Background-Vascular endothelial growth factor (VEGF) promotes angiogenesis, a mediator of disease progression in cervical cancer. Bevacizumab, a humanized anti-VEGF monoclonal antibody, has single-agent activity in previously treated, recurrent disease. Most patients in whom recurrent cervical cancer develops have previously received cisplatin with radiation therapy, which reduces the effectiveness of cisplatin at the time of recurrence. We evaluated the effectiveness of bevacizumab and nonplatinum combination chemotherapy in patients with recurrent, persistent, or metastatic cervical cancer.

Background On August 14, 2014, the United States Food and Drug Administration approved the anti-angiogenesis drug, bevacizumab, for women with advanced cervical cancer based on a 2012 interim analysis of 271 deaths on GOG protocol 240. We now report the planned protocol-specified final analysis of the primary objective, overall survival (OS). Methods A phase III randomized trial using a 2×2 factorial design was conducted to determine whether intravenous chemotherapy [(cisplatin 50 mg/m2 plus paclitaxel 135 or 175 mg/m2) or (topotecan 0.75 mg/m2 days 1–3 plus paclitaxel 175 mg/m2)] with or without bevacizumab (15 mg/kg) improves OS in recurrent/persistent/metastatic cervical cancer. Patients were prospectively stratified by performance status, prior radiosensitizing platinum, and disease status. We estimated enrolling 450 patients with 346 deaths at final analysis to provide 90% power to detect a 30% reduction in risk of death. Findings On March 7, 2014, 348 deaths occurred among 452 patients. Regimens administering bevacizumab continued to demonstrate significant improvement in OS: 16.8 vs 13.3 mos (HR 0.77;95% CI 0.62–0.95;p=0.0068). Updated progression-free survival also favored bevacizumab (HR 0.68;95% CI 0.56–0.84;p=0.0002). Final OS among 20% (n=91) not treated with prior pelvic radiotherapy was 24.5 (bevacizumab) vs 16.8 mos (without bevacizumab). Fistula (any grade) occurred in 14.5% (n=32) receiving bevacizumab (all previously irradiated). Grade 3+ fistula developed in 5.9% (n=13) and did not result in surgical emergency, sepsis and/or death. Post-progression OS was not significantly different among those who did and did not receive bevacizumab (median 8.4 vs 7.1 mos: HR 0.32;95% CI 0.66–1.05;p=0.06). Interpretation The benefit conferred by incorporation of bevacizumab is sustained with extended follow-up as evidenced by the survival curves remaining separated. Following progression on bevacizumab, a negative rebound effect was not observed. This represents proof-of-concept of the efficacy and tolerability of anti-angiogenesis therapy in advanced cervical cancer. Funding National Cancer Institute (USA).

Background-Vascular endothelial growth factor (VEGF) promotes angiogenesis, a mediator of disease progression in cervical cancer. Bevacizumab, a humanized anti-VEGF monoclonal antibody, has single-agent activity in previously treated, recurrent disease. Most patients in whom recurrent cervical cancer develops have previously received cisplatin with radiation therapy, which reduces the effectiveness of cisplatin at the time of recurrence. We evaluated the effectiveness of bevacizumab and nonplatinum combination chemotherapy in patients with recurrent, persistent, or metastatic cervical cancer.