Improved survival with bevacizumab in advanced cervical cancer

Abstract

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.).

Figure 1. Enrollment, Randomization, and Follow-up of the Study Patients.

All 452 patients (225 in the chemotherapy-alone group and 227 in the chemotherapy-plus-bevacizumab group) who underwent randomization were included in the efficacy analysis. Because data on adverse events were not included for 6 patients in the chemotherapy-alone group, the safety analysis in this group included 219 patients. Because data on adverse events were not included for 7 patients in the chemotherapy-plus-bevacizumab group, the safety analysis in this group included 220 patients. A total of 15 patients randomly assigned to chemotherapy alone crossed over to salvage bevacizumab at the time of disease progression. PFS denotes progression-free survival.

Figure 2. Progression-free and Overall Survival, According to the Chemotherapy Regimen.

Shown are progression-free survival (Panel A) and overall survival (Panel B) among patients assigned to cisplatin–paclitaxel (CP) chemotherapy with or without bevacizumab and those assigned to topotecan–paclitaxel (TP) chemotherapy with or without bevacizumab. An interim analysis showed that as compared with CP with or without bevacizumab, TP with or without bevacizumab was associated with a significantly higher risk of progression but did not significantly affect overall survival.

Figure 3. Effect of Incorporation of Bevacizumab on Survival.

Panel A shows overall survival and Panel B shows progression-free survival among patients who received either chemotherapy regimen plus bevacizumab or either chemotherapy regimen alone. Panel C shows overall survival among patients who received cisplatin–paclitaxel with or without bevacizumab, and Panel D shows overall survival among those who received topotecan–paclitaxel with or without bevacizumab. In Panel E, a forest plot shows the effect of chemotherapy with bevacizumab(experimental), as compared with chemotherapy with out bevacizumab (control), on overall survival, stratified according to multiple prognostic factors. A positive treatment benefit (orange) is indicated. The upper bound of the confidence interval for histologic type was truncated at 2.5. Its true upper bound, 7.07, resulted from a small sample. An interaction test was performed, and nothing was found to be significant. The factor with the smallest P value was histologic type (P = 0.07).