Tewari KS et al. – This study reported overall survival (OS) and adverse events in patients with advanced cervical cancer treated with bevacizumab. The authors concluded that incorporation of bevacizumab resulted in a sustained benefit with extended follow–up (evidenced by OS curves remaining separated). No negative rebound effect was observed following progression while receiving bevacizumab (shorter survival following cessation of bevacizumab than following cessation of chemotherapy alone). These observations demonstrated proof–of–concept of the efficacy and tolerability of antiangiogenesis therapy in advanced cervical cancer.

Methods

• Randomized, controlled, open–label, phase 3 trial in patients with metastatic, persistent, or recurrent cervical carcinoma from 81 centers in the USA, Canada, and Spain.
• Inclusion criteria comprised patients with Gynecologic Oncology Group (GOG) performance status score of 0 or 1; adequate renal, hepatic, and bone marrow function; adequately anticoagulated thromboembolism; urine protein to creatinine ratio of <1; and measurable disease.
• Ineligibility criteria included patients who received chemotherapy for recurrence and those with non–healing wounds or active bleeding conditions.
• Patients (N = 452) were randomized in 1:1:1:1 (blocking used; block size of 4) to intravenous chemotherapy of either cisplatin (50 mg/m2 on day 1 or 2) plus paclitaxel (135 mg/m2 or 175 mg/m2 on day 1) or topotecan (0.75 mg/m2 on days 1–3) plus paclitaxel (175 mg/m2 on day 1), with or without intravenous bevacizumab (15 mg/kg on day 1) in 21–day cycles until disease progression, unacceptable toxic effects, voluntary withdrawal by the patient, or complete response.
• Randomization was stratified by GOG performance status (0 vs 1), previous radiosensitizing platinum–based chemotherapy, and disease status (recurrent or persistent vs metastatic).
• OS (intention–to–treat [ITT] population) and adverse events (all patients who received treatment and submitted adverse event information) were assessed at the second interim and final analysis (masked Data and Safety Monitoring Board).

Results

• A total of 452 patients were enrolled (April 6, 2009, to January 3, 2012), with 50% (n = 225) in the 2 chemotherapy–alone groups and 50% (n = 227) in the 2 chemotherapy plus bevacizumab groups.
• A total of 348 deaths occurred (March 7, 2014), meeting the prespecified cutoff of the final analysis.
• The chemotherapy plus bevacizumab groups continued to demonstrate significant improvement in OS compared with the chemotherapy–alone groups (16.8 months in the chemotherapy plus bevacizumab groups vs 13.3 months in the chemotherapy–alone groups; hazard ratio 0.77 [95% CI 0.62–0.95]; P = .007).
• Patients who did not receive previous pelvic radiotherapy showed final OS of 24.5 months versus 16.8 months (0.64 [0.37–1.10]; P = .11).
• No significant difference was observed in post–progression OS between the chemotherapy plus bevacizumab (8.4 months) and chemotherapy–alone groups (7.1 months; 0.83 [0.66–1.05]; P = .06).
• Fistula (any grade) was observed in 15% of 220 patients in the chemotherapy plus bevacizumab group versus 1% of 220 patients in the chemotherapy–alone group (all previously irradiated in both the groups).
• Grade 3 fistula developed in 6% versus <1% and none of the fistulas resulted in surgical emergencies, sepsis, or death.