# GUIDELINE OBJECTIVES
The objective of this guideline is to update a previous guideline on chemotherapy options for women with recurrent, metastatic, or persistent cervical cancer. The primary outcomes of interest are overall survival rate and quality of life. Other outcomes of interest include response rate, progression-free survival rate, and adverse effects. Second-line or higher therapy options are outside the scope of this guideline.

# TARGET POPULATION
These recommendations apply to women with metastatic, recurrent, or persistent cervical cancer for whom systemic therapy is indicated. This includes women with squamous cell carcinoma, adenosquamous carcinoma, or adenocarcinoma of the cervix.

# INTENDED USERS
The intended users of this guideline are gynecologic oncologists or oncologists treating gynecologic cancers in the province of Ontario.

# RECOMMENDATIONS, KEY EVIDENCE, AND JUSTIFICATION RECOMMENDATION 1
It is recommended that all patients with recurrent, metastatic or persistent cervical cancer be offered the opportunity to participate in randomized clinical trials, if available, that evaluate the efficacy of and adverse effects of systemic therapy regimens.

# Summary of Key Evidence and Justification for Recommendation 1
This recommendation is the opinion of the Working Group and was adopted from the previous version of this guideline.

# RECOMMENDATION 2
Cisplatin with paclitaxel is recommended for this patient population, and cisplatin in other combinations, including cisplatin-vinorelbine, cisplatin-gemcitabine, and cisplatin-topotecan may also be considered. The substitution of carboplatin for cisplatin in these combinations is also recommended for this target population because carboplatin is associated with fewer adverse effects and greater ease of administration. The selection of combination chemotherapy will depend on toxicity profile, patient preference, and other factors; for example, cisplatin combinations may be preferred in cases of allergic reaction or of difficulty with bone marrow suppression.

# Summary of Key Evidence and Justification for Recommendation 2
GOG-0204  which included patients with a performance status 1 (meaning that they were restricted in physically strenuous activities but ambulatory) compared the combinations cisplatin-vinorelbine, cisplatin-gemcitabine, and cisplatin-topotecan with the reference arm cisplatin-paclitaxel, with OS as the primary endpoint. This study was terminated early because the comparator groups were unlikely to demonstrate any of the combinations statistically superior to the reference arm, thus justifying the recommendation that each of these combinations could be considered options for the target population.
Paclitaxel (175 mg/m 2 of body surface area for 3 hours on day 1 in combination with carboplatin (area under the curve 5 1h d1) has been tested as an alternative to the standard, but more toxic, paclitaxel (135 mg/m 2 24h d1) and cisplatin (50 mg/m 2 2h d2) in a Japan Clinical Oncology Group phase III noninferiority trial in stage IVB, persistent, or recurrent cervical cancer (JCOG-0505). This study, published as an abstract, followed 253 patients for 17.4 months and demonstrated the noninferiority of carboplatinpaclitaxel compared with cisplatin-paclitaxel (overall survival rate  17.5 versus 18.3 months; hazard ratio 0.99; adjusted 90% confidence interval 0.79 to 1.25; noninferiority p=0.032). Lower rates of neutropenia, febrile neutropenia, creatinine levels, and early treatment discontinuation due to adverse effects were experienced by patients in the carboplatin combination group, as well as higher rates of thrombocytopenia and neuropathy. There was a significantly higher nonhospitalization period, a proxy for quality of life, for patients in the carboplatin-paclitaxel arm. Based on these results, and on the feasibility of administration, carboplatin-paclitaxel is recommended as a treatment option for recurrent, metastatic, or persistent cervical cancer.

# RECOMMENDATION 3
Bevacizumab in combination with cisplatin-paclitaxel is recommended for a specific subset of the target population, which includes only patients that match the characteristics of the GOG-0240 study population. Carboplatin may be substituted for cisplatin in this patient population, based on the justification given under Key Evidence and Justification below.
The subset includes patients with primary stage IVB (has spread to parts of the body away from the cervix, such as the liver, intestines, lungs, or bones) recurrent, or persistent disease not amenable to curative treatment with surgery and/or radiotherapy, who have performance status scores of 1, adequate renal, hepatic, and bone marrow function, and not including those patients previously treated with chemotherapy for recurrence or those with nonhealing wounds, active bleeding conditions or inadequately anticoagulated thromboembolism. In addition, GOG-0240 did not include patients with stage IIIB cancer (local extension to pelvic sidewall) or IVA cancer (invasion into bladder or rectum). For more details on the GOG-0240 patient population, see the study details provided at clinicaltrials.gov.
Contraindications to bevacizumab include: 

# Summary of Key Evidence and Justification for Recommendation 3
Results detected a significant overall survival rate advantage of chemotherapy with cisplatin (50 mg/m 2 and paclitaxel (135 or 175 mg/m 2 d1) or topotecan (0.75 mg/m 2 d1 to d3) and paclitaxel (175 mg/m 2 d1) with bevacizumab (15 mg/kg of body weight d1) (HR], 0.71; 98% CI, 0.54-0.95; p=0.004, one-sided) versus these chemotherapy options without bevacizumab. Cycles were repeated at 21-day intervals. There was also a significant difference in OS for cisplatin-paclitaxel with bevacizumab compared with cisplatin-paclitaxel without bevacizumab (median OS: 17.5 versus 14.3 months, HR, 0.68; 95% CI, 0.48-0.97; p=0.04, one-sided). Patients in the bevacizumab arm experienced more hypertension of grade 2 or higher, thromboembolitic events of grade 3 or higher, and gastrointestinal fistula of grade 3 or higher; however, no significant differences in quality of life were detected. As in GOG-0204, patients in this trial had a performance status of 1. The discontinuation rate was 25% with patients in the bevacizumab group versus 16% of patients in the group that did not receive bevacizumab.
Although GOG-0240 tested bevacizumab with cisplatin and paclitaxel, the noninferiority of carboplatin-paclitaxel demonstrated in JCOG-0505, its more favourable toxicity profile and ease of administration, as well as its demonstrated efficacy in other disease sites  provide support for the recommendation for carboplatin.

# Qualifying Statement for Recommendation 3
There may be a risk of thrombocytopenia with the combination of carboplatin and bevacizumab. However, estimates of the level of risk for this adverse event are not available, as the combination was not tested in the patient population for this guideline. Updating All PEBC documents are maintained and updated through an annual assessment and subsequent review process. This is described in the PEBC Document Assessment and Review Protocol, available on the CCO website at: 
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