Background: For women with advanced ovarian cancer, surgery and platinum-based chemotherapy are the standard treatment, but the prognosis is poor. Angiogenesis is involved in ovarian cancer. Bevacizumab, a vascular endothelial growth factor (VEGF) inhibitor, has shown tumor response and delayed progression in women with ovarian cancer in early clinical trials. Two new, phase 3 studies have examined its effect on progression-free survival (PFS) and overall survival (OS) in women with advanced ovarian cancer.
Design: In the international Gynecologic Oncology Group (GOG)-0218 study, 1873 women (median age, 60 years) with newly diagnosed stage III (incompletely resectable) or stage IV epithelial ovarian cancer who had undergone debulking surgery were randomized to receive 1 of 3 treatment options for 22 cycles of 3 weeks each: standard chemotherapy (carboplatin plus paclitaxel, cycles 1-6) followed by placebo (cycles 7-22); standard chemotherapy plus bevacizumab
The second study, the International Collaboration on Ovarian Neoplasms (ICON7) trial, had a similar design, but only 91% of the 1528 patients enrolled in the study had stage III or IV ovarian cancer; 9% had high-risk early-stage disease, and 30% were at high risk for progression. Patients (median age, 57 years) were randomized to receive either standard chemotherapy (carboplatin plus paclitaxel) every 3 weeks for 6 cycles or standard chemotherapy plus bevacizumab 7.5 mg/kg every 3 weeks for 5 or 6 cycles and continue with bevacizumab for an additional 12 cycles, or until disease progression occurred.
Summary: In GOG-0218, after a median follow-up of 17.4 months, median PFS was 14.1 months in patients who received bevacizumab throughout the study (hazard ratio [HR] for progression or death vs standard chemotherapy only, 0.717; 95% confidence interval [CI], 0.625-0.824; P = .001) versus 11.2 months in those who received bevacizumab only in the initial cycles (HR, 0.908; CI, 0.795-1.040; P = .16) and 10.3 months for those who received only standard chemotherapy. The difference in OS between the treatment groups was not significant. Hypertension was the only adverse event that was significantly more common in those who received bevacizumab throughout the entire period (22.9%) or in the initial cycles (16.5%) than in those receiving standard chemotherapy (7.2%).
In the ICON7 study, after a median follow-up of 19.4 months, the median PFS differed by approximately 2 months between the bevacizumab group and the standard chemotherapy group: 19.0 months versus 17.3 months, respectively (HR, 0.81; 95% CI, 0.70-0.94; P = .004). Among patients at high risk for progression, however, the difference between the 2 treatment groups was much greater: 15.9 months versus 10.3 months, respectively (HR, 0.68; 95% CI, 0.55-0.85; P = .001). At 42 months, the OS in women at high risk was 36.6 months versus 28.8 months (P = .002). As in the GOG-0218 study, hypertension was more common in the bevacizumab group than in the standard chemotherapy group (18% vs 2%, respectively). Thromboembolic events were also more frequent in the bevacizumab group (7% vs 3%, respectively).
Takeaway: These 2 phase 3 studies showed that bevacizumab added to standard paclitaxel/carboplatin chemotherapy improved both PFS and OS by several months for women in the high-risk category. The median OS in the treatment arm had not yet been reached. The HR of 0.85 indicates only a modest improvement over standard chemotherapy alone. Furthermore, the toxicity range was expanded to include hypertension and the risk of bowel perforation. The dosage of bevacizumab was different in each of the studies, but not enough to produce a major difference in outcome. The study by Perrin and the ICON7 group used a dose of 7.5 mg/kg for 12 cycles (compared with 15 mg/kg for 16 cycles).
Do these studies establish that this combination should be a first-line therapy for high-risk patients with ovarian cancer? I agree with the authors of the GOG-0218 study, who suggest that further studies are needed to assess how to integrate bevacizumab into the standard front-line therapies of neoadjuvant or intraperitoneal chemotherapy. The optimal duration of therapy and its cost-effectiveness are both important questions that need to be answered before combination chemotherapy plus bevacizumab becomes the standard of care for high-risk ovarian cancer.
Burger RA, et al. Incorporation of bevacizumab in the primary treatment of ovarian cancer. N Engl J Med. 2011;365:2473-2483; Perren TJ, et al. A phase 3 trial of bevacizumab in ovarian cancer. N Engl J Med. 2011;365:2484-2496.