Cancer of the cervix uteri

4.1.1 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 also disregarded for staging purposes as it does not in itself alter either the prognosis or management. The margins should be reported to be negative for disease. If the margins of the cone biopsy are positive for invasive cancer, the patient is allocated to Stage IB1.18

Clinically visible lesions, and those with larger dimensions, are allocated to Stage IB, subdivided in the latest staging as IB1, IB2, and IB3 based on the maximum diameter of the lesion.

4.1.2 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.

Imaging evaluation may now be used in addition to clinical examination where resources permit. The revised staging permits the use of any of the imaging modalities according to available resources, i.e. ultrasound, CT, MRI, positron emission tomography (PET), to provide information on tumor size, nodal status, and local or systemic spread. 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.19-23 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, 25-28 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.31-33 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 para-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 assessment (r) or whether pathological confirmation is available (p). In due course, the data can be analyzed and reported accordingly.

FIGO no longer mandates any biochemical investigations or investigative procedures; however, in patients with frank invasive carcinoma, a chest X-ray, and assessment of hydronephrosis (with renal ultrasound, intravenous pyelography, CT, or MRI) should be done. The bladder and rectum are evaluated by cystoscopy and sigmoidoscopy only if the patient is clinically symptomatic. Cystoscopy is also recommended in cases of a barrel-shaped endocervical growth and in cases where the growth has extended to the anterior vaginal wall. Suspected bladder or rectal involvement should be confirmed by biopsy and histologic evidence. Bullous edema alone does not warrant a case to be allocated to Stage IV.

5.1.1 Microinvasive cervical carcinoma: FIGO Stage IA

5.1.2 Invasive cervical carcinoma: FIGO Stage IB1, IB2, IIA1

Surgical treatment is the preferred modality for the treatment of Stage IB1, IB2, and IIA1 lesions. It would usually consist of type C radical hysterectomy with pelvic lymphadenectomy.52-54 The routes of surgery may be open or minimally invasive, i.e. laparoscopic or robotic.

5.1.3 FIGO Stage IB3 and IIA2

In Stage IB3 and IIA2, the tumors are larger and the likelihood of high risk factors such as positive lymph nodes, positive parametria, or positive surgical margins that increase the risk of recurrence and require adjuvant radiation after surgery are high. Other risk factors that increase the risk of pelvic recurrence even when nodes are not involved include: largest tumor diameter greater than 4 cm, LVSI, and invasion of outer one-third of the cervical stroma.64, 65 In such cases, adjuvant whole pelvic irradiation reduces the local failure rate and improves progression-free survival compared with patients treated with surgery alone.65 However, the dual modality treatment increases the risk of major morbidity to the patient.

The treatment modality must, therefore, be determined based on the availability of resources and tumor- and patient-related factors. Concurrent platinum-based chemoradiation (CCRT) is the preferred treatment option for Stage IB3 to IIA2 lesions. It has been demonstrated that the prognosis is more favorable with CCRT, rather than radiotherapy alone, as postoperative adjuvant therapy as well in terms of overall survival, progression-free survival, and local and distant recurrences.52, 66, 67

In areas where radiotherapy facilities are scarce, neoadjuvant chemotherapy (NACT) has been used with the goal of: (1) down-staging of the tumor to improve the radical curability and safety of surgery; and (2) inhibition of micrometastasis and distant metastasis. There is no unanimity of view as to whether it improves prognosis compared with the standard treatment.68, 69

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

5.1.4 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

5.2.1 Radiation therapy for early stage disease (FIGO Stage IA, IB1, IB2, and IIA1)

Although surgery is preferred for early stage disease, in cases with contraindications for surgery or anesthesia, radiotherapy provides equally good results in terms of local control and survival. Treatment decision should be made on the basis of clinical, anatomic, and social factors. Patients with microinvasive disease have been treated by intracavitary radiation therapy (ICRT) alone with good results if surgery is contraindicated owing to medical problems. Selected patients with very small Stage IB1 disease (less than 1 cm) may also be treated with ICRT alone, particularly if there are relative contraindications to external beam radiation therapy (EBRT).79 A dose of 60–65 Gy equivalent is usually prescribed to Point A. Combination of EBRT and ICRT is also an option for such patients.

Both surgery and radiotherapy remain viable options for early stage disease. Definitive radiotherapy or concurrent chemoradiation (CCRT) is preferred in patients likely to require postoperative radiotherapy to avoid compounding treatment-related morbidity. There is a single randomized trial comparing surgery and radiotherapy52 but none comparing surgery to CCRT, which is the current standard in patients treated by definitive radiotherapy. Landoni et al.52 randomized patients with IB or IIA cervical cancer to surgery with or without postoperative radiotherapy (PORT) versus definitive radiotherapy alone. PORT was administered to 64% of patients in the surgery arm. 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

5.2.2 Adjuvant radiotherapy

Following radical hysterectomy, PORT with or without chemotherapy is indicated for patients with adverse pathologic factors such as positive pelvic nodes, parametrial infiltration, positive margins, deep stromal invasion, etc. According to various prognostic factors, patients may be categorized into high-risk, intermediate-risk, or low-risk disease. High-risk disease includes patients with either positive surgical margins or lymph node metastases or parametrial spread, and such patients should be offered PORT with chemotherapy since the GOG 109 trial has shown overall survival advantage.67 Intermediate-risk patients with any two of three factors (tumor size more than 4 cm, lymphovascular invasion, deep stromal invasion) require PORT64, 81 and no chemotherapy should be offered to these patients. All other patients following radical hysterectomy are termed as low-risk disease patients and do not need any adjuvant therapy.

Tumor size of more than 4 cm is a well-known risk factor. Since 2009 it was incorporated in the FIGO staging system as Stage IB2 and now in the 2018 staging revision as Stage IB3. Recent literature, especially with the advent of more and more fertility sparing surgery suggests tumor size more than 2 cm is a risk factor.82-91. In a recent study, Gemer et al.91 evaluated various clinical and pathologic risk factors that may reduce the rate of multimodality treatment of early cervical cancer. The authors observed that 89% of patients with tumors 2 cm or greater and LVSI received radiotherapy and 76% of patients with tumors 2 cm or greater and depth of invasion greater than 10 mm received radiotherapy. They suggest that in patients with early cervical cancer, evaluation of tumor size and LVSI should be undertaken before performing radical hysterectomy to tailor treatment and to reduce the rate of employing both radical hysterectomy and chemoradiation. In view of the above-mentioned emerging literature, tumor size of more than 2 cm has been taken as the first cut-off in the 2018 revision of the FIGO staging system.

PORT consists of whole pelvic EBRT to cover the tumor bed and draining lymph node areas. A dose of 45–50 Gy is usually prescribed. Intensity modulated radiation therapy (IMRT), an advanced and refined technique of irradiation, has been explored in the postoperative setting to reduce the toxicity.92, 93 A recent Phase III trial93 revealed improved patient reported outcomes at week five with IMRT, with no difference after treatment completion. Therefore, postoperative pelvic IMRT remains investigational until further data are published.

The role of vaginal brachytherapy boost following EBRT is not clear; however, it may be considered for patients with close or positive margins, large or deeply invasive tumors, parametrial or vaginal involvement, or extensive LVSI.94 Vaginal cuff brachytherapy is usually delivered by ovoids or cylinders to the upper one-third of the residual vagina and should include two weekly fractions of high dose rate (HDR) brachytherapy of 6 Gy each prescribed to 5 mm from the vaginal cylinder/ovoid surface.

5.2.3 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

5.2.4 Radiation therapy for FIGO Stage IIB–IVA

Concurrent chemoradiation is considered the standard treatment for patients with locally advanced cervical cancer (LACC). The chemotherapy regimen is intravenous administration of weekly cisplatin during the course of EBRT.

Based on the results of five large randomized trials67, 97-100 that tested addition of chemotherapy to pelvic radiation, the National Cancer Centre issued an alert in 1999 that all patients with locally advanced cervical cancer should receive CCRT.67 These studies67, 97-100 demonstrated that CCRT had a significant survival advantage of 10%–15% at 5 years after treatment compared with radiotherapy alone. A subsequent meta-analysis showed maximum benefit of chemoradiation of 6% in Stage IB2 (now termed IB3) to Stage IIB and only 3% benefit in Stage IIIB patients.101 Concurrent chemoradiotherapy also reduced local and distant recurrence, and improved disease-free survival.

A once-weekly infusion of cisplatin (40 mg/m² weekly with appropriate hydration) for 5–6 cycles during external beam therapy is a commonly used concurrent chemotherapy regimen.99, 102 For patients who are unable to receive platinum chemotherapy, 5–fluorouracil-based regimens are an acceptable alternative.102-104 Data on the toxicity associated with concurrent chemotherapy and extended field irradiation are limited.105, 106

Additional adjuvant chemotherapy after concurrent chemoradiotherapy is being explored in an international randomized controlled trial (OUTBACK Trial).107

The combination of EBRT and ICRT maximizes the likelihood of locoregional control while minimizing the risk of treatment complications. The primary goal of EBRT is to sterilize local disease and to shrink the tumor to facilitate subsequent ICRT. Standard EBRT should deliver a dose of 45–50 Gy to the whole pelvis by 2 or 4 field box technique (Table 3) encompassing uterus, cervix, adnexal structures, parametria, and pelvic lymph nodes. Although EBRT is commonly delivered by a Cobalt-60 teletherapy machine in several low-resource countries, linear accelerators are preferred nowadays as they provide higher energy beams resulting in more homogeneous dose delivery to deep tissues with relative sparing of superficial tissues. Recently, conformal radiotherapy techniques like 3D-CRT and IMRT are increasingly being used with encouraging results in terms of reduced toxicity owing to relative sparing of normal tissues (Fig. 1).

Although EBRT plays an important role in the treatment of cervical cancer, ICRT is also an extremely important component of curative treatment of cervical cancer since it delivers a high central dose to the primary tumor and reduced doses to adjacent normal organs owing to sharp dose fall-off.

Standard ICRT is usually performed using a tandem and two ovoids, or a tandem and ring. Any of the dose rate systems, namely low-dose-rate (LDR), high-dose-rate (HDR), or pulsed-dose-rate (PDR) may be practiced as all three yield comparable survival rates.108 The dose is usually prescribed to Point A or to high-risk clinical target volume (HRCTV) if image-based planning is used.

With an LDR system, a dose of 30–40 Gy is prescribed in one or two sessions. With HDR, various dose fraction schedules are used, employing a dose of 5.5–8 Gy by 3–5 weekly fractions. Owing to resource constraints and long travelling distances in low-resource countries, delivering three instead of five fractions is often more realistic and allows for treatment of a higher number of patients. The total combined dose with EBRT and ICRT should be in the range of 80–90 Gy. Though PDR is rarely used, the overall treatment time and dose in PDR remains almost the same as in LDR except that the treatment is given in multiple hourly pulses each lasting for a few minutes.

If ICRT is not feasible either due to distorted anatomy or inadequate dosimetry, then interstitial brachytherapy should be considered. Interstitial brachytherapy consists of insertion of multiple needles/catheters into the primary tumor and parametria (Fig. 2) through the perineum with the help of a template. Due to the risk of trauma to normal structures like bowel and bladder, use of ultrasound imaging (especially transrectal) is suggested during the implant procedure.109

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.

5.2.5 FIGO Stage IVB/distant metastases

Presentation with distant metastatic disease is rare, reported in about 2% of cases. A management plan should consider that the median duration of survival with distant metastatic disease is approximately 7 months.

Concurrent chemoradiation may have better response than systemic chemotherapy with overall and disease-free survivals of 69% and 57%, respectively, reported in patients with positive para-aortic and supraclavicular lymph nodes.112 Currently there is no role for prophylactic extended field radiotherapy (EFRT) in locally advanced cervical cancer. When para-aortic nodes are involved, EFRT with concurrent chemotherapy should be used. IMRT may be used in such patients to reduce the toxicity.

Despite limited response rates, cisplatin has been the standard chemotherapy used in the setting of distant metastatic disease.113 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. Cisplatin may be combined with taxanes, topotecan, 5-fluorouracil, gemcitabine, or vinorelbine.114 Carboplatin-paclitaxel combination has also been successful in these cases.

Patients with an ECOG (Eastern Cooperative Oncology Group) performance status of 0–2 may be considered for palliative systemic chemotherapy. Where feasible, these patients could be offered participation in clinical trials, especially when the interval to relapse is less than 12 months.

GOG 240 studied the efficacy of antiangiogenic therapy with bevacizumab, a humanized anti-VEGF monoclonal antibody. When incorporated in the treatment of recurrent and metastatic cervical cancer, it showed increased overall survival (17.0 months vs 13.3 months, HR for death 0.71, 98% CI 0.54–0.95, P=0.004 in a one-sided test).115 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.

5.2.6 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, 117 the outcome for such patients even after PORT remains very poor with 5-year recurrence-free survival of 49%,33 and therefore CCRT is generally added. In a study from India, Sharma et al.116 reported the results of 83 patients treated with PORT following either inadvertent simple hysterectomy (33 patients) or radical hysterectomy (50 patients). The 5-year recurrence-free survival was found to be significantly inferior in patients who underwent PORT after inadvertent simple hysterectomy (49% vs 72%, respectively; P=0.04). PORT, therefore, does not compensate for lack of adequate surgery.

In centres where the expertise is available, some of these patients may be found suitable for repeat laparotomy with parametrectomy and pelvic lymphadenectomy. The procedure is challenging due to previous scarring, adhesions, and distortion of anatomy, but does have the potential for curative surgery as well as allow assessment of the need for adjuvant CCRT.118

5.4.1 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.71-75 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.129-136 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

5.4.2 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 long-term 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.

5.5.1 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 and symptoms associated with cerebral metastases, palliative radiotherapy should be given via larger fractions over shorter periods of time. Commonly used schedules include large single fractions, 20 Gy in five fractions, and 30 Gy in 10 fractions.