Adding Bevacizumab to Chemotherapy Improves Survival in Advanced Cervical Cancer
Retreatment with cisplatin has reduced effectiveness in patients with recurrent cervical cancer who have received cisplatin with radiation therapy. In a 2×2 factorial phase III trial reported in The New England Journal of Medicine, Tewari et al compared cisplatin/paclitaxel vs nonplatinum chemotherapy with topotecan/paclitaxel, both with and without bevacizumab (Avastin), in patients with advanced cervical cancer. Although there was no advantage for the topotecan/paclitaxel combination, the addition of bevacizumab to chemotherapy was associated with significantly prolonged overall survival.
Study Details
In the trial, 425 patients were randomly assigned to receive cisplatin at 50 mg/m2 and paclitaxel at 135 or 175 mg/m2 on day 1 (n = 114), topotecan at 0.75 mg/m2 on days 1 to 3 and paclitaxel at 175 mg/m2 on day 1 (n = 111), cisplatin/paclitaxel plus bevacizumab at 15 mg/kg on day 1 (n = 115), or topotecan/paclitaxel plus bevacizumab (n = 112). Treatment cycles were repeated every 21 days. Treatment groups were well balanced for age, histology, performance status, previous use of a radiosensitizing platinum agent, and disease status; 72% of patients had recurrent disease, 11% had persistent disease, and > 70% of patients in each group had previously received platinum-based chemoradiotherapy. The primary endpoint was overall survival.
Chemotherapy Comparison
At interim analysis, topotecan/paclitaxel with or without bevacizumab was associated with significantly reduced median progression-free survival (5.7 vs 7.6 months, hazard ratio [HR] = 1.39, P = .008) compared with cisplatin/paclitaxel with or without bevacizumab, but there was no significant difference in median overall survival (12.5 vs 15 months, HR = 1.20, P = .88). There was also no significant difference between the two chemotherapy groups in overall survival among patients with previous exposure to platinum or among those with no previous exposure. The data and safety monitoring committee concluded that topotecan was not a superior (or inferior) substitute for cisplatin.
Benefit of Bevacizumab
After median follow-up of 20.8 months, bevacizumab-containing treatment was associated with significantly prolonged median overall survival (17.0 vs 13.3 months, HR = 0.71, P = .004) and progression-free survival (8.2 vs 5.9 months, HR = 0.67, P = .002) vs the combined chemotherapy groups. Bevacizumab-containing treatment was associated with significantly prolonged overall survival compared with cisplatin/paclitaxel (17.5 vs 14.3 months, HR = 0.68, P = .04) and nonsignificantly prolonged overall survival vs topotecan/paclitaxel (16.2 vs 12.7 months, HR = 0.74, P = .09).
Hazard ratios for overall survival favored bevacizumab-containing therapy for all age, performance status, previous platinum radiation therapy status, disease status, topotecan or no topotecan treatment, race, histology, and pelvic disease subgroups except adenocarcinoma histology. Those hazard ratios were significant for the subgroups of patients who were aged 48 to 56 years, had Eastern Cooperative Oncology Group performance status of 1, had received prior platinum radiation therapy, had recurrent or persistent disease, were of black race, were of nonblack race, had squamous histology, and had pelvic disease.
Response rates were higher in all bevacizumab patients compared with chemotherapy alone (48% vs 36%, P = .008, including complete response in 28 vs 14 patients, P = .03), for the bevacizumab-containing treatment vs cisplatin/paclitaxel comparison (50% vs 45%, P = .051, including complete response in 17 vs 9 patients), and for the bevacizumab-containing treatment vs topotecan/paclitaxel comparison (47% vs 27%, P = .002, including complete response in 11 vs 5 patients).
Adverse Events
Hypertension of ≥ grade 2 was significantly more common with bevacizumab-containing regimens than with chemotherapy alone (25% vs 2%, P < .001), although no patients discontinued bevacizumab due to hypertension. Gastrointestinal (3% vs 0%) or genitourinary fistulas (3% vs < 1%) of ≥ grade 3 were significantly more common with bevacizumab (6% vs 0%, P = .002), as were thromboembolic events of ≥ grade 3 (8% vs 1%, P = .001).
Neutropenia of ≥ grade 4 was also significantly more common with bevacizumab (35% vs 26%, P = .04). There were no significant differences between groups in frequency of febrile neutropenia of ≥ grade 3 or pain of ≥ grade 2. Proteinuria of ≥ grade 3 occurred in 2% vs 0% of patients. Gastrointestinal and genitourinary bleeding was uncommon, and no clinically relevant central nervous system bleeding was observed. Fatal adverse events occurred in 1.8% of patients in both groups.
The investigators concluded, “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.”
Krishnansu S. Tewari, MD, of the University of California, Irvine, is the corresponding author of The New England Journal of Medicine article.
The study was funded by the National Cancer Institute. For full disclosures of the study authors, visit www.nejm.org.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
