Review Article on Expectant Management in Genitourinary Malignancies (Prostate, Bladder, Kidney)

Active surveillance for prostate cancer

Daniela K. Shill1, Monique J. Roobol2, Behfar Ehdaie3, Andrew J. Vickers4, Sigrid V. Carlsson3,4,5
1
Hunter College, New York, NY, USA; 2Department of Urology, Erasmus University Medical Center, Rotterdam, The Netherlands; 3Department
of Surgery (Urology Service), Memorial Sloan Kettering Cancer Center, New York, NY, USA; 4Department of Epidemiology and Biostatistics,
Memorial Sloan Kettering Cancer Center, New York, NY, USA; 5Department of Urology, Institute of Clinical Sciences, Sahlgrenska Academy at
University of Gothenburg, Sweden
Contributions: (I) Conception and design: DK Shill, MJ Roobol, SV Carlsson; (II) Administrative support: None; (III) Provision of study materials
or patients: None; (IV) Collection and assembly of data: DK Shill, SV Carlsson, AJ Vickers; (V) Data analysis and interpretation: All authors; (VI)
Manuscript writing: All authors; (VII) Final approval of manuscript: All authors.
Correspondence to: Sigrid V. Carlsson. 485 Lexington avenue, 10017, New York, NY, USA. Email: [email protected].

Abstract: Many men diagnosed with localized prostate cancer can postpone definitive treatment without
raising their risk of metastasis or death from disease. Active surveillance (AS) is a method of monitoring
select men, with the option of switching to active treatment upon signs of progression, thereby avoiding the
well-known side-effects of surgery and radiotherapy. This review analyzes the data from long-running AS
cohorts to determine the safety and efficacy of AS. We conducted a narrative review of recently published
data, including 14 articles from 13 AS cohorts. The cohorts used varying inclusion criteria, with reported
differences in clinical T stage and Gleason Score (Grade Group), among other features. Some studies (n=5)
limited their cohorts to low-risk patients, while others (n=8) also included intermediate-risk patients. The
heterogeneity of the cohorts produced mixed results, with the risk of prostate cancer metastasis ranging from
0.1–1.0% at 10 years and the risk of prostate cancer mortality ranging from 0–1.9% at 10 years. However,
the majority of studies reported risks of less than 0.5% at 10 years for both metastasis and death. For most
cohorts, half of men remained untreated for 5–10 years, with estimates ranging from 37% receiving active
treatment in the Toronto cohort to 73% in the Prostate Cancer Research International AS (PRIAS) study.
Current data do not support the use of negative magnetic resonance imaging (MRI) to avoid scheduled
biopsy. Taken together, the data collected from these AS cohorts suggests that AS is a safe approach for men
with low-grade prostate cancer and some men with intermediate risk disease. AS should be more broadly
implemented for eligible patients to avoid the decreases in quality of life from undergoing active treatment.
Studies expanding the inclusion criteria and further defining a subset of men with favorable intermediate-risk
prostate cancer who might safely benefit from AS are needed to assess the long-term outcomes of using AS
in intermediate-risk groups.

Keywords: Active surveillance (AS); expectant management; watchful waiting; prostate cancer; cohort; program

Submitted Oct 26, 2020. Accepted for publication Mar 25, 2021.
doi: 10.21037/tau-20-1370
View this article at: http://dx.doi.org/10.21037/tau-20-1370

Introduction cause of cancer death among men and causing an estimated

359,000 deaths in 2018. As the male population ages and
Prostate cancer is currently the second most common growths, these numbers are expected to increase to 740,000
cancer diagnosis among men worldwide, with an estimated deaths by 2040 (1).
close to 1.3 million cases in 2018, expected to nearly double Early diagnosis of prostate cancer can increase the chances
to 2.3 million cases by 2040 (1). Death due to prostate of effective monitoring and treatment, while diagnosis at
cancer is also common, representing the sixth leading later stages when the cancer is beyond the window of cure,

© Translational Andrology and Urology. All rights reserved. Transl Androl Urol 2021;10(6):2809-2819 | http://dx.doi.org/10.21037/tau-20-1370
2810 Shill et al. AS for prostate cancer

or has metastasized, is more likely to lead to death (2,3). (Grade Group 2) prostate cancer (intermediate risk) may be
Early diagnosis rates have dramatically increased with the considered for AS as well (11). Intermediate risk prostate
widespread use of prostate specific antigen (PSA) screening, cancer is indeed a broad, heterogeneous group. This review
including many slow-growing, indolent prostate cancers, also seeks to identify which patients are the most clinically
which pose minimal threat and do not have to lead to appropriate candidates for AS by examining various metrics
treatment upfront. Given the psychological and physical tolls of completion, notably the percentage of patients who
of prostate cancer treatment, finding alternative methods for progressed to treatment, the rates of metastasis, and the
men with low-risk, localized prostate cancer diagnoses can mortality rates of patients within the cohort studies.
help to lower the burden of disease and improve quality of
life for affected men (4).
Search strategy
Active surveillance (AS) is an approach that uses a
combination of PSA testing, digital rectal examinations This review focused on updating the findings of 13 well-
(DRE), and prostate biopsies to monitor prostate cancer established and long-running AS cohorts that were
in men rather than immediately advising treatment for previously identified in a review paper conducted by
low-risk/favorable-intermediate risk, localized prostate Kinsella et al. in 2018 (7). These cohorts were located at the
cancers (5-7). Some AS programs also incorporate magnetic following institutions: Memorial Sloan Kettering Cancer
resonance imaging (MRI) at baseline and as part of the Center (MSK), The Johns Hopkins University School of
follow-up protocol. Using AS can help delay or forgo Medicine (Johns Hopkins), University of California-San
treatment for these men by monitoring the cancer closely Francisco Helen Diller Family Comprehensive Cancer
for changes and adjusting accordingly, therefore mitigating Center (UCSF), Erasmus University Medical Center
overtreatment. Curative therapy for prostate cancer, (PRIAS), The Miller School of Medicine (University of
surgery and radiotherapy, often result in detrimental side Miami), The Royal Marsden Hospital (Royal Marsden),
effects that can severely impact quality of life, including The Nuffield Department of Surgical Sciences (ProtecT),
urinary incontinence, sexual dysfunction, and bowel University of Toronto Sunnybrook Hospital (Toronto),
dysfunction. The potential benefits of AS therefore include Copenhagen Prostate Cancer Center (University of
the preservation of sexual, urinary, and bowel functions in Copenhagen), St. Vincent’s Prostate Cancer Centre (St.
afflicted men (8). While the proportion of US men with Vincent’s Australia), The Sahlgrenska University Hospital
low risk prostate cancer choosing AS was, for many years, (Goteborg), Fred Hutchinson Cancer Research Center
only about 10%, this figure is steadily increasing and is now (Canary PASS), and the Fondazione IRCCS Istituto
closer to 50% (9). Nazionale Tumori Milan (Milan).
The aim of this paper is to review AS as an alternative Updates on these studies were identified through a
to immediate active treatment in men with low-risk and systematic search of the Scopus database conducted on July
favorable-intermediate risk, localized prostate cancer 1, 2020, limited to publications after 2016. The search used
across different cohort studies. The American Urological the unique IDs of the authors and cohort names, as well as
Association (AUA) recommends “AS as the best available the following keywords to identify studies focused on AS:
care option for very low risk localized prostate cancer “active surveillance”, “expectant management”, “watchful
patients” and “as the preferable care option for most waiting”, “prostate AND cancer”, “follow-up”, “cohort”,
low risk localized prostate cancer patients”. Regarding “program”, and “programme”.
intermediate risk, the AUA acknowledges that “AS may Results from this search strategy were then screened by
be offered to select patients with favorable intermediate two authors independently (DKS and SVC) for inclusion
risk localized prostate cancer; however, patients should be in this review. A hand and cited reference search was
informed that this comes with a higher risk of developing conducted to retrieve additional updated articles.
metastases compared to definitive treatment” (10). If AS
is now the preferred option for the initial management
Findings
of most men with localized, very low-risk and low-risk
prostate cancer, current guidelines including the American We first summarize the findings for the 13 included AS
Society of Clinical Oncology (ASCO) guidelines have cohorts. We then describe current literature and evidence
supported that select men with low-volume Gleason 3+4 regarding MRI, biomarkers, studies on AS for men with

© Translational Andrology and Urology. All rights reserved. Transl Androl Urol 2021;10(6):2809-2819 | http://dx.doi.org/10.21037/tau-20-1370
Translational Andrology and Urology, Vol 10, No 6 June 2021 2811

intermediate risk prostate cancer and quality of life on AS. The rest of the studies included a mixed range of
patients. Most cohorts did not exceed a maximum clinical
T stage of T2C [MSK (14), UCSF (15), PRIAS (18),
Active surveillance cohorts
University of Miami (25), ProtecT (17), University of
Cohort selection Toronto (22), Goteborg (19), and Canary PASS (20)]. The
intermediate-risk cohort at MSK similarly recruited patients
This search strategy yielded 418 results, which were screened
with a maximum clinical T stage of T2C (2 patients had
for eligibility for this review based on their relevance to
T3A) (13). There was a lack of consensus around maximum
the 13 AS cohorts of interest. The final review included
PSA levels for these mixed-risk groups, with some studies
14 articles for 13 cohorts in full-text (12-25) (https://cdn.
suggesting limits of 10 ng/mL (18,25) and others suggesting
amegroups.cn/static/public/tau-20-1370-1.pdf). These
a 20 ng/mL limit (17,19,20,22). Several of the studies had
cohorts were dispersed around the world, with 6 cohorts
no identified PSA maximum in their reports (13-15).
located in North America (12-15,20,22,25), 5 located in
Most mixed-risk cohorts also recruited patients with
Europe (16,17,19,21,24), 1 located in Australia (23), and a maximum Grade Group score of GG2 [MSK (13),
1 based in multiple countries (18). UCSF (15), PRIAS (18), University of Miami (25),
University of Toronto (22), Goteborg (19), and Canary
Cohort demographics PASS (20)]. The ProtecT cohort had no Grade Group
restrictions, enrolling patients up to Grade Group 5 (17).
The cohorts chosen represented a wide range of patient Many of the studies had no reported restrictions of the
demographics, as well as a wide range of inclusion criteria number of positive biopsy cores in their patients. Of the
that created heterogeneity across the studies. The median cohorts with established limits, most restricted to 2 or
patient age ranged from 62 years [ProtecT (17)] to 68 years 3 positive cores [MSK (13), Johns Hopkins (12), University
[University of Toronto (22)], and the number of participants of Miami (25), and University of Copenhagen (21)]. Others
ranged from 219 [MSK (13)] to 5,302 [PRIAS (18)]. The restricted based on the percentage of positive biopsy cores
median follow-up ranged from 2.3 years to 10 years. out of the total taken, with St. Vincent’s Australia (23)
The cohorts evaluated in this review used varying limiting to less than 20%, Milan (16) to less than 25%, and
sets of inclusion criteria to determine patient eligibility Royal Marsden (24) to less than 50%.
for AS. Some cohorts had highly restrictive criteria and
enrolled only low-risk patients, while others created mixed-
risk cohorts by enrolling patients with a wider range of Follow-up regimen and intervention criteria
clinical characteristics. Of the 13 cohorts, 5 exclusively Details of the AS follow-up regimens of these cohorts have
enrolled low-risk patients, while 8 included low-risk and been described elsewhere (7,12-26). In brief, AS protocols
intermediate risk-patients. are variable and heterogeneous across cohorts. Most
cohorts utilized regular monitoring with PSA (e.g., every
Inclusion criteria 3–6 months), DRE (e.g., every 6–12 months), confirmatory
biopsy (e.g., within 1–1.5 years), and follow-up biopsy
Of the studies enrolling only low-risk patients, those with the (e.g., at 1–3-year intervals). In recent years, several cohorts
most restrictive criteria mainly allowed only very-low-risk have included regular MRI (e.g., every 1–3 years). Some
patients with a maximum clinical T stage of T2A, a maximum protocols employed less intense monitoring (e.g., PSA every
PSA level of 10 ng/mL, a maximum of Grade Group 1, no 3 months and biopsy every 3–4 years) whereas others used
more than 2–3 cores positive, and no more than 50% cancer more intense surveillance (e.g., PSA and DRE every 6–
involvement in any core [Johns Hopkins (12), University 12 months, MRI and re-biopsy every 1–3 years).
of Copenhagen (21), and Milan (16)]. Others were less The wide variety of AS protocols and various reasons
restrictive, allowing patients with a maximum clinical T stage for switching to radical treatment has been documented
of T2B [Royal Marsden (24) and St. Vincent’s Australia (23)] previously (7,26-28). The main reason for conversion to
and increasing the maximum PSA level to 15 ng/mL and active treatment is reclassification; upgrading to Grade
Grade Group criteria to Grade Group 2 for patients older Group 2 or higher, >2 cores or >50% of any core involved
than 65 [Royal Marsden (24)]. are frequently utilized triggers. Some cohorts also initially

© Translational Andrology and Urology. All rights reserved. Transl Androl Urol 2021;10(6):2809-2819 | http://dx.doi.org/10.21037/tau-20-1370
2812 Shill et al. AS for prostate cancer

used PSA velocity or PSA doubling time cut-offs to trigger similarly low, with many reporting no deaths or a risk of
intervention although this has generally changed to using 0% at 7.5 years and longer [MSK (13,14), University of
PSA kinetics to prompt further clinical investigation. Miami (25), University of Copenhagen (21), St. Vincent’s
Patient choice or anxiety are reasons for up to 20% of Australia (23), Canary PASS (20), and Milan (16)]. Reported
patients (27,28). prostate cancer deaths ranged from 1 out of 5302 patients
in the PRIAS cohort (18) to 15 out of 993 patients in the
University of Toronto study (22). The estimated risk of
Patient outcomes
prostate cancer death, with 95% confidence intervals,
The outcomes of interest evaluated in this review were ranged from 0% at 10 years [MSK (14)] to 1.2% at
the risk of prostate cancer metastasis, the risk of prostate 10 years [ProtecT (17)] and from 0.1% at 15 years [Johns
cancer death, and the risk of switching to active treatment. Hopkins (12)] to 4.0% at 15 years [Goteborg (19)].
Variations in inclusion or exclusion criteria, methods of A previous meta-analysis conducted by Enikeev et al.
reporting risk estimates, length of follow-up, AS protocols, evaluated prostate cancer outcomes in 17 cohorts, comparing
and triggers for intervention created differences in AS in low-risk and intermediate-risk patients. The results
outcomes across the 13 cohorts. from their meta-analysis corroborated our findings in this
review of 13 cohorts, showing that outcomes of AS vary
Prostate cancer metastasis greatly by risk group and clinical characteristics, making
appropriate patient selection a priority (29). The outcomes
The risk of prostate cancer metastasis was low across all among very-low-risk and low-risk patients support that AS
studies, with many cohorts reporting no patients with distant is a safe strategy for those patients in both the intermediate-
metastases within 5–10 years [University of Miami (cohort and long-term (https://cdn.amegroups.cn/static/public/tau-
size N=230) (25), St. Vincent’s Australia (N=650) (23), 20-1370-1.pdf).
Canary PASS (N=905) (20), and Milan (N=818) (16)], while
some cohorts did not report any data on risk of metastatic
disease [Royal Marsden (N=471) (24) and University Conversion to active treatment
of Copenhagen (N=317) (21)]. Two additional cohorts The risk of converting to active treatment varied depending
also reported no estimates for risk of distant metastases, on the intervention thresholds that were used by the
although one of those cohorts reported 2 patients with individual institutions. About half of the patients remained
lymph node metastatic disease [MSK (N=219) (13)], while untreated for 5 to 10 years. The risk of switching to active
the other cohort had 4 patients with bone metastatic disease treatment over time ranged from 24% at 5 years [MSK (14)]
[UCSF (N=1,916) (15)]. Other cohorts similarly reported to 52% at 5 years [PRIAS (18)] and from 36% at 10 years (14)
the crude number of distant metastases in patients, ranging to 73% at 10 years (18). The cohorts that reported shorter
from 8 out of 5,302 patients in the PRIAS study (18) to follow-up times saw a probability of active treatment
33 out of 545 patients in the ProtecT study (17). It should between 11% at 2 years [Royal Marsden (24)] and 29% at
be noted, however, that the cohort of patients enrolled in 2 years [Milan (16)]. The longest-running cohort, located
the monitoring arm of the ProtecT trial does not mimic
at University of Toronto, saw a risk of 45% at 20 years for
the cohort of men carefully selected for contemporary AS
conversion to active treatment (22). This creates a range
programs, and as such, the estimate from the ProtecT trial
of treatment-free survival across the different AS cohorts,
is likely an overestimate. The remaining cohorts reported
with a majority of patients postponing any form of active
their data as risk estimates for distant metastases, ranging
treatment for at least 5 years after initial diagnosis.
from 0.1% (95% CI: 0.04–0.6%) at 10 years [Johns Hopkins
(N=1,818) (12)] to 1.0% (95% CI: 0–4%) at 10 years
[Goteborg (N=474) (19)] and from 0.1% (95% CI: 0.04– MRI, biomarkers, intermediate-risk studies,
0.6%) at 15 years (12) to 7.0% (3–16%) at 15 years (19). quality of life

Prostate MRI in active surveillance protocols

Prostate cancer mortality
MRI is used in some AS protocols. MRI is frequently
The risk of prostate cancer death in the AS cohorts was used at the start of AS, alongside physical exams and

© Translational Andrology and Urology. All rights reserved. Transl Androl Urol 2021;10(6):2809-2819 | http://dx.doi.org/10.21037/tau-20-1370
Translational Andrology and Urology, Vol 10, No 6 June 2021 2813

confirmatory biopsy, to confirm AS eligibility and to scan confirmatory biopsy resulted in 50% fewer AS failures and
for the presence of undetected high-grade and large tumors less grade progression over 2 years compared to the biopsy
in the prostate that might have previously been overlooked. alone (36). The ASIST study also provided evidence of
MRI is also used throughout AS protocols as a means of varying positive predictive value for detecting clinically
monitoring the risk of progression for patients undergoing significant prostate cancer between the participating study
AS. Current urology guidelines [including e.g., National sites, highlighting the importance of high-quality MRI,
Comprehensive Cancer Network (NCCN) (30) and experienced radiologists and high-quality targeted biopsy to
American Urological Association (AUA) (31)] emphasize maximize utility (37).
considerations of utilizing MRI at some point during AS to However, several studies have found that MRI alone is
improve the diagnostic specificity, particularly at the start not an effective substitute for systematic biopsies and raise
of AS. MRI can be an effective supplement to traditional concerns that the Giganti et al. study missed aggressive
confirmatory and surveillance biopsies, allowing for more cancers in men who were not biopsied on the basis of
targeted biopsies compared to systematic biopsies alone MRI findings. A study by Liss et al. in 2020 concluded that
(26,32,33). Recent studies have investigated the use of systematic biopsies should continue to be used for patients,
MRI as an eventual replacement for surveillance biopsies regardless of their MRI results (38). A systematic review
in specific patient populations. The increased use of MRI by Schoots et al. in 2018 found that MRI-targeted biopsies
has the potential to mitigate the unwanted consequences alone would miss 10% of cancer grade progressions,
of repeat biopsies, such as patient anxiety, discomfort, and while systematic biopsies alone would miss 7% of cancer
infectious complications. grade progressions on AS, emphasizing the need to use
Whether MRI can be used to replace AS follow-up both to maximize the detection of potentially aggressive
biopsy for some patients remains controversial. A study cancers (39). An AS cohort evaluated by Chesnut et al. in
by Stavrinides et al. in 2020 claimed that an MRI-led AS 2020 showed that replacing biopsies with MRI can result
cohort, where monitoring and interventions were guided in missing Grade Group 2 or higher disease in 169 of
using MRI results rather than systematic biopsies, had 1,000 patients, exposing too many patients at risk of
similar outcomes in rates of AS “discontinuation, mortality undetected disease progression (5). Taken together, the
and metastasis” compared to traditional AS cohorts (34). current evidence suggests that the greatest utility of MRI
However, the rates of metastasis were relatively high, 4 and targeted biopsies comes from its use in conjunction
cases out of 300 men with Grade Group 2 disease, despite with systematic biopsies in AS programs, rather than in its
relatively short follow-up (~5 years), and while confidence use as a direct replacement. In particular, a negative MRI
intervals for rates of metastasis were not presented, they are should not be used to forgo a scheduled surveillance biopsy
unlikely to exclude unacceptable risks of metastasis. at the current time.
A second paper apparently supporting the MRI approach
is that of Giganti et al., who studied a UK cohort of 553
Biomarkers for prostate cancer in active surveillance
patients on AS for low- and intermediate-risk prostate
cancer (up to Gleason Score 3+4) using the PRECISE The use of biomarkers has expanded in recent years as an
recommendations for MRI stratification. They observed additional method for refining risk stratification in select
that patients without radiological progression on MRI patient populations. In particular, identifying mutations
(PRECISE 1–3) during AS had a very low likelihood of in the BRCA2 gene can help prevent adverse outcomes.
progression on biopsy. However, patients were biopsied BRCA2 gene mutations have been associated with worse
based on MRI findings, and hence—as acknowledged by the outcomes on AS, prompting the need for closer monitoring
authors—there is a high risk of verification bias with this for these at-risk patients when enrolled in AS cohorts (40).
study design: if patients without positive MRI findings are Studies have evaluated the short-term effects of using
not biopsied, these patients will not have adverse findings, tissue-based molecular biomarkers [Oncotype DX Genomic
and it will appear, in the short term at least, as though Prostate Score (GPS), Prolaris Cell Cycle Progression
negative MRI means no progression (35). (CCP) score, GenomeDx Decipher score, and ProMark]
A secondary analysis of a recent randomized controlled alongside routine clinical indicators, although prospective
trial conducted by Klotz et al. in 2020—the AS MRI (ASIST) long-term outcomes of using biomarkers in AS populations
study—suggested that performing a baseline MRI before have not been evaluated (40). Data suggests that these

© Translational Andrology and Urology. All rights reserved. Transl Androl Urol 2021;10(6):2809-2819 | http://dx.doi.org/10.21037/tau-20-1370
2814 Shill et al. AS for prostate cancer

tissue-based assays can be utilized in prostate cancer favorable intermediate-risk disease could benefit from
patients with higher volume Grade Group 1 or favorable AS protocols, as long as their cancer remains stable (48).
intermediate risk Grade Group 2 to help guide clinical Parameters for careful selection have not been clearly defined
decision making and provide more data for determining across the current guidelines, making it difficult to accurately
a management protocol (40,41). However, at the present assess which patients would benefit the most from postponing
time, tissue-based biomarkers have not been recommended active treatment. In analyzing data from several randomized
for routine use and should not be used for patients who control trials comparing immediate treatment to conservative
have clear clinical indications for either an AS protocol or treatment [Scandinavian Prostate Cancer Group-4 (SPCG-4),
immediate active treatment (40). Prostate Cancer Intervention Versus Observation Trial
PSA kinetics offers little predictive value and is not (PIVOT), and Prostate Testing for Cancer and Treatment
being utilized as an independent trigger for intervention. (ProtecT)], Klotz suggested that candidates for AS among
However, PSA density has proven to be useful, with a intermediate-risk patients (GG2) should have a low percentage
higher PSA density associated with an increased risk for of Gleason pattern 4 and a low PSA density, and would be
biopsy reclassification, allowing it to be used as a threshold required to be carefully monitored to evaluate for signs of
for inclusion in AS cohorts (41). Urinary markers (PCA3, progression (48,49). Klotz also recommends strict guidelines
TMPRSS2:ERG, ExoDx, SelectMDx) have also been that include the use of MRI in men with GG2, with ≤5–10%
evaluated, although the data is largely inconclusive across Gleason pattern 4 and either a negative MRI or a positive MRI
different studies and needs further validation (41-43). In followed by a favorable targeted biopsy before undergoing
the prospective multi-institutional Canary PASS study, an AS protocol (48). The use of genetic risk factors [e.g.,
PCA3 was associated with cancer reclassification in the first BRCA 1/2 gene mutations, HOXB13 gene mutation, DNA-
surveillance biopsy, but had minimal improvement over gene repair mutations (ATM, CHEK2, MSH2), and single-
clinical variables (44). Both the Prostate Health Index (PHI) nucleotide polymorphisms] can also be used to identify
and 4Kscore blood biomarkers have been shown to be appropriate AS candidates among intermediate-risk patients,
associated with improved prediction of clinically significant as a significant proportion of AS failures might be caused by
prostate cancer (42). In the PASS study, addition of the 4K undetected genetic predispositions towards more aggressive
panel (free-, total-, intact- PSA and hk2) to a clinical model cancers (48).
including variables such as prostate volume and number of A meta-analysis showed that AS was a viable first
prior biopsies improved predictions of high-grade prostate management option for carefully selected and monitored
cancer in the first biopsy after diagnosis above and beyond men with intermediate-risk prostate cancer. AS for select
clinical information, however the 4K panel did not add intermediate-risk prostate cancer patients showed beneficial
value at subsequent surveillance biopsies (45). In the Johns results in the short-term, with similar rates of treatment
Hopkins AS cohort, baseline and serial measurements of as well as adverse oncologic outcome at 5 years across
PHI was associated with biopsy reclassification during AS, both low-risk and intermediate-risk groups following
although the authors did not test whether the marker added AS protocols (29). On longer term follow-up at 10 or 15
to a predictive model including clinical variables (46). years, there are higher although still relatively low rates
Detailed pathology may also be informative to help of metastasis in intermediate risk patients (29). The use of
determine risk. There is growing evidence that presence of MRI as part of a comprehensive risk assessment at baseline
invasive cribriform and/or intraductal carcinoma portend of AS can also be helpful in facilitating the selection of
a poorer prognosis, and have therefore been proposed appropriate intermediate risk patients for AS. Even though
as exclusion criteria for AS (47). However, this remains the studies in the meta-analysis, the Klotz review, and our
unproven. review all had varying inclusion criteria and often used
different AS protocols, these combined results suggest that
AS is a safe option for postponing treatment and could be
Intermediate-risk studies
used in specific groups of low-intermediate-risk prostate
In the past, there has been a reluctance to enroll intermediate- cancer patients, particularly in the first few years post
risk patients into AS cohorts as the presence of pattern 4 diagnosis.
disease has been an indication for active treatment. However, Given the higher rates of adverse outcomes in intermediate-
recent studies have shown that carefully-selected men with risk patients after 10 or more years on AS, it could be

© Translational Andrology and Urology. All rights reserved. Transl Androl Urol 2021;10(6):2809-2819 | http://dx.doi.org/10.21037/tau-20-1370
Translational Andrology and Urology, Vol 10, No 6 June 2021 2815

preferable to employ more stringent monitoring, particularly this collaboration between patients and physicians can help
in later years, and potentially consider switching intermediate- to reduce adverse effects on quality of life (4,57).
risk patients to active treatment at higher rates than their
low-risk counterparts. Using data from genetic markers can
Future directions
also guide these decisions and decrease the risk of missing
the opportunity to administer effective treatment (48). The Movember Foundation’s Global Action Plan Prostate
Intermediate-risk prostate cancer patients can benefit from a Cancer Active Surveillance (GAP3) cohort (58) will the
wide range of potential interventions, including radiotherapy discoveries of the last 5 years change the future?” by MJR
and radical prostatectomy, but AS should also be offered as in this series of TAU—will continue to expand its database
an option for patients according to their clinical presentation, with additional centers, increasing follow-up, and also with
including consideration of total length of Gleason pattern 4 additional parameters (e.g., imaging modalities, biomarkers,
and personal preferences (50). genomics, and follow-up after AS including biochemical
recurrence after treatment, risk of metastasis and survival).
Currently, the GAP3 cohort includes over 21,000 men from
Quality of life under active surveillance
28 cohorts, of which over 1,000 patients have at least 10
Some physicians have hesitated to recommend AS to their years follow-up. On the basis of this comprehensive dataset,
patients out of a fear of invoking anxiety, elevating stress, and critical research questions in AS will be addressed focusing
causing other adverse mental health outcomes (51,52). Self- on reducing the burden of being on AS while maintaining
evaluations from prostate cancer patients undergoing AS safety.
show that AS patients assess their quality of life positively and Ongoing efforts are focused on tailoring AS to
show high ratings across all health state utilities (51). In the individual patient needs and disease characteristics, thus
randomized ProtecT trial, comparing radical prostatectomy, aiming to design dynamic risk-based AS strategies that
radiotherapy and active monitoring, there were no significant ensures safety, improves the experience of AS and lessens
between group differences in anxiety at any time or in the patient burden of intensive monitoring. Research
cancer-related quality of life at 5 years of follow-up (53). investigating whether MRI and/or biomarkers can replace
Indeed, a systematic review of 34 studies (12,497 patients) surveillance biopsy is ongoing (33,59). Risk calculators
suggested that rates of anxiety and depression in AS groups such as the Canary Prostate Active Surveillance Study Risk
are either lower or equivalent to rates in population control Calculators (PASS-RCs) are also being studied to help
groups, showing that remaining on AS does not negatively predict reclassification on biopsy (60). A recent modeling
impact mental health (54). A study looking more specifically study accounting for variation in AS protocols between four
at prostate cancer-related anxiety included 413 men on AS. It large AS cohorts suggested that biennial biopsies could be
was common for men to report mild prostate cancer-specific an alternative to annual biopsies (61). An ongoing large-
anxiety after the initiation of AS (29% during the first year), scale randomized trial, Prostate Cancer Active Surveillance
however anxiety decreased significantly with time as most Trigger trial (PCASTt/SPCG-17), will shed further light on
patients adjusted, and the majority reported low anxiety levels how to optimize current AS protcols by comparing current
within 2 years (55). In comparison, low psychological well- clinical care to an AS protocol with standardized triggers
being at 12- and 24-months follow-up in patients undergoing based on MRI and PSA density to elicit repeat biopsies and
radical prostatectomy has been reported, emphasizing the MRI and histopathological progression to trigger radical
need for broader availability of psychological resources for treatment (62).
patients undergoing active treatment (52).
Additionally, due to the regimented follow-up procedures
Conclusions
part of AS protocols, patients in AS programs feel increased
control over their cancer rather than uncertainty, helping Current data are clear that AS should be the standard of
to minimize cancer-related fears and anxieties (56). This care in patients with pattern 3 disease (Grade Group 1) and
increased control also comes from the decision-making can be considered in carefully selected men with low volume
process, which allows patients to have autonomy over their favorable intermediate risk disease. Future studies should
management protocol and improves patient well-being (57). focus on further refining the eligibility for AS and triggers
AS protocols that consider patient preferences and allow for active treatment. Many of the guidelines in place

© Translational Andrology and Urology. All rights reserved. Transl Androl Urol 2021;10(6):2809-2819 | http://dx.doi.org/10.21037/tau-20-1370
2816 Shill et al. AS for prostate cancer

currently use varying inclusion criteria, and it is likely that fees from Koelis, outside the submitted work. Dr. Vickers
many men who could benefit from AS are excluded. Using reports personal fees from Arctic Partners, personal fees
MRI and biomarkers to guide the selection of intermediate- from Opko, personal fees from Steba, personal fees from
risk patients suitable for AS can allow many men to benefit InsightTec, during the conduct of the study; In addition,
from avoidance or delay of curative therapy without Dr. Vickers has a patent Arctic Partners issued. The authors
risking progression of their disease to an aggressive form. have no other conflicts of interest to declare.
Finally, studies focusing on improving our understanding
of factors that influence the acceptance, adherence to and Ethical Statement: The authors are accountable for all
discontinuation of AS across various populations worldwide aspects of the work in ensuring that questions related
should be encouraged. to the accuracy or integrity of any part of the work are
appropriately investigated and resolved.

Acknowledgments
Open Access Statement: This is an Open Access article
We sincerely thank Research Informationist Lindsay Boyce, distributed in accordance with the Creative Commons
MLIS for assistance with the literature search and Dr. Laura Attribution-NonCommercial-NoDerivs 4.0 International
Liberman, Office of Faculty Development, Memorial Sloan License (CC BY-NC-ND 4.0), which permits the non-
Kettering Cancer Center, New York, USA, for the 2020 commercial replication and distribution of the article with
Summer Clinical Oncology Research Experience (SCORE) the strict proviso that no changes or edits are made and the
Program that enabled DKS's work on this study. original work is properly cited (including links to both the
Funding: SVC's, AJV's and BE's work on this paper was formal publication through the relevant DOI and the license).
supported in part by funding from the National Institutes of See: https://creativecommons.org/licenses/by-nc-nd/4.0/.
Health/National Cancer Institute (P30-CA008748) and the
Sidney Kimmel Center for Prostate and Urologic Cancers.
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Cite this article as: Shill DK, Roobol MJ, Ehdaie B, Vickers
AJ, Carlsson SV. Active surveillance for prostate cancer. Transl
Androl Urol 2021;10(6):2809-2819. doi: 10.21037/tau-20-1370

© Translational Andrology and Urology. All rights reserved. Transl Androl Urol 2021;10(6):2809-2819 | http://dx.doi.org/10.21037/tau-20-1370