration [109]. Early surgery is indicated if there is suspicion of a
concomitant inguinal hernia or underlying testicular pathology [110, 111] (LE: 2). Persistence of a simple scrotal
hydrocele beyond twelve months of age may be an indication for surgical correction. There is no evidence that
this type of hydrocele risks testicular damage. The natural history of hydrocele is poorly documented beyond
the age of two years and according to a systematic review there is no good evidence to support current
practice. Delaying surgery may reduce the number of procedures necessary without increasing morbidity [112].
The question of contralateral disease should be addressed by both history and physical examination
at the time of initial consultation (LE: 2) [113]. In late-onset hydrocele, suggestive of a non-communicating
hydrocele, there is a reasonable chance of spontaneous resolution (75%) and expectant management of six
to nine months is recommended [114]. In the paediatric age group, the operation consists of ligation of patent
processus vaginalis via inguinal incision and the distal stump is left open, whereas in hydrocele of the cord the
cystic mass is excised or unroofed [103, 108, 110] (LE: 4). In expert hands, the incidence of testicular damage
during hydrocele or inguinal hernia repair is very low (0.3%) (LE: 3). Sclerosing agents should not be used
because of the risk of chemical peritonitis in communicating processus vaginalis peritonei [108, 110] (LE: 4).
The scrotal approach (Lord or Jaboulay technique) is used in the treatment of a secondary non-communicating
hydrocele.
Summary of evidence LE
In the majority of infants, surgical treatment of hydrocele is not indicated within the first twelve months 2a
due to the tendency for spontaneous resolution. Little risk is taken by initial observation as progression
to hernia is rare.
In the paediatric age group, an operation would generally involve ligation of the patent processus 4
vaginalis via inguinal incision.
Recommendations LE GR
In the majority of infants, observe hydrocele for twelve months prior to considering surgical 2a B
treatment.
Perform early surgery if there is suspicion of a concomitant inguinal hernia or underlying 2b B
testicular pathology.
Perform a scrotal ultrasound in case of doubt about the character of an intrascrotal mass. 4 C
Do not use sclerosing agents because of the risk for chemical peritonitis. 4 C
Epididymitis affects two age groups: less than one year and twelve to fifteen years [118, 141, 142]. One study
predicted the annual incidence of epididymitis around 1.2 per 1,000 children [143]. Perinatal torsion of the
testis most often occurs prenatally. Bilateral torsion comprises 11-21% of all perinatal cases [144]. Most cases
are extravaginal in contrast to the usual intravaginal torsion, which occurs during puberty.
In general the duration of symptoms is shorter in testicular torsion (69% present within twelve hours) and
torsion of the appendix testes (62%) compared to epididymitis (31%) [117, 118, 142].
In the early phase, location of the pain can lead to diagnosis. Patients with acute epididymitis
experience a tender epididymis, whereas patients with testicular torsion are more likely to have a tender
testicle, and patients with torsion of the appendix testis feel isolated tenderness of the superior pole of the
testis [142].
An abnormal (horizontal) position of the testis is more frequent in testicular torsion than
epididymitis [117]. Looking for absence of the cremasteric reflex is a simple method with 100% sensitivity
and 66% specificity for testicular torsion [141, 146] (LE:3). Elevation of the scrotum may reduce complaints in
epididymitis, but not in testicular torsion.
Fever occurs more often in epididymitis (11-19%). The classical sign of a “blue dot” was found only
in 10-23% of patients with torsion of the appendix testis [116, 117, 141, 147]. In many cases, it is not easy to
determine the cause of acute scrotum based on history and physical examination alone [115-120, 141, 147].
A positive urine culture is only found in a few patients with epididymitis [119, 141, 147, 148]. It
should be remembered that a normal urinalysis does not exclude epididymitis. Similarly, an abnormal urinalysis
does not exclude testicular torsion.
Doppler US is useful to evaluate acute scrotum, with 63.6-100% sensitivity and 97-100% specificity,
and a positive predictive value of 100% and negative predictive value of 97.5% [149-154] (LE: 3). The use
of Doppler US may reduce the number of patients with acute scrotum undergoing scrotal exploration, but it
is operator-dependent and can be difficult to perform in pre-pubertal patients [151, 155]. It may also show a
misleading arterial flow in the early phases of torsion and in partial or intermittent torsion. Of key importance,
persistent arterial flow does not exclude testicular torsion. In a multicentre study of 208 boys with torsion of the
testis, 24% had normal or increased testicular vascularisation [151]. A comparison with the other side should
always be done
Better results were reported using high-resolution US (HRUS) for direct visualisation of the spermatic cord twist
with a sensitivity of 97.3% and specificity of 99% [151, 156] (LE: 2).
Scintigraphy and, more recently, dynamic contrast-enhanced subtraction MRI of the scrotum
also provide a comparable sensitivity and specificity to US [157-160]. These investigations may be used
when diagnosis is less likely and if torsion of the testis still cannot be excluded from history and physical
examination. This should be done without inordinate delays for emergency intervention [147].
The diagnosis of acute epididymitis in boys is mainly based on clinical judgement and adjunctive
investigation. However, it should be remembered that findings of secondary inflammatory changes in the
absence of evidence of an extra-testicular nodule by Doppler US might suggest an erroneous diagnosis of
epididymitis in children with torsion of the appendix testes [161]. Pre-pubertal boys with acute epididymitis
have an incidence of underlying urogenital anomalies of 25-27.6%. Complete urological evaluation in all
children with acute epididymitis is still debatable [119, 141, 143].
External cooling before exploration and several medical treatments seem effective in reducing ischaemia-
reperfusion injury and preserving the viability of the torsed and the contralateral testis [173-177]. It is good
clinical practice to perform fixation also of the contralateral testis in prenatal and neonatal torsion, although
there is no literature to support this and to remove an atrophied testicle.
3.4.4 Follow-up
Patients require follow-up mainly for fertility issues and hormonal consequences. Despite timely and adequate
detorsion and fixation of the testicle, up to half of the patients may develop testicular atrophy, even when intra-
operatively assessed as viable, and should be counseled accordingly [178].
3.4.4.1 Fertility
The results vary and are conflicting. In one study, unilateral torsion of the testis seriously intervened with
subsequent spermatogenesis in about 50% of the patients and produced borderline impairment in another
20% [167]. Although, 30% of affected testicles with mumps orchitis show a degree of atrophy, long-term
outcome in terms of fertility is not conclusive [179].
A recent study showed a normal pregnancy rate after unilateral testicular torsion, with no difference
between the patients undergoing orchidopexie and those after orchidectomy [180].
3.4.5 Summary of evidence and recommendations for the management of acute scrotum in
children
Summary of evidence LE
Diagnosis of testicular torsion is based on presentation and physical exam.
Doppler US is an effective imaging tool to evaluate acute scrotum and comparable to scintigraphy and 2a
dynamic contrast-enhanced subtraction MRI.
Neonates with acute scrotum should be treated as surgical emergencies. 3
Recommendations LE GR
Do not delay intervention since testicular torsion is a paediatric urological emergency. 3 A
In neonates, also explore the contralateral scrotum. 3 C
Base the clinical decision on physical examination. The use of Doppler ultrasound to evaluate 2a B
acute scrotum is useful, but this should not delay the intervention.
Manage torsion of the appendix testis conservatively. Perform surgical exploration in equivocal 3 B
cases and in patients with persistent pain.
Perform urgent surgical exploration in all cases of testicular torsion within 24 hours of symptom 3 C
onset. In prenatal torsion the timing of surgery is usually dictated by clinical findings.
3.5 Hypospadias
The pathology may be different after skin release and should be reclassified accordingly. Anatomical location of
meatus may not always be enough to explain the severity and the complex nature of this pathology. Therefore,
a simple classification related to severity of the problem, which takes into account penile length, glans size,
shape, urethral plate quality and penile curvature is commonly used. In that classification there are 2 types:
• mild hypospadias (glanular or penile isolated hypospadias without associated chordee, micropenis or
scrotal anomaly);
• severe hypospadias (penoscrotal, perineal hypospadias with associated chordee and scrotal anomalies).
The diagnostic evaluation also includes an assessment of associated anomalies, which are:
• cryptorchidism (in up to 10% of cases of hypospadias);
• open processus vaginalis or inguinal hernia (in 9-15%).
Severe hypospadias with unilaterally or bilaterally impalpable testis, or with ambiguous genitalia, requires a
complete genetic and endocrine work-up immediately after birth to exclude DSD, especially congenital adrenal
hyperplasia.
Urine trickling and ballooning of the urethra requires exclusion of meatal stenosis. The relationship
between the severity of the hypospadias and associated anomalies of the upper- or lower urinary tract were not
confirmed [191] (LE: 3).
3.5.5 Management
3.5.5.1 Indication for reconstruction and therapeutic objectives
Differentiation between functionally necessary and aesthetically feasible operative procedures is important for
therapeutic decision making.
The functional indications for surgery are:
• proximally located (ectopic) meatus;
• ventrally deflected or spraying urinary stream;
• meatal stenosis;
• curved penis.
The cosmetic indications, which are strongly linked to the psychology of the parent or future patient’s
psychology, are:
• abnormally located meatus;
• cleft glans;
• rotated penis with abnormal cutaneous raphe;
• preputial hood;
• penoscrotal transposition;
• split scrotum.
As all surgical procedures carry the risk of complications, thorough pre-operative counselling of the parents is
crucial.
For distal forms of hypospadias, a range of other techniques is available (e.g. Mathieu, urethral advancement)
[212] (LE: 2b). The TIP technique has become an option for proximal hypospadias as well [204-208]. However,
urethral plate elevation and urethral mobilisation should not be combined with TIP repair because it results
in focal devascularisation of the neourethra with symptomatic stricture development [213] (LE: 2b). The onlay
technique using a preputial island flap is a standard repair, preferred in proximal hypospadias, if a plate is
unhealthy or too narrow [199]. An onlay preputial graft is an option for single-stage repair [214] (LE: 2b).
If the continuity of the urethral plate cannot be preserved, single or two-stage repairs are used. For the former,
a modification of the tubularised flap (Duckett tube), such as a tube-onlay or an inlay-onlay flap, or onlay
No
Paediatric urologist
reconstruction
Reconstruction
required
Distal Proximal
Chordee No chordee
Urethral Urethral
plate cut plate preserved
Thiersch Duplay,
TIP, Mathieu, Two-stage,
MAGPI, tube-onlay Onlay, TIP
advancement Koyanagi repair
DSD = disorders of sex development; GAP = glans approximation procedure; TIP = tubularised incised plate
urethroplasty; MAGPI = meatal advancement and glanuloplasty incorporated.
A meta-analysis of complication rates of TIP repair found lower complication rate and incidence of
re-operations in primary distal repairs (in 4.5%) than in primary proximal repairs (in 12.2%) and in secondary
repair (in 23.3%) [204-208, 228]. One should expect a predictable outcome with complication rates below
10% in distal hypospadias (fistula, meatal stenosis, dehiscence, recurrent ventral curvature, and haematoma)
[233, 234]. A similar incidence of fistula (3.4-3.6%) can be expected after the Mathieu and TIP repairs of distal
hypospadias [208, 235, 236].
The complication rate of TIP and onlay repairs of primary severe hypospadias is similar, 24% and 27%,
respectively. It is higher in free graft and in preputial island tube urethroplasty [199]. The complication rate of
single-stage Koyanagi and Hayashi modification repairs goes up 61%, according to a comparative study [220,
228]. Staged buccal mucosa graft requires a redo grafting in 13% of patients, after the second stage more
than one third of patients have complications, mostly with some degree of graft fibrosis [235, 237]. A recent
long-term study on two-stage flap repair showed a complication rate of 68% [228], another study showed a
re-operation rate of 28% [211, 228].
3.5.6 Follow-up
Long-term follow-up is necessary up to adolescence to detect urethral stricture, voiding dysfunctions and
recurrent penile curvature. Up to half of complications requiring re-operation present after the first year post-
operatively [238] (LE: 2b).
Obstructive flow curve is common after hypospadias repair and while most are not clinically
significant, long-term follow-up is required [239-242] (LE: 2a). Urine flow is significantly lower in patients after
hypospadias surgery, especially in those who had corrected chordee, but without significant association with
lower urinary symptoms [243] (LE: 2a).
Objective scoring systems have been developed in order to evaluate the results of hypospadias surgery (HOSE)
[244] (LE: 2b) and cosmetic appearance (HOPE-Hypospadias Objective Penile Evaluation) [245] (LE: 2a). The
Pediatric Penile Perception Score (PPPS) is a reliable instrument to assess penile self-perception in children
after hypospadias repair and for appraisal of the surgical result by parents and uninvolved urologists [246] (LE:
2a).
Adolescents and adults, who have undergone hypospadias repair in childhood, have a slightly
higher rate of dissatisfaction with penile size, especially proximal hypospadias patients, but their sexual
behaviour is not different from that of control groups [247, 248] (LE: 2a-b). Another long-term follow-up of
men born with hypospadias revealed, in a controlled study, that these patients are less satisfied with penile
cosmetic outcome according to all parameters of the PPS, there was a difference in penile length (9,7 vs 11.6
cm) and more patients had lower maximum urinary flow; and more prominent results were found in proximal
hypospadias vs. controls [228, 249].
According to a systematic review of long-term patient satisfaction with cosmetic outcomes [250]:
• patient perception of penile size does not differ greatly from the norm;
• patients approaching puberty have a more negative perception and are more critical about the cosmetic
outcomes of surgery;
• patients report high levels of perception of deformity and social embarrassment.
Summary of evidence LE
The suggested age at surgery for primary hypospadias repair is 6 - 18 (24) months. 3
The therapeutic objectives are to correct the penile curvature, to form a neo-urethra of an adequate 4
size, to bring the new meatus to the tip of the glans, if possible, and to achieve an overall acceptable
cosmetic appearance.
Androgen stimulation therapy results in increased penile length and glans circumference. 1B
The complication rate is about 10% in distal and 25% in proximal hypospadias one-stage repairs. 3
Higher and variable rate (between 28 and 68%) can occur in two-stage repairs.
Sexual functions are usually well preserved. 2b
Recommendations GR
At birth, differentiate isolated hypospadias from disorders of sex development which are mostly A
associated with cryptorchidism or micropenis.
Counsel parents on functional indications for surgery, aesthetically feasible operative procedures A
(psychological, cosmetic indications) and possible complications.
In children diagnosed with proximal hypospadias and a small appearing penis, reduced glans B
circumference or reduced urethral plate, pre-operative hormonal androgen stimulation treatment is an
option and the body of evidence to accentuate its harms and benefits is inadequate.
For distal hypospadias, use original and modified tubularised incised plate urethroplasty; use the B
onlay urethroplasty or two-stage procedures in more severe hypospadias. A treatment algorithm is
presented (Figure 3). Correct significant (> 30 degrees) curvature of the penis.
Ensure long-term follow-up to detect urethral stricture, voiding dysfunctions and recurrent penile A
curvature.
Use validated objective scoring systems to assist in evaluating the functional and cosmetic outcome. A
Curvature > 30° is considered clinically significant; curvature > 60° may interfere with satisfactory sexual
intercourse in adulthood (LE: 4). Minor penile curvature may be the result of ventral penile skin deficiency only
and should be distinguished from corporal anomalies. For penile curvature associated with hypospadias or
epispadias refer to the relevant chapters.
3.6.3 Management
The treatment is surgical, starting with an artificial erection to determine the degree of curvature and to
check symmetry after the repair [258]. The ultimate goal of any surgical method used to correct the curvature
is to achieve corpora of similar size. Various procedures are in use ranging from rather simple de-gloving
and plication procedures, to corporal rotation, use of free dermal or tunica vaginalis grafts, to complete
penile disassembly techniques [259, 260]. Reviews comparing the outcome of Nesbit/modified Nesbit
procedures [261] to plication procedures [262] were able to demonstrate that while there is a decreased risk of
3.6.4 Summary of evidence and recommendations for the management of congenital penile
curvature
Summary of evidence LE
Isolated congenital penile curvature is relatively uncommon. 2a
Congenital penile curvature is often associated with hypospadias. 2a
Diagnosis is usually made late in childhood. 2a
The penis only appears abnormal when erect. 1b
Congenital penile curvature can cause aesthetic as well as functional sexual problems. 1b
Congenital penile curvature is treated with surgery. 1b
The goal of surgery is to achieve corpora of similar size. 1b
Recommendations LE GR
Ensure that a thorough medical history is taken and a full clinical examination done to rule out 1a A
associated anomalies in boys presenting with congenital curvature.
Provide photo documentation of the erect penis from different angles as a prerequisite in the 1b A
preoperative evaluation.
Perform surgery after weighing aesthetic as well as functional implications of the curvature. 2b B
At the beginning as well as at the end of surgery perform artificial erection tests. 2a A
3.7.3 Management
There is no evidence that treatment of varicocele at paediatric age will offer a better andrological outcome than
an operation performed later. Beneficial effect of pubertal screening and treatment for varicocele regarding
chance of paternity has been questioned according to a corresponding questionnaire in adult patients [283]
(LE: 4). The recommended indication criteria for varicocelectomy in children and adolescents are [268]:
• varicocele associated with a small testis;
• additional testicular condition affecting fertility;
• bilateral palpable varicocele;
• pathological sperm quality (in older adolescents);
• symptomatic varicocele [283].
Testicular (left + right) volume loss in comparison with normal testes is a promising indication criterion, once the
normal values are available [284]. Repair of a large varicocele, causing physical or psychological discomfort,
may also be considered. Other varicoceles should be followed-up until a reliable sperm analysis can be
performed (LE: 4).
Surgical intervention is based on ligation or occlusion of the internal spermatic veins. Ligation is
performed at different levels:
• inguinal (or subinguinal) microsurgical ligation;
• suprainguinal ligation, using open or laparoscopic techniques [285-288].
The advantage of the former is the lower invasiveness of the procedure, while the advantage of the latter is a
considerably lower number of veins to be ligated and safety of the incidental division of the internal spermatic
at the suprainguinal level.
For surgical ligation, some form of optical magnification (microscopic or laparoscopic) should be
used because the internal spermatic artery is 0.5 mm in diameter at the level of the internal ring [285, 287]. The
recurrence rate is usually < 10%.
Lymphatic-sparing varicocelectomy is preferred to prevent hydrocele formation and testicular
hypertrophy development and to achieve a better testicular function according to the LHRH stimulation test
[273, 285, 286, 289] (LE: 2). The methods of choice are subinguinal or inguinal microsurgical (microscopic)
repairs, or suprainguinal open or laparoscopic lymphatic-sparing repairs [285, 287, 290, 291]. Intrascrotal
application of isosulphan blue was recommended to visualise the lymphatic vessels [292, 293]. In suprainguinal
approach, an artery sparing varicocelectomy may not offer any advantage in regards to catch-up growth and is
associated with a higher incidence of recurrent varicocele [294, 295].
Angiographic occlusion of the internal spermatic veins also meets the requirements of lymphatic sparing
repair. It is based on retrograde or antegrade sclerotisation of the internal spermatic veins [296, 297]. However,
although this method is less invasive and may not require general anaesthesia, it is associated with radiation
burden, which is less controllable in the antegrade technique [268, 296, 297] (LE: 2).
Summary of evidence LE
Varicocele becomes more frequent at the beginning of puberty and is found in 14-20% of adolescents.
Fertility problems are expected in up to 20% of adolescents with a varicocele.
Pubertal patients with a left grade II and III varicocele have the left testis smaller in up to 70%; in late 1b
adolescence the contralateral right testis also becomes smaller.
After adolescent varicocelectomy, left testis catch-up growth and improvement in sperm parameters 1a
has been demonstrated.
There is no evidence that treatment of varicocele at paediatric age will offer a better andrological 1b
outcome than an operation performed later.
Division of testicular lymphatics leads to hydrocele in up to 40% and to testicular hypertrophy. 1b
Recommendations LE GR
Examine varicocele in the standing position and classify into three grades. 4 A
Use scrotal ultrasound to detect venous reflux without Valsalva manoeuvre in the supine and
upright position and to discriminate testicular hypoplasia.
In pre-pubertal boys and in isolated right varicocele perform standard renal ultrasound to
exlude a retroperitonal mass.
Perform surgery for: 2 B
• varicocele associated with a small testis (size difference of > 2 mL or 20%);
• additional testicular condition affecting fertility;
• pathological sperm quality (in older adolescents);
• bilateral palpable varicocele;
• symptomatic varicocele.
Use some form of optical magnification (microscopic or laparoscopic magnification) for 2 B
surgical ligation.
Use lymphatic-sparing varicocelectomy to prevent hydrocele formation and testicular 2 A
hypertrophy.
(1) Plastic bag attached to the cleaned genitalia: This technique is most often used in daily practice. It is helpful
when the culture results are negative. Also, if the dipstick is negative for both leukocyte esterase and nitrite,
or microscopic analysis is negative for both pyuria and bacteriuria, UTI can be excluded without the need for
confirmatory culture [315]. However, if the genitalia are not cleaned and culture is delayed, a high incidence of
false-positive results (85-99%) can be found [316, 317].
(2) Clean-catch urine collection: The infant is placed in the lap of a parent or member of the nursing staff, who
holds a sterile foil bowl underneath the infant’s genitalia. The infant is offered oral fluids and urine collection is
awaited [318]. This is time consuming and requires proper instruction of the parents. There seems to be a good
correlation between the results of urine culture obtained by this method and suprapubic aspiration (SPA), with
a false-positive rate of 5% and false-negative rate of 12% [318, 319]; however the contamination rate is higher
compared to SPA [320].
(3) Bladder catheterisation: In female infants and also in neonates, this technique may be an alternative to SPA,
however with a higher contamination rate [321]. In a prospective study using bladder catheterisation in febrile
children aged < 36 months, contamination was defined by multiple pathogens, non-pathogens, or colony
counts < 10,000 cfu/mL. True UTI was found in 10% of children and 14% of the cultures were contaminated.
Univariate analysis of potential predictors identified age less than six months, difficult catheterisation, and
uncircumcised boys. In children less than six months and uncircumcised boys a new, sterile catheter with each
repeated attempt at catheterisation may lead to less contamination [322] otherwise SPA should be the method
of choice.
(4) Suprapubic bladder aspiration: This is the most sensitive method to obtain an uncontaminated urine sample
in this age group [322-324]. Using US to assess bladder filling, simplifies SPA and improves the diagnostic yield
of obtaining a urine specimen from 60% to 97% [323, 324]. Complications are rare and have been reported in
only 0.22% of cases, ranging from transient haematuria to bowel perforation [325]. However, bladder puncture
causes more pain than catheterisation in infants less than two months old [326].
In older, toilet-trained, children who can void on command, after carefully retracting the foreskin and cleaning
the glans penis in boys and spreading the labia and cleaning the peri-urethral area in girls, the use of clean
catch, especially midstream urine, could be an acceptable technique for obtaining urine. After cleaning the
urethral meatus and perineum with gauze and liquid soap twice, the risk of contamination was reduced from
23.9% (41/171) to 7.8% (14/171) in a randomised trial [327].
If the clinical situation necessitates, and for differential diagnosis of sepsis, it is most appropriate
to obtain an adequate urine sample by catheterisation or SPA [319]. In infants, a bag can only be used if
the dipstick is negative, otherwise the urine should be obtained through catheterisation or SPA. This is also
recommended in children, who are severely ill and a UTI needs to be excluded or confirmed. Blood sampling is
dependent on the clinical situation.
(1) Dipsticks: These are appealing because they provide rapid results, do not require microscopy, and are
ready to use. Leukocyte esterase (as a surrogate marker for pyuria) and nitrite (which is converted from dietary
nitrates by most Gram-negative enteric bacteria in the urine) are the most frequent markers, and are usually
combined in a dipstick test. The conversion of dietary nitrates to nitrites by bacteria takes approximately four
hours in the bladder [319, 328]. However, nitrite is not a very sensitive marker for infants, who empty their
bladder frequently, and not all urinary pathogens reduce nitrate to nitrite. The test is helpful when the result is
positive, because it is highly specific (i.e. there are few false-positive results) [319, 329].
Table 1: Sensitivity and specificity of component of urinalysis, alone and in combination [319]*
(2) Microscopy: This is the standard method of assessing pyuria after centrifugation of the urine with a
threshold of five white blood cells (WBCs) per high-power field (25 WBC/μL) [325]. In uncentrifuged urine, > 10
WBC/μL has been demonstrated to be sensitive for UTI [330] and this could perform well in clinical situations
[331]. However, this is rarely done in an outpatient setting.
(3) Flow imaging analysis technology: This is being used increasingly to classify particles in uncentrifuged urine
specimens [332]. The numbers of WBCs, squamous epithelial cells and red cells correlate well with those found
by manual methods [319].
Table 2: Criteria for UTI in children (adapted from the EAU Guidelines on Urological Infections [337])
Urine specimen from suprapubic Urine specimen from bladder Urine specimen from midstream
bladder puncture catheterisation void
Any number of cfu/mL (at least 10 > 103 - 105 cfu/mL > 104 cfu/mL with symptoms
identical colonies) > 105 cfu/mL without symptoms
Pyuria without bacteriuria (sterile pyuria) may be due to incomplete antibiotic treatment, urolithiasis, or foreign
bodies in the urinary tract, and infections caused by Mycobacterium tuberculosis or Chlamydia trachomatis.
3.8.3.5 Imaging
3.8.3.5.1 Ultrasound
Renal and bladder US within 24 hours is advised in infants with febrile UTI to exclude obstruction of the
upper and lower urinary tract. Abnormal results are found in 15% of cases, and 1-2% have abnormalities that
3.8.4 Management
3.8.4.1 Administration route
The choice between oral and parenteral therapy should be based on patient age; clinical suspicion of
urosepsis; illness severity; refusal of fluids, food and/or oral medication; vomiting; diarrhoea; non-compliance;
and complicated pyelonephritis (e.g. urinary obstruction). As a result of the increased incidence of urosepsis
and severe pyelonephritis in newborns and infants aged less than two months, parenteral antibiotic therapy
is recommended. Electrolyte disorders with life-threatening hyponatraemia and hyperkalaemia based on
pseudohypoaldosteronism can occur in these cases [353, 354].
Parental combination treatment with ampicillin and an aminoglycoside (e.g. tobramycin or
gentamicin) or respectively a third-generation cephalosporin achieves excellent therapeutic results (high
efficacy of aminoglycosides, respectively cephalosporins against common uropathogens; enterococcus gap is
closed with ampicillin). Compared to the division in two doses, a daily single dose of aminoglycosides is safe
and effective [310, 355, 356].
The choice of agent is also based on local antimicrobial sensitivity patterns, and should later be
adjusted according to sensitivity testing of the isolated uropathogen [319]. Not all available antibiotics are
approved by the national health authorities, especially in infancy. In uncomplicated nephritis, both oral and
parenteral treatment can be considered, because both are equally effective in children without urinary tract
abnormalities. Some studies have demonstrated that once daily parenteral administration of gentamicin or
ceftriaxone in a day treatment centre is safe, effective and cost-effective in children with UTI [355, 357, 358].
Complicated UTI/close
Boys > 12 months Infant/girl monitoring i.v. antibiotic
treatment
Critical
Imaging Good clinical
Exclusion of status or no
after response
reflux/VCUG/DMSA response
recurrent
infections
Further Consider
evaluation of transient
upper tract urinary
function diversion
(renal
scan/MRI)
Exclusion of
VUR (VCUG)
Toilet trained children: exclusion of BBD
BBD = Bladder Bowel Dysfunction; DMSA = technetium99-labelled dimercaptosuccinic acid; MRI = magnetic
resonance imaging; UTI = urinary tract infection; VCUG = voiding cystourethrography; VUR = vesicoureteral
reflux.
Table 5: F
requently used antibacterial agents used for the treatment of cystitis and cystourethritis
(Dosages for children up to twelve years of age)*
3.8.4.4 Chemoprophylaxis
Long-term antibacterial prophylaxis should be considered in cases of high susceptibility to UTI and risk of
acquired renal damage. Some recently published prospective, randomised studies do not support the efficacy
of antibacterial prophylaxis [371-374]. However, two recently published prospective randomised trails as well
as one meta-analysis demonstrated a significant risk reduction of developing another UTI by using continuous
antibiotic prophylaxis [360, 375, 376] (see also Chapter 3.13 on VUR).
Cranberry juice as well as probiotics may also prevent recurrence of UTI as demonstrated by RCTs [377-379]. A
cochrane review could not rule out some benefit of using probiotics [380].
3.8.5 Summary of evidence and recommendations for the management of UTI in children
Summary of evidence LE
Urinary tract infection represents the most common bacterial infection in children less than 2 years of 1b
age. The incidence varies depending on age and sex.
Classifications are made according to the site, episode, severity, symptoms and complicating factors. 2b
For acute treatment, site and severity are most important.
The number of colony forming units (cfu) in the urine culture can vary and is related to the method of 2b
specimen collection, diuresis, and time and temperature of storage until cultivation occurs.
The classical definition of > 105 cfu/mL in voided urine is still used to define a significant UTI. 3
Changes in DMSA clearance during acute UTI indicate pyelonephritis or parenchymal damage. If it is 2a
positive, reflux may be present.
3.9.4 Management
Treatment of LUTD consists of LUT rehabilitation, mostly referred to as urotherapy, meaning non-surgical, non-
pharmacological, treatment of LUT function. It is a very broad therapy field, incorporating many treatments
used by urotherapists and other healthcare professionals [397]. In case of comorbidity due to bowel problems
it is advised to treat the bowel first, since bowel problems may sustain any bladder problems [394]. Urotherapy
can be divided into standard therapy and specific interventions. It is strongly advised not to use terms such as
“standard therapy” or “maintenance therapy” without defining the design of these treatments.
A success rate of 80% has been described for urotherapy programmes, independent of the components
of the programme. However, the evidence level is low as most studies of urotherapy programmes are
retrospective and non-controlled. A recently published multicentre controlled trial of cognitive treatment,
placebo, oxybutynin, bladder and pelvic floor training did not report better results with oxybutynin and pelvic
floor training compared to standard therapy [396] (LE: 1b).
3.9.5 Summary of evidence and recommendations for the management of day-time lower urinary
tract conditions
Summary of evidence LE
The term; ‘bladder bowel dysfunction’ is to be used rather than ‘dysfunctional elimination syndrome 4
and voiding dysfunction’.
Day-time LUTS has a high prevalence (2% to 20%). 2
Recommendations LE GR
Use a stepwise approach, starting with the least invasive treatment in managing day-time 4 B
lower urinary tract dysfunction (LUTD) in children.
Initially offer urotherapy involving: non-invasive training and re-education, and non-invasive 2 B
neurostimulation.
If present, treat bladder bowel dysfunction bowel dysfunction first, before treating the lower 2 B
urinary tract condition.
Use pharmacotherapy (mainly antispasmodics and anticholinergics) as second line therapy. 1 C
Re-evaluate in case of therapy resistance; this may consist of videourodynamics and magnetic 3 C
resonance imaging of lumbosacral spine, guiding to off-label treatment (e.g. some of the
non-licensed drugs in children, botulinum toxin injection and sacral nerve stimulation). Such
treatment should only be offered in highly experienced centres.
3.10.4 Management
Before using alarm treatment or medication, simple therapeutic interventions should be considered.
3.10.4.3 Medication
In the case of high night-time diuresis, success rates of 70% can be obtained with desmopressin (DDAVP),
either as tablets (200-400 μg), or as sublingual DDAVP oral lyophilisate (120-240 μg). A nasal spray is no longer
recommended due to the increased risk of overdose [418, 419] (LE: 1). Relapse rates are high after DDAVP
discontinuation [415] however recently, structured withdrawal has shown lower relapse rates [420] (LE: 1).
In the case of small bladder capacity, treatment with antispasmodics or anticholinergics is
possible [415]. However, when these medications are necessary, the condition is no longer considered to
be monosymptomatic. Imipramine, which has been popular for treatment of the enuresis, achieves only a
moderate response rate of 50% and has a high relapse rate. Furthermore, cardiotoxicity and death from
overdose are described, its use should therefore be discouraged as the first line therapy [421] (LE: 1). Figure 5
presents stepwise assessement and management options for nocturnal enuresis.
Nocturnal enuresis
Initial assessment
Monosymptomatic
Nocturnal enuresis
Uroflowmetry, urine
Alarm or desmopressin
volume, osmolarity
Still wet
Urotherapy, Ab, Ach,
Biofeedback
Summary of evidence LE
Chronobiology of micturition in which the existence of a circadian clock has been proven in kidney, 1
brain and bladder and disturbances in this chronobiology play a major role in the pathophysiology of
enuresis.
Recommendations LE GR
Do not treat children less than 5 years of age in whom spontaneous cure is likely. 2 A
Use voiding diaries or questionnaires to exclude day-time symptoms. 2 A
Perform a urine test to exclude the presence of infection or potential causes such as diabetes 2 B
insipidus.
Offer supportive measures in conjunction with other treatment modalities, of which 1 A
pharmacological and alarm treatment are the two most important. When used alone they have
limited success.
This is mainly a classification based on urodynamic findings. The understanding of the pathophysiology of
disorders is essential to plan a rational treatment plan for each individual patient. In meningomyelocele, most
patients will present with hyper-reflexive detrusor and dyssynergic sphincter, which is a dangerous combination
as pressure is built up and the upper tract is threatened.
3.11.3.1.2 Uroflowmetry
As uroflowmetry is the least invasive of all urodynamic tests, it can be used as an initial screening tool. It
provides an objective way of assessing the efficiency of voiding, and, together with an ultrasonographic
examination, the residual urine volume can also be determined. Unlike in children with non-neurogenic voiding
dysfunction, uroflowmetry will rarely be used as a single investigational tool in children with neurogenic
bladders, as it does not provide information on bladder storage, yet it may be very practical to monitor
emptying in the follow-up. The main limitation of a urodynamic study is the need for the child to be old enough
to follow instructions and void on request.
Recording of pelvic floor or abdominal skeletal muscle activity by electromyography (EMG) during
uroflowmetry can be used to evaluate coordination between detrusor and the sphincter. As it is a non-invasive
test, combined uroflowmetry and EMG may be very useful in evaluating sphincter activity during voiding [430-
433] (LE: 3; GR: C).
3.11.3.2 Cystometry
Although moderately invasive and dependent on a co-operative child, cystometry in children provides valuable
information regarding detrusor contractility and compliance. The amount of information obtained from each
study is related to the degree of interest and care given to the test.
It is important to be aware of the alterations in filling and emptying detrusor pressures as the
infusion rates change during cystometry. Slow fill cystometry (filling rate < 10 mL/min) is recommended by the
ICCS for use in children [434]. However, it has been suggested that the infusion rate should be set according to
the child’s predicted capacity, based on age and divided by 10 or 20 [412].
Several clinical studies using conventional artificial fill cystometry to evaluate neurogenic bladder
in children have reported that conventional cystometry provides useful information for diagnosis and follow-up
3.11.4 Management
The medical care of children with myelodysplasia with a neurogenic bladder requires constant observation and
adaptation to new problems. In the first years of life, the kidneys are highly susceptible to back-pressure and
infection. During this period, the emphasis is on documenting the pattern of NDSD and assessing the potential
for functional obstruction and VUR. The early study and treatment of patients is essential for decreasing renal
impairment, reducing the need for surgery and improving the continence options [446].
A simple algorithm can be used for management of these patients (Figure 6).
Time at diagnosis
Early CIC
Augmentation Augmentation
procedures procedures
3.11.4.1 Investigations
An abdominal US obtained as soon as possible after birth will detect hydronephrosis or other upper
genitourinary tract pathology. Following US, a VCUG, preferably a VUD study should be obtained to evaluate
the LUT. Measurement of residual urine during both US and cystography should also be done. These studies
provide a baseline for the appearance of the upper and lower urinary tracts, can facilitate the diagnosis of
hydronephrosis or VUR, and can help identify children at risk for upper genitourinary tract deterioration and
impairment of renal function.
A urodynamic evaluation can be done after some weeks, and needs to be repeated at regular
intervals, in combination with evaluation of the upper tract [447-449] (LE: 3).
Botulinum toxin injections: In neurogenic bladders that are refractory to anticholinergics, injection of botulinum
toxin into the detrusor muscle is a novel treatment alternative. Initial promising results in adults has resulted
in its use in children. It has been shown that this treatment has beneficial effects on clinical and urodynamic
variables. Complete continence was achieved in 65-87% of patients; in most studies mean maximum detrusor
pressure was reduced to at least 40 cmH2O and bladder compliance was increased to at least 20 cmH2O/mL.
However, findings are limited by the lack of controlled trials and studies involving small patient numbers [409,
469-473]. Botulinum toxin seems to be more effective in bladders with obvious detrusor muscle over-activity,
whereas non-compliant bladders without obvious contractions are unlikely to respond [473-478].
The most commonly used dose of botulinum toxin is 10 U/kg with a maximum dose of 200 U. No
dose study has been performed in children and there is no evidence regarding the optimal dose. Currently, it
is unclear how many times this treatment can be repeated, although repetitive treatment has been found to be
safe in adults [409, 479-481].
Injection of botulinum toxin in therapy-resistant bladders appears to be an effective and safe
treatment alternative (LE: 3). Urethral sphincter botulinum-A toxin injection has been shown to be effective in
decreasing urethral resistance and improve voiding. The evidence is still too low to recommend its routine use
in decreasing outlet resistance, but it could be considered as an alternative in refractory cases [482, 483].
3.11.4.6 Sexuality
Sexuality, while not an issue in childhood, becomes progressively more important as the patient gets older.
This issue has historically been overlooked in individuals with myelodysplasia. However, patients with
myelodysplasia do have sexual encounters. Studies indicate that at least 15-20% of males are capable of
fathering children and 70% of females can conceive and carry a pregnancy to term. It is therefore important to
counsel patients about sexual development in early adolescence.
3.11.6 Summary of evidence and recommendations for the management of neurogenic bladder
Summary of evidence LE
Neurogenic detrusor-sphincter dysfunction may result in different forms of LUTD and ultimately result 2a
in incontinence, UTIs, VUR, and renal scarring.
In children, the most common cause of NDSD is myelodysplasia (a group of developmental anomalies 2
that result from defects in neural tube closure).
Bladder sphincter dysfunction correlates poorly with the type and level of the spinal cord lesion. 2a
Therefore, urodynamic and functional classifications are more practical in defining the extent of the
pathology and in guiding treatment planning.
Children with neurogenic bladder can have disturbances of bowel function as well as urinary function 2a
which require monitoring and, if needed, management.
The main goals of treatment are prevention of urinary tract deterioration and achievement of 2a
continence at an appropriate age.
Injection of botulinum toxin into the detrusor muscle in children who are refractory to anticholinergics, 2a
has been shown to have beneficial effects on clinical and urodynamic variables.
Recommendations LE GR
In all babies, start intermittent catheterisation soon after birth, except for babies without any 2 B
clear sign of outlet obstruction. If intermittent catheterisation is delayed, closely monitor babies
for urinary tract infections and upper tract changes.
Use anticholinergic drugs as initial treatment in children with overactive bladders. Clinical 2 B
improvement is common but usually insufficient.
Use injection of botulinum toxin into the detrusor muscle as an alternative in childen who are 2 B
refractory to anticholinergics.
Use a bladder augmentation procedure, using a segment of intestine, in case of therapy- 2 B
resistant overactivity of the detrusor, or small capacity and poor compliance causing upper
tract damage and incontinence.
Use augmentation with additional bladder outlet procedures when both the bladder and outlet 3 B
are deficient. Simple augmentation will suffice in most low-capacity, high-pressure bladders.
Augment with an additional continent stoma after bladder outlet surgery and in patients with 3 B
urethral catheterisation limitations.
Follow-up of neurogenic bladder patients will be life-long. Follow-up includes monitoring 3 B
of renal and bladder function as well as ensuring that sexuality and fertility issues receive
particular care as the child gets older and moves into adulthood.
3.12 Dilatation of the upper urinary tract (UPJ and UVJ obstruction)
3.12.1 Epidemiology, aetiology and pathophysiology
Dilatation of the UUT remains a significant clinical challenge in deciding which patient will benefit from
Postnatal US
Diuretic renography
* A diagnostic work-up including VCUG must be discussed with the parents, as it is possible that, even if reflux
is detected, it may have absolutely no clinical impact. However, it should be borne in mind that reflux has been
detected in up to 25% of cases of prenatally detected and postnatally confirmed hydronephrosis [522].
US = ultrasound.
3.12.3 Management
3.12.3.1 Prenatal management
Counselling the parents of an affected child is one of the most important aspects of care. The prognosis is
hopeful for a hydronephrotic kidney, even if it is severely affected, as it may still be capable of meaningful renal
function, unlike a severely hypoplastic and dysplastic kidney.
It is important to be able to tell the parents exactly when they will have a definitive diagnosis for
their child and what this diagnosis will mean. In some cases, however, it will be immediately obvious that the
child is severely affected; there will be evidence of massive bilateral dilatation, bilateral hypoplastic dysplasia,
progressive bilateral dilatation with oligohydramnios, and pulmonary hypoplasia.
Intrauterine intervention is rarely indicated and should only be performed in well-experienced
centres [526].
Due to the heterogeneity of the published literature it was not possible to draw strong conclusions as to
whether CAP is superior to observation alone in children diagnosed with ANH. In the first RCT, a prospective
longitudinal study [527], female gender, uncircumcised males, lack of CAP, high-grade hydronephrosis,
hydroureteronephrosis and VUR were found to be the independent predictors for the development of UTI.
The second RCT included in the SR, was published as an abstract only, presented limited data [528]. This trial
seemed to focus mainly on patients with ANH and VUR and did not report any beneficial effect of CAP on UTI
rates, but details on the study population were limited.
Key findings of the SR are that CAP may or may not be superior to observation in children with antenatal
hydronephrosis in terms of decreasing UTI. Due to the low data quality it was also not possible to establish
whether boys or girls are at a greater risk of developing a UTI, or ascertain the presence or absence of VUR
impacts UTI rates. A correlation between VUR-grade and UTI could not be established either. However, non-
circumcised infants, children diagnosed with high-grade hydronephrosis and hydroureteronephrosis were
shown to be at higher risk of developing a UTI.
The SR also tried to identify the most effective antibiotic regimen and present data on adverse effects but due
to heterogeneity, the available data could not be statistically compared. The most commonly used antibiotic in
infants with antenatal hydronephrosis is trimethoprim, but only one study reported side effects [527].
In conclusion, based on the currently available evidence, the benefits and harms of CAP in children with
antenatal hydronephrosis remain unproven. Uncircumcised infants and infants with hydroureteronephrosis
Well-established benefits of conventional laparoscopy over open surgery are the decreased length of hospital
stay, better cosmesis, less post-operative pain and early recovery [531, 532]. A recent meta-analysis in children
has shown that laparoscopic pyeloplasty (LP) was associated with decreased length of hospital stay and
complication rates but prolonged operative time when compared to open pyeloplasty (OP). Additionally, both
LP and OP had equal success rates [533]. Robotic-assisted laparoscopic pyeloplasty (RALP) has all the same
advantages as LP plus better maneuverability, improved vision, ease in suturing and increased ergonomics but
higher costs [534, 535]. There does not seem to be any clear benefit of minimal invasive procedures in a very
young child but current data is insufficient to defer a cut-off age.
3.12.3.3 Megaureter
The treatment options of secondary megaureters are reviewed in Chapter 3.13.3.
3.12.4 Conclusion
The use of routine perinatal sonography has resulted in increased detection of hydronephrosis caused by UPJ
or UVJ obstruction. Meticulous and repeat postnatal evaluation is mandatory to try to identify obstructive cases
at risk of renal deterioration and requiring surgical reconstruction. Surgical methods are quite standardised and
have a good clinical outcome.
Summary of evidence LE
Nowadays, most hydronephrotic kidneys have already been diagnosed prenatally during a maternal 2
US investigation.
Ureteropelvic junction obstruction is the leading cause of hydronephrotic kidneys (40%). 1
In children diagnosed with antenatal hydronephrosis, a systematic review could not establish any 1b
benefits or harms related to continuous antibiotic prophylaxis.
In children diagnosed with antenatal hydronephrosis, non-circumcised infants (LE: 1a), children 2
diagnosed with high-grade hydronephrosis (LE: 2) and hydroureteronephrosis (LE: 1b) were shown to
be at higher risk of developing UTI.
Recommendations LE GR
Include serial ultrasound (US) and subsequent diuretic renogram and sometimes voiding 2 B
cystourehrography (VCUG) in postnatal investigations.
Offer continuous antibiotic prophylaxis to the sub-group of children with antenatal hydronephrosis 2 A
who are at high risk of developing urinary tract infection (uncircumcised infants (LE: 1a), children
diagnosed with hydroureteronephrosis (LE: 2) and high-grade hydronephrosis (LE: 2)).
Decide on surgical intervention based on the time course of the hydronephrosis and the 2 B
impairment of renal function.
Offer surgical intervention in case of an impaired split renal function due to obstruction or a 2 B
decrease of split renal function in subsequent studies and increased anteroposterior diameter
on the US, and grade IV dilatation as defined by the Society for Fetal Urology.
Offer pyeloplasty when ureteropelvic junction obstruction has been confirmed clinically or with 2 B
serial imaging studies.
Do not offer surgery as a standard for primary megaureters since most do not require surgical 2 B
intervention.
Table 7: Grading system for VUR on VCUG, according to the International Reflux Study Committee [577]
Grade I Reflux does not reach the renal pelvis; varying degrees of ureteral dilatation
Grade II Reflux reaches the renal pelvis; no dilatation of the collecting system; normal fornices
Grade III Mild or moderate dilatation of the ureter, with or without kinking; moderate dilatation of the
collecting system; normal or minimally deformed fornices
Grade IV Moderate dilatation of the ureter with or without kinking; moderate dilatation of the collecting
system; blunt fornices, but impressions of the papillae still visible
Grade V Gross dilatation and kinking of the ureter, marked dilatation of the collecting system; papillary
impressions no longer visible; intraparenchymal reflux
Recommendations GR
Inform parents of children with vesicoureteric reflux (VUR) that siblings and offspring have a high A
prevalence of VUR.
Use renal ultrasound (US) for screening of sibling(s). A
Use voiding cystourethrography (VCUG) if there is evidence of renal scarring on US or a history of B
urinary tract infection.
Do not screen older toilet-trained children since there is no added value in screening for VUR. B
3.13.2.5 Children with lower urinary tract symptoms and vesicoureteric reflux
Detection of LUTD is essential in treating children with VUR. It is suggested that reflux with LUTD resolves
faster after LUTD correction, and that patients with LUTD are at higher risk for developing UTI and renal
scarring [552, 591]. The co-existence of both conditions should be explored in any patient who has VUR.
If there are symptoms suggestive of LUTD (e.g. urgency, wetting, constipation or holding manoeuvres), an
extensive history and examination, including voiding charts, uroflowmetry and residual urine determination, will
reliably diagnose underlying LUTD.
In LUTD, VUR is often low-grade and US findings are normal, and there is no indication for
performing VCUG in all children with LUTD, but the presence of febrile infections should be meticulously
investigated. The co-existence of LUTD and VUR means it would be better to do a test covering both
conditions, such as a videourodynamic study (VUDS). Any patient with LUTD and a history of febrile UTI
should be investigated with a VUDS, if available. Furthermore, any child who fails standard therapy for LUTD
should undergo urodynamic investigation. At this stage, combining a urodynamic study with VCUG is highly
recommended.
3.13.3.1.1 Follow-up
Regular follow-up with imaging studies (e.g. VCUG, nuclear cystography, or DMSA scan) is part of the
conservative management to monitor spontaneous resolution and kidney status. Conservative management
should be dismissed in all cases of febrile breakthrough infections, despite prophylaxis, and intervention should
be considered.
3.13.4 Summary of evidence and recommendations for the management of vesicoureteric reflux in
childhood
Summary of evidence LE
There is no evidence that correction of persistent low-grade reflux (grades I-III) without symptoms and 4
normal kidneys offers a significant benefit.
The traditional approach of initial medical treatment after diagnosis and shifting to interventional 2
treatment in case of breakthrough infections and new scar formation needs to be challenged, because
the treatment should be tailored to different risk groups.
Surgical correction should be considered in patients with persistent high-grade reflux (grades IV/V). 2
There is no consensus about the timing and type of surgical correction. The outcome of open surgical
correction is better than endoscopic correction for higher grades of reflux, whereas satisfactory results
can be achieved by endoscopic injection for lower grades.
The choice of management depends on the presence of renal scars, clinical course, grade of reflux, 2
ipsilateral renal function, bilaterality, bladder function, associated anomalies of the urinary tract,
age, compliance, and parental preference. Febrile UTI, high-grade reflux, bilaterality, and cortical
abnormalities are considered to be risk factors for possible renal damage. The presence of LUTD is an
additional risk factor for new scars.
Recommendations GR
Initially treat all patients diagnosed within the first year of life with continuous antibiotic prophylaxis, C
regardless of the grade of reflux or presence of renal scars.
Offer immediate, parenteral antibiotic treatment for febrile breakthrough infections. A
Offer definitive surgical or endoscopic correction to patients with frequent breakthrough infections. A
Offer surgical correction to patients with persistent high-grade reflux (grades IV/V) if intervention is B
needed; the outcome of open surgical correction is better than endoscopic correction for higher
grades of reflux, whereas satisfactory results can be achieved by endoscopic injection for lower
grades.
Initially manage all children presenting at age one to five years conservatively. B
Offer surgical repair to children presenting with high-grade reflux or abnormal renal parenchyma. B
Offer close surveillance without antibiotic prophylaxis to children presenting with lower grades of reflux B
and without symptoms.
Ensure that a detailed investigation for the presence of lower urinary tract dysfunction (LUTD) is done A
in all children after toilet-training. If LUTD is found, the initial treatment should always be for LUTD.
Consider surgical correction, if parents prefer definitive therapy to conservative management. B
Endoscopic treatment is an option for all children with low grades of reflux.
However, bladder stones are still common in underdeveloped areas of the world and are usually ammonium
acid urate and uric acid stones, strongly implicating dietary factors [624]. Patients with augmented bladder
constitute another important group with a risk of up to 15% [625].
The incidence and characteristics of stones show a wide geographical variation in children. Although urinary
stone disease is generally considered to be a relatively rare disease, it is quite common in some parts of the
world. Paediatric stone disease is endemic in Turkey, Pakistan and in some South Asian, African and South
American states. However, recent epidemiological studies have shown that the incidence of paediatric stone
disease is also increasing in the Western world [626-628], especially in girls, Caucasian ethnicity, African
Americans and older children [629]. More than 70% of stones in children contain calcium oxalate, while
infection stones are found more frequently in younger children [630].
Hypercalciuria: This is defined by a 24-hour urinary calcium excretion of more than 4 mg/kg/day
(0.1 mmol/kg/day) in a child weighing < 60 kg. In infants younger than three months, 5 mg/kg/day (0.125 mmol/
kg/day) is considered to be the upper limit for normal calcium excretion [631].
Hypercalciuria can be classified as either idiopathic or secondary. Idiopathic hypercalciuria is
diagnosed when clinical, laboratory, and radiographic investigations fail to delineate an underlying cause
leading to hypercalcaemia. Urinary calcium may increase in patients with high sodium chloride intake.
Secondary hypercalciuria occurs when a known process produces excessive urinary calcium. In secondary
(hypercalcemic) hypercalciuria, a high serum calcium level may be due to increased bone resorption
(hyperparathyroidism, hyperthyroidism, immobilisation, acidosis, metastatic disease) or gastrointestinal
hyperabsorption (hypervitaminosis D) [632].
A good screening test for hypercalciuria compares the ratio of urinary calcium to creatinine. The normal
calcium-to-creatinine ratio in children is less than 0.2. If the calculated ratio is higher than 0.2, repeat testing
is indicated. Neonates and infants have a higher calcium excretion and lower creatinine excretion than older
children [631, 632]. If the follow-up ratios are normal, then no additional testing for hypercalciuria is needed.
In rare primary hyperoxaluria, one of the two liver enzymes that play a role in the metabolism of oxalate may
be deficient. With increased deposition of calcium oxalate in the kidneys, renal failure may ensue in resulting
deposition of calcium oxalate in other tissues (oxalosis). The diagnosis is made upon laboratory findings of
severe hyperoxaluria and clinical symptoms. The definitive diagnosis requires liver biopsy to assay the enzyme
activity.
Other forms of hyperoxaluria, as mentioned earlier, may be due to hyperabsorption of oxalate in
inflammatory bowel syndrome, pancreatitis and short bowel syndrome. Yet, the majority of children have
‘mild’ (idiopathic) hyperoxaluria, with urine oxalate levels elevated only mildly in these cases. The treatment
of hyperoxaluria consists of the promotion of high urine flow, restriction of dietary oxalate and regular
calcium intake. Pyridoxine may be useful in reducing urine levels, especially in primary hyperoxaluria. Citrate
administration increases inhibitory urine activity [637, 645] (LE: 4).
Hypocitraturia: Citrate is a urinary stone inhibitor. Citrate acts by binding to calcium and by directly inhibiting
the growth and aggregation of calcium oxalate as well as calcium phosphate crystals. Thus low urine citrate
may be a significant cause of calcium stone disease. In adults, hypocitraturia is the excretion of citrate in urine
of less than 320 mg/day (1.5 mmol/day) for adults; this value must be adjusted for children depending on body
size [646-648].
Hypocitraturia usually occurs in the absence of any concurrent symptoms or any known metabolic
derangements. It may also occur in association with any metabolic acidosis, distal tubular acidosis or
diarrhoeal syndromes.
Environmental factors that lower urinary citrate include a high protein intake and excessive salt
intake. Many reports emphasise the significance of hypocitraturia in paediatric calcium stone disease. The
presence of hypocitraturia ranges from 30% to 60% in children with calcium stone disease [648, 649].
The restoration of normal citrate levels is advocated to reduce stone formation, although there are few relevant
studies in children. Hypocitraturia is treated by potassium citrate at a starting dose of 1 mEq/kg, given in two
divided doses [647] (LE: 3). The side effects of potassium citrate are very rare and most of the time they include
non-specific gastrointestinal complaints. Potassium citrate should be used with caution in hyperkalemic and
chronic renal failure conditions.
Alkalinisation of urine is the mainstay of therapy and prevention for uric acid stones. Citrate preparations are
useful as alkalinising agents. Maintaining a urine pH of 6 to 6.5 is sufficient to prevent uric acid stones [637].
In cases who failed with conservative measures with sustaining hyperuricosuria and hyperuricemia, stone
recurrences or myeloproliferative diseases, allopurinol (10 mg/kg) may be used. This medication may cause
several drug reactions (rash, diarrhoea, eosinophilia) and should be cautiously used in chronic renal failure
patients.
Figure 8 provides an algorithm of how to perform metabolic investigations in urinary stone disease in children
and how to plan medical treatment accordingly.
Stone analysis
Mg Ammonium
Calciumstones
phosphate Uric acid stone Cystine
CaOX-CaPO
(struvite)
urine pH urine pH
urine culture urine and serum urine cystine
uric acid levels level
possibly acidicurine
ureaseproducing hyperuricosuria cystinuria
bacteria hyperuricemia
urine - blood pH
serum PTH hypercalcaemia urine - blood Ca - uric acid levels,urine
Mg,pH
Phosphate
> 5.5
urine Ca-Oxalate-Citrate-Mg-Uric A -Phosphate
K-citrate
Regular calcium
diet Alkali
intake Citrate
(normal calcium replacement
Diet low in ox. replacement
low sodium (K-citrate)
K-citrate K- citrate
intake) allopurinol
pyridoxine
HCTZ (diuretic)
3.14.4 Management
With the advance of technology stone management has changed from open surgical approaches to
endoscopic techniques that are less invasive. Deciding the type of treatment depends on the number, size,
location, stone composition and the anatomy of the urinary tract [659, 662, 663]. Expectant management
is the initial management in children with asymptomatic small size stones (< 4-5 mm ) with a possibility of
spontaneous clearance. There is no consensus on the size of stones for different ages eligible for clearance
and the duration of conservative follow-up. Adult literature reveals the benefits of medical expulsive therapy
(MET) using α-blockers. Although, experience in children is limited showing different results [664], a recent
meta-analysis of three randomised and two retrospective studies demonstrate that treatment with MET results
in increased odds of spontaneous ureteral stone passage and a low rate of adverse events [665]. Currently,
most paediatric stones can easily be managed by shockwave lithotripsy (SWL). Endoscopic treatment can be
applied for ureteric and bladder stones. Percutaneous removal of stones is also possible for kidney stones in
Complications arising from SWL in children are usually self-limiting and transient. The most common are:
• renal colic;
• transient hydronephrosis;
• dermal ecchymosis;
• UTI;
• formation of Steinstrasse;
• sepsis;
• rarely, haemoptysis.
In children with sterile pre-operative urine cultures, antibiotic prophylaxis to decrease infectious complications
is not recommended [693]. However, every effort should be made to sterilise the urine before performing SWL,
ureteroscopy (URS), or percutaneous nephrolithotomy (PNL).
Because of the smaller size of the probes, laser energy is easier to use in smaller instruments and is more
useful for paediatric cases [694-703].
3.14.4.3 Ureterorenoscopy
The increasing availability of smaller size endourological equipment has made it possible to manage paediatric
ureteral stones using endoscopic techniques.
The technique used in children is similar to the one used in adults. It is strongly recommended
that guide wires are used and the procedure is performed using direct vision. Routine balloon dilation of
ureterovesical junction and ureteral stenting are controversial. In general, ureteric dilatation is being performed
much less and only in selected cases. There is a tendency to use hydrodilation more because it is similarly
effective [693, 695, 696, 729-732] (LE: 3; GR: B).
Different lithotripsy techniques, including ultrasonic, pneumatic and laser lithotripsy, have all been
shown to be safe and effective. Because of the smaller size of the probes, laser energy is easier to use in
smaller instruments and is more useful for paediatric cases [694-703].
All studies reporting the use of endoscopy for ureteric stones in children have clearly demonstrated that there
is no significant risk of ureteric strictures or reflux with this mode of therapy (LE: 1; GR: A). The risk of post-
operative hydronephrosis depends on the presence of impacted stone and ureteral injury during operation
[733]. A multi-institutional study on the use of semi-rigid ureteroscopy for ureteral calculi in children has
revealed that the procedure is effective with a 90% stone-free rate and efficacy quotient. The study also
focused on the factors affecting the complication rates. The authors found that although operating time, age,
institutional experience, orifice dilation, stenting and stone burden were significant on univariate analysis,
multivariate analysis revealed that operating time was the only significant parameter affecting the complication
rate [734].
A recent literature review contains a growing number of case series on the use of flexible
ureterorenoscopic interventions in children. Both intrarenal and ureteric stones can be treated using this
approach [735-739]. In these series, the authors generally did not use active orifice dilation, but attempted to
3.14.5 Summary of evidence and recommendations for the management of urinary stones
Summary of evidence LE
The incidence of stone disease in children is increasing. 2
Contemporary surgical treatment is based on minimally invasive modalities. Open surgery is very 2a
rarely indicated.
The term ‘clinically insignificant residual fragments’ is not appropriate for children since most of them 2b
become symptomatic and require intervention.
Recommendations LE GR
Use plain abdominal X-ray and ultrasound (US) as the primary imaging techniques for the 2b B
diagnosis and follow-up of stones.
Use low-dose non-contrast computed tomography (CT) in cases with a doubtful diagnosis, 2a B
especially of ureteral stones or complex cases requiring surgery.
Perform a metabolic and anatomical evaluation in any child with urinary stone disease. 2a B
Any kind of interventional treatment should be supported with medical treatment for the 2a B
underlying metabolic abnormality, if detected.
Open surgery may be done under circumstances in which the child is very young with large 2a B
stones, in association with congenital problems requiring surgical correction and/or with severe
orthopedic deformities that limit positioning for endoscopic procedures.
Use appropriately-sized instruments in order to decrease the number of complications during 2b B
surgical treatment.
3.15.1.1 Ureterocele
Ureterocele is 4-7 times more frequent in female than in male patients; the overall incidence in autopsies is
around one in 4,000 children. Around 80% is associated with the upper pole ureter in duplicated systems and
20% in single systems. About 10% of ureteroceles are bilateral [748].
In cases of prenatal diagnosis, at birth, US confirms the ureteral dilatation that ends at the upper pole of a renal
duplication. It also demonstrates the presence of a ureterocele in the bladder, with a dilated ureter behind the
bladder.
At this point, it is important to assess the function of the upper pole using nuclear renography
of the region of interest. This is best assessed with DMSA [762-764]. Magnetic resonance urography may
visualise the morphological status of the upper pole and lower moieties and of the contralateral kidney, but
cannot reliably predict histology [765]. Based on the prevalence of high-grade reflux, VCUG is mandatory
for identifying ipsilateral or contralateral reflux, and assessing the degree of intra-urethral prolapse of the
ureterocele [766]. Urethrocystoscopy may reveal the pathology in cases where it is difficult to make the
differential diagnosis between ureterocele and ectopic mega-ureter.
Ultrasound, radionuclide studies (DMSA, VCUG, MR urography, high-resolution MRI, and cystoscopy) are the
diagnostic tools to assess function, to detect reflux and rule out ipsilateral compression of the lower pole and
urethral obstruction [768]. In some cases, the large ectopic ureter presses against the bladder and can look like
a pseudo-ureterocele [769, 770].
Girls who present with lifelong minimal urinary incontinence, never being dry, normal bladder
function, complete emptying, and normal US are very suspicious for ectopic ureter. This needs to be excluded
or confirmed by MRI as the most sensitive method [771]. Filling the bladder with methylene blue and checking
for clear urine output from the vagina can give clear evidence of extra-sphincteric ureteral ectopia. This test is
also helpful in confirming a vesicovaginal fistula (in this case blue fluid drains from the vagina).
3.15.4 Management
3.15.4.1 Ureterocele
Management is controversial with a choice between a non-operative approach, endoscopic decompression,
ureteral re-implantation, partial nephroureterectomy, or complete primary reconstruction [772-777]. The choice
of a therapeutic modality depends on the following criteria: clinical status of the patient (e.g. urosepsis); patient
age; function of the upper pole; presence of reflux or obstruction of the ipsilateral or contralateral ureter;
presence of bladder neck obstruction caused by ureterocele; intravesical or ectopic ureterocele; and parents’
and surgeon’s preferences [778]. When the diagnosis is made by US, prophylactic antibiotic treatment is
indicated until a VCUG is performed.
3.15.4.1.2 Re-evaluation
Conservative treatment may be adopted in asymptomatic patients without any bladder outlet obstruction,
severe hydroureteronephrosis of the ureterocele moiety or high-grade (over grade III) reflux [778, 779]. If
decompression is effective and there is no reflux (~25% of cases and more often in intravesical ureterocele),
the patient is followed-up conservatively. After an endoscopic incision, most of the children with an extravesical
ureterocele (50-80%) need a secondary procedure, compared with only 18% of those with an intravesical
ureterocele [750]. Secondary surgery is necessary if decompression is not effective, significant reflux is
present, or there is obstruction of the ipsi- or contralateral ureters, and/or bladder neck obstruction or retained
ureterocele [780].
Surgery may vary from upper pole nephrectomy to complete unilateral LUT reconstruction [756,
776, 781-784]. In an ectopic ureterocele with severe hydroureteronephrosis and without reflux, the primary
upper tract approach without endoscopic decompression (partial upper-pole nephroureterectomy, pyelo/
ureteropyelo/ureterostomy and upper-pole ureterectomy) has an 80% chance of being the definitive treatment
[778, 785].
Figure 9: A
lgorithm for the management of duplex system ureteroceles after the first 3-6 months of life
[778]
DSU
DSU = duplex system ureterocele; HUN = hydroureteronephrosis; UPPN = upper pole partial nephrectomy;
VUR = vesicoureteric reflux to the lower pole.
Summary of evidence LE
Ureterocele and ectopic ureter are associated with complete renal duplication, but they also occur in a 1
single system.
In most cases, in young children (first years of life) diagnosis is done by US. 1
In older children clinical symptoms will prompt assessment. 1
Management includes a conservative approach, endoscopic decompression, partial 3
nephroureterectomy, or complete primary reconstruction. Choice of treatment will depend on:
• clinical status of the patient (e.g., urosepsis);
• patient age;
• function of the upper pole;
• presence of reflux or obstruction of the ipsilateral or contralateral ureter;
• presence of bladder neck obstruction caused by ureterocele;
• intravesical or ectopic ureterocele;
• and parents’ and surgeon’s preferences.
Recommendations LE GR
Ureterocele Diagnosis Use ultrasound (US), radionuclide studies (mercaptoacetyltriglycine 3 B
(MAG3)/dimercaptosuccinic acid (DMSA)), voiding
cystourethrography (VCUG), magnetic resonance urography, high-
resolution magnetic resonance imaging (MRI), and cystoscopy to
assess function, to detect reflux and rule out ipsilateral compression
of the lower pole and urethral obstruction.
Treatment Select treatment based on symptoms, function and reflux as 3 B
well on surgical and parenteral choices: observation, endoscopic
decompression, ureteral re-implantation, partial nephroureterectomy,
complete primary reconstruction.
Offer conservative treatment to patients (single/duplex systems) with
no hydronephrosis and no symptoms, the risk for renal injury is low
and conservative treatment is a good option.
Offer endoscopic treatment to patients with reflux; open
re-implantation especially in dilating reflux provides better results.
Offer, early endoscopic decompression to patients with an
obstructing ureterocele. In half to two-thirds of children with an
extravesical ureterocele a secondary procedure is needed (compared
to 20-25% of those with an intravesical ureterocele).
Offer heminephrectomy to patients with a non-functioning moiety and
symptoms.
Ectopic Diagnosis Use US, DMSA scan, VCUG or MRI for a definitive diagnosis. 3 B
ureter Treatment Select the most appropriate treatment option based on the function 3 B
of the upper urinary tract.
Offer (hemi-)nephroureterectomy in poorly or non-functioning
moieties.
Offer ureteral re-implantation, ureteroureterostomy or
ureteropyelostomy to patients with a functioning renal moiety,
especially in cases in which the upper pole has function worth
preserving.
3.16.1.1 Micropenis
Micropenis is a small but otherwise normally formed penis with a stretched length of < 2.5 SD below the mean
[793, 794, 797].
Besides an idiopathic micropenis, two major causes of abnormal hormonal stimulation have been identified:
• hypogonadotropic hypogonadism (due to an inadequate secretion of GnRH);
• hypergonadotropic hypogonadism (due to failure of the testes to produce testosterone).
The penis is measured on the dorsal aspect, while stretching the penis, from the pubic symphysis to the tip of
the glans [793]. The corpora cavernosa are palpated, the scrotum is often small, and the testes may be small
and descended. Micropenis should be distinguished from buried and webbed penis, which is usually of normal
size. The initial evaluation has to define whether the aetiology of the micropenis is central (hypothalamic/
pituitary) or testicular. A paediatric endocrinology work-up has to be carried out immediately. Karyotyping is
mandatory in all patients with a micropenis. Endocrine testicular function is assessed (baseline and stimulated
testosterone, LH and FSH serum levels). Stimulated hormone levels may also give an idea of the growth
potential of the penis. In patients with non-palpable testes and hypogonadotropic hypogonadism, laparoscopy
should be carried out to confirm vanishing testes syndrome or intra-abdominal undescended hypoplastic
testes. This investigation can be delayed until the age of one year [794].
Pituitary or testicular insufficiency are treated by the paediatric endocrinologist. In patients with
testicular failure and proven androgen sensitivity, androgen therapy is recommended during childhood and at
puberty to stimulate the growth of the penis [798-801] (LE: 2). In the presence of androgen insensitivity, good
outcome of sexual function is questioned and gender conversion can be considered [802-804].
Apparent male
Severe hypospadias associated with bifid scrotum
Undescended testis/testes with hypospadias
Bilateral non-palpable testes in a full-term apparently male infant
Apparent female
Clitoral hypertrophy of any degree, non-palpable gonads
Vulva with single opening
Indeterminate
Ambiguous genitalia
These investigations will provide evidence of congenital adrenal hyperplasia (CAH), which is the most
frequently occurring DSD. If this evidence is found, no further investigation is needed. If not, then the laboratory
work-up should proceed further.
The hCG stimulation test is particularly helpful in differentiating the main syndromes of 46XYDSD
by evaluating Leydig cell potential. When testosterone metabolism is evaluated, the presence or absence of
metabolites will help to define the problem. An extended stimulation can help to define phallic growth potential
and to induce testicular descent in some cases of associated cryptorchidism.
Each patient presenting with DSD should be assigned a gender as quickly as a thorough diagnostic evaluation
permits. Minimal time needed is 48 hours. During this period any referral to gender should be avoided, better to
address the patient as “the child”, “your child”.
Diagnostic role
• Clinical examination
• Ultrasound
• Genitography
• Cystoscopy
• Diagnostic laparoscopy
Therapeutic role
• Masculinising surgery
• Feminising surgery
• Gonadectomy
Palpable gonad. If it is possible to feel a gonad, it is almost certainly a testis; this clinical finding therefore
virtually excludes 46XXDSD.
Medical photography can be useful but requires sensitivity and consent [805].
Phallus. The phallus should be measured. A cotton bud placed at the suprapubic base of the implant of the
stretched phallus allows for a good measurement of phallic length.
Urogenital sinus opening. The opening of the urogenital sinus must be well evaluated. Is there only one opening
visible? Can a hymenal ring be seen? What does the fusion of the labioscrotal folds look like; do the folds show
rugae or some discolouration?
3.16.2.3.2 Investigations
Ultrasound can help to describe the palpated gonads or to detect non-palpable gonads. However, the
sensitivity and specificity are not high. On US, the Mülllerian structures can be evaluated. Is there a vagina? Are
there some abdominal gonads? Is there a vaginal or utriculur structure visible [806, 807]?
General anaesthesia. In some cases, further examinations under general anaesthesia can be helpful. On
cystoscopy, the urogenital sinus can be evaluated and the level of confluence between the bladder neck and
the bladder. Cystoscopy can also be used to evaluate the vagina or utriculus, e.g. the presence of a cervix at
the top of the vagina can be important information.
Laparoscopy is necessary to obtain a final diagnosis on the presence of impalpable gonads and on the
presence of Müllerian structures. If indicated, a gonadal biopsy can be performed [808, 809].
3.16.3 Management
Referring to the consensus document [793, 794], it is clear that the timing of surgery is much more
controversial than it used to be. The rationale for early surgery includes:
• beneficial effects of oestrogen on infant tissue;
• avoiding complications from anatomical anomalies;
• minimising family distress;
• mitigating the risks of stigmatisation and gender-identity confusion [810].
However, adverse outcomes have led to recommendations to delay unnecessary surgery to an age when
the patient can give informed consent. Surgery that alters appearance is not urgent. Early surgery should be
reserved for those patients with high confluent urogenital tracts, girls with severely masculinised genitalia
and boys with undervirilised genitals. Vaginoplasty should be delayed until puberty and milder forms of
masculinisation should not be treated surgically. Recently the ESPU and SPU have taken a position in the
debate on surgery for DSD [811].
Separation of the vagina and the urethra is preserved for high confluence anomalies. Many techniques for
urogenital sinus repair have been described, but their outcome has not been evaluated prospectively [815,
816].
Vaginoplasty should be performed during the teenage years. Every technique (self-dilatation, skin or bowel
substitution) has its specific advantages and disadvantages [817]. All carry a potential for scarring that would
require further surgery before sexual function was possible.
Aesthetic refinements. The goals of genital surgery are to maximise anatomy to allow sexual function and
romantic partnering. Aesthetics are important in this perspective. The reconstruction of minor labiae from an
enlarged clitoral hood is an example of aesthetic refinement.
Excision of Mullerian structures. In the DSD patient assigned a male gender, Müllerian structures should be
excised. There is no evidence on whether utricular cysts need to be excised.
Phalloplasty. Increasing experience of phalloplasty in the treatment of female to male transsexual patients has
led to reports about the reliability and feasibility of this technique. It has therefore become available to treat
severe penile inadequacy in DSD patients.
Aesthetic refinements. These include correction of penoscrotal transposition, scrotoplasty and insertion of
testicular prostheses.
3.16.4 Summary of evidence and recommendations for the management of disorders of sex
development
Summary of evidence LE
Timing of surgery will be dependent on the severity of the condition and on the assigned sex. 4
In boys the surgical correction will mainly consist of hypospadias repair and orchiopexy, so the timing 2
will follow the recommendations for hypospadias repair and orchiopexy (from six months onwards and
before two years of age).
Recommendations GR
Treat disorders of sex development (DSD) within a multi-disciplinary team. A
Refer children to experienced centres where neonatology, paediatric endocrinology, paediatric urology, A
child psychology and transition to adult care are guaranteed.
Do not delay treatment of any neonate presenting with ambiguous genitalia since salt-loss in a A
46XX CAH girl can be fatal.
Gender assignment is imminent and should be based on multi-disciplinary consensus taking into B
account the latest knowledge.
Do not delay surgical treatment in girls presenting with severe anomalies. B
Offer more conservative approaches in less severe cases, in consultation with the parents. B
Follow the recommendations for boys, for hypospadias repair and orchiopexy (from six months A
onwards and before two years of age).
Type I (90-95%). ‘In the most common type there is a ridge lying on the floor of the urethra, continuous with
the verumontanum, which takes an anterior course and divides into two fork-like processes in the region of the
bulbo-membranous junction. These processes are continued as thin membranous sheets, direct upward and
forward which may be attached to the urethra throughout its entire circumference. It is generally supposed that
the valves have complete fusion anteriorly, leaving only an open channel at the posterior urethral wall. Yet, the
fusion of the valves anteriorly may not be complete in all cases, and at this point a slight separation of the folds
exists’ [826].
Type III. ‘There is a third type which has been found at different levels of the posterior urethra and which
apparently bears no such relation to the verumontanum. This obstruction was attached to the entire
circumference of the urethra, with a small opening in the centre’ [826]. The transverse membrane described
has been attributed to incomplete dissolution from the urogenital portion of the cloacal membrane [827]. The
embryology of the urethral valves is poorly understood. The membrane may be an abnormal insertion of the
mesonephric ducts into the foetal cloaca [828].
During prenatal US screening, bilateral hydroureteronephrosis and a distended bladder are suspicious signs of
a urethral valve. Also a thick-walled bladder and a dilated posterior urethra (‘keyhole’ sign) make a PUV likely.
In one study, however, the keyhole sign was not found to be a reliable predictor (p = 0.27) [829]. In the presence
of increased echogenicity of the kidney, dilatation of the urinary tract and oligohydramnion, the diagnosis of a
PUV should strongly be considered.
Voiding cystourethrogram confirms a PUV diagnosis. This study is essential whenever there is a
question of an infravesical obstruction, as the urethral anatomy is well outlined during voiding. A secondary
reflux is observed in at least 50% of patients with PUV [830]. Reflux is consistently associated with renal
dysplasia in patients with PUV. It is generally accepted that reflux in the renal units acts as a ‘pressure pop-
off valve’, which would protect the other kidney, leading to a better prognosis [831]. Other types of pop-
off mechanism include bladder diverticula and urinary extravasation, with or without urinary ascites [832].
However, in the long-term, a supposed protective effect did not show a significant difference compared to
other patients with PUV [833, 834].
Nuclear renography with split renal function is important to assess kidney function (DMSA or
MAG3). Creatinine, blood urea nitrogen and electrolytes should be monitored closely during the first few days.
A nadir creatinine of 80 μmol/L is correlated with a better prognosis [821]. Initial management includes a multi-
disciplinary team involving a paediatric nephrologist.
3.17.4 Management
3.17.4.1 Antenatal treatment
About 40-60% of PUV are discovered before birth [835]. The intrauterine obstruction leads to a decreased
urine output, which could result in an oligohydramnios. Amniotic fluid is necessary for normal development of
the lung and its absence may lead to pulmonary hypoplasia, causing a life-threatening problem. Intrauterine
attempts have been made to treat a foetus with PUV.
As renal dysplasia is not reversible, it is important to identify those foetuses with good renal
function. A sodium level below 100 mmol/L, a chloride value of < 90mmol/L and an osmolarity below
200 mOsm/L found in three foetal urine samples gained on three different days are associated with a better
prognosis [836].
The placing of a vesicoamniotic shunt has a complication rate of 21-59%, dislocation of the shunt
occurs in up to 44%, mortality lies between 33% and 43%, and renal insufficiency is above 50% [836-838].
Although shunting is effective in reversing oligohydramnios, it makes no difference to the outcome and longterm
results of patients with PUV [837, 838]. The PLUTO-trail (randomised study) could not prove a benefit of placing a
shunt [839].
Foetal valve treatment e.g laser ablation has a high complication rate without evidence for the
effectiveness of these interventions. Therefore this should be still considered as an experimental intervention
[840, 841].
Valve ablation. When the medical situation of the neonate has stabilised and the creatinine level decreased, the
next step is to remove the intravesical obstruction. In cases were the urethra is too small to safely pass a small
faetal cystoscope, a suprapubic diversion is performed until valve ablation can be performed. Small paediatric
cystoscopes and resectoscopes are now available either to incise, ablate or to resect the valve at the 4-5, 7-8
or 12 o’clock position, or at all three positions, depending on the surgeon’s preference. It is important to avoid
Vesicostomy. If the child is too small and/or too ill to undergo endoscopic surgery, a suprapubic diversion is
performed to drain the bladder temporarily. If initially a suprapubic tube has been inserted, this can be left in
place for six to twelve weeks. Otherwise, a cutaneous vesicostomy provides an improvement or stabilisation
of the UUT in over 90% of cases [844]. Although there has been concern that a vesicostomy could decrease
bladder compliance or capacity, so far there are no valid data to support these expectations [845, 846].
High diversion. If bladder drainage is insufficient to drain the UUT, high urinary diversion should be considered.
Diversion may be suitable if there are recurrent infections of the upper tract, no improvement in renal function
and/or an increase in upper tract dilatation, despite adequate bladder drainage. The choice of urinary diversion
depends on the surgeon’s preference for high loop ureterostomy, ring ureterostomy, end ureterostomy or
pyelostomy, with each technique having advantages and disadvantages [847-849]. Reconstructive surgery
should be delayed until the UUT has improved as much as can be expected.
Reflux is very common in PUV patients (up to 72%) and it is described bilaterally in up to 32% [850].
During the first months of life, antibiotic prophylaxis may be given especially in those with high-grade reflux
[600] and in those with a phimosis, circumcision can be discussed in order to reduce the risk of UTIs [851].
However, there are no randomised studies to support this for patients with PUV. High-grade reflux is associated
with a poor functioning kidney and is considered a poor prognostic factor [819, 852]. However, early removal of
the renal unit seems to be unnecessary, as long as it causes no problems. It may be necessary to augment the
bladder and in this case the ureter may be used [853].
3.17.5 Follow-up
Life-long monitoring of these patients is mandatory, as bladder dysfunction (‘valve bladder’) is not uncommon
and the delay in day- and night-time continence is a major problem [821, 830]. Poor bladder sensation and
compliance, detrusor instability and polyuria (especially at night) and their combination are responsible for
bladder dysfunction. In those with bladder instability, anticholinergic therapy can improve bladder function.
However, with a low risk of reversible myogenic failure (3/37 patients in one study) [854, 855]. In patients with
poor bladder emptying α-blocker can be used to reduce the PVR urine, as demonstrated in one study with
42 patients using terazosin (mean PVR) was reduced from 16 to 2 mL) [856] and in another study tamsulosin
was effective [857]. Between 10% and 47% of patients may develop end-stage renal failure [819-821]. High
creatinine nadir and severe bladder dysfunction are risk factors for renal replacement therapy [858]. Renal
transplantation in these patients can be performed safely and effectively [859, 860]. Deterioration of the graft
function is mainly related to LUTD [860, 861]. An assessment and treatment algorithm is provided in Figure 10.
Confirm diagnosis
No stabilisation
Bladder drainage
Consider diversion
• Close follow-up
• Monitor urinary infection
• Monitor renal function
• Monitor night-time polyuria
and bladder over-extension
CIC = clean intermittent catheterisation; OAB = overactive bladder; PUV = posterior urethral valve;
RF = renal function; UT = urinary tract; UUT = upper urinary tract; VCUG = voiding cystourethrogram.
3.17.6 Summary
Posterior urethral valves are one of the few life-threatening congenital anomalies of the urinary tract found
during the neonatal period and despite optimal treatment result in renal insufficiency in nearly one-third of
cases. Bilateral hydroureteronephrosis and a distended bladder are suspicious signs of a PUV in neonates. A
VCUG confirms a PUV diagnosis. Nuclear renography with split renal function is important to assess kidney
function and serum creatinine nadir above 80 μmol/L is correlated with a poor prognosis.
Postnatal treatment includes bladder drainage either transurethral or suprapubic and if the child is
stable enough, endoscopic incision of the valve is performed. If a child is too small and/or too ill to undergo
endoscopic surgery, a vesicostomy is an option for bladder drainage. If bladder drainage is insufficient to drain
the UUT, high urinary diversion should be considered.
In all patients life-long monitoring is mandatory, as bladder dysfunction is quite common and may
cause progressive upper tract deterioration, if not managed properly. In the long run between 10% and 47% of
patients may develop end-stage renal failure. Renal transplantation in these patients can be performed safely
and effectively.
Summary of evidence LE
Posterior urethral valves are one of the few life-threatening congenital anomalies of the urinary tract 1b
found during the neonatal period.
Despite optimal treatment nearly one-third of the patients end up in renal insufficiency. 2b
Bilateral hydroureteronephrosis and a distended bladder are suspicious signs on US; a VCUG 2b
confirms the diagnosis.
Serum creatinine nadir above 80 μmol/L is correlated with a poor prognosis. 2a
In the long run between 10% and 47% of patients develop end-stage renal failure due to primary 2a
dysplasia and/or further deteroration because of bladder dysfunction.
Renal transplantation in these patients is safe and effective, if the bladder function is normalised.
Recommendations LE GR
Diagnose posterior urethral valves (PUV) initially by ultrasound (US) but a voiding 3 B
cystourethrogram (VCUG) is required to confirm the diagnosis. Assess split renal function by
dimercaptosuccinic acid (DMSA) scan or mercaptoacetyltriglycine (MAG3) clearance. Serum
creatinine is the prognostic marker.
Vesico-amniotic shunt antenatally is not recommended to improve renal outcome. 1b A
Offer endoscopic valve ablation after bladder drainage and stabilisation of the child. 3 B
Offer suprapupic diversion for bladder drainage if the child is too small for urethral surgery.
Offer a high urinary diversion if bladder drainage is insufficient to drain the UUT and the child
remains unstable.
Monitor bladder- and renal function lifelong, in all patients. 3 B
3.18.1.3.1 Haematuria
Haematuria may be a reliable finding. In severe renal injuries, 65% suffer visible haematuria and 33% non-
visible, while only 2% have no haematuria at all [866].
The radiographic evaluation of children with suspected renal trauma remains controversial. Some
centres rely on the presence of haematuria to diagnose renal trauma, with a threshold for renal involvement
of 50 RBCs/HPF. Although this may be a reliable threshold for significant non-visible in trauma, there have
been many reports of significant renal injuries that manifest with little or even no blood in the urine [867]. It is
therefore compulsory to consider all the clinical aspects involved, including the history, physical examination,
consciousness of the child, overall clinical status and laboratory findings to decide on the diagnostic algorithm
and whether or not a child needs further imaging studies.
Recommendations GR
Use imaging in all children who have sustained a blunt or penetrating trauma with any level of B
haematuria, especially when the history reveals a deceleration trauma, direct flank trauma or a fall
from a height.
Use rapid spiral computed tomography scanning for diagnostic and staging purposes. B
Manage most injured kidneys conservatively. B
Offer surgical intervention in case of haemodynamic instability and a Grade V renal injury. A
3.18.2.2 Management
Immediate repair during abdominal exploration is rare. Minimally invasive procedures are the method of
choice, especially since many ureteral injuries are diagnosed late after the traumatic event. Percutaneous or
nephrostromy tube drainage of urinomas can be successful, as well as internal stenting of ureteral injuries
[873].
If endoscopic management is not possible, primary repair of partial lacerations should be followed
by internal stenting. The management of complete lacerations, avulsions or crush injuries depends on
the amount of ureter lost and its location. If there is an adequate healthy length of ureter, a primary
ureteroureterostomy can be performed. If primary re-anastomosis is not achievable, distal ureteral injuries can
be managed using a psoas bladder hitch, Boari flap or even nephropexy. Proximal injuries can be managed
using transureteroureterostomy, autotransplantation or ureteral replacement with bowel or appendix [874].
3.18.2.3 Recommendations for the diagnosis and management of paediatric ureteral trauma
Recommendations GR
Diagnose suspected ureteral injuries by retrograde pyelogram.
However, in the initial phase of an injury, it is very likely that ureteral injuries will not be detected by A
routine imaging methods, including contrast-enhanced spiral computed tomography.
Manage ureteral injuries endoscopically, using internal stenting or drainage of a urinoma, either B
percutaneously or via a nephrostomy tube.
Manage distal and proximal ureteral injuries with open surgery. B
Manage distal injuries with direct re-anastomosis and ureteroneocystostomy. B
Manage proximal injuries, with transureteroureterostomy, ureteral replacement with bowel or appendix, B
or even autotransplantation.
Blunt trauma is the most common cause of significant bladder injury. In adults, bladder injury is often
associated with pelvic fractures. This is less common in children because the paediatric bladder sits above
the pelvic ring. In a large prospective study, only 57% of children with pelvic fractures also had a bladder injury
compared to 89% of adults [875].
Intra-peritoneal bladder ruptures are more common in children because of the bladder’s exposed position and
the acute increase in pressure during trauma. These cause the bladder to burst at its weakest point, i.e. the
dome. Extraperitoneal lesions occur in the lower half of the bladder and are almost always associated with
pelvic fractures. A cystogram will show extravasation into the perivesical soft tissue in a typical flame pattern
and the contrast material is confined to the pelvis.
3.18.3.2 Management
Contusions usually present with varying degrees of haematuria and are treated with catheter drainage alone.
3.18.3.3 Recommendations for the diagnosis and management of paediatric bladder injuries
Recommendations GR
Use retrograde cystography to diagnose suspected bladder injuries.
Ensure that the bladder has been filled to its full capacity and an additional film is taken after drainage. A
Manage extra-peritoneal bladder ruptures conservatively with a transurethral catheter left in place for A
seven to ten days.
Do not delay treatment of intra-peritoneal bladder ruptures by surgical exploration and repair as well A
as post-operative drainage for seven to ten days.
The main goals in the surgical repair of posterior urethral injuries are:
• Providing a stricture-free urethra.
• Avoiding the complications of urinary incontinence and impotence.
Suprapubic drainage and late urethral reconstruction was first attempted because immediate surgical repair
had a poor outcome, with significant bleeding and high rates of incontinence (21%) and impotence in up to
56% of cases [882]. In adults, a study of the success rates of delayed repair reported re-structure rates of
11-30%, continence rates of 90-95% and impotence rates of 62-68% [883]. However, in children, there is
much less experience with delayed repair. The largest paediatric series of delayed repair in 68 boys reported a
success rate of 90% [884]. Another study reported strictures and impotence in 67% of boys, although all the
boys were continent [883].
An alternative to providing initial suprapubic drainage and delayed repair is primary realignment of
the urethra via a catheter. The catheter is usually put in place during open cystostomy by passing it from either
the bladder neck or meatus and through the injured segment. In a series of fourteen children undergoing this
procedure, this resulted in a stricture rate of 29% and incontinence in 7% of patients [885].
Recommendations GR
Assess the urethra by retrograde urethrogram in case of suspected urethral trauma. A
Perform a rectal examination to determine the position of the prostate. B
Manage bulbous urethral injuries conservatively with a transurethral catheter. B
Manage posterior urethral disruption by either: C
• primary reconstruction;
• primary drainage with a suprapubic catheter alone and delayed repair;
• primary re-alignment with a transurethral catheter.
Although hypoglycaemia is an important issue in children, research has shown that hypoglycaemia is
uncommon if children are still fed up to four hours before the induction of anaesthesia [891]. Newborns often
have low glycogen stores and impaired gluconeogenesis, both of which can be helped by limiting the period of
pre-operative starvation and feeding with glucose-containing solutions. It is important to monitor blood glucose
and to adjust the glucose supply continuously in neonates and children who are small for their age, as this
helps to prevent excessive fluctuation in blood glucose levels [892].
Table 15: Hourly and daily fluid requirements according to body weight
The fasting deficit is calculated by multiplying the hourly maintenance fluid requirement by the number of hours
of fluid restriction. It is recommended that 50% of the fasting deficit is replaced in the first hour and 25% in the
second and third hours [896]. Berry (1986) proposed simplified guidelines for fluid administration according to
the child’s age and severity of surgical trauma [897] (Table 16).
Five percent dextrose with one-quarter- to half-normal saline is often used as a maintenance fluid, while
balanced salt solution or normal saline is used as replacement fluid. Blood losses are replaced with a 1:1 ratio
of blood or colloid or a 3:1 ratio of crystalloid. However, the administration of a large volume of normal saline
can cause dilutional acidosis or hyperchloremic acidosis, while a large volume of balanced salt solution, such
as lactated Ringer’s solution, can decrease serum osmolality, which is not beneficial in patients with decreased
intracranial compliance. If appropriate, albumin, plasma, synthetic colloids, and blood should be administered
[892].
Third-space losses may vary from 1 mL/kg/h for a minor surgical procedure to 15-20 mL/kg/h for
major abdominal procedures, or even up to 50 mL/kg/h for surgery of necrotising enterocolitis in premature
infants. Third-space losses should be replaced with crystalloids (normal saline or Ringer’s lactate) [890].
Most of the fluids required during surgery are needed to replace fasting deficit or third-space losses,
which are mainly extracellular fluids. Hydrating solutions should contain high concentrations of sodium and
chloride and low concentrations of bicarbonate, calcium and potassium.
Intra-operative hypoglycaemia is rare in children. In contrast, hyperglycaemia is commonly
encountered during anaesthesia and surgery. The replacement fluid should be free of dextrose or should
not have > 1% dextrose. Current recommendations include the use of low-dextrose-containing solutions for
maintenance fluid therapy, except in patients who are at high risk of hypoglycaemia [886, 895]. Intra-operative
administration of glucose-free isotonic hydrating solutions should be the routine practice for most procedures
in children over four to five years of age. In infants and young children, 5% dextrose solutions should be
avoided, but it is appropriate to use 1% or 2% dextrose in lactated Ringer’s solution [890].
3.19.3 Summary of evidence and recommendations for the management of post-operative fluid
management
Summary of evidence LE
Children are not simply smaller physiological versions of adults. They have their own unique metabolic 2
features, which must be considered during surgery.
Recommendations GR
Ensure that shorter pre-operative fasting periods apply for elective surgeries (up to four hours). B
Use fluids with lower dextrose concentrations since hyperglycaemia is common in children, compared B
to intra-operative hypoglycaemia (which is very rare).
Do not routinely use hypotonic fluid in hospitalised children because they are at high risk of developing A
hyponatraemia.
Assess the baseline and daily levels of serum electrolytes, glucose, urea and/or creatinine in every B
child who receives intravenous fluids, especially in intestinal surgery (e.g. ileal augmentation),
regardless of the type of solution chosen since there is an increased risk of electrolyte abnormalities in
children undergoing such surgery.
Start early oral fluid intake in patients scheduled for minor surgical procedures. A
3.20.3.2 Circumcision
Circumcision without anaesthesia, irrespective of age, is not recommended. Circumcision requires proper
pain management [937]. Despite this, adequate pain management is still below expectation [938]. Potential
analgesic interventions during circumcision include the use of a dorsal penile nerve block (DPNB) or ring block,
topical anaesthetics (e.g. lidocaine-prilocaine cream, or 4% liposomal lidocaine cream), a less painful clamp
(e.g. Mogen clamp), a pacifier, sucrose, and swaddling, preferably in combination [939-943].
Although DPNB and topical anaesthetics seem to have a similar post-operative analgesic effect,
DPNB is still the most preferred method [944] (LE: 1a). Ultrasound guidance may improve the results, with an
increase in procedural time [945, 946]. Caudal blockade methods have similar efficacy compared to DPNB.
However, parents should be informed about the more frequent incidence of post-operative motor weakness
and micturition problems [947-952].
90
Name Route of Dose Side effects General remarks Caution
administration
Non-narcotics
Acetaminophen Rectal 40 mg/kg loading, 20 mg/kg/dose Nephrotoxicity, Most common used analgesic Slow onset time and variable absorption via
4 times/day hepatotoxicity (neonates) Antipyretic effect the rectal route; dividing the vehicle is not
Oral 15-40 mg/kg, followed by 30 mg/ Opioid-sparing effect recommended.
kg/8 h Wide safety range Total dose should not exceed: 100 mg/kg for
Intravenous Propacetamol (prodrug) children; 75 mg/kg for infants; 60 mg/kg for
term and preterm neonates > 32 weeks post-
conceptual age; and 40 mg/kg for preterm
neonates < 32 weeks post-conceptual age
Ibuprofen Oral, rectal 4-10 mg/kg/dose 3-4 times/day Better analgesic than Safety not established for infants < 6 months old
paracetamol
Diclofenac Tablet, syrup, 1-1.5 mg/kg 2-3 times/day Nephrotoxicity, Better than ibuprofen > 6 years old
suppository gastrointestinal disturbances
Ketorolac Oral, IV, IM 0.2-0.5 mg/kg every 6 h (48 h) Opioid-sparing effect
Total dose < 2 mg/kg/day,
maximum 5 days
Ketamine Oral, rectal, IM, < 2 mg/kg (IM)
SC, IV, < 1 mg/kg (IV, epidural)
intraspinal
Metamizole, Oral, IM 10-15 mg/kg/dose (max 40 mg/ Risk of agranulocytosis, not Very effective antipyretic Not approved in some countries including USA,
dipyrone Oral drop kg total) clarified definitely Sweden, Japan and Australia
10-15 mg/kg
1 drop/kg/dose, up to 4 times/day
Narcotics
Opioids Nausea, vomiting, dyspepsia,
constipation, urinary retention,
respiratory depression,
drowsiness, euphoria
Tramadol (weak Oral, rectal, IV, 2-3 mg/kg/dose (oral, drop) Nausea, vomiting, pruritus Does not inhibit prostaglandin An IM injection is not recommended.
opioid) IM (dose can 1-2 mg/kg/dose (oral, tablet) and rash synthesis Slow IV infusion.
be repeated 4-6 1.5-3 mg/kg/dose (rectal) Be careful in patients taking psychoactive
times/day) 0.75-2 mg/kg/dose (IM) medications and with seizures
91
3.20.3.4 Bladder and kidney surgery
Continuous epidural infusion of local anaesthetics [979-981], as well as systemic (intravenous) application
of analgesics [982], has been shown to be effective. Ketorolac is an effective agent that is underused. It
decreases the frequency and severity of bladder spasms and the length of post-operative hospital stay and
costs [971, 983-986].
Open kidney surgery is particularly painful because all three muscle layers are cut during
conventional loin incision. A dorsal lumbotomy incision may be a good alternative because of the shorter post-
operative hospital stay and earlier return to oral intake and unrestricted daily activity [987].
Caudal blocks plus systemic analgesics [988], and continuous epidural analgesia, are effective in
terms of decreased post-operative morphine requirement after renal surgery [989, 990]. However, when there
is a relative contraindication to line insertion, a less experienced anaesthetist is available, or parents prefer it
[991], non-invasive regimens composed of intra-operative and post-operative analgesics may be the choice.
Particularly in this group of patients, stepwise analgesia protocols can be developed [992]. For laparoscopic
approaches, intra-peritoneal spraying of local anaesthetic before incision of the perirenal fascia may be
beneficial [993].
Table 18: A simple pain management strategy for paediatric urological surgery
3.20.4 Summary of evidence and recommendations for the management of post-operative pain
Summary of evidence LE
Neonates experience pain. 3
Pain may cause behavioural and somatic sequelae. 3
Every institute must develop their own well-structured strategy for post-operative analgesia. 4
Recommendations GR
Prevent/treat pain in children of all ages. B
Evaluate pain using age-compatible assessment tools. B
Inform patients and parents accurately. B
Use pre-emptive and balanced analgesia in order to decrease the side effects of opioids. B
4. REFERENCES
1. Stein, R., et al. Urinary tract infections in children: EAU/ESPU guidelines. Eur Urol, 2015. 67: 546.
https://www.ncbi.nlm.nih.gov/pubmed/25477258
2. Tekgul, S., et al. EAU guidelines on vesicoureteral reflux in children. Eur Urol, 2012. 62: 534.
https://www.ncbi.nlm.nih.gov/pubmed/22698573
3. Radmayr, C., et al. Management of undescended testes: European Association of Urology/European
Society for Paediatric Urology Guidelines. J Pediatr Urol, 2016.
https://www.ncbi.nlm.nih.gov/pubmed/27687532
4. Silay, M.S., et al. The role of antibiotic prophylaxis in antenatal hydronephrosis: A systematic review.
J Ped Urol, 2017. prior to print
5. CONFLICT OF INTEREST
All members of the Paediatric Urology Guidelines Panel have provided disclosure statements on all
relationships that they have that might be perceived to be a potential source of a conflict of interest. This
information is publically accessible through the European Association of Urology website: http://www.uroweb.
org/guidelines/. This Guidelines document was developed with the financial support of the EAU. No external
sources of funding and support have been involved. The EAU is a non-profit organisation, and funding is limited
to administrative assistance and travel and meeting expenses. No honoraria or other reimbursements have
been provided.
2. METHODS 6
2.1 Evidence sources 6
2.2 Peer review 7
6. REFERENCES 46
7. CONFLICT OF INTEREST 66
2. METHODS
2.1 Evidence sources
For the 2017 Urological Trauma Guidelines, new and relevant evidence has been identified, collated and
appraised through a structured assessment of the literature. A broad and comprehensive literature search,
covering all sections of the Urological Trauma Guidelines was performed. Databases searched included
Medline, EMBASE, and the Cochrane Libraries, covering a time frame between January 2005 and May 31st
2016. A total of 14,498 unique records were identified, retrieved and screened for relevance. A detailed search
strategy is available online: http://uroweb.org/guideline/urological-trauma/?type=appendices-publications. The
majority of identified publications were comprised of case reports and retrospective case series. The lack of
high-powered randomised controlled trials (RCTs) makes it difficult to draw meaningful conclusions. The panel
recognises this critical limitation.
Specific sections were updated by way of systematic reviews based on topics or questions
prioritised by the Guideline Panel. These reviews were performed using standard Cochrane systematic review
methodology; http://www.cochranelibrary.com/about/about-cochrane-systematic-reviews.html.
Systematic review results included in the 2017 Urological Trauma Guidelines include:
• Is conservative/minimally-invasive management of Grade 4-5 renal trauma safe and effective compared
with open surgical exploration [6]?
• What are the comparative outcomes of early endoscopic re-alignment versus suprapubic diversion alone
for pelvic fracture related urethral injuries [7]?
Recommendations in this text are assessed according to their level of evidence (LE) and Guidelines
are given a grade of recommendation (GR), according to a classification system modified from the Oxford
Centre for Evidence-Based Medicine Levels of Evidence [8]. Additional methodology information can be found
Penetrating trauma is further classified according to the velocity of the projectile into:
1. high-velocity projectiles (e.g. rifle bullets - 800-1,000 m/sec);
2. medium-velocity projectiles (e.g. handgun bullets - 200-300 m/sec);
3. low-velocity items (e.g. knife stab).
High-velocity weapons inflict greater damage because the bullets transmit large amounts of energy to the
tissues. They form a temporary expansive cavitation that immediately collapses and creates shear forces and
destruction in a much larger area then the projectile tract itself. Cavity formation disrupts tissue, ruptures blood
vessels and nerves, and may fracture bones away from the path of the missile. In lower velocity injuries, the
damage is usually confined to the projectile tract.
Blast injury is a complex cause of trauma as it commonly includes both blunt and penetrating
Proposals for changes to the AAST classification include a sub-stratification of the intermediate grade injury
into grade 4a (low-risk cases likely to be managed non-operatively) and grade 4b (high-risk cases likely to
benefit from angiographic embolisation, repair or nephrectomy), based on the presence of radiographic risk
factors, including peri-renal haematoma, intravascular contrast extravasation and laceration complexity [36],
as well as a suggestion that grade 4 injuries comprise all collecting system injuries, including ureteropelvic
junction (UPJ) injuries of any severity and segmental arterial and venous injuries, while grade 5 injuries should
include only hilar injuries, including thrombotic events [37].
Recommendations LE GR
Assess haemodynamic stability upon admission. 3 A*
Obtain a history from conscious patients, witnesses and rescue team personnel with regard to 4 A*
the time and setting of the incident.
Record past renal surgery, and known pre-existing renal abnormalities (ureteropelvic junction 4 A*
obstruction, large cysts, lithiasis).
*Upgraded based on panel consensus.
Recommendations LE GR
Test for haematuria in a patient with suspected renal injury. 3 A*
Measure creatinine level to identify patients with impaired renal function prior to injury. 3 C
*Upgraded based on panel consensus.
Intraoperative pyelography
One-shot, intraoperative IVP remains a useful technique to confirm the presence of a functioning contralateral
kidney in patients too unstable to undergo pre-operative imaging [62]. The technique consists of a bolus
intravenous injection of 2 mL/kg of radiographic contrast followed by a single plain film taken after ten minutes.
Radionuclide scans
Radionuclide scans do not play a role in the immediate evaluation of renal trauma patients.
Most patients with grade 4 and 5 injuries present with major associated injuries, and consequently often
undergo exploration and nephrectomy [70], although emerging data indicate that many of these patients can
be managed safely with an expectant approach [71]. An initially conservative approach is feasible in stable
patients with devitalised fragments [72], although these injuries are associated with an increased rate of
complications and late surgery [73]. Patients diagnosed with urinary extravasation from solitary injuries can
be managed without major intervention with a resolution rate of > 90% [71, 74]. Similarly, unilateral main
arterial injuries are normally managed non-operatively in a haemodynamically stable patient with surgical repair
reserved for bilateral artery injuries or injuries involving a solitary functional kidney. Conservative management
is also advised in the treatment of unilateral complete blunt arterial thrombosis. However, a blunt arterial
thrombosis in multiple trauma patients is usually associated with severe injuries and attempts at repair are
usually unsuccessful [75].
Available evidence regarding angioembolisation in penetrating renal trauma is sparse. One older study found
angioembolisation is three times more likely to fail in penetrating trauma [76]. However, angioembolisation has
been used successfully to treat arteriovenous fistulae and psuedoaneurysms in the non-operative management
of penetrating renal trauma [93]. With studies reporting successful non-operative management of penetrating
renal trauma, angioembolisation must be critically considered in this setting [93, 94].
Recommendations LE GR
Manage stable patients with blunt renal trauma conservatively with close monitoring of vital 3 B
signs.
Manage isolated grade 1-3 stab and low-velocity gunshot wounds in stable patients, 3 B
expectantly.
Treat patients with active bleeding from renal injury, but without other indications for immediate 3 B
abdominal operation, with angioembolisation.
Proceed with renal exploration in the presence of persistent haemodynamic instability, 3 B
expanding or pulsatile peri-renal haematoma, grade 5 vascular injury or in case of exploration
for associated injuries.
Attempt renal reconstruction if haemorrhage is controlled and there is sufficient viable renal 3 B
parenchyma.
4.1.4 Follow-up
The risk of complications in patients who have been treated conservatively increases with injury grade. Repeat
imaging two to four days after trauma minimises the risk of missed complications, especially in grade 3-5
blunt injuries [117]. The usefulness of frequent CT scanning after injury has never been satisfactorily proven.
Computed tomography scans should always be performed on patients with fever, unexplained decreased
haematocrit or significant flank pain. Repeat imaging can be safely omitted for patients with grade 1-4 injuries
as long as they remain clinically well [118].
Nuclear scans are useful for documenting and tracking functional recovery following renal
reconstruction [119]. Follow-up should involve physical examination, urinalysis, individualised radiological
investigation, serial blood pressure measurement and serum determination of renal function [72]. A decline
in renal function correlates directly with injury grade; this is independent of the mechanism of injury and the
method of management [120, 121]. Follow-up examinations should continue until healing is documented
and laboratory findings have stabilised, although checking for latent renovascular hypertension may need
to continue for years [122]. In general, the literature is highly limited on the long-term consequences of renal
tissue trauma.
4.1.4.1 Complications
Early complications, occurring less than one month after injury, include bleeding, infection, perinephric
abscess, sepsis, urinary fistula, hypertension, urinary extravasation and urinoma. Delayed complications
include bleeding, hydronephrosis, calculus formation, chronic pyelonephritis, hypertension, arteriovenous
fistula, hydronephrosis and pseudo-aneurysms. Delayed retroperitoneal bleeding may be life-threatening and
selective angiographic embolisation is the preferred treatment [123]. Perinephric abscess formation is best
managed by percutaneous drainage, although open drainage may sometimes be required. Percutaneous
management of complications may pose less risk of renal loss than re-operation, when infected tissues make
reconstruction difficult [97].
Renal trauma is a rare cause of hypertension, and is mostly observed in young men. The frequency
of post-traumatic hypertension is estimated to be less than 5% [124, 125]. Hypertension may occur acutely as
a result of external compression from peri-renal haematoma (Page kidney), or chronically due to compressive
Recommendations LE GR
Repeat imaging in case of fever, worsening flank pain, or falling haematocrit. 3 B
Follow-up approximately three months after major renal injury with physical examination, 3 C
urinalysis, individualised radiological investigation, including nuclear scintigraphy, serial blood
pressure measurements and renal function tests.
Table 4.1.2: Incidence and aetiology of commonest iatrogenic renal trauma during various procedures
Large haematomas after biopsy (0.5-1.5%) are caused by laceration or arterial damage [134]. Renal artery and
intraparenchymal pseudo-aneurysms (0.9%) may be caused by percutaneous biopsy, nephrostomy, and partial
nephrectomy (0.43%) [135]. In percutaneous nephrolithotomy (PCNL), haemorrhage is the most dangerous
iatrogenic renal trauma, especially when punctures are too medial or directly entering the renal pelvis. Other
injuries include AVF or a tear in the pelvicaliceal system.
Iatrogenic renal injuries associated with renal transplantation include AVF, intrarenal pseudo-
aneurysms, arterial dissection and arteriocaliceal fistulas. Pseudo-aneurysm is a rare complication of allograft
biopsy. Although the overall complication rate following biopsy in transplanted kidneys is 9% (including
haematoma, AVF, visible haematuria and infection), vascular complications requiring intervention account for
4.1.5.3 Diagnosis
Haematuria is common after insertion of nephrostomies, but massive retroperitoneal haemorrhage is rare.
Following percutaneous biopsy, AVF may occur with severe hypertension. A pseudo-aneurysm should
be suspected if the patient presents with flank pain and decreasing haematocrit, even in the absence of
haematuria.
During PCNL, acute bleeding may be caused by injury to the anterior or posterior segmental
arteries, whilst late post-operative bleeding may be caused by interlobar and lower-pole arterial lesions, AVF
and post-traumatic aneurysms [141]. Duplex US and CT angiography can be used to diagnose vascular
injuries. A close watch on irrigation fluid input and output is required to ensure early recognition of fluid
extravasation. Intra-operative evaluation of serum electrolytes, acid-base status, oxygenation, and monitoring
of airway pressure are good indicators of this complication.
In arterial dissection related to transplantation, symptoms include anuria and a prolonged
dependence on dialysis. Doppler US can demonstrate compromised arterial flow. Dissection can lead to
thrombosis of the renal artery and/or vein.
After angioplasty and stent-graft placement in the renal artery, during which wire or catheters may
enter the parenchyma and penetrate through the capsule, possible radiological findings include AVF, pseudo-
aneurysm, arterial dissection and contrast extravasation. Common symptoms of pseudo-aneurysms are
flank pain and visible haematuria within two or three weeks after surgery [142]. Transplant AVF and pseudo-
aneurysms may be asymptomatic or may cause visible haematuria or hypovolemia due to shunting and the
‘steal’ phenomenon, renal insufficiency, hypertension, and high output cardiac failure.
Patients with extrarenal pseudo-aneurysms (post-transplantation) may present with infection/
bleeding, swelling, pain and intermittent claudication. Doppler US findings for AVFs include high-velocity,
low-resistance, spectral waveforms, with focal areas of disorganised colour flow outside the normal vascular
borders, and possibly a dilated vein [143]. Pseudo-aneurysms appear on US as anechoic cysts, with intracystic
flow on colour Doppler US.
Potential complications of retained sponges include abscess formation, fistula formation to the skin
or intestinal tract, and sepsis. Retained sponges may look like pseudo-tumours or appear as solid masses.
Magnetic resonance imaging clearly shows the characteristic features [144]. Absorbable haemostatic agents
may also produce a foreign body giant cell reaction, but the imaging characteristics are not specific. Retained
stents, wires, or fractured Acucise cutting wires may also present as foreign bodies and can serve as a nidus
for stone formation [145].
4.1.5.4 Management
If a nephrostomy catheter appears to transfix the renal pelvis, significant arterial injury is possible. The
misplaced catheter should be withdrawn and embolisation may rapidly arrest the haemorrhage. Computed
tomograpghy can also successfully guide repositioning of the catheter into the collecting system [146].
Small subcapsular haematomas after insertion of nephrostomies resolve spontaneously, whilst AVFs are best
managed by embolisation. AVF and pseudo-aneurysms after biopsy are also managed by embolisation [147].
During PCNL, bleeding can be venous or arterial. In major venous trauma with haemorrhage,
patients with concomitant renal insufficiency can be treated without open exploration or angiographic
embolisation using a Council-tip balloon catheter [148]. In the case of profuse bleeding at the end of a PCNL,
conservative management is usually effective. The patient should be placed in the supine position, clamping
the nephrostomy catheter and forcing diuresis. Super-selective embolisation is required in less than 1% of
cases and has proved effective in more than 90% [149]. Short-term deleterious effects are more pronounced
in patients with a solitary kidney, but long-term follow-up shows functional and morphological improvements
[150]. Termination of PCNL if the renal pelvis is torn or ruptured is a safe choice. Management requires close
monitoring, placement of an abdominal or retroperitoneal drain and supportive measures [151]. Most surgical
4.1.5.5 Summary of evidence and recommendations for the management of iatrogenic renal injuries
Summary of evidence LE
Iatrogenic renal injuries are procedure-dependent (1.8-15%). 3
Significant injury requiring intervention is rare. 3
The most common injuries are vascular. 3
Renal allografts are more susceptible. 3
Injuries occurring during surgery are rectified immediately. 3
Symptoms suggestive of a significant injury require investigation. 3
Recommendations LE GR
Repeat imaging in case of fever, worsening flank pain, or falling haematocrit. 3 B
Follow-up approximately three months after major renal injury with physical examination, 3 C
urinalysis, individualised radiological investigation, including nuclear scintigraphy, serial blood
pressure measurements and renal function tests.
Renal exploration
(reconstruction or
nephrectomy)‡
Abnormal IVP,
or expanding
Emergency laparotomy/One-shot IVP
haematoma
pulsatile
Unstable
angioembolisation
Observation
Normal IVP
and selective
Angiography
Vascular
Grade 4-5
Determine haemodynamic stability
antibiotics
Parenchymal
renal trauma*
angioembolisation
and selective
Angiography
spiral CT scan with
Contrast enhanced
Visible haematuria
delayed images†
Grade 3
antibiotics
Stable
Non-visible haematuria
Rapid deceleration
associated injuries
injury or major
Observation
Grade 1-2
* Suspected renal trauma results from reported mechanism of injury and physical examination.
† Renal imaging: CT scans are the gold standard for evaluating blunt and penetrating renal injuries in stable
patients. In settings where CT is not available, the urologist should rely on other imaging modalities (IVP,
angiography, radiographic scintigraphy, MRI).
‡ Renal exploration: Although renal salvage is a primary goal for the urologist, decisions concerning the viability
of the organ and the type of reconstruction are made during the operation.
CT = computed tomography; Ht = haematocrit; IVP = intravenous pyelography.
Evaluation of penetrating
renal trauma*
Stable Unstable
*
Renal exploration
Grade 1-2 Grade 3 Grade 4- 5 (reconstruction or
nephrectomy) ‡
Observation, Associated
bed rest, serial Ht, injuries requiring
antibiotics laparotomy
Angiography
and selective
angioembolisation
Suspected renal trauma results from reported mechanism of injury and physical examination.
† Renal imaging: CT scans are the gold standard for evaluating blunt and penetrating renal injuries in stable
patients. In settings where CT is not available, the urologist should rely on other imaging modalities (IVP,
angiography, radiographic scintigraphy, MRI).
‡ Renal exploration: Although renal salvage is a primary goal for the urologist, decisions concerning the viability
of the organ and the type of reconstruction are made during the operation.
CT = computed tomography; Ht = haematocrit.
Iatrogenic ureteral trauma can result from various mechanisms: ligation or kinking with a suture, crushing
from a clamp, partial or complete transection, thermal injury, or ischaemia from devascularisation [164-
166]. It usually involves damage to the lower ureter [160, 164, 165, 167]. Gynaecological operations are
the commonest cause of iatrogenic trauma to the ureters (Table 4.2.1), but it may also occur in colorectal
operations, especially abdominoperineal resection and low anterior resection [168]. The incidence of urological
iatrogenic trauma has decreased in the last twenty years [164, 169] due to improvements in technique,
instruments and surgical experience.
Risk factors for iatrogenic trauma include conditions that alter the normal anatomy, e.g. advanced
malignancy, prior surgery or irradiation, diverticulitis, endometriosis, anatomical abnormalities, and major
haemorrhage [164, 168, 170]. Occult ureteral injury occurs more often than reported and not all injuries are
diagnosed intra-operatively. In gynaecological surgery, if routine intra-operative cystoscopy is used, the
detection rate of ureteral trauma is five times higher than usually reported [170, 171].
Procedure Percentage %
Gynaecological [167, 171, 172]
Vaginal hysterectomy 0.02 – 0.5
Abdominal hysterectomy 0.03 – 2.0
Laparoscopic hysterectomy 0.2 – 6.0
Urogynaecological (anti-incontinence/prolapse) 1.7 – 3.0
Colorectal [166, 171, 173] 0.15 – 10
Ureteroscopy [169]
Mucosal abrasion 0.3 – 4.1
Ureteral perforation 0.2 – 2.0
Intussusception/avulsion 0 – 0.3
Radical prostatectomy [174]
Open retropubic 0.05 – 1.6
Robot-assisted 0.05 – 0.4
4.2.3 Diagnosis
The diagnosis of ureteral trauma is challenging, therefore, a high index of suspicion should be maintained. In
penetrating external trauma, it is usually made intra-operatively during laparotomy [175], while it is delayed in
most blunt trauma and iatrogenic cases [164, 167, 176].
4.2.5 Management
Management of a ureteral trauma depends on many factors concerning the nature, severity and location of
the injury. Immediate diagnosis of a ligation injury during an operation can be managed by de-ligation and
stent placement. Partial injuries can be repaired immediately with a stent or urine diversion by a nephrostomy
tube. Stenting is helpful because it provides canalisation and may decrease the risk of stricture [164]. On the
other hand, its insertion has to be weighed against potentially aggravating the severity of the ureteral injury.
Immediate repair of ureteral injury is usually advisable. However, in cases of unstable trauma patients, a
‘damage control’ approach is preferred with ligation of the ureter, diversion of the urine (e.g. by a nephrostomy),
and a delayed definitive repair [180]. Injuries that are diagnosed late are usually treated first by a nephrostomy
tube with or without a stent [164].
Endo-urological treatment of delayed-diagnosed ureteral injuries by internal stenting, with or without
dilatation, is the first step in most cases. It is performed either retrogradely or antegradely through a PCN, and
it has a variable success rate of 14 to 89% in published series [181-183]. An open surgical repair is necessary
in case of failure. The basic principles for any surgical repair of a ureteral injury are outlined in Table 4.2.2. Wide
debridement is highly recommended for gunshot wound injuries due to the ‘blast effect’ of the injury.
4.2.6 Summary of evidence and recommendations for the management of ureteral trauma
Summary of evidence LE
Iatrogenic ureteral trauma gives rise to the commonest cause of ureteral injury. 3
Gunshot wounds account for the majority of penetrating ureteral injuries, while MVAs account for most 3
blunt injuries.
Ureteral trauma usually accompanies severe abdominal and pelvic injuries. 3
Haematuria is an unreliable and poor indicator of ureteral injury. 3
The diagnosis of ureteral trauma is often delayed. 2
Pre-operative prophylactic stents do not prevent ureteral injury, but may assist in its detection. 2
Endo-urological treatment of small ureteral fistulae and strictures is safe and effective. 3
Major ureteral injury requires ureteral reconstruction following temporary urinary diversion. 3
Recommendations LE GR
Visually identify the ureters to prevent ureteral trauma during abdominal and pelvic surgery. 3 A*
Beware of concomitant ureteral injury in all abdominal penetrating trauma, and in deceleration- 3 A*
type blunt trauma.
Use pre-operative prophylactic stents in high-risk cases. 2 B
*Upgraded following panel consensus.
Non-iatrogenic trauma
blunt
penetrating
Iatrogenic trauma
external
internal
foreign body
External IBT occurs most often during obstetric and gynaecological procedures, followed by general surgical
and urological interventions [197]. Main risk factors are previous surgery, inflammation and malignancy [197].
Internal IBT mainly occurs during TURB. Reported risk factors are larger tumours, older age, pre-treated
bladders (previous TURB, intravesical instillations) and location at the bladder dome [211, 212]. There is
conflicting evidence whether bipolar TURB can reduce the risk of bladder perforation due to obturator jerk
for tumours at the lateral wall [213, 214]. Perforations requiring intervention are rare (0.16-0.57%) [211].
Extraperitoneal perforations are more frequent than intraperitoneal perforations [212, 215].
Signs of external IBT are extravasation of urine, visible laceration, clear fluid in the surgical field, appearance
of the bladder catheter, and blood and/or gas in the urine bag during laparoscopy [198]. Direct inspection is
the most reliable method of assessing bladder integrity [197]. Intravesical instillation of methylene blue may be
helpful to detect smaller lesions [219]. If bladder perforation is close to the trigone, the ureteric orifices should
be inspected [197, 198].
Internal IBT is suggested by cystoscopic identification of fatty tissue, a dark space between
detrusor muscle fibres, or the visualisation of bowel [209]. Signs of major perforation are the inability to distend
the bladder, a low return of irrigation fluid, and abdominal distension [220].
Clinical signs and symptoms of an iatrogenic bladder trauma not recognised during surgery include
haematuria, abdominal pain, abdominal distension, ileus, peritonitis, sepsis, urine leakage from the wound,
decreased urinary output, and increased serum creatinine [197, 198]. An IBT during hysterectomy or caesarean
delivery can be complicated by respective vesico-vaginal or vesico-uterine fistula [198, 221].
Symptoms of an intravesical foreign body include dysuria, recurrent urinary tract infection,
4.3.3.2.2 Cystoscopy
Cystoscopy is the preferred method for detection of intra-operative bladder injuries, as it may directly visualise
the laceration. Cystoscopy can localise the lesion in relation to the position of the trigone and ureteral orifices
[224]. A lack of bladder distension during cystoscopy suggests a large perforation.
Cystoscopy is recommended to detect perforation of the bladder (or urethra) following suburethral
sling operations by the retropubic route [207]. Routine intra-operative cystoscopy during benign gynaecologic
procedures significantly increases the intra-operative detection rate, however the post-operative detection rate
remains unaffected [225]. Based on these findings, routine cystoscopy during benign gynaecologic procedures
cannot be generally recommended, although the threshold to perform it should be low in case of suspicion of
bladder injury. Cystoscopy is also preferred to diagnose a foreign body [216, 217].
4.3.3.2.4 Ultrasound
Demonstration of intraperitoneal fluid or an extraperitoneal collection suggests intraperitoneal or
extraperitoneal perforation, respectively. However, US alone is insufficient in the diagnosis of bladder trauma.
4.3.4 Prevention
The risk of bladder injury is reduced by emptying the bladder by urethral catheterisation in every procedure
where the bladder is at risk [219, 226]. Furthermore, the balloon of the catheter can aid in identification of
the bladder [219]. For tumours at the lateral wall, obturator nerve block or general anesthesia with adequate
muscle relaxation can reduce the incidence of internal IBT during TURB [214]. The use of combat pelvic
protection systems reduces the risk of bladder and other genito-urinary injuries due to the blast mechanism of
improvised explosive devices [196, 227].
4.3.6 Follow-up
Continuous bladder drainage is required to prevent elevated intravesical pressure and to allow the bladder
to heal [197, 234]. Conservatively treated bladder injuries (traumatic or external IBT) are followed by planned
cystography scheduled to evaluate bladder healing, with catheter removal in case of absence of contrast
extravasation [190]. The first cystography is planned seven to ten days after injury. In case of ongoing leakage,
cystoscopy must be performed to rule out bony fragments in the bladder and, if absent, cystography is done
after one week [190].
After operative repair of a simple injury in a healthy patient, the catheter can be removed after
seven to ten days without need for a control cystography [234, 235]. After repair of a complex injury (trigone
involvement, ureteric reimplantation) or in the case of risk factors of wound healing (e.g. use of steroids,
malnutrition), control cystography is advised [234, 235].
For conservatively treated internal IBT, a catheter duration of five and seven days for extraperitoneal
and intraperitoneal perforations, respectively, is proposed [212, 215].
Summary of evidence LE
The risk of bladder perforation during mid-urethral sling operations for stress urinary incontinence is 1a
lower for the obturator route compared to the retropubic route.
The combination of pelvic fracture and visible haematuria is highly suggestive of bladder injury. 3
Recommendations LE GR
Perform cystography in case of suspicion of a iatrogenic bladder injury in the post-operative 3 B
setting.
Perform cystography (conventional or computed tomography imaging) in the presence of 3 B
visible haematuria and pelvic fracture.
Cystography should be performed with filling of the bladder with at least 350 mL of dilute 3 B
contrast.
Use cystoscopy to rule out bladder injury after suburethral sling procedure by the retropubic 1a A
route.
Manage a blunt extraperitoneal bladder injury caused by blunt trauma conservatively, in 3 B
the absence of bladder neck involvement and/or associated injuries that require surgical
intervention.
Manage intraperitoneal injuries caused by blunt trauma by surgical exploration and repair. 3 A*
Manage small uncomplicated iatrogenic intraperitoneal bladder injuries conservatively. 3 B
Perform control cystography to assess bladder wall healing after repair of a simple injury in a 2a C
healthy patient.
Perform control cystography to assess bladder wall healing after repair of a complex injury or 2a A*
in case of risk factors for wound healing.
*Upgraded following panel consensus.
Procedure Percentage
Catheterisation 32% of iatrogenic urethral strictures (52% bulbar urethra)
Urethral instrumentation for therapy and/or
diagnosis
Treatment for prostatic disease 1.1-8.4% urethral stricture rate
Transurethral surgery (e.g. TURB/TURP) 2.2-9.8% urethral stricture rate
Radical prostatectomy (Radical prostatectomy 0.5-32% bladder neck constriction; no difference between
and external-beam radiation therapy) LRP and RALP (relative risk: 1.42; 95% confidence interval
for relative risk, 0.40-5.06; p = 0.59)
Radiotherapy (percutaneous or brachytherapy) 6% urethral stricture rate, 0.3-3.0% urinary fistula rate
Radical prostatectomy and external-beam
radiation therapy. This combination has the
greatest risk for the formation of a urethral
stricture
Cryotherapy
High-intensity focused ultrasound
Treatment for bladder disease
Transurethral resection of the bladder
Cystectomy 3.1% subneovesical obstruction, 1.2% neovesicourethral
anastomotic strictures, 0.9% urethral strictures
Injury during major abdominal and pelvic
operations
TURB = transurethral resection of the bladder; TURP = transurethral resection of the prostate;
LRP = laparoscopic radical prostatectomy; RALP = robot-assisted laparoscopic radical prostatectomy;
Cause Example
Blunt trauma Vehicular accidents
Fall astride (‘straddle’) e.g. on bicycle, fences, inspection covers
Kicks in the perineum
Sexual intercourse Penile fractures
Urethral intraluminal stimulation
Penetrating trauma Gunshot wounds
Stab wounds
Dog bites
External impalement
Penile amputations
Constriction bands Paraplegia
Iatrogenic injuries Endoscopic instruments
Urethral catheters/dilators
A female urethral injury should be suspected from the combination of a pelvic fracture with blood at the vaginal
introitus, vaginal laceration, haematuria, urethrorrhagia, labial swelling and/or urinary retention [262, 265, 266].
Vaginal examination is indicated to assess vaginal lacerations [190].
Symptoms of urethral lesions caused by improper catheterisation or instrumentation are penile and/
or perineal pain (100%) and urethral bleeding (86%) [240]. Failure to accurately diagnose and treat urethral
injuries may lead to significant long-term sequelae, mostly presenting as strictures [286, 287].
The following classification of urethral injuries is based on retrograde urethrography (Table 4.4.3) [261]:
Anterior urethra
Partial disruption
Complete disruption
Posterior urethra
Stretched but intact
Partial disruption
Complete disruption
Complex (involves bladder neck/rectum)
*According to the 2004 Consensus Panel on Urethral Trauma [261].
4.4.2.3 Summary
Prior to deferred management, the combination of retrograde urethrography and antegrade cysto-
urethrography is standard [261]. The location and extent of the obliteration is diagnosed [261]. An MRI of the
pelvis provides valuable additional information, which can help to determine the most appropriate surgical
strategy [261, 283]. If the competence of the bladder neck is not clear upon antegrade cysto-urethrography, a
suprapubic cystoscopy is advised [261].
Post-operative follow-up protocols include the use of retrograde urethrograms and voiding cysto-
urethrograms at the time of catheter removal. Following this, urine flow charts as well as post-void residual
urine, cystoscopy and urine culture, should be performed at variable intervals.
Insertion of a suprapubic catheter is always a good solution in urgent situations [261, 284]. However, insertion
of a suprapubic catheter is not without risk, especially in the unstable trauma patient where the bladder is
often displaced by the pelvic haematoma or because of poor bladder filling due to haemodynamic shock or
concomitant bladder injury. In these circumstances, an attempt at urethral catheterisation can be carried out by
experienced hands. It is extremely unlikely that the gentle passage of a urethral catheter will do any additional
damage [236, 262, 266, 272, 273, 295]. If there is any difficulty, a suprapubic catheter should be placed under
US guidance and direct vision [236].
Endoscopic re-alignment is the preferred technique [262, 284]. Using a flexible/rigid cystoscope and biplanar
fluoroscopy, a guidewire is placed inside the bladder. Over this, a catheter is placed into the bladder. If
necessary, two cystoscopes can be used: one retrograde (per urethra) and one antegradely (suprapubic route
through the bladder neck) [292, 297, 298]. The duration of catheter stay varies between four and eight weeks
among series [190, 292, 297, 298].
It is important to avoid traction on the Foley balloon catheter since it can damage the remaining
sphincter mechanism at the bladder neck. Concomitant bladder neck or rectal injuries or presence of bony
fragments inside the bladder must be repaired immediately.
The reasons for immediate repair of bladder neck and rectal injury are:
• unrepaired bladder neck injury risks incontinence and infection of pelvic fractures;
• unrepaired rectal injury carries the obvious risk of sepsis and fistula, early exploration is indicated to
evacuate contaminated haematomas and to perform colostomy if necessary.
Immediate endoscopic re-alignment can also be performed when the patient is on the operating table for other
surgery. Early endoscopic re-alignment (immediate or delayed primary, see below) is also possible in a stable
patient without significant concomitant injuries [297, 298].
With modern endoscopic re-alignment procedures, acceptable complication rates have been
Most posterior urethral distraction defects are short and can be treated using a perineal anastomotic repair
[261, 303]. The key objective of the operation is to achieve a tension-free anastomosis between two healthy
urethral ends (i.e. after complete excision of any scar tissue) [284, 303].
After resection of fibrosis and spatulation of both healthy urethral ends, the gap between both ends
is bridged by the so-called ‘elaborated perineal approach’, which is a series of consecutive manoeuvres, first
described by Webster and Ramon [309] with reported success rates of 80-98% [310-314].
Most urethral stenoses are short and can be treated by mobilisation of the bulbar urethra, with or
without separation of the corpora cavernosa [303]. This is in contrast to the situation in developing countries,
where stenoses are more complex and where additional manoeuvres, such as inferior pubectomy and
supracrural re-routing or a combined abdominoperineal approach, are needed more often [299, 311].
A number of situations may prevent the use of perineal anastomotic repair, either as an initial or as a
salvage therapy. These situations probably represent < 5% of cases (Table 4.4.4) [315, 316].
Outcome after deferred urethroplasty is excellent with a stricture rate of around 10% [309, 318]. Deferred
urethroplasty is unlikely to result in additional ED [303, 318]. Decompression of the erectile nerves after excision
of the scar tissue might explain the amelioration of erectile function after urethroplasty [318]. Incontinence is
rare with deferred urethroplasty (< 4%) [303] and is usually due to incompetence of the bladder neck [284, 311].
Standard therapy is a deferred urethroplasty at a minimum of three months after trauma, using a one-stage
perineal approach, whenever possible.
Retrograde urethrography/
flexible urethroscopy
Cause of urethral
trauma
If associated with
Blunt Penetrating
penile rupture
No stricture Stricture
Retrograde urethrogram
Prostatomembranous disruption
No Yes
Stricture Urethrotomy
Option:
endoscopic realignment
Delayed urethroplasty
if patient is stable
(< day 14)
Catheterisation
Urethrogram Resolved
by urologist
Endoscopic
guide-wire placement
and catheter insertion
Follow-UP
If stricture is If stricture is
short and flimsy longer and denser
Endoscopic
Dilation optical bladder
neck incision
If failure
Open surgery
Urinary diversion
(reanastomosis)
Summary of evidence LE
Blunt trauma accounts for more than 90% of urethral injuries. 3
In penile fracture, the urethra is involved in 20% of cases. 4
The male posterior urethra is injured in 4-19% of pelvic fracture cases. In industrialised societies pelvic 3
fracture-related injuries of the posterior urethra are the most common non-iatrogenic injuries.
Erectile dysfunction occurs in 20-60% of patients after traumatic urethral rupture. 3
Recommendations LE GR
Evaluate urethral injuries with flexible cystoscopy and/or retrograde urethrography. 3 B
Treat blunt anterior urethral injuries by suprapubic diversion. 3 C
Treat partial posterior urethral ruptures by urethral or suprapubic catheterisation. 3 C
Perform early endoscopic re-alignment when feasible. 2a B
Manage complete posterior urethral disruption with suprapubic diversion and delayed 2a A*
urethroplasty.
*Upgraded following panel consensus.
4.4.4.1 Summary of evidence and recommendations for the management of iatrogenic urethral trauma
Summary of evidence LE
Iatrogenic causes are the most common type of urethral injury in Europe, and therefore the most 2a
common cause of urethral stricture formation.
Implementing training programmes on urinary catheter insertion significantly improves the rate of 3
catheter-related complications.
New technologies represent an additional source of urethral injury. 3
Recommendations LE GR
Provide appropriate training to reduce the risk of traumatic catheterisation. 3 A*
Preform urethral instrumentation when there are valid clinical indications. 4 A*
Keep duration of catheterisation to a minimum. 4 A*
*Upgraded following panel consensus.
Penetrating injuries account for 20% of genito-urinary trauma, with 40-60% of all penetrating genito-urinary
lesions involving the external genitalia [267, 330]. Thirty-five per cent of all genito-urinary gunshot wounds
involve the genitalia [325]. In a recent series of wartime genito-urinary injuries, 71.5% of 361 operations
involved the external genitalia - the majority caused by IEDs and other explosive ordinance, while smaller
numbers of injuries were due to gunshot injuries [331]. In both males and females, penetrating genital injuries
occur with other associated injuries in 70% of patients. In males, penetrating scrotal injuries affect both testes
in 30% of cases compared with 1% in blunt scrotal injuries [325, 332]. Self-mutilation of the external genitalia
has also been reported in psychotic patients and trans-sexuals [333]. Genital burns are rare in isolation, usually
due to industrial flame or chemicals in adults, and all but the full thickness type are treated conservatively [334].
4.5.2.2 Bites
4.5.2.2.1 Animal bites
Although animal bites are common, bites injuring the external genital are rare. Wounds are usually minor,
but have a risk of wound infection. The most common bacterial infection caused by a dog bite is
Pasturella multicida, which accounts for up to 50% of infections [338]. Other commonly involved organisms
are Escherichia coli, Streptococcus viridans, Staphylococcus aureus, Eikenella corrodens, Capnocytophaga
canimorsus, Veillonella parvula, Bacteroides and Fusobacterium spp. [333, 338, 339]. Antibiotics should be
prescribed in accordance with local resistance patterns [340-342].
The possibility of rabies infection must be considered. If rabies infection is suspected, vaccination
should be considered taking into account the geographical location, animal involved, specific nature of the
wound and the type of attack (provoked/unprovoked). Besides vaccination, local wound management is
an essential part of post-exposure prophylaxis. High-risk patients should be vaccinated with human rabies
immunoglobulin and human diploid cell vaccine [343, 344].
The thickness of the tunica albuginea in the flaccid state (approximately 2 mm) decreases in erection to 0.25-
0.5 mm, and is therefore more vulnerable to traumatic injury [355, 356]. Penile fracture is associated with a
sudden cracking or popping sound, pain and immediate detumescence. Local swelling of the penile shaft
develops quickly, due to enlarging haematoma. Bleeding may spread along the fascial layers of the penile shaft
and extend to the lower abdominal wall if Buck’s fascia is also ruptured. Sometimes, the rupture of the tunica
may be palpable. Less severe penile injuries can be distinguished from penile fracture, as they are not usually
associated with detumescence [351].
A thorough history and examination usually confirm the diagnosis, but in some cases imaging may be useful.
Cavernosography, US or MRI [351, 357-359] can identify lacerations of the tunica albuginea in unclear cases
[360], or provide reassurance that the tunica is intact. If a concomitant urethral injury is suspected, a retrograde
urethrogram may be performed, however, flexible cystoscopy under anaesthesia during exploration/repair is
more usually employed.
Subcutaneous haematoma, without associated rupture of the cavernosal tunica albuginea, does not require
surgical intervention. In these cases, non-steroidal analgesics and ice-packs are recommended [361].
When a penile fracture is diagnosed, surgical intervention with closure of the tunica albuginea is recommended,
it ensures the lowest rate of negative long-term sequelae and has no negative effect on the psychological well-
being of the patient [362]. The approach is usually through a circumferential incision proximal to the coronal
sulcus which enables complete degloving of the penis. Increasingly, local longitudinal incisions centred on the
area of fracture or ventral longitudinal approaches are currently used [289]. Further localisation may be gained
with a flexible cystoscopy performed prior to incision, if urethral trauma is suspected and eventually proven.
Surgical closure of the tunica should be carried out using absorbable sutures. Post-operative
complications were reported in up to 20% of cases, development of plaques or nodules following surgery,
post-operative curvature formation and ED occur in 13.9%, 2.8% and 1.9% of patients, respectively [351].
Conservative management of penile fracture is not recommended, as it significantly increases the rate of post-
operative complications [351]. It increases complications, such as penile abscess, missed urethral disruption,
penile curvature, and persistent haematoma requiring delayed surgical intervention [363]. Late complications
after conservative management were fibrosis and angulations in 35% and impotence in up to 62% [352, 363].
The principles of care are debridement of devitalised tissue, with the preservation of as much viable tissues
as possible, haemostasis, diversion of urine in selected cases and the removal of foreign bodies. Tissues of
questionable viability may be left for subsequent definitive surgery. If a subsequent immediate or delayed repair
is needed, depending on the type of injury and the extent of tissue damage, it usually takes place four to six
weeks after the trauma has occurred.
The surgical approach depends upon the site and extent of the injury, but a subcoronal incision with
penile degloving usually gives good exposure. Initially, a defect in the tunica albuginea should be closed after
copious irrigation. If there has been too much tissue loss, the defect can be repaired either immediately or after
delay with a patch (either from an autologous saphenous vein or xenograft). If a concomitant urethral injury is
suspected, a pre- or peri-operative urethrogram or cystoscopy is useful to diagnose any urethral involvement,
to define its position, and to decide upon the incision used.
The severed penis should be washed with sterile saline, wrapped in saline-soaked gauze, placed in a sterile
bag and immersed in iced water. The penis must not come into direct contact with the ice. A pressure dressing
or a tourniquet should be placed around the penile stump to prevent excessive blood loss. Re-attachment
can be achieved in a non-microsurgical way, a technique which probably gives higher rates of post-operative
urethral stricture and more problems with loss of sensation [365]. When operating microscopically, the corpora
cavernosa and urethra are firstly aligned and repaired. Subsequently, the dorsal penile arteries, the dorsal vein
and the dorsal nerves are anastomosed. The cavernosal arteries are generally too small to anastomose. The
fascia and skin are closed in layers and both a urethral and a supra-pubic catheter are placed.
If the severed penis cannot be found, or is unsuitable for re-attachment, then the end should be closed as it
is done in partial penectomy. Later reconstruction may be employed to lengthen the penis (e.g. suspensory
ligament division and V-Y plasty, pseudo-glans formation with split-thickness skin grafting, etc). A delayed
major reconstructive procedure, i.e. phalloplasty (either radial artery or pubic), is sometimes required for injuries
which leave a very small or non-functioning penile stump [364].
4.5.4.1.2 Haematocoele
Conservative management is recommended in haematoceles smaller than three times the size of the
contralateral testis [370]. In large haematoceles, non-operative management can fail, and delayed surgery
(more than three days) is often required. Patients with large haematoceles have a higher rate of orchiectomy
than patients who undergo early surgery, even in non-ruptured testes [325, 333, 371-373]. Early surgical
intervention results in preservation of the testis in more than 90% of cases compared to delayed surgeries
which result in orchiectomy in 45-55% of patients [373]. In addition, non-operative management is also
associated with prolonged hospital stays. Therefore, large haematoceles should be treated surgically,
irrespective of the presence of testicular contusion or rupture. At the very least, the blood clot should be
evacuated from the tunica vaginalis sac to relieve disability and hasten recovery. Patients initially treated non-
operatively may eventually need delayed surgery if they develop infection or undue pain.
Ultrasound should be performed to determine intra- and/or extra-testicular haematoma, testicular contusion,
or rupture [375-383]. However, the literature is contradictory as to the usefulness of US compared to clinical
examination alone. Some studies have reported convincing findings with a specificity of up to 98.6% [356].
Others reported poor specificity (78%) and sensitivity (28%) for the differentiation between testicular rupture
and haematocele, while accuracy is as low as 56% [376]. Colour Doppler-duplex US may provide useful
information when used to evaluate testicular perfusion. If scrotal US is inconclusive, testicular CT or MRI
may be helpful [384]. However, these techniques did not specifically increase the detection rates of testicular
rupture. It is therefore essential to surgically explore equivocal patients whenever imaging studies cannot
definitively exclude testicular rupture. This involves exploration with evacuation of blood clots and haematoma,
excision of any necrotic testicular tubules and closure of the tunica albuginea, usually with running absorbable
sutures (e.g. 3/0 Vicryl).
Prophylactic antibiotics are recommended after scrotal penetrating trauma, although data to support this
approach is lacking. Tetanus prophylaxis is mandatory. Post-operative complications were reported in 8% of
patients who underwent testicular repair after penetrating trauma [267].
Extended laceration of scrotal skin requires surgical intervention for skin closure. Due to the elasticity of the
scrotum, most defects can be primarily closed, even if the lacerated skin is only minimally attached to the
scrotum [333]. Local wound management with extensive initial wound debridement and washout is important
for scrotal convalescence. In the case of extensive loss of genital tissue, e.g. IED blast injury, complex and
staged reconstructive surgical procedures are often required [331].
Blunt vulvar or perineal trauma may be associated with voiding problems and bladder catheterisation is usually
required. Vulvar haematomas usually do not require surgical intervention, although they can cause a significant
blood loss, which sometimes even requires blood transfusion. Data are scarce [388], but in haemodynamically
stable women, non-steroidal anti-inflammatory medication and cold packs are generally successful. Yet, in
Although antibiotics are often recommended after major vulvar trauma, there is no data to support this
approach. It is important to emphasise that vulvar haematoma and/or blood at the vaginal introitus are
indications for vaginal exploration under sedation or general anaesthesia. The aim is to identify possible
associated vaginal and/or rectal injuries [337]. Flexible or rigid cystoscopy has been recommended to exclude
urethral and bladder injury [336, 337]. In the case of vulvar laceration, suturing after conservative debridement
is indicated. If there are associated injuries to the vagina, these can be repaired immediately by primary
suturing.
4.5.6 Summary of evidence and recommendations for the management of genital trauma
Summary of evidence LE
Most genital injuries, in males and females, are caused by blunt trauma. 3
Recommendations LE GR
Treat penile fractures surgically, with closure of tunica albuginea. 2a B
Explore the injured testis in all cases of testicular rupture and in those with inconclusive 3 B
ultrasound findings.
Recommendations LE GR
Manage polytrauma patients in designated major trauma centres within a trauma network. 3 A*
Involve urologists in cases of associated urological injury. 3 A*
*Upgraded following panel consensus.
Identifying which patients benefit from the damage control mode requires critical decision-making by the
trauma team leader. Prior preparedness and regular communication between the surgical, critical care and
anaesthetic teams are vital [399]. Damage control principles have been successfully adopted in the context of
civilian mass casualty events, military field surgery, and initial treatment in rural areas with long-range transfers
[396, 400].
5.3.1 Summary of evidence and recommendations for management principles of polytrauma and
associated urological injury
Summary of evidence LE
Damage control principles govern the management of severely injured polytrauma patients. 4
Recommendation LE GR
Follow damage control principles in the management of severely injured polytrauma patients. 4 A*
*Upgraded following panel consensus.
At laparotomy, it is considered best practice not to explore the injured kidney if there is no active haemorrhage,
even if delayed exploration is then necessary [79]. In unstable patients, packing the renal fossa and transferring
the patient to the surgical intensive care unit is the option of choice for damage control. A planned second-
look laparotomy is then performed [180]. However, in patients with significant ongoing haemorrhage, speedy
nephrectomy is required. It is recommended that the contralateral kidney should at least be palpated prior to
nephrectomy [402].
In patients who are packed temporarily and who become sufficiently stable in the intensive setting,
radiological assessment allows definitive management to begin. Computed tomography allows the kidney
injury to be graded, documents the presence of a contralateral kidney, and helps to determine whether or not
intervention (radiological or surgical) is necessary.
Recommendations LE GR
Manage life-threatening bleeding from renal injury by urgent nephrectomy. 4 B*
Manage profuse non-arterial bleeding by renal packing as a damage control measure. 4 B*
Use angioembolisation as an effective haemostatic measure. 4 B*
*Upgraded based on panel consensus
If a ureteral injury is suspected but not clearly identified, a drain should be sited. If urine leaks post-operatively,
a nephrostomy should be arranged. If a partial ureteral tear is identified (less than half a circumference) and the
ureter is otherwise healthy, a double J-stent may be inserted over a guide wire through the tear, and the tear
quickly closed with fine interrupted absorbable stitches.
When complete ureteral injuries are identified, definitive repair should not be performed. Dissection of the
ureteral stumps should be avoided as it interferes with the blood supply. Temporary measures to control urine
spillage should be performed:
• a single J or 8 French feeding tube is inserted into the ureter;
• the end of the disrupted proximal ureter is secured over the tube, which is exteriorised and secured to the
skin.
The distal ureteral stump does not need to be ligated and any unnecessary manipulation should be avoided.
Intra-operative placement of a nephrostomy tube is time-consuming and should be avoided [112, 180].
Tying off the injured ureteral segment and inserting a percutaneous nephrostomy post-operatively is a viable
alternative [404]. Rarely, in cases with severe associated injuries of the ipsilateral kidney, nephrectomy is
required.
Recommendations LE GR
Rule out ureteral injury in penetrating abdominal trauma. 4 A*
Treat ureteral injury with ‘tube’ urinary diversion if repair is not performed. 4 C
*Upgraded following panel consensus.
5.4.3.1 Recommendations for the management of bladder trauma and urethral injury
Recommendations LE GR
Provide urinary drainage by either the suprapubic or urethral route. 3 A
Triage should be performed at each stage from the pre-hospital setting to the emergency department and
repeated as the clinical situation evolves. Ultimately, the individual in charge is responsible for directing
specialty surgical teams, including urologists, and assigning them responsibility for specific patients as dictated
by the specific injuries.
6. REFERENCES
1. Tekgül, S., et al. EAU Guidelines on Paediatric Urology 2017. In: EAU Guidelines Edn. Presented
at the EAU Annual Congress London 2017, European Association of Urology, Guidelines Office,
Arnhem, The Netherlands.
https://uroweb.org/guideline/paediatric-urology/
2. Martinez-Pineiro, L., et al. EAU Guidelines on Urethral Trauma. Eur Urol, 2010. 57: 791.
http://www.ncbi.nlm.nih.gov/pubmed/20122789
3. Summerton, D.J., et al. EAU guidelines on iatrogenic trauma. Eur Urol, 2012. 62: 628.
http://www.ncbi.nlm.nih.gov/pubmed/22717550
4. Lumen, N., et al. Review of the current management of lower urinary tract injuries by the EAU
Trauma Guidelines Panel. Eur Urol, 2015. 67: 925.
http://www.ncbi.nlm.nih.gov/pubmed/25576009
5. Serafetinides, E., et al. Review of the current management of upper urinary tract injuries by the EAU
Trauma Guidelines Panel. Eur Urol, 2015. 67: 930.
http://www.ncbi.nlm.nih.gov/pubmed/25578621
7. CONFLICT OF INTEREST
All members of the Urological Trauma Guidelines working group have provided disclosure statements of
all relationships that they have that might be perceived as a potential source of a conflict of interest. This
information is publically accessible through the European Association of Urology website: http://uroweb.org/
guidelines/. This guidelines document was developed with the financial support of the European Association of
Urology. No external sources of funding and support have been involved. The EAU is a non-profit organisation
and funding is limited to administrative assistance and travel and meeting expenses. No honoraria or other
reimbursements have been provided.
2. METHODOLOGY 13
2.1 Methods 13
2.2 Review 13
2.3 Future goals 13
4. DIAGNOSTIC EVALUATION 25
4.1 General Evaluation 25
4.1.1 History 25
4.1.1.1 Anxiety, depression, and overall function 25
4.1.1.2 Urological aspects 25
4.1.1.3 Gynaecological aspects 26
4.1.1.4 Gastrointestinal aspects 26
4.1.1.5 Peripheral nerve aspects 26
4.1.1.6 Myofascial aspects 27
4.1.2 Physical Evaluation 27
4.2 Supplemental evaluation 28
4.2.1 Assessing pain and related symptoms 28
5. MANAGEMENT 37
5.1 Conservative management 37
5.1.1 Pain education 37
5.1.2 Physical therapy 37
5.1.3 Psychological therapy 39
5.1.4 Dietary treatment 39
5.2 Pharmacological management 40
5.2.1 Drugs for chronic pelvic pain syndrome 40
5.2.1.1 Mechanisms of action 40
5.2.1.2 Comparisons of agents used in pelvic pain syndromes 40
5.2.2 Analgesics 44
5.2.2.1 Mechanisms of action 45
5.2.2.2 Comparisons within and between groups in terms
of efficacy and safety 45
5.3 Surgical management 47
5.3.1 Surgery 47
5.3.2 Neuromodulation 49
5.3.3 Nerve blocks 50
5.4 Summary of evidence and recommendations: management 50
5.4.1 Management of PPS 50
5.4.2 Management of BPS 51
5.4.3 Management of scrotal pain syndrome 52
5.4.4 Management of urethral pain syndrome 52
5.4.5 Management of gynaecological aspects of chronic pelvic pain 53
5.4.6 Management of anorectal pain syndrome 53
5.4.7 Management of pudendal neuralgia 53
5.4.8 Management of sexological aspects in CPP 53
5.4.9 Management of pelvic floor dysfunction 54
5.4.10 Management of chronic/non-acute urogenital pain by opioids 54
7. REFERENCES 55
8. CONFLICT OF INTEREST 81
This guideline aims to expand the awareness of caregivers in the field of abdominal and pelvic pain and to
assist those who treat patients with abdominal and pelvic pain in their daily practice. The guideline is a useful
instrument not only for urologists, but also for gynaecologists, surgeons, physiotherapists, psychologists and
pain doctors.
It must be emphasised that clinical guidelines present the best evidence available to the experts. However
following guideline recommendations will not necessarily result in the best outcome. Guidelines can never
replace clinical expertise when making treatment decisions for individual patients, but rather help to focus
decisions - also taking personal values and preferences/individual circumstances of patients into account.
Guidelines are not mandates and do not purport to be a legal standard of care.
Two chapters were added at that time: Chapter 5 ‘Gastrointestinal aspects of chronic pelvic pain’ and Chapter
7 ‘Sexological aspects of chronic pelvic pain’. In the 2014 edition minor revisions were made in Chapters 5
‘Gastrointestinal aspects of chronic pelvic pain’ and 8 ‘Psychological aspects of chronic pelvic pain’.
For the 2015 edition the Panel critically reviewed the sub-chapter on bladder pain syndrome which is now a
comprehensive part of the guideline [5].
In 2016, the guideline was rewritten in such a way that it is centred around pain instead of being organ-centred
and furthermore restructured in accordance with the template used in all other non-oncology guidelines of the
EAU.
1.5 Terminology
Phenotyping
Phenotyping is describing the condition. For example, chronic bladder pain may be associated with the
presence of Hunner’s ulcers and glomerulation on cystoscopy, whereas other bladder pain conditions may
have a normal appearance on cystoscopy. These are two different phenotypes. The same is true for irritable
bowel syndrome (IBS), which may be sub-divided into that associated primarily with diarrhoea or that with
constipation. Phenotyping is based upon mechanisms when they are known (e.g., infection, ischaemic,
autoimmune, or neuropathic). In the absence of well-defined mechanisms, describing the condition by its
symptoms, signs and, where possible, by investigations, has been demonstrated to have clinical and research
validity in many situations. When pain is the main symptom and pain as a disease process is considered the
cause, the condition is often referred to as a pain syndrome - a well-defined collection of symptoms, signs and
investigation results associated with pain mechanisms and pain perception as the primary complaint.
Terminology
Terminology is the words that are used within classification, both to name the phenotype and within the
definition of the phenotype. Examples of names for phenotypes associated with the bladder include interstitial
cystitis, painful bladder syndrome or bladder pain syndrome (BPS). The EAU, the International Society for the
study of BPS (ESSIC), the International Association for the Study of Pain (IASP) and several other groups now
prefer the term bladder pain syndrome. In the pain syndromes, the role of the nervous system in generating the
sensations is thought to be pivotal, but the term syndrome is also comprehensive and takes into account the
emotional, cognitive, behavioural, sexual and functional consequences of the chronic pain.
When defining the phenotype, the terminology used in that definition must also be clear and if necessary
defined. One of the most important guiding principles is that spurious terminology should be avoided. Terms
that end in “itis” in particular should be avoided unless infection and or inflammation is proven and considered
to be the cause of the pain [6]. It must be appreciated that end-organ inflammation may be secondary and
neurogenic in origin and not a primary cause of the pain.
Taxonomy
Taxonomy places the phenotypes into a relationship hierarchy. The EAU approach sub-divides CPP into
conditions that are pain syndromes and those that are non-pain syndromes. The latter are conditions that have
well-recognised pathology (e.g., infection, neuropathy or inflammation), whereas the former syndromes do not
and pain as a disease process is the mechanism. Other terms for the non-pain syndromes include “classical
conditions”, “well-defined conditions” and “confusable diseases”. Although the EAU approach deals primarily
with urological conditions, this approach to classification can be applied to all conditions associated with pain
perception within the pelvis; the classification has been developed to include non-urological pain and was
accepted by the IASP for publication in January 2012.
Importance of classification
It should be obvious to all that a condition cannot be treated unless it is defined. However, the reasons for
classifying CPP go far beyond that.
Research platform
Only by clearly defining the phenotype being investigated can research be valued or applied to the clinical
situation.
Patient needs
A diagnosis, or name, for a set of symptoms can provide patients with a sense of being understood, as well
as hope for relief. It may therefore help in acceptance of the problem as chronic, resolution of unfounded
fears about its implications (if not life-threatening), and engagement in therapeutic endeavours, as well as in
self-management. However, it may also lead to accessing information of variable quality associated with the
diagnosis or name, and the possibility of generating new concerns about long-term consequences or about
appropriateness of treatment.
IASP definitions
Sub-dividing pain syndromes
There is much debate on the sub-divisions of the pain syndromes within the hierarchical taxonomy. The EAU
has led the way in this regard and the guiding principles are as follows [2]:
1. The pain syndromes are defined by a process of exclusion. In particular, there should be no evidence of
infection or inflammation. Investigations by end-organ specialists should therefore be aimed at obtaining
a differential diagnosis; repeated, unnecessary investigations are detrimental in the management of
chronic pain syndromes.
2. A sub-division phenotype should only be used if there is adequate evidence to support its use. For
instance, in non-specific, poorly localised pelvic pain without obvious pathology, only the term chronic
pelvic pain syndrome (CPPS) should be used. If the pain can be localised to an organ, then a more
specific term, such as rectal pain syndrome, may be used. If the pain is localised to multiple organs,
then the syndrome is a regional pain syndrome and the term CPPS should once again be considered.
As well as defining the patient by a specific end-organ phenotype, there are several other more general
descriptors that need to be considered. These are primarily psychological (e.g., cognitive or emotional),
sexual, behavioural and functional. Psychological and behavioural factors are well-established factors
which relate to quality of life (QoL) issues and prognosis. In North America a research programme, the
MAPP program (Multi-disciplinary Approach to the study of Chronic Pelvic Pain research) has been
devised to investigate the importance of these factors and looks at all types of pelvic pain irrespective of
the end-organ where the pain is perceived. It also looks at systemic disorder associations, such as the
co-occurrence of fibromyalgia, facial pain, or auto-immune disorders.
3. In 2004 this expert panel introduced the concept of managing the polysymptomatic nature of CPP, since
then others have developed their own schemes, such as Nickel’s UPOINT [7], modified by Magri et al. [8].
In light of these and other publications, the symptom classification table has been updated (Table 1).
The debate in relation to sub-dividing the pain syndromes remains ongoing. As more information is collected
suggesting that the central nervous system (CNS) is involved, and indeed may be the main cause of many
CPP conditions (e.g., bladder, genitalia, colorectal or myofascial), there is a general tendency to move away
from end-organ nomenclature. Only time and good research will determine whether this is appropriate. To
enable such research, it is essential to have a framework of classification within which to work. Any hierarchical
taxonomy must be flexible to allow change.
Hyperaesthesia Avoidance
Intermittent chronic anal Allodynia
Hyperalegesie
Peripheral nerves Pudendal pain syndrome
CUTANEOUS
Trophic changes
Sensory changes
7
Pain syndromes
The original EAU classification [2] was inspired by the IASP classification [9] and much work around what has
become known as “pain as a disease” and its associated psychological, behavioural, sexual and functional
correlates. After ten years of work developing the initial ideas, an updated version was accepted by IASP
Council for publication in January 2012.
In the case of documented nociceptive pain that becomes chronic/persistent through time, pain must have
been continuous or recurrent for at least six months. That is, it can be cyclical over a six-month period, such
as the cyclical pain of dysmenorrhoea. Although arbitrary, six months was chosen because three months was
not considered long enough if cyclical pain conditions are included. If non-acute and central sensitisation pain
mechanisms are well documented, then the pain may be regarded as chronic, irrespective of the time period.
Cyclical pain is included in the classification and hence dysmenorrhoea needs to be considered as a chronic
pain syndrome if it is persistent and associated with negative cognitive, behavioural, sexual, or emotional
consequences.
Chronic pelvic pain may be sub-divided into conditions with well-defined classical pathology (such as infection
or cancer) and those with no obvious pathology. For the purpose of this classification, the term “specific
disease-associated pelvic pain” is proposed for the former, and “chronic pelvic pain syndrome” for the latter.
The following classification only deals with Chronic Pelvic Pain Syndrome.
Functional pain disorders may not express significant pathology in the organs that appear responsible for the
primary symptoms, but they are associated with substantial neurobiological, physiological and sometimes
anatomical changes in the CNS.
Multi-system sub-division
It is recognised that the end-organ where the pain is perceived may not be the centre of pain generation.
This classification is based upon the most effective and accepted method of classifying and identifying
different pain syndromes, that is, by site of presentation. It is argued that keeping the end-organ name in the
classification is inappropriate because, in most cases, there are multi-systemic causes and effects, with the
result that symptoms are perceived in several areas. This is an area in which discussions are ongoing, and
despite there being strong arguments for both keeping and dispensing with end-organ classification, the
authors have not taken the umbrella approach of referring to all pain perceived in the pelvis as CPPS.
Dyspareunia
Dyspareunia is defined as pain perceived within the pelvis associated with penetrative sex. It tells us nothing
about the mechanism and may be applied to women and men. It is usually applied to penile penetration, but is
often associated with pain during insertion of any object. It may apply to anal as well as vaginal intercourse. It
is classically sub-divided into superficial and deep.
2. METHODOLOGY
2.1 Methods
References used in this text are assessed according to their Level of Evidence (LE) and Guidelines are given
a Grade of Recommendation (GR), according to a classification system modified from the Oxford Centre for
Evidence-based Medicine Levels of Evidence [13]. Additional methodology information can be found in the
general Methodology section of this print, and online at the EAU website: http://www.uroweb.org/guideline/. A
list of Associations endorsing the EAU Guidelines can also be reviewed online at the above address.
The 2012 full text update was based on a systematic review of literature using the Embase and Medline
databases, the Cochrane Central Register of controlled trials and the PsycINFO and Bandolier databases to
identify the best evidence from randomised controlled trials (RCTs) (Level of Evidence 1 (LE: 1)) according
to the rating schedule adapted from the Oxford Centre for Evidence-based Medicine Levels of Evidence
[13]. Where no LE: 1 literature could be identified the search was moved down to the next lower level on the
rating scale. Extensive use of free text ensured the sensitivity of the searches, resulting in a substantial body
of literature to scan. Searches covered the period January 1995 to July 2011 and were restricted to English
language publications.
For the 2017 print, a scoping search was performed, covering all areas of the guideline starting from the last
cut-off date of July 2011 with a cut-off date of May 2016. Embase, Medline, the Cochrane Central Register of
Controlled Trials and CINAHL databases were searched and were restricted to English language publications.
A total of 3,489 unique records were identified, retrieved and screened for relevance of which 47 publications
were selected for inclusion in the 2017 guidelines. A detailed search strategy is available online: https://uroweb.
org/guideline/chronic-pelvic-pain/. The gynaecological aspects of the guideline were not updated in this edition
but will be updated in 2018.
2.2 Review
This document was subject to peer review prior to publication in 2015.
• What are the benefits and harms of electrical neuromodulation vs. best clinical practice or no treatment in
CPP? [14].
3.1.1 Incidence
No adequate data on incidence were found.
3.1.2 Prevalence
In a large study in Europe undertaken in 2004 [15] it was found that chronic pain of moderate to severe intensity
occurs in 19% of adult Europeans, seriously affecting the quality of their social and working lives. There are
some differences between countries but not much spread is seen.
Pelvic pain syndromes do have an impact on QoL [18, 19]. This may result in depression, anxiety, impaired
emotional functioning, insomnia and fatigue [18, 20]. If these aspects are identified and targeted early in the
diagnostic process, the associated pain symptoms may also improve [21]. Addressing co-morbidities will help
in further improving QoL [22]. Quality of life assessment is therefore important in patients with pelvic pain and
should include physical, psychosocial and emotional tools, using standardised and validated instruments [19].
The impact of pain on QoL has been assessed in an extensive European study [15]. In-depth interviews with
4,839 respondents with chronic pain (about 300 per country) showed: 66% had moderate pain (NRS = 5-7) and
34% had severe pain (NRS = 8-10), 46% had constant pain, 54% had intermittent pain. 59% had suffered with
pain for two to fifteen years, 21% had been diagnosed with depression because of their pain, 61% were less
able or unable to work outside their home, 19% had lost their job and 13% had changed jobs because of their
pain. 60% visited their doctor about their pain two to nine times in the last six months. Only 2% were currently
treated by a pain management specialist.
3.1.4 Costs
No adequate data on costs were found.
The endocrine system is involved in visceral function. Significant life events, and in particular, early life events
may alter the development of the hypothalamic-pituitary-adrenal axis and the chemicals released. Increased
vulnerability to stress is thought to be partly due to increased corticotrophin-releasing hormone (CRH) gene
expression. Up-regulation of CRH has been implicated in several pain states such as rectal hypersensitivity to
rectal distension. This model suggests an action of CRH on mast cells. A range of stress-related illnesses have
been suggested, e.g. IBS and BPS. There is evidence accumulating to suggest that the sex hormones also
modulate both nociception and pain perception. Stress can also produce long-term biological changes which
may form the relation between chronic pain syndromes and significant early life and adverse life events [23].
Asking the patient about these events is important as they have an effect on a patient’s psychological wellbeing
[24-26].
Genetics also play a role in assessing the risk of developing chronic pain. An individual who has one chronic
pain syndrome is more likely to develop another. Family clusters of pain conditions are also observed and
animals can be bred to be more prone to apparent chronic pain state. A range of genetic variations have
been described that may explain the pain in certain cases; many of these are to do with subtle changes
Studies about integrating the psychological factors are few but the quality is high. Psychological factors are
consistently found to be relevant in the maintenance of persistent pelvic and urogenital pain with current
neurobiological understanding of pain. Beliefs about pain contribute to the experience of pain [29] and
symptom-related anxiety and central pain amplification may be measurably linked, as in IBS [30]. Central
sensitisation has been demonstrated in symptomatic endometriosis [31] and central changes are evident in
association with dysmenorrhoea and increasingly recognised as a risk for female pelvic pain [32]. The various
mechanisms of CNS facilitation, amplification and failure of inhibition, mean that there is no simple relationship
between physical findings, pain experienced and resulting distress and restriction of activities. Diagnoses that
assign women’s pain to psychological origins, as is common in primary care [33] due to scepticism about the
reality or severity of their pain [34], undermines any therapeutic relationship [35]. Division of aetiology into
organic vs. psychogenic is unscientific. Pelvic pain and distress may be related [36, 37] in men as well as in
women [38]; the same is true of painful bladder and distress [39]. In a large population based study of men,
CPPS was associated with prior anxiety disorder [40]. The only systematic review [41] of risk factors for chronic
non-cyclical pelvic pain in women included, as well as medical variables: sexual or physical abuse (OR from
1.51 to 3.49); psychological problems such as anxiety (OR: 2.28, 95% CI: 1.41- 3.70) and depression (OR: 2.69,
95% CI: 1.86-3.88); multiple somatic problems (OR: 4.83, 95% CI: 2.50-9.33); and psychosomatic symptoms
(OR: 8.01, 95% CI: 5.16-12.44).
Many studies have reported high rates of childhood sexual abuse in adults with persistent pain, particularly
in women with pelvic pain [42, 43]. In these studies it is suggested that there is increased frequency of
sexual abuse or trauma history, anxiety and depression in women with CPP [44-48]. The only prospective
investigation into the relationship between childhood sexual abuse, physical abuse, or neglect, and “medically
unexplained pain”, including pelvic pain, used court records to compare women with a definite history with
matched classmates [26] and concluded that physically and sexually abused individuals were not at risk for
increased pain, although women with pain problems as adults were more likely to report earlier sexual or
physical abuse or neglect. The correlation between childhood victimisation and pain may concern retrospective
explanations for pain; controlling for depression significantly weakens the relationship between childhood
abuse and adult pain [49]. Disentangling the influences and inferences requires further prospective studies or
careful comparisons [23]. There is some evidence for a specific relationship between rape and CPP (and with
fibromyalgia and functional gastrointestinal disorders) [50]; and, recent sexual assault may prompt presentation
of pelvic pain [42, 51]. Few studies have been found of sexual or physical abuse in childhood and pelvic pain in
men, although it has known adverse effects on health [50, 52]. In the BACH study, it was found that men who
reported having experienced sexual, physical, or emotional abuse had increased odds (3.3 compared to 1.7)
for symptoms suggestive of CPP. The authors suggested that clinicians may wish to screen for abuse in men
presenting with symptoms suggestive of CPP. Conversely, clinicians may wish to inquire about pelvic pain in
patients who have experienced abuse [53].
1. Ongoing acute pain mechanisms [54] (such as those associated with inflammation or infection), which
may involve somatic or visceral tiss