Incorporation of Bevacizumab in the Primary Treatment of Ovarian Cancer

Abstract

Previous studies have shown that vascular endothelial growth factor (VEGF) promotes progression in epithelial ovarian cancer and that blockade of VEGF inhibits growth of this tumor and metastasis. Bevacizumab is a humanized anti-VEGF monoclonal antibody that has single-agent activity in women with recurrent ovarian tumors. This multinational double-blind placebo-controlled trial was designed to evaluate the addition of bevacizumab to standard front-line ovarian cancer therapy in patients with stage III or IV epithelial ovarian cancer. All eligible patients with previously untreated incompletely resectable stage III or any stage IV epithelial ovarian cancer after maximal debulking surgery were randomized to 1 of 3 groups (control, bevacizumab-initiation treatment, and bevacizumab-throughout treatment). Each of the 3 regimens was composed of 22 three-week cycles, with intravenous infusions during first 6 cycles of both carboplatin at an area under the curve of 6 and paclitaxel at a dose of 175 mg/m2 of body-surface area (carboplatin and paclitaxel (CP) therapy). The control group received CP therapy with placebo added in cycles 2 through 22; bevacizumab-initiation group received CP therapy with addition of bevacizumab (15 mg/kg body weight) in cycles 2 through 6 and placebo in cycles 7 through 22; and the bevacizumab-throughout group received CP therapy with addition of bevacizumab (15 mg/kg body weight) in cycles 2 through 22. Progression-free survival according to treatment group was the primary study end point. A total of 1873 women were enrolled from 336 institutions in 4 countries. Analysis of progression-free survival showed mean survival of 10.3 months in the control group, 11.2 in the bevacizumab-initiation group, and 14.1 in the bevacizumab-throughout group. Compared with the control group, there was a lower, but statistically nonsignificant, decrease in the hazard of progression or death in the bevacizumab-initiation group (hazard ratio, 0.908; 95% confidence interval, 0.795–1.040; P = 0.16). In contrast, the hazard was significantly lower in the bevacizumab-throughout group (hazard ratio, 0.717; 95% confidence interval, 0.625–0.824; P < 0.001). At the time of the primary analysis, 76.3% of patients were alive, with no significant differences in overall survival between groups. Hypertension of grade 2 or higher that required medical intervention was significantly more common in the bevacizumab-initiation group (16.5%) and the bevacizumab-throughout group (22.9%) compared with the control group (7.2%) (P < 0.05 for both comparisons). Gastrointestinal wall disruption requiring medical therapy occurred in 2.8% of patients in the bevacizumab-initiation group, 2.6% in the bevacizumab-throughout group, and 1.2% of patients in the control group. These findings show that addition of bevacizumab during and up to 10 months after CP therapy prolongs the median progression-free survival by 4 months in patients with advanced ovarian cancer.