Vascular endothelial growth factor is a key promoter of angiogenesis and disease progression in epithelial ovarian cancer. Bevacizumab, a vascular endothelial growth factor inhibitor, has shown activity in this condition. Two RCTs published in the New England Journal of Medicine have evaluated its use in the treatment of ovarian cancer.

The first study conducted by the International Collaboration on Ovarian Neoplasms (ICON7)  involved 1528 women (median age 57 years), 90% of whom had epithelial ovarian cancer, 69% serous histologic type, 9% high-risk early-stage disease, 30% high risk for progression, and 70% stage IIIC or IV. They were randomised to carboplatin (AUC 5 or 6) and paclitaxel (175mg/m2), given every 3 weeks for 6 cycles, or to this regimen plus bevacizumab (7.5mg/kg), given concurrently every 3 weeks for 5 or 6 cycles and continued for 12 additional cycles or until disease progression. The outcome measures included progression free survival, first analysed per protocol and then updated, and interim overall survival.

The following findings were reported at 36 months

• Progression free survival (restricted mean) was 20.3 months with standard therapy vs. 21.8 months with standard therapy plus bevacizumab (hazard ratio for progression or death with bevacizumab added = 0.81; 95% CI, 0.70 to 0.94; p= 0.004).

• Non-proportional hazards were detected (i.e. treatment effect was not consistent over time on the hazard function scale; P<0.001), with a maximum effect at 12 months, coinciding with the end of planned bevacizumab treatment and diminishing by 24 months.

• Bevacizumab was associated with more toxic effects; most often hypertension of grade 2 or higher (18%, vs. 2% with chemotherapy alone).

• In the updated analyses, progression-free survival (restricted mean) at 42 months was 22.4 months without bevacizumab vs. 24.1 months, with bevacizumab (p = 0.04); in patients at high risk for progression, the benefit was greater with bevacizumab than without it, with progression-free survival (restricted mean) at 42 months of 14.5 months with standard therapy alone and 18.1 months with bevacizumab added, with respective median overall survival of 28.8 and 36.6 months.

The researchers conclude from these findings that bevacizumab improved progression-free survival in women with ovarian cancer, and the benefits relating to both progression-free and overall survival were greater among those at high risk for disease progression.

The second study from the Gynecologic Oncology Group (GOG), with progression-free survival as the primary end point, involved 1873 patients with newly diagnosed stage III (incompletely resectable) or stage IV epithelial ovarian cancer, who had undergone debulking surgery. They all received chemotherapy consisting of IV paclitaxel (175mg/m2) plus carboplatin at an AUC of 6, for cycles 1 through 6, plus a study treatment for cycles 2 through 22, each cycle of 3 weeks’ duration; and were randomised to receive one of three treatments:

• The control treatment was chemotherapy with placebo added in cycles 2 through 22.

• Bevacizumab-initiation treatment was chemotherapy with bevacizumab (15 mg/kg) added in cycles 2 through 6 and placebo added in cycles 7 through 22.

• Bevacizumab-throughout treatment was chemotherapy with bevacizumab added in cycles 2 through 22.

The following findings were reported:

• Median progression-free survival was 10.3 months in the control group, 11.2 in the bevacizumab-initiation group, and 14.1 in the bevacizumab-throughout group.

• Relative to control treatment, the hazard ratio for progression or death was 0.908 (95% CI, 0.795 to 1.040; p = 0.16) with bevacizumab initiation and 0.717 (0.625 to 0.824; p<0.001) with bevacizumab throughout.

• At the time of analysis, 76.3% of patients were alive, with no significant differences in overall survival among the three groups.

• The rate of hypertension requiring medical therapy was higher in the bevacizumab-initiation group (16.5%) and the bevacizumab-throughout group (22.9%) than in the control group (7.2%).

• Gastrointestinal-wall disruption requiring medical intervention occurred in 1.2%, 2.8%, and 2.6% of patients in the control group, the bevacizumab-initiation group, and the bevacizumab-throughout group, respectively.

The researchers conclude from these findings that “use of bevacizumab during and up to 10 months after carboplatin and paclitaxel chemotherapy prolongs the median progression-free survival by about 4 months in patients with advanced epithelial ovarian cancer.