Helen Huang

BACKGROUND: Standard chemotherapy for newly diagnosed ovarian cancer is a platinum-taxane combination. The Gynecologic Oncology Group conducted a randomized, phase 3 trial that compared intravenous paclitaxel plus cisplatin with intravenous paclitaxel plus intraperitoneal cisplatin and paclitaxel in patients with stage III ovarian cancer. METHODS: We randomly assigned patients with stage III ovarian carcinoma or primary peritoneal carcinoma with no residual mass greater than 1.0 cm to receive 135 mg of intravenous paclitaxel per square meter of body-surface area over a 24-hour period followed by either 75 mg of intravenous cisplatin per square meter on day 2 (intravenous-therapy group) or 100 mg of intraperitoneal cisplatin per square meter on day 2 and 60 mg of intraperitoneal paclitaxel per square meter on day 8 (intraperitoneal-therapy group). Treatment was given every three weeks for six cycles. Quality of life was assessed. RESULTS: Of 429 patients who underwent randomization, 415 were eligible. Grade 3 and 4 pain, fatigue, and hematologic, gastrointestinal, metabolic, and neurologic toxic effects were more common in the intraperitoneal-therapy group than in the intravenous-therapy group (P< or =0.001). Only 42 percent of the patients in the intraperitoneal-therapy group completed six cycles of the assigned therapy, but the median duration of progression-free survival in the intravenous-therapy and intraperitoneal-therapy groups was 18.3 and 23.8 months, respectively (P=0.05 by the log-rank test). The median duration of overall survival in the intravenous-therapy and intraperitoneal-therapy groups was 49.7 and 65.6 months, respectively (P=0.03 by the log-rank test). Quality of life was significantly worse in the intraperitoneal-therapy group before cycle 4 and three to six weeks after treatment but not one year after treatment. CONCLUSIONS: As compared with intravenous paclitaxel plus cisplatin, intravenous paclitaxel plus intraperitoneal cisplatin and paclitaxel improves survival in patients with optimally debulked stage III ovarian cancer.

BACKGROUND: Vascular endothelial growth factor is a key promoter of angiogenesis and disease progression in epithelial ovarian cancer. Bevacizumab, a humanized anti-vascular endothelial growth factor monoclonal antibody, has shown single-agent activity in women with recurrent tumors. Thus, we aimed to evaluate the addition of bevacizumab to standard front-line therapy. METHODS: In our double-blind, placebo-controlled, phase 3 trial, we randomly assigned eligible patients with newly diagnosed stage III (incompletely resectable) or stage IV epithelial ovarian cancer who had undergone debulking surgery to receive one of three treatments. All three included chemotherapy consisting of intravenous paclitaxel at a dose of 175 mg per square meter of body-surface area, plus carboplatin at an area under the curve of 6, for cycles 1 through 6, plus a study treatment for cycles 2 through 22, each cycle of 3 weeks' duration. The control treatment was chemotherapy with placebo added in cycles 2 through 22; bevacizumab-initiation treatment was chemotherapy with bevacizumab (15 mg per kilogram of body weight) 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 primary end point was progression-free survival. RESULTS: Overall, 1873 women were enrolled. The 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% confidence interval [CI], 0.795 to 1.040; P=0.16) with bevacizumab initiation and 0.717 (95% CI, 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. CONCLUSIONS: The 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. (Funded by the National Cancer Institute and Genentech; ClinicalTrials.gov number, NCT00262847.).

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. METHODS: Using a 2-by-2 factorial design, we randomly assigned 452 patients to chemotherapy with or without bevacizumab at a dose of 15 mg per kilogram of body weight. Chemotherapy consisted of cisplatin at a dose of 50 mg per square meter of body-surface area, plus paclitaxel at a dose of 135 or 175 mg per square meter or topotecan at a dose of 0.75 mg per square meter on days 1 to 3, plus paclitaxel at a dose of 175 mg per square meter on day 1. Cycles were repeated every 21 days until disease progression, the development of unacceptable toxic effects, or a complete response was documented. The primary end point was overall survival; a reduction of 30% in the hazard ratio for death was considered clinically important. RESULTS: Groups were well balanced with respect to age, histologic findings, performance status, previous use or nonuse of a radiosensitizing platinum agent, and disease status. Topotecan-paclitaxel was not superior to cisplatin-paclitaxel (hazard ratio for death, 1.20). With the data for the two chemotherapy regimens combined, the addition of bevacizumab to chemotherapy was associated with increased overall survival (17.0 months vs. 13.3 months; hazard ratio for death, 0.71; 98% confidence interval, 0.54 to 0.95; P=0.004 in a one-sided test) and higher response rates (48% vs. 36%, P=0.008). Bevacizumab, as compared with chemotherapy alone, was associated with an increased incidence of hypertension of grade 2 or higher (25% vs. 2%), thromboembolic events of grade 3 or higher (8% vs. 1%), and gastrointestinal fistulas of grade 3 or higher (3% vs. 0%). CONCLUSIONS: The addition of bevacizumab to combination chemotherapy in patients with recurrent, persistent, or metastatic cervical cancer was associated with an improvement of 3.7 months in median overall survival. (Funded by the National Cancer Institute; GOG 240 ClinicalTrials.gov number, NCT00803062.).