Intl J Gynecology Obste - 2021 - Bhatla - Cancer of The Cervix Uteri 2021 Update
Intl J Gynecology Obste - 2021 - Bhatla - Cancer of The Cervix Uteri 2021 Update
Intl J Gynecology Obste - 2021 - Bhatla - Cancer of The Cervix Uteri 2021 Update
See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
DOI: 10.1002/ijgo.13865
1
Department of Obstetrics and
Gynecology, All India Institute of Medical Abstract
Sciences, New Delhi, India
Since the publication of the 2018 FIGO Cancer Report, giant strides have been made
2
Department of Obstetrics and
Gynecology, Keio University School of
in the global effort to reduce the burden of cervical cancer, with the World Health
Medicine, Tokyo, Japan Organization (WHO) rolling out a global strategy for cervical cancer elimination, aim-
3
Department of Radiation Oncology, All ing for implementation by 2030. In over 130 countries, including low-and middle-
India Institute of Medical Sciences, New
Delhi, India income countries, HPV vaccination is now included in the national program. Screening
4
International Agency for Research on has seen major advances with wider implementation of HPV testing. These interven-
Cancer, Lyon, France
tions will take a few years to show their impact. Meanwhile, over half a million new
Correspondence cases are added each year. FIGO’s revised staging of cervical cancer (2018) has been
Neerja Bhatla, Department of Obstetrics
widely implemented and retrospective analyses of data based on the new staging have
and Gynecology, All India Institute of
Medical Sciences, New Delhi, India. been published. Minimally invasive surgery has been shown to be disadvantageous in
Email: [email protected]
women with cervical cancer. This chapter discusses the management of cervical cancer
based on the stage of disease, including attention to palliation and quality of life issues.
KEYWORDS
cancer, cervix, FIGO Cancer Report, HPV vaccination, radiation, screening, staging, surgery
1 | I NTRO D U C TI O N canal, which extends from the internal os to the external os, is lined by
columnar epithelium. Almost all cases of cervical carcinoma originate
Globally, cervical cancer continues to be one of the most common can- from the ecto-or endocervical mucosa in the transformation zone, the
cers among females, being the fourth most common after breast, colorec- area of the cervix between the old and new squamocolumnar junction.
tal, and lung cancer. GLOBOCAN 2020 estimated that, worldwide, there The ability to easily visualize and sample the cervix contributed
were approximately 604 000 new cases of cervical cancer, with 342 000 to very early understanding of the natural history of cervical can-
deaths annually.1 The majority of new cases and deaths (approximately cer. The fact that it needs little or no anesthesia for treatment by
85% and 90%, respectively) occur in low-and middle-income countries freezing or burning led to the development of simple outpatient
(LMICs), where it is the third most common cancer among women. techniques of screening and prevention.
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© 2021 The Authors. International Journal of Gynecology & Obstetrics published by John Wiley & Sons Ltd on behalf of International Federation of Gynecology
and Obstetrics
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wileyonlinelibrary.com/journal/ijgo Int J Gynecol Obstet. 2021;155(Suppl. 1):28–44.
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BHATLA et al. 29
(hrHPV) types, which is termed the “necessary” cause of cervical HPV vaccination was launched in 2006. Three prophylactic HPV
cancer. Persistent HPV infection denotes the presence of the same vaccines are currently available for use in females and males from the
type-specific HPV DNA on repeated sampling after 6–12 months. age of 9 years for the prevention of premalignant lesions and cancers
More than 80% of women followed over time will acquire at least affecting the cervix, vulva, vagina, and anus caused by hrHPV types: a
one hrHPV infection, which shows its ubiquitous nature and ease bivalent vaccine targeting HPV 16 and HPV 18; a quadrivalent vaccine
of transmission. However, only one-tenth of all infections become targeting HPV 6 and HPV 11 in addition to HPV 16 and HPV 18; and a
persistent, and these women could develop cervical precancerous le- nonavalent vaccine targeting HPV types 31, 33, 45, 52, and 58 in addi-
sions. Of the estimated 604 000 new cervical cancer cases annually tion to HPV 6, 11, 16, and 18. In addition, the last two vaccines target
worldwide, HPV 16 and HPV 18 account for 71% of cases; while HPV anogenital warts caused by HPV 6 and 11. Recently, a bivalent HPV
types 31, 33, 45, 52, and 58 account for another 19% of cervical can- vaccine (Cecolin; Xiamen Innovax Biotech Co., Ltd) has been licensed
cer cases.2,3 It is well documented that nearly 90% of incident HPV in China and is currently undergoing the WHO prequalification pro-
infections are cleared within a period of 2 years from the acquisition cess. All the vaccines are recombinant vaccines composed of virus-like
of infection and persist only in about 10% of women.4 It is debatable particles and are not infectious since they do not contain viral DNA.
whether the virus is completely cleared or whether it remains latent For girls and boys aged 9–14 years, a two-dose schedule (0.5 mL at 0
in basal cells with the potential for reactivation in some cases. and 6–12 months, i.e. the second dose should be given 6–12 months
Knowledge of HPV epidemiology and its role in causation of after the first dose) is recommended. Those aged 15 years and older,
cancer has resulted in the development of two major strategies for and immunocompromised patients irrespective of age, must receive
prevention and early detection, namely: (1) HPV vaccination; and (2) three doses (0.5 mL at 0, 1–2, and 6 months, as per the manufacturer's
screening for precancerous lesions. Although elimination of cervi- recommendation).7 WHO has reviewed the latest data and concluded
cal cancer is a real possibility, the tragedy is that even today many that there is no safety concern regarding HPV vaccines.8
LMICs lack effective intervention programs. The World Health At the population level, there is evidence for the effectiveness of
Organization (WHO) has called for a global initiative for elimination HPV vaccination in terms of reduced prevalence of hrHPV types, ano-
of cervical cancer as a public health problem by implementing the genital warts, and high-grade cervical abnormalities (CIN2+) caused by
following 90%–70%–90% triple pillar intervention strategy before the vaccine types among young women; with some evidence of cross-
the year 20305: protection against nonvaccine types also.9 A recent systematic review
and meta-analysis involving 60 million individuals with follow up to
• 90% of girls fully vaccinated with two doses of HPV vaccine by 8 years after vaccination indicated that 5–8 years after vaccination,
the age of 15 years; the following outcomes significantly declined: (1) prevalence of HPV
• 70% of women screened using a high-performance screening test 16 and 18 by 83% (RR 0.17; 95% CI, 0.11–0.25) in 13–19-year-old girls,
at the age of 35 and 45 years; and and by 66% (RR 0.34; 95% CI, 0.23–0.49) in women aged 20–24 years;
• 90% of women detected with cervical lesions to receive treat- (2) prevalence of HPV 31, 33, and 45 by 54% (RR 0.46; 95% CI, 0.33–
ment and care. 0.66) in girls aged 13–19 years; (3) anogenital warts by 67% (RR 0.33;
95% CI, 0.24–0.46) in girls aged 15–19 years, by 54% (RR 0.46; 95%
WHO has set an incidence threshold of four cases per 100 000 CI, 0.36–0.60) in women aged 20–24 years, and by 31% (RR 0.69; 95%
women for pragmatic elimination. While high-income countries are CI, 0.53–0.89) in women aged 25–29 years. CIN2+ decreased signifi-
already well advanced in implementing the above policy, the experi- cantly by 51% (RR 0.49; 95% CI, 0.42–0.58) among screened girls aged
ence in LMICs is highly variable. 15–19 years and by 31% (RR 0.69; 95% CI, 0.57–0.84) among women
aged 20–24 years.9 Programs with multicohort vaccination and high
vaccination coverage had a greater direct impact and herd effects. The
3.1 | Primary prevention of cervical cancer with impact of HPV vaccination on significantly reducing the risk of invasive
HPV vaccination cervical cancer has also been shown recently in a Swedish follow-up
evaluation of 1 672 983 girls and women who were 10–30 years of age
The estimated cross-sectional HPV prevalence worldwide among from 2006 through 2017.10 Cervical cancer was diagnosed in only 19
healthy women aged over 30 years is around 11.7%, with the high- vaccinated women and in 538 unvaccinated women.
est in Sub-
Saharan Africa at around 24%, and country-
specific Recent studies have reported evidence for effectiveness of a
6
prevalence ranging between 2% and 42% globally. Age-specific single dose in preventing high-risk HPV infections similar to three or
cross-sectional HPV prevalence peaks at 25% in women younger two doses. Results from ongoing purpose-designed, prospectively
than 25 years, which suggests that the infection is predominantly randomized clinical trials assessing the efficacy and immunogenicity
transmitted through the sexual route following sexual debut. Thus, of single-dose HPV vaccination compared to currently used sched-
prophylactic HPV vaccination as a preventive strategy should tar- ules are awaited, which will further clarify the role of one dose in
get women before initiation of sexual activity, focusing on girls aged preventing cervical neoplasia.11–13 There is no evidence of type re-
10–14 years. placement following vaccination.14,15
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30 BHATLA et al.
It is estimated that, without vaccination, the global burden of acetic acid. In view of its feasibility, it has been widely implemented in
cervical cancer among young girls born between 2005–2014 birth opportunistic settings in many low-income countries in Sub-Saharan
cohorts will be 11.6 million cases by 2094. Four-fifths of this bur- Africa. A single-visit approach (SVA) for screening with rapid diagno-
den will be in 25 countries in Africa (5.6 million cases) and Asia (4.5 sis and treatment improves coverage, eliminates follow-up visits, and
million cases), with 51.3% of the overall expected burden of 5.9 mil- improves cost-efficiency in low-resource settings. 22–24 VIA screen-
lion cervical cancer cases over a lifetime affecting birth cohorts in ing is particularly suitable for SVA and WHO has issued guidelines
India, Nigeria, China, Tanzania, Indonesia, Uganda, the Democratic for implementing SVA in public health settings. 25
Republic of the Congo, Ethiopia, and Kenya. Another 2.8 million Introducing a cervical cancer screening program in a country
cases, corresponding to 24.2% of the total burden, would be in should be preceded by policy and managerial guidelines that clearly
17 countries, mostly in Sub-Saharan Africa (South Africa, Malawi, indicate the target age group, screening test and screening intervals,
Zambia, Mozambique, Angola, Zimbabwe, Madagascar, Mali, Ghana, methods to reach target women, management of screen-positive
and Burkina Faso); Asia (Pakistan, Bangladesh, and the Philippines); women (triaging and treating or SVA), treatment methods (cryother-
the Americas (Brazil, Mexico, and the USA); and Russia. The re- apy, thermal ablation, loop electrosurgical excisions procedure [LEEP])
maining 24.5% (2.8 million cases) in unvaccinated birth cohorts is for CIN lesions, and criteria for type of treatment for prevalent cer-
expected to occur in the remaining 159 countries. It has been es- vical cancers detected by screening. 25,26 Availability of adequate in-
timated that worldwide HPV vaccination with high coverage could frastructure and trained human resources is critical for initiating and
prevent about 8.7 million cases by 2094.16 sustaining the various inputs of the program. A program information
system supported by a database and linkage with other information
systems such as cancer registration, mortality registers, and health
3.2 | Secondary prevention of cervical cancer by insurance databases is important for monitoring and evaluation. The
early detection and treatment of precancerous lesions screening strategy chosen must be feasible, simple, safe, accurate,
acceptable, and easily accessible to the highest-risk women. In stud-
Screening is an important strategy in the global elimination of cervi- ies from Bangladesh and India it has been observed that following
cal cancer. While HPV vaccination aims to prevent cervical neopla- the right approach to organize several components and meticulous
sia by preventing HPV infection, screening aims to detect prevalent attention to quality is crucial for the success of a screening program
cervical precancerous lesions such as high-grade CIN and adenocar- and not merely the choice of a good screening test. 27 A judicious
cinoma in-situ early, and effectively treat them to prevent invasive combination of HPV vaccination and screening has enormous poten-
cancer and decrease cervical cancer mortality rates. It will therefore tial to eliminate cervical cancer in the foreseeable future.
remain a priority for cervical cancer prevention for several decades.
Several cervical screening strategies have been used effectively
in varied settings: conventional cytology (Pap smear); in recent years, 4 | S TAG I N G O F C E RV I C A L C A N C E R
liquid-based cytology (LBC) and HPV testing; and, in LMICs, visual in-
spection with acetic acid (VIA).17 While screening with Pap smear at Invasive cervical cancer spreads by direct extension into the parame-
regular intervals has resulted in substantial decline in cervical cancer trium, vagina, uterus, and adjacent organs, i.e. bladder and rectum.
risk in high-income countries, it is resource-intensive, needs repeated It also spreads along the lymphatic channels to the regional lymph
rounds to compensate for poor sensitivity, and is not feasible in low- nodes, namely, obturator, external iliac, internal iliac, and thence to
resource settings where poor organization, coverage, and lack of qual- the common iliac and para-aortic nodes. Distant metastasis to lungs,
17
ity assurance result in suboptimal outcomes. HPV-based screening liver, and skeleton by the hematogenous route is a late phenomenon.
has higher sensitivity and accuracy, lower variability and better re- The cervix was the first organ to be assigned a clinical staging
producibility compared with conventional or LBC. In the context of system for cancer by FIGO in 1958. Subsequently the pathologic
declining HPV infections in vaccinated populations, many healthcare (TNM) staging followed, which has been used for the purpose of
systems are switching to primary HPV screening, whose higher nega- documenting nodal and metastatic disease status. In 2018, the FIGO
tive predictive value allows extended screening intervals or even a sin- Gynecologic Oncology Committee revised the staging to allow the
gle lifetime screening in low-resource settings.18,19 Recent European option of clinical, radiological, or pathological findings, as available,
guidelines strongly recommend primary HPV-based screening over to assign the stage. A corrigendum to this staging was published
20
standard cytology-
based screening. Currently The Netherlands, thereafter, with some modifications. The revised staging is shown in
Turkey, Finland, Italy, Sweden, and the UK are implementing HPV Table 1. 28 The main changes are:
21
screening nationally or regionally. Countries such as Australia,
Argentina, Chile, and Mexico are implementing HPV-based screening • The horizontal dimension of a microinvasive lesion is no longer
programs. This has increased the colposcopy referral rates, but also re- considered.
sulted in higher detection rates of CIN3+ lesions and cervical cancers. • Tumor size has been stratified further into three subgroups: IB1
VIA screening involves detection of acetowhite lesions on the ≤2 cm, IB2 >2–≤4 cm, and IB3 >4 cm.
cervix 1 minute after the application of 3%–5% freshly prepared • Lymph node positivity, which correlates with poorer oncologic
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BHATLA et al. 31
The revised FIGO staging is closely aligned with the latest TNM 5.1 | Squamous epithelial tumors
29
staging. The stage is allocated after all imaging and pathology
reports are available. It is not to be altered later, for example at • Squamous cell carcinoma, HPV-associated
recurrence. • Squamous cell carcinoma, HPV-independent
• Squamous cell carcinoma NOS
5 | H I S TO PATH O LO G Y
5.2 | Glandular tumors
It is essential that all cancers must be confirmed by microscopic
examination. Cases are classified as carcinomas of the cervix if the • Adenocarcinoma NOS
primary growth is in the cervix. All histologic types must be included. • Adenocarcinoma, HPV-associated
Stage Description
I The carcinoma is strictly confined to the cervix (extension to the uterine corpus should be disregarded)
IA Invasive carcinoma that can be diagnosed only by microscopy, with maximum depth of invasion ≤5 mma
IA1 Measured stromal invasion ≤3 mm in depth
IA2 Measured stromal invasion >3 and ≤5 mm in depth
IB Invasive carcinoma with measured deepest invasion >5 mm (greater than Stage IA); lesion limited to the cervix uteri with size
measured by maximum tumor diameterb
IB1 Invasive carcinoma >5 mm depth of stromal invasion and ≤2 cm in greatest dimension
IB2 Invasive carcinoma >2 and ≤4 cm in greatest dimension
IB3 Invasive carcinoma >4 cm in greatest dimension
II The carcinoma invades beyond the uterus, but has not extended onto the lower third of the vagina or to the pelvic wall
IIA Involvement limited to the upper two-thirds of the vagina without parametrial involvement
IIA1 Invasive carcinoma ≤4 cm in greatest dimension
IIA2 Invasive carcinoma >4 cm in greatest dimension
IIB With parametrial involvement but not up to the pelvic wall
III The carcinoma involves the lower third of the vagina and/or extends to the pelvic wall and/or causes hydronephrosis or
nonfunctioning kidney and/or involves pelvic and/or para-aortic lymph nodes
IIIA The carcinoma involves the lower third of the vagina, with no extension to the pelvic wall
IIIB Extension to the pelvic wall and/or hydronephrosis or nonfunctioning kidney (unless known to be due to another cause)
IIIC Involvement of pelvic and/or para-aortic lymph nodes (including micrometastases)c , irrespective of tumor size and extent
(with r and p notations)d
IIIC1 Pelvic lymph node metastasis only
IIIC2 Para-aortic lymph node metastasis
IV The carcinoma has extended beyond the true pelvis or has involved (biopsy proven) the mucosa of the bladder or rectum. A
bullous edema, as such, does not permit a case to be allotted to Stage IV
IVA Spread of the growth to adjacent pelvic organs
IVB Spread to distant organs
a
Imaging and pathology can be used, where available, to supplement clinical findings with respect to tumor size and extent, in all stages. Pathological
findings supersede imaging and clinical findings.
b
The involvement of vascular/lymphatic spaces should not change the staging. The lateral extent of the lesion is no longer considered.
c
Isolated tumor cells do not change the stage but their presence should be recorded.
d
Adding notation of r (imaging) and p (pathology) to indicate the findings that are used to allocate the case to Stage IIIC. For example, if imaging
indicates pelvic lymph node metastasis, the stage allocation would be Stage IIIC1r; if confirmed by pathological findings, it would be Stage IIIC1p. The
type of imaging modality or pathology technique used should always be documented. When in doubt, the lower staging should be assigned.
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32 BHATLA et al.
• Adenocarcinoma, HPV-independent, gastric type However, ultrasound has also been shown to have good diagnostic
• Adenocarcinoma, HPV-independent, clear cell type accuracy in expert hands.33 The modality used in assigning staging
• Adenocarcinoma, HPV-independent, mesonephric type should be noted for future evaluation. Imaging can identify addi-
• Adenocarcinoma, HPV-independent, NOS tional prognostic factors that can guide the choice of the most ap-
• Endometrioid adenocarcinoma NOS propriate treatment modality.
• Carcinosarcoma NOS For detection of nodal metastasis greater than 10 mm, PET-C T is
• Adenosquamous carcinoma more accurate than CT and MRI, with false-negative results in 4%–
• Mucoepidermoid carcinoma 15% of cases.34–36 In areas with a high prevalence of tuberculosis and
• Adenoid basal carcinoma inflammation, especially HIV-endemic areas, large lymph nodes are
• Carcinoma, undifferentiated, NOS not necessarily metastatic. The clinician may make the decision on
imaging or, when possible, can use fine needle aspiration or biopsy
to exclude metastases. This is especially true in advanced stages,
5.3 | Mixed epithelial and mesenchymal tumors where surgical assessment of para-aortic lymph nodes by minimally
invasive surgery or laparotomy may be used to tailor treatment ac-
• Adenosarcoma cording to extent of disease.37–39 Surgical exclusion of para-aortic
lymph node involvement has been reported to correlate with prog-
nosis better than radiographic exclusion alone.40
5.4 | Germ cell tumors A review of 22 articles that assessed the safety and impact of pre-
treatment para-aortic lymph node surgical staging (PALNS) found that
• Endodermal sinus tumor 18% (range, 8%–42%) of patients with Stage IB–IVA cervical cancer
• Yolk sac tumor NOS had para-aortic lymph node metastases.41 The mean complication
• Choriocarcinoma NOS rate of PALNS was 9% (range 4%–24%), with lymphocyst formation
being the most common. In another study, up to 35% of clinically as-
sessed Stage IIB and 20% of Stage III tumors were reported to have
6 | D I AG N OS I S A N D E VA LUATI O N O F positive para-aortic nodes.42 In the revised staging, all these cases will
C E RV I C A L C A N C E R be assigned to Stage IIIC as lymph node involvement confers a worse
prognosis.43 If only pelvic nodes are positive, it is Stage IIIC1; if para-
6.1 | Microinvasive disease aortic nodes are also involved it is Stage IIIC2. A further notation must
be added to indicate whether this allocation is based on only imaging
Diagnosis of Stages IA1 and IA2 is made on microscopic examination assessment (r) or whether pathological confirmation is available (p). In
of a cone biopsy specimen, obtained by LEEP or cold knife conization, due course, these data can be analyzed and reported accordingly.
which includes the entire lesion. It can also be made on a trachelec- FIGO no longer mandates any biochemical investigations or investi-
tomy or hysterectomy specimen. The depth of invasion should not be gative procedures; however, in patients with frank invasive carcinoma,
greater than 3 or 5 mm, respectively, from the base of the epithelium. a chest X-ray and assessment of hydronephrosis (with renal ultrasound,
The horizontal dimension is no longer considered in the 2018 revision CT, or MRI) should be done. The bladder and rectum are evaluated by
as it has not been shown to impact survival. Note must be made of cystoscopy and sigmoidoscopy only if the patient is clinically symp-
lymphovascular space involvement, which does not alter the stage, tomatic. Cystoscopy is also recommended in cases of a barrel-shaped
but may affect the treatment plan. The margins should be reported to endocervical growth and in cases where the growth has extended
be negative for disease. If the margins of the cone biopsy are positive to the anterior vaginal wall. Suspected bladder or rectal involvement
for invasive cancer, the patient is allocated to Stage IB1.31 should be confirmed by biopsy and histologic evidence. Bullous edema
alone does not warrant a case to be allocated to Stage IV.
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BHATLA et al. 33
to the stage of disease. Table 2 shows the types of radical hyster- With normal follow-up at 5 years, the patient can return to the
ectomy. In Stage IVA, selected cases may be suitable for pelvic routine screening schedule according to the national guidelines.53
exenteration. Other tests, including imaging are not recommended routinely and
may be performed if required on a case-by-case basis.
18793479, 2021, S1, Downloaded from https://obgyn.onlinelibrary.wiley.com/doi/10.1002/ijgo.13865 by Cochrane Mexico, Wiley Online Library on [08/11/2022]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
34 BHATLA et al.
sexual function, and consequent deterioration of the postoperative Melamed et al.62 conducted a nationwide observational study in the
quality of life.58,59 USA and demonstrated a 4-year mortality of 9.1% among cervical
In young women desiring fertility sparing, a radical trachelectomy cancer patients treated with MIS and 5.3% among those who un-
may be performed, indicated for Stage IA2–IB1 tumors.60 The cervix derwent open surgery (HR 1.65; 95% CI, 1.22–2.22). Uppal et al.63
along with the parametrium is removed followed by anastomosis of reported recurrence-free survival outcomes for a cohort of 700
the uterus with the vaginal end. Trachelectomy can be done by open patients with open or MIS radical hysterectomy. After propensity
abdominal, vaginal, or by minimally invasive routes. When a vaginal matching, they found that the recurrence risk at 5 years was 6.1%
approach is planned, the pelvic nodes are first removed laparoscop- with open surgery and 14.4% with MIS (HR 2.93; 95% CI, 1.22–7.0).
ically and sent for frozen section to confirm node negativity; then A European cohort study (SUCCOR study) reviewed 1272 patients
proceed with the radical trachelectomy vaginally. Alternatively, the with FIGO Stage IB1 patients and found that the risk of recurrence
nodes may first be assessed by conventional pathological methods for MIS-treated patients was twice as high as that with open surgery
and the radical trachelectomy done as a second surgery after 1 week. (HR 2.07; 95% CI, 1.35–3.15).64 Paik et al.65 reviewed 738 women
who underwent radical hysterectomy for FIGO Stages IB–IIA cer-
FIGO Stage IB2 and IIA1 vical cancer. They also demonstrated that MIS had inferior disease-
In FIGO Stages IB2 and IIA1 cervical cancer, surgery or radiotherapy free survival compared with those who had open surgery (HR 2.74;
can be chosen as the primary treatment depending on other patient 95% CI, 1.3–5.7). This evidence suggests that MIS for cervical cancer
factors and local resources, as both have similar outcomes. The ad- could result in an excess risk of recurrence or death compared with
vantages of surgical treatment are: (1) that it is feasible to determine an open approach.
the postoperative stage precisely on the basis of histopathologic find- In the study by Uppal et al.,63 among tumors less than 2 cm diam-
ings, thereby enabling individualization of postoperative treatment; eter, 4.4% recurrences were noted in the open group versus 11.5%
(2) that it is possible to treat cancers that are likely to be resistant to in the MIS group (HR 2.83; 95% CI, 1.1–7.18, P = 0.019) and prior
radiotherapy; and (3) that it is possible to conserve ovarian function. conization was associated with a lower risk of recurrence (4.9% vs
Intraoperative transpositioning of the ovaries high in the paracolic 16.2%, P = 0.001). However, the SUCCOR study revealed no differ-
gutters away from the radiation field, in case it should be required ence in oncologic outcome between the open and MIS approach in
subsequently, is also feasible. The preservation of ovarian and sexual tumors less than 2 cm. Patients who underwent MIS using a uterine
function makes surgery the preferred mode in younger women. Type manipulator had 2.76 times higher risk of relapse (HR 2.76; 95% CI,
C radical hysterectomy is the standard procedure for the treatment 1.75–4.33; P < 0.001) whereas MIS with protective vaginal closure
of cervical cancer, consisting of removal of the uterus, parametrium, had similar rates of relapse as open surgery (HR 0.63; 95% CI, 0.15–
upper vagina, and a part of the paracolpium, along with pelvic lym- 2.59; P < 0.52).64 Currently two prospective randomized trials are
phadenectomy. As for the adjacent connective tissues, the anterior evaluating the role of MIS in cervical cancer. The first is the Robot
vesicouterine ligament (anterior and posterior leaf), lateral cardinal lig- assisted Approach to Cervical Cancer (RACC), a Swedish multicenter
aments, and posterior sacrouterine and rectovaginal ligaments are cut prospective trial in which the use of a uterine manipulator is not al-
from the uterus at sufficient distances from their attachments to the lowed, and closure of the vagina before colpotomy is recommended
uterus. Pelvic lymphadenectomy is an important component of this but not mandatory.66 The second is the multicenter randomized con-
surgical procedure. The regional lymph node excision includes the par- trolled trial designed in China in which the use of a uterine manipula-
ametrial nodes, obturator nodes, external, internal, and common iliac tor and the method of vaginal excision is to be reported.67
nodes. The route of surgery used was laparotomy or MIS, either lapa- The role of SLN mapping in cervical cancer is still experimental
roscopic or robotic. However, the LACC trial (Laparoscopic Approach and needs more evidence to include it into routine practice. It may
to Cervical cancer), a randomized trial that compared overall survival have some role in early-stage cervical cancer, i.e. FIGO Stages IA,
with open surgery versus laparoscopy or robotic surgery in early- IB1, and IB2.68–70 Dual labeling using blue dye and radiocolloid in-
stage cervical cancer, showed a decreased overall survival in the MIS creases the accuracy of SLN detection.71,72 More recently, indo-
group (3 of 312 vs 19 of 319, HR 6.00; 95% CI, 1.48–20.3, P = 0.004). cyanine green dye with near infrared technique has been used in
Disease-free survival events were also three-fold increased in the MIS both the open and minimally invasive approaches. Pelvic lymph-
group (7 of 312 vs 27 of 319, HR 3.74; 95% CI, 1.63–8.58, P = 0.002). adenectomy needs to be considered if LVSI is present. In the only
Rates of intraoperative complications did not differ by treatment re- randomized trial of SLN resection alone or SLN plus pelvic lymph-
ceived (11% in both). The most common sites of recurrence were as adenectomy (SENTICOL-
2) in early cervical cancer, among 206
follows: in the open arm, the vaginal vault (3/7, 43%); in the MIS arm, patients no false-negative case was observed in the SLN plus lymph-
pelvis (7/24, 29%), pelvis along with multiple sites in abdomen (7/24, adenectomy arm. Lymphatic morbidity was significantly lower in
29%). The authors concluded that hysterectomy by a minimally inva- the SLN arm than in the SLN plus lymphadenectomy arm (31.4%
sive route was associated with higher rates of recurrence than the vs 51.5%, P = 0.0046), as was the rate of postoperative neurolog-
open approach in early-stage cervical cancer patients.61 ical symptoms (7.8% vs 20.6%, P = 0.01, respectively). The 3-year
Subsequent to the LACC trial, several multi-institutional obser- recurrence-free survival was not significantly different between the
vational studies have confirmed inferior survival outcomes with MIS. two arms.73 Currently the SENTICOL-III study is ongoing, which will
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BHATLA et al. 35
randomize 950 patients and will compare disease-free survival and Such cases, or in the case of such a recurrence, pelvic exenteration
health-related quality of life outcomes between SLN and SLN plus can be considered but usually has a poor prognosis.82–84
74
pelvic lymphadenectomy.
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36 BHATLA et al.
7.2.2 | Adjuvant radiotherapy PORT or CCRT.54 It is well known that the addition of adjuvant ra-
diotherapy to surgery increases morbidity and thus compromises
Following radical hysterectomy, PORT with or without chemotherapy quality of life.102,103 Additionally, combined modality treatment will
is indicated for patients with adverse pathologic factors. According unnecessarily overburden the surgical and radiation facilities, which
to various prognostic factors, patients may be categorized into high-, are already inadequate in low-resource countries. Therefore, CCRT
intermediate-, or low-risk disease. High-risk disease includes patients is the standard of care for Stage IB3 and IIA2 disease. CCRT includes
with either positive surgical margins or lymph node metastases or para- external radiation and intracavitary brachytherapy.101
metrial spread, and such patients should be offered PORT with chemo-
therapy since the GOG 109 trial has shown overall survival advantage.78
Intermediate-risk patients with any two of three factors (tumor size 7.2.4 | Radiation therapy for FIGO Stages IIB–IVA
more than 4 cm, lymphovascular invasion, deep stromal invasion) re-
quire PORT76,89 and no chemotherapy should be offered to these pa- CCRT is considered the standard treatment for patients with lo-
tients. All other patients following radical hysterectomy are termed as cally advanced cervical cancer, based on the results of large ran-
low-risk disease patients and do not need any adjuvant therapy. domized trials that tested addition of chemotherapy to pelvic
Tumor size of more than 4 cm is a well-known risk factor. It was radiation.78,104–108 These studies demonstrated that CCRT had a
incorporated in the FIGO staging system (2009) as Stage IB2 and sub- significant survival advantage of 10%–15% at 5 years after treat-
sequently in the FIGO 2018 staging revision as Stage IB3. Recent lit- ment compared with radiotherapy alone, and also reduced local and
erature, especially with the advent of more and more fertility sparing distant recurrence. A subsequent meta-analysis showed maximum
surgery suggests tumor size more than 2 cm is a risk factor.90–98 Gemer benefit of chemoradiation of 6% in Stage IB2 (now termed IB3) to
et al.98 evaluated various clinical and pathologic risk factors that may Stage IIB and only 3% benefit in Stage IIIB patients.109
reduce the rate of multimodality treatment of early cervical cancer. The weekly infusion of cisplatin (40 mg/m2 weekly with
A once-
authors observed that 89% of patients with tumors 2 cm or greater and appropriate hydration) for 5–6 cycles during external beam ther-
LVSI received radiotherapy and 76% of patients with tumors 2 cm or apy is a commonly used concurrent chemotherapy regimen.109,110
greater and depth of invasion greater than 10 mm received radiother- For patients who are unable to receive platinum chemotherapy,
apy. They suggest that in patients with early cervical cancer, evaluation 5-fluorouracil based regimens are an acceptable alternative.110–112
of tumor size and LVSI should be undertaken before performing radical Data on the toxicity associated with concurrent chemotherapy and
hysterectomy to tailor treatment and to reduce the rate of employing extended field irradiation are limited.112
both radical hysterectomy and chemoradiation. In view of the above- Additional adjuvant chemotherapy after concurrent chemora-
mentioned emerging literature, tumor size of more than 2 cm has been diotherapy is being explored in an international randomized con-
taken as the first cutoff in the FIGO 2018 revision of the staging system. trolled trial (OUTBACK).113 The ongoing Phase III INTERLACE trial
PORT consists of whole pelvic EBRT to cover the tumor bed and will assess the role of induction chemotherapy plus CCRT as first-
draining lymph node areas. A dose of 45–50 Gy is usually prescribed. line treatment for LACC.114
Intensity modulated radiation therapy (IMRT), an advanced and re- The combination of EBRT and ICRT maximizes the likelihood of
fined technique of irradiation, has been explored in the postoperative locoregional control while minimizing the risk of treatment compli-
setting to reduce the toxicity.99,100 A recent Phase III trial100 revealed cations. The primary goal of EBRT is to sterilize local disease and
improved patient reported outcomes at week five with IMRT, with to shrink the tumor to facilitate subsequent ICRT. Standard EBRT
no difference after treatment completion. Therefore, postoperative should deliver a dose of 45–50 Gy to the whole pelvis by the 2-or
pelvic IMRT remains investigational until further data are published. 4-field box technique (Table 3) encompassing the uterus, cervix,
The role of vaginal brachytherapy boost following EBRT is not adnexal structures, parametria, and pelvic lymph nodes. Although
clear; however, it may be considered for patients with close or pos- EBRT is commonly delivered by a Cobalt-60 teletherapy machine
itive margins, large or deeply invasive tumors, parametrial or vagi- in several low-resource countries, linear accelerators are now pre-
101
nal involvement, or extensive LVSI. Vaginal cuff brachytherapy is ferred as they provide higher energy beams resulting in more ho-
usually delivered by ovoids or cylinders to the upper one-third of the mogeneous dose delivery to deep tissues with relative sparing of
residual vagina and should include two weekly fractions of high dose superficial tissues. Recently, conformal radiotherapy techniques like
rate (HDR) brachytherapy of 6 Gy each prescribed to 5 mm from the 3D-CRT and IMRT are increasingly being used with encouraging re-
vaginal cylinder/ovoid surface. sults in terms of reduced toxicity owing to relative sparing of nor-
mal tissues (Figure 1). Recently, the results of MRI-guided adapted
brachytherapy in the LACC (EMBRACE-I) study showed a 5-year
7.2.3 | Radiation therapy for FIGO local control of 92% with 5-year incidence of grade 3–5 morbidity
Stages IB3 and IIA2 as follows: 6.8% for genitourinary events, 8.5% for gastrointestinal
events, 5.7% for vaginal events, and 3.2% for fistulae.115
Although feasible, surgery as initial treatment is not encouraged for Standard ICRT is usually performed using a tandem and two
patients with Stage IB3 and IIA2 disease since 80% of them require ovoids, or a tandem and ring. Any of the dose-rate systems, namely
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BHATLA et al. 37
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38 BHATLA et al.
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BHATLA et al. 39
vault cytology does not significantly improve the detection of early selection regarding the associated physical and psychological de-
disease recurrence. mands. A PET/CT scan is the most sensitive noninvasive test to de-
Women under the age of 50 years who have lost ovarian function termine any sites of distant disease, and should be performed prior
should be considered for menopausal hormone therapy. As women to exenteration, if possible.137–139 Patient assessment and counsel-
age, the routine exam should also include other age-indicated well- ing regarding the implications and ability to manage stoma and os-
woman checks to ensure quality of life, including assessment of thy- tomy sites must also be addressed prior to surgery.140 The overall
roid and renal status. survival is 10% but careful selection of patients has been reported
to yield a five-year survival with pelvic exenteration in the order of
30%–60%,82–84 and an operative mortality of less than 10%.141
7.4 | Recurrent disease
Recurrences may occur locally in the pelvic or para-aortic lymph 7.4.2 | Para-aortic nodal recurrence
nodes the patient may develop distant metastases, or there may
be a combination thereof. The risk of both pelvic and distant failure The second most common site of recurrence is in the para-aortic
increases in proportion to tumor volume.128,129 Most recurrences lymph nodes. Where there is isolated para-aortic nodal recurrence,
are seen within 3 years and prognosis is poor as most patients die curative-
intent radiation therapy or chemoradiation can achieve
from progressive disease, with uremia the most common terminal long-term survival in approximately 30% of cases.142
event.128,129 The treatment plan depends on the patient's perfor-
mance status, site, and extent of recurrence and/or metastases, and
prior treatment received.130 7.5 | Comprehensive palliative care
If there is extensive local disease or distant metastatic disease,
the patient is assigned to palliative therapy, with best supportive Symptom control is the essence of palliative care and plays a major
care. However, if the performance status is good and there is only role in maintaining dignity and quality of life. Common symptoms and
limited metastatic disease, a trial of platinum doublet chemotherapy signs of advanced cervical cancer include pain, ureteric obstruction
along with bevacizumab is justified as depicted in GOG 240 trial,123 causing renal failure, hemorrhage, malodorous vaginal discharge,
after counseling the patient and her family on the limited benefits in lymphedema, and fistula. Patients require support from the corre-
terms of response rate and progression-free survival.131 sponding clinical services as well as psychosocial care and support
for their families and caregivers. Typically, a tiered approach to pain
is practiced. Access to oral morphine is improving within LMICs and
7.4.1 | Local recurrence is an important aspect of palliative care. The availability of homecare
teams in many regions and involvement of nongovernmental organi-
The pelvis is the most common site of recurrence. Good prognostic zations in this effort can help minimize the need to transport the
factors are the presence of an isolated central pelvic recurrence with patient to hospital and save costs. In terminal cases, some patients
no involvement of the pelvic sidewall, a long disease-free interval may also require the services of a hospice facility.
from previous therapy, and if the largest diameter of the recurrent
tumor is less than 3 cm.131
When the pelvic relapse follows primary surgery, it may be 7.5.1 | Palliative radiotherapy
treated by either radical chemoradiation or pelvic exenteration.
Confirmation of recurrence with a pathologic specimen obtained by Short-course radiotherapy is very effective in palliation of distress-
biopsy is essential prior to proceeding with either therapy. Radical ing symptoms. Although there is no standard dose fraction sched-
irradiation with or without concurrent chemotherapy may result in ule, a dose of 20 Gy in five fractions over 1 week or 30 Gy in 10
5-year disease-free survival rates of 45%–74% with isolated pelvic fractions over 2 weeks is commonly practiced.143 In patients with
132–134
failure after primary surgery. The extent of recurrent disease severe vaginal bleeding, a short course of EBRT may be tried and,
and involvement of pelvic lymph nodes are prognostic factors for if it fails, ICRT can be highly effective in controlling the intractable
survival.135 bleeding.144 Control of bleeding is usually achieved after 12–48 h of
Concurrent chemotherapy with either cisplatin and/or radiotherapy.
5-fluorouracil may improve outcome.136 In patients with pain arising from enlarged para-aortic or supra-
Pelvic exenteration may be feasible in some patients in whom clavicular nodes, skeletal metastases,145 and symptoms associated
there is no evidence of intraperitoneal or extrapelvic spread, and with cerebral metastases, palliative radiotherapy should be given via
there is a clear tumor-free space between the recurrent disease and larger fractions over shorter periods of time. Commonly used sched-
the pelvic sidewall.82–84 Owing to its high morbidity, it is reserved for ules include large single fractions, 20 Gy in five fractions, and 30 Gy
those with expected curative potential and requires careful patient in 10 fractions.
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40 BHATLA et al.
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BHATLA et al. 41
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