Carboplatin and paclitaxel (CP) plus bevacizumab, followed by bevacizumab maintenance, may now offer another treatment option for women diagnosed with any of a constellation of advanced ovarian cancers — epithelial ovarian cancer, primary peritoneal cancer, or fallopian tube cancer. Support for this regimen comes from an international phase III Gynecologic Oncology Group (GOG) study that demonstrated prolonged progression-free survival (PFS) with the addition of concomitant and maintenance bevacizumab to CP compared with CP alone in patients receiving frontline treatment for advanced ovarian cancer.

“Bevacizumab is the first moleculartargeted and first antiangiogenic agent to demonstrate benefit in this population, and bevacizumab combined with chemotherapy followed by bevacizumab maintenance should be considered as one standard option for these patients,” said Robert A. Burger, MD, of Fox Chase Cancer Center, who presented the potentially practice-changing results of the GOG-0218 study during the Plenary Session (Abstract LBA1) at ASCO's 2010 Annual Meeting.

As Discussant Elizabeth A. Eisenhauer, MD, of the National Cancer Institute of Canada Clinical Trials Group and Queen’s University, Canada, explained, CP has ruled as standard frontline therapy for advanced ovarian cancer for about a decade. However, even with this therapy, the majority of patients die from their disease. Recent efforts to better address the unmet survival need among these women have prompted a flurry of phase III trials evaluating the addition of an angiogenesis inhibitor in ovarian cancer management. GOG-0218 constitutes the first of these phase III studies to be reported, and according to Dr. Eisenhauer, “its strengths are many.”

The double-blind, placebo-controlled, phase III trial enrolled nearly 1,900 patients with chemotherapy-naive stage III or IV epithelial ovarian cancer, primary peritoneal cancer, or fallopian tube cancer in the United States, Canada, South Korea, and Japan. All women underwent abdominal surgery for staging and maximal tumor debulking before being randomly assigned to one of three treatment arms: (1) CP plus placebo during the induction phase (cycles 1 to 6), followed by placebo maintenance (cycles 7 to 22); (2) CP plus concurrent bevacizumab during induction, followed by placebo maintenance; and (3) CP plus concurrent bevacizumab during induction, followed by bevacizumab maintenance. Bevacizumab was not administered during the first 21-day induction cycle so as to limit postsurgical bleeding complications. The entire treatment schedule took 15 months to complete.

Although overall survival was originally selected as the primary endpoint, this was changed to PFS to accord with international consensus as a more appropriate endpoint for frontline phase III trials in this patient population, as well as pressure by patients to unblind their treatment assignment in the event of disease progression. The investigators monitored disease progression based on radiographic evidence, CA-125 measurements, and global clinical deterioration. Overall survival, safety, and quality of life comprised the secondary endpoints.

Patients had a median age of 60, 84% were white, and 93% had a GOG performance status of 0 or 1. Despite attempts at maximal tumor debulking, only 34% had optimally debulked stage III disease; 40% had stage III suboptimally debulked disease; 26% had stage IV disease.

	Figure 1. Abbreviations: BEV, bevacizumab; CI, confi dence interval; CP, carboplatin/paclitaxel; GOG, Gynecologic Oncology Group; HR, hazard ratio; PFS, progression-free survival.

After a median follow-up of 17.4 months (range: 0 to 50.7 months), PFS was significantly prolonged by 3.8 months with CP plus concomitant and maintenance bevacizumab compared with CP alone (14.1 months compared with 10.3 months, respectively; hazard ratio [HR] = 0.717; p < 0.0001; Fig. 1). Moreover, all patient subgroups analyzed exhibited consistent improvements in PFS with the concomitant and maintenance bevacizumab regimen regardless of disease stage, performance status, and patient age (HRs ranged from 0.618 to 0.763).

No significant difference in PFS was observed between the arm that received CP plus concomitant bevacizumab only and the arm that received CP alone (11.2 months compared with 10.3 months, respectively; HR = 0.908; p = 0.080).

The investigators have not yet discerned any differences in overall survival across the three arms; however, the survival data are not yet mature. At the time of data analysis, median overall survival ranged from 38.7 to 39.7 months, and 1-year survival ranged from 90.4% to 91.3%.

The addition of bevacizumab to CP appeared well tolerated, with no unexpected adverse events observed. Although hypertension — a known side effect of bevacizumab — occurred significantly more often in the bevacizumab arms compared with the control arm (p < 0.05), the incidences of all other adverse events were similar across arms, including neutropenia (57.7% to 63.3%) and thromboembolic events (6.0% to 7.4%). Dr. Burger emphasized that gastrointestinal perforation events did not markedly increase with use of bevacizumab (2.6% to 2.8% in the bevacizumab arms compared with 1.2% in the control arm), and bleeding complications were rare in all arms (0.8% to 2.4%).

Dr. Eisenhauer offered several insights on the GOG-0218 outcomes. “On the basis of today’s results, I believe the use of bevacizumab in standard clinical practice may be premature. A PFS gain of only 3.8 months may not be meaningful to patients,” she said. “We need the mature overall survival and quality-of-life results…to understand the full story of the [effect] of this advance. I hope these data will show that there is a clear and meaningful survival gain for these women who desperately need it.”