Cancer of the cervix uteri

Since the publication of the last FIGO Cancer Report there have been giant strides in the global effort to reduce the burden of cervical cancer, with WHO announcing a call for elimination. In over 80 countries, including LMICs, HPV vaccination is now included in the national program. Screening has also seen major advances with implementation of HPV testing on a larger scale. However, these interventions will take a few years to show their impact. Meanwhile, over half a million new cases are added each year. Recent developments in imaging and increased use of minimally invasive surgery have changed the paradigm for management of these cases. The FIGO Gynecologic Oncology Committee has revised the staging system based on these advances. This chapter discusses the management of cervical cancer based on the stage of disease, including attention to palliation and quality of life issues.


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Bhatla Et al. of cases; while HPV types 31,33,45,52, and 58 account for another 19% of cervical cancer cases 2,3 It is well documented that nearly 90% of incident HPV infections are not detectable within a period of 2 years from the acquisition of infection and persist only in a small proportion. It is debatable whether the virus is completely cleared or whether it remains latent in basal cells with the potential for reactivation in some cases. Persistent HPV infection denotes the presence of the same type-specific HPV DNA on repeated sampling after 6-12 months. Only one-tenth of all infections become persistent, and these women could develop cervical precancerous lesions.
This knowledge has resulted in the development of new initiatives for prevention and early detection. The two major approaches for control of cervical cancer involve: (1) prevention of invasive cancer by HPV vaccination; and (2) screening for precancerous lesions.
Prevention and elimination are potential possibilities but the tragedy is that it is not yet prevented on a large scale in many LMICs due to lack of efficient and effective intervention programs. WHO has recently given a call to action for elimination of cervical cancer. This is foreseeable if implemented in earnest in successful public health programs achieving high coverage.

| Primary prevention of cervical cancer with HPV vaccination
The fact that more than 80% of women followed over time will acquire at least one high-risk HPV infection suggests the ubiquitous nature of the HPV infection and reflects the ease of transmission. The estimated cross-sectional HPV prevalence worldwide among healthy women is around 11.7%, with the highest in Sub-Saharan Africa at around 24%, and country-specific prevalence ranging between 2% and 42% globally 4 Age-specific cross-sectional HPV prevalence peaks at 25% in women aged less than 25 years, which suggests that the infection is predominantly transmitted through the sexual route following sexual debut. Thus, prophylactic HPV vaccination as a preventive strategy should target women before initiation of sexual activity, focusing on girls aged 10-14 years.
Three prophylactic HPV vaccines are currently available in many countries for use in females and males from the age of 9 years for the prevention of premalignant lesions and cancers affecting the cervix, vulva, vagina, and anus caused by high-risk HPV types: a bivalent vaccine targeting HPV16 and HPV18; a quadrivalent vaccine targeting HPV6 and HPV11 in addition to HPV16 and HPV18; and a nonavalent vaccine targeting HPV types 31, 33, 45, 52, and 58 in addition to HPV 6,11,16,and 18. The last two vaccines target anogenital warts caused by HPV 6 and 11 in addition to the above-mentioned malignant and premalignant lesions. All the vaccines are recombinant vaccines composed of virus-like particles (VLPs) and are not infectious since they do not contain viral DNA.
For girls and boys aged 9-14 years, a two-dose schedule (0.5 mL at 0 and 5-13 months) is recommended. If the second vaccine dose is administered earlier than 5 months after the first dose, a third dose is recommended. For those aged 15 years and above, and for immunocompromised patients irrespective of age, the recommendation is for three doses (0.5 mL at 0, 1, 6 months). 5 WHO has reviewed the latest data and concluded that there is no safety concern regarding HPV vaccines. 5 There is evidence for the effectiveness of vaccination at the population level in terms of reduced prevalence of high-risk HPV types, and reduction in anogenital warts and high-grade cervical abnormalities caused by the vaccine types among young women; there is some evidence of cross-protection from nonvaccine types also. There is no evidence of type replacement [6][7][8] Recent observational studies have reported evidence for effectiveness in preventing high-risk HPV infections following a single dose and further long-term follow-up will clarify the role of one dose in preventing cervical neoplasia. 9,10

| Secondary prevention of cervical cancer by early detection and treatment of precancerous lesions
Even with the advent of effective vaccines, screening will remain a priority for cervical cancer prevention for several decades. Cervical cancer screening has been successful in preventing cancer by detection and treatment of precursor lesions, namely, high-grade cervical intraepithelial neoplasia (CIN 2 and 3) and adenocarcinoma in-situ (AIS).
Several cervical screening strategies have been found to be effective in varied settings. The tests used widely include conventional cytology (Pap smear), in recent years liquid-based cytology and HPV testing, and, in LMICs, visual inspection with acetic acid (VIA). 11 While the Pap smear is still the major workhorse of screening and is associated with substantial declines in cervical cancer risk in high-income countries, it is a challenging and resource intensive technology that is not feasible in low-resource settings 11 where poor organization, coverage, and lack of quality assurance result in suboptimal outcomes. In the context of declining HPV infections after the introduction of HPV vaccines a decade ago, many healthcare systems are considering switching to primary HPV screening, which has higher sensitivity and negative predictive value, and allows extended screening intervals or even a single lifetime screening in lowresource settings. 12,13 VIA involves detection of acetowhite lesions on the cervix 1 minute after application of 3%-5% freshly prepared acetic acid. In view of its feasibility, VIA screening has been widely implemented in opportunistic settings in many low-income countries in Sub-Saharan Africa. A single-visit approach (SVA) for screening with rapid diagnosis and treatment improves coverage, eliminates follow-up visits, and makes screening more time and cost-efficient in low-resource settings. 14-16 VIA screening is particularly suitable for SVA and WHO has issued guidelines for implementing SVA in public health settings.
A single screening modality will never be universally applicable, but it is possible to adapt cost-effective means of cervical cancer screening to each country. The screening strategy chosen must be feasible, simple, safe, accurate, acceptable, and easily accessible to highest-risk women. A judicious combination of HPV vaccination and screening has enormous potential to eliminate cervical cancer in the foreseeable future.

| FIGO STAGING
Cervical cancer spreads by direct extension into the parametrium, vagina, uterus and adjacent organs, i.e., bladder and rectum. It also spreads along the lymphatic channels to the regional lymph nodes, namely, obturator, external iliac and internal iliac, and thence to the common iliac and para-aortic nodes. Distant metastasis to lungs, liver, and skeleton by the hematogenous route is a late phenomenon.
Until now, the FIGO staging was based mainly on clinical examination with the addition of certain procedures that were allowed by FIGO to change the staging. In 2018, this has been revised by the FIGO Gynecologic Oncology Committee to allow imaging and pathological findings, where available, to assign the stage. The revised staging is shown in

| Microinvasive disease
Diagnosis of Stage IA1 and IA2 is made on microscopic examination of a LEEP (loop electrosurgical excision procedure) or cone biopsy specimen, which includes the entire lesion. It can also be made on a trachelectomy or hysterectomy specimen. The depth of invasion should not be greater than 3 mm or 5 mm, respectively, from the base of the epithelium, either squamous or glandular, from which it originates. The horizontal dimension is no longer considered in the 2018 revision as it is subject to many artefactual errors. Note must be made of lymphovascular space involvement, which does not alter the stage, but may affect the treatment plan. Extension to the uterine corpus is T A B L E 1 FIGO staging of cancer of the cervix uteri (2018).

| Invasive disease
In the case of visible lesions, a punch biopsy may generally suffice, but if not satisfactory a small loop biopsy or cone may be required. Clinical assessment is the first step in allocation of staging. The accuracy of various methods depends on the skill of the operator.
MRI is the best method of radiologic assessment of primary tumors greater than 10 mm. [19][20][21][22][23] However, ultrasound has also been shown to have good diagnostic accuracy in expert hands. 24 The modality used in assigning staging should be noted for future evaluation. Imaging has the advantage of the ability to identify additional prognostic factors, which can guide the choice of treatment modality. The goal is to identify the most appropriate method and to avoid dual therapy with surgery and radiation as this has the potential to greatly augment morbidity.
For detection of nodal metastasis greater than 10 mm, PET-CT is more accurate than CT and MRI, with false-negative results in 4%-15% of cases. 20,[25][26][27][28] In areas with a high prevalence of tuberculosis and inflammation, especially HIV-endemic areas, large lymph nodes are not necessarily metastatic. The clinician may make the decision on imaging or, when possible, can use fine needle aspiration or biopsy to establish or exclude metastases. 27,29,30 This is especially true in advanced stages, where surgical assessment of para-aortic lymph nodes may be used to tailor treatment according to extent of disease. [31][32][33] They can be accessed by minimally invasive surgery or laparotomy. Surgical exclusion of para-aortic lymph node involvement has been reported to have a better prognosis than radiographic exclusion alone. 34 A review of 22 articles that assessed the safety and impact of pretreatment para-aortic lymph node surgical staging (PALNS) found that 18% (range, 8%-42%) of patients with Stage IB-IVA cervical cancer had para-aortic lymph node metastases. 35 The mean complication rate of PALNS was 9% (range 4%-24%), with lymphocyst formation being the most common. In another study, up to 35% of clinically assessed Stage IIB and 20% of Stage III tumors were reported to have positive para-aortic nodes. 36 In the revised staging, all these cases will be assigned to Stage IIIC as lymph node involvement confers a worse prognosis. 37 If only pelvic nodes are positive, it is Stage IIIC1; if paraaortic nodes are also involved it is Stage IIIC2. A further notation must be added to indicate whether this allocation is based on only imaging assessment (r) or whether pathological confirmation is available (p). In due course, the data can be analyzed and reported accordingly.

| Pathologic staging
In case a surgical specimen is available or where image-guided fineneedle aspiration cytology has been done, the pathologic report is an important source for accurate assessment of the extent of disease. As in the case of imaging, the pathologic methods should also be recorded for future evaluation. The stage is to be allocated after all imaging and pathology reports are available. It cannot be altered later, for example at recurrence. The 2018 FIGO staging includes involvement of nodes and thus enables both the selection and evaluation of therapy, as well as estimation of the prognosis and calculation of end results.
The FIGO and TNM classifications have been virtually identical in describing the anatomical extent of disease. The TNM nomenclature has hitherto been used for the purpose of documenting nodal and metastatic disease status. 38 The revised FIGO classification is now more closely aligned with the TNM classification in this respect as well.
In some cases, hysterectomy is performed in the presence of unsuspected invasive cervical carcinoma that is diagnosed later on histopathology. Such cases cannot be clinically staged or included in therapeutic statistics for obvious reasons, but reporting them separately is desirable.

| Histopathology
It is essential that all cancers must be confirmed by microscopic exam-

| MANAGEMENT OF CERVICAL CANCER
Management of cervical cancer is primarily by surgery or radiation therapy, with chemotherapy a valuable adjunct.

| Surgical management
Surgery is suitable for early stages, where cervical conization, total simple hysterectomy, or radical hysterectomy may be selected according to the stage of disease and extent of spread of cervical cancer. Table 2 shows the types of radical hysterectomy. In Stage IVA, there is a place for pelvic exenteration in selected cases.

| Stage IA1
The treatment is completed with cervical conization unless there is lymphovascular space invasion (LVSI) or tumor cells are present at the surgical margin. In women who have completed childbearing or elderly women, total extrafascial hysterectomy may also be recommended. 40 Any route can be chosen, i.e. abdominal, vaginal, or laparoscopic. When LVSI is evident, pelvic lymphadenectomy should be considered, along with modified radical hysterectomy. 41,42 If fertility is desired, cervical conization with close follow-up will be adequate.

| Stage IA2
Since there is a small risk of lymph node metastases in these cases, [42][43][44][45] pelvic lymphadenectomy is performed in addition to type B radical hysterectomy or more radical surgery. 46 FIGO Stage IB1 is considered as low risk with the following criteria: largest tumor diameter less than 2 cm, cervical stromal invasion less than 50%, and no suspicious lymph nodes on imaging. The standard management is a type C radical hysterectomy, but modified radical hysterectomy may be considered in these cases. Pelvic lymphadenectomy should always be included on account of the high frequency of lymph node involvement. 46,47 A pelvic nerve-sparing surgical procedure is recommended in patients undergoing radical hysterectomy, in so far as radical curability is maintained, as intrapelvic injuries to the autonomic nerves (i.e. hypogastric nerve, splanchnic nerve, and pelvic plexus) often lead to impairment of urination, defecation, and sexual function, and consequent deterioration of the postoperative quality of life (QOL). 55,56 In young women desiring fertility sparing, a radical trachelectomy may be performed, indicated for Stage IA2-IB1 tumors measuring less than or equal to 2 cm in largest diameter. 57 The   63 Further studies may be required to further confirm these findings.

| FIGO Stage IB3 and IIA2
In The extent of surgery after NACT remains the same, i.e. radical hysterectomy and pelvic lymphadenectomy. The greater difficulty is in determining the indications for adjuvant therapy which are often kept the same as those after primary surgery. 66,67 However, it must be remembered that NACT may give a false sense of security by masking the pathologic findings and thus affecting evaluation of indications for adjuvant radiotherapy/CCRT. NACT surgery is best reserved for research settings or those areas where radiotherapy is unavailable. This is especially true in patients with very large tumors or adenocarcinoma, which have lower response rates. 70

| FIGO Stage IVA or recurrence
Rarely, patients with Stage IVA disease may have only central disease without involvement to the pelvic sidewall or distant spread. Such cases, or in case of such a recurrence, pelvic exenteration can be considered but usually has a poor prognosis. 71-75

| Radiation management
In LMICs, the majority of patients present with locally advanced disease, 76 where surgery plays a limited role, and radiotherapy has an important role. Over the last two decades, development of sophisticated planning and delivery techniques, and introduction of computer technology and imaging have galvanized the practice of radiotherapy, resulting in improved clinical outcome and reduced toxicity. 77,78 Apart from its curative role, radiotherapy can also be used as adjuvant therapy for operated patients to prevent locoregional recurrence, although the role of "dual modality" is discouraged, and as palliative therapy for alleviating distressing symptoms in patients with advanced incurable disease.

| Radiation therapy for early stage disease (FIGO Stage IA, IB1, IB2, and IIA1)
Although surgery is preferred for early stage disease, in cases with The two treatment arms resulted in similar overall survival (83%) and disease-free survival (74%); severe morbidity was higher in the surgery arm (28% vs 12%), likely due to contributions from both treatment modalities. An update of the same trial with 20-year follow-up data has shown marginally better results with radiotherapy compared with surgery (77% vs 72%, P=0.280). 80 Multivariate analysis confirmed that risk factors for survival are histopathologic type (P=0.020), tumor diameter (P=0.008), and lymph node status (P<0.001). 80

| Radiation therapy for FIGO Stage IB3 and IIA2
Although feasible, surgery as initial treatment is not encouraged for patients with Stage IB3 and IIA2 disease since 80% of them require PORT or CCRT. 52 It is well known that the addition of adjuvant radiotherapy to surgery increases morbidity and thus compromises the quality of life. 95,96 Additionally, combined modality treatment will unnecessarily overburden the surgical and radiation facilities, which are already inadequate in low-resource countries. Therefore, CCRT is the standard of care for Stage IB3 and IIA2 disease. CCRT includes external radiation and intracavitary brachytherapy. 65,66  (Table 3)   Completion of the radiotherapy protocol within the stipulated time is an important goal as it has a direct correlation on the outcome. In retrospective analyses, patients whose radiotherapy treatment times exceeded 9-10 weeks had significantly higher rates of pelvic failure when compared with women whose treatment was completed in less than 6-7 weeks. 110,111 Currently the recommendation is to complete the entire protocol of EBRT and brachytherapy within 8 weeks. Given low response rates to cisplatin alone after concurrent chemoradiation, recent evidence supports the use of platinum doublets over cisplatin alone, although with very modest benefits in response rates.

| FIGO Stage IVB/distant metastases
Cisplatin may be combined with taxanes, topotecan, 5-fluorouracil, gemcitabine, or vinorelbine. 114 Carboplatin-paclitaxel combination has also been successful in these cases. The treatment is presently expensive and patients and their families need to be counseled. Adverse effects include increased incidence of hypertension, thromboembolic events, and gastrointestinal fistulae.

| Radiation therapy after inadvertent incomplete surgery
Invasive cervical cancer may be found during pathologic evaluation of the specimen of a simple hysterectomy for an apparent benign condition. Inadvertent simple hysterectomy is considered inadequate surgery for invasive cervical carcinoma and subsequent therapy is required for all such cases. In such a situation, the extent of the disease should be assessed by a PET/CT scan if available, or a pelvic and abdominal CT or MRI scan, and chest imaging. The subsequent treatment plan is formulated based on the histologic and radiologic findings.
Although PORT for patients following inadvertent simple hysterectomy has been shown to be beneficial, 116

| Post-treatment follow-up
In a systematic review of 17 retrospective studies that followed up women treated for cervical cancer, the median time to recurrence ranged from 7 to 36 months after primary treatment. 119

| Recurrent disease
Recurrences may occur locally in the pelvic or para-aortic, the patient may develop distant metastases, or there may be a combination thereof. The risk of both pelvic and distant failure increases in proportion to tumor volume. 120,121 Most recurrences are seen within 3 years and the prognosis is poor, as most patients die from progressive disease with uremia being the most common terminal event. 119

| Local recurrence
The pelvis is the most common site of recurrence and patients who have only locally recurrent disease after definitive therapy, whether surgery or radiotherapy, are in a more favorable situation as the disease is potentially curable. Good prognostic factors are the presence of an isolated central pelvic recurrence with no involvement of the pelvic sidewall, a long disease-free interval from previous therapy, and the largest diameter of the recurrent tumor is less than 3 cm. 74,124 When the pelvic relapse follows primary surgery, it may be treated by either radical chemoradiation or pelvic exenteration. Confirmation of recurrence with a pathologic specimen obtained by biopsy is essential prior to proceeding with either therapy. Radical irradiation with or without concurrent chemotherapy) may result in 5-year disease-free survival rates of 45%-74% with isolated pelvic failure after primary surgery. 125,126 The extent of recurrent disease and involvement of pelvic lymph nodes are prognostic factors for survival. 127 Concurrent chemotherapy with either cisplatin and/or 5-fluorouracil may improve outcome. 128 IMRT is reported to be superior to conventional concurrent chemoradiation yielding better dose sparing of small bowel, rectum, and bladder than chemoradiation with significantly higher 5-year overall survival and progression-free survival rates (35.4% vs 21.4%; 26.1% and 15.1%, respectively).

Pelvic exenteration may be feasible in some patients in whom
there is no evidence of intraperitoneal or extrapelvic spread, and there is a clear tumor-free space between the recurrent disease and the pelvic sidewall. [71][72][73][74][75] Owing to its high morbidity, it is reserved for those with expected curative potential and requires careful patient selection regarding the associated physical and psychological demands. A PET/CT scan is the most sensitive noninvasive test to determine any sites of distant disease, and should be performed prior to exenteration, if possible. [129][130][131][132][133][134][135][136] Patient assessment and counseling regarding the implications and ability to manage stoma and ostomy sites must also be addressed prior to surgery. 137 The overall survival is 10% but careful selection of patients has been reported to yield a 5-year survival with pelvic exenteration in the order of 30%-60%, 71,72,74 and an operative mortality of less than 10%. 138

| Para-aortic nodal recurrence
The second most common site of recurrence is in the para-aortic lymph nodes. Where there is isolated para-aortic nodal recurrence, curative-intent radiation therapy or chemoradiation, can achieve longterm survival in approximately 30% of cases. 139 Better outcomes are seen in asymptomatic patients with low-volume recurrences occurring more than 24 months from initial treatment.

| Comprehensive palliative care
Symptom control is the essence of palliative care and plays a major role in maintaining dignity and quality of life. As the disease progresses, patients may present with a wide range of symptoms that need to be managed with individual attention. Patients require support from the corresponding 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 is an important aspect of palliative care. The availability of home care teams in many regions and involvement of nongovernmental organizations in this effort can help minimize the need to transport the patient to hospital and save costs too. In terminal cases, some patients may require the services of a hospice facility as well.

| Palliative radiotherapy
Common symptoms in patients with advanced incurable disease include vaginal bleeding, pelvic pain, malodorous discharge, and symptoms related to metastatic disease, which may be distressing to the patient. Short course radiotherapy is very effective in palliation of such symptoms. Although there is no standard dose fraction schedule, a dose of 20 Gy in five fractions over 1 week or 30 Gy in 10 fractions over 2 weeks is commonly practiced. 140 In patients with severe vaginal bleeding, a short course of EBRT may be tried and, if it fails, ICRT can be highly effective in controlling the intractable bleeding. 141 Control of bleeding is usually achieved after 12-48 hours of radiotherapy.
In patients with pain arising from enlarged para-aortic or supraclavicular nodes, skeletal metastases, 142

| Cervical cancer during pregnancy
Adequate management of these patients requires a multidisciplinary team. The plan must be discussed with the patient and, preferably, her partner, as their wishes are to be respected.
Broadly, the management of cervical cancer in pregnancy follows the same principles as in the nonpregnant state. Before 16-20 weeks of pregnancy, patients are treated without delay. The mode of therapy can be either surgery or chemoradiation depending on the stage of the disease. Radiation often results in spontaneous abortion of the conceptus. From the late second trimester onward, surgery and chemotherapy can be used in selected cases while preserving the pregnancy. 143 When the diagnosis is made after 20 weeks, delaying definitive treatment is a valid option for Stages IA2 and IB1 and 1B2, which has not been shown to have any negative impact on the prognosis compared with nonpregnant controls. [144][145][146] Timing of delivery requires a balance between maternal and fetal health interests. When delivered at a tertiary center with appropriate neonatal care, delivery by classical cesarean and radical hysterectomy at the same time is undertaken not later than 34 weeks of pregnancy.
For more advanced disease, the impact of treatment delay on survival is not known. Neoadjuvant chemotherapy may be administered to prevent disease progression in women with locally advanced cervical cancer when a treatment delay is planned. 147,148

AUTHOR CONTRIBUTIONS
All authors contributed to the manuscript at all stages including design, planning, data abstraction, and manuscript writing.

ACKNOWLEDGMENTS
This chapter reworks and updates the information pub-