The addition of bevacizumab (Avastin) to chemotherapy prolongs overall survival in women with metastatic cervical cancer compared with chemotherapy alone, according to the results of a randomized phase III study presented at the Plenary Session of the ASCO Annual Meeting.1 Women on the bevacizumab-containing arms lived an average of 4 months longer than those on chemotherapy alone.
“This study was a triple-header. The combination of chemotherapy plus an antiangiogenic drug increased overall survival and also improved progression-free survival and response rates. No new side effects were reported, and all serious adverse events occurred in less than 10% of patients. Further, the addition of bevacizumab did not come at an increased cost in quality of life,” stated Krishnansu S. Tewari, MD, Assistant Professor in the Department of Obstetrics & Gynecology at University of California, Irvine.
“This study is the first one to show an overall survival benefit in cervical cancer. This represents a paradigm shift. Cervical cancer occurs mainly in young women, who suffer the bulk of the disease burden,” said Jyoti D. Patel, MD, Associate Professor of Medicine at Robert H. Lurie Comprehensive Cancer Center of Northwestern University in Chicago, who moderated a press conference devoted to Plenary Session presentations.
More than 500,000 cases of cervical cancer and 250,000 related deaths are reported each year worldwide. Approximately 4,000 women die of cervical cancer each year in the United States, and the death rate is so low because of Pap screening. Human papillomavirus (HPV) infection causes cervical cancer, and the average age at diagnosis is 47 years. Treatment options are limited for advanced-stage disease and for relapses. Cisplatin/paclitaxel doublet is the standard of care.
“Although standard chemotherapy can cure patients, those who relapse after initial treatment are resistant to cisplatin. The drug is less effective due to previous exposure to cisplatin, so new treatment options are needed. Angiogenesis is an attractive target to pursue,” Dr. Tewari told listeners.
Gynecologic Oncology Group (GOG) 240 was a randomized study that enrolled 452 women with recurrent or persistent stage IVB cervical cancer despite previous initial treatment with chemotherapy. Participants were randomized to one of four arms: chemotherapy alone with cisplatin/paclitaxel (control arm); topotecan/paclitaxel (a cisplatin-free arm); and each regimen plus bevacizumab. No previous chemotherapy for tumor recurrence was allowed.
One of the goals of the trial was to see whether topotecan substituted for cisplatin would improve outcomes. However, no significant difference in survival was found between the two chemotherapy arms in an earlier interim analysis, Dr. Tewari said. For the present analysis of bevacizumab vs no bevacizumab, results were pooled for the two chemotherapy-alone arms and the two bevacizumab-containing arms.
Overall survival was significantly improved with bevacizumab by 3.7 months. Median overall survival was 13.3 months in the chemotherapy-alone arms vs 17.0 months in the bevacizumab arms (29% reduction in risk of death; P = .0035). “We feel that this nearly 4-month improvement in survival is clinically meaningful in a group of patients who typically don’t respond very well to treatment,” Dr. Tewari said.
Bevacizumab improved progression-free survival as well. Median progression-free survival was 5.9 months with chemotherapy vs 8.2 months with chemotherapy plus bevacizumab, a difference that was highly significant (P = .0002). Response rates were 36% with chemotherapy alone vs 48% with bevacizumab.
Adverse Events and Cost Issues
There were four fatal adverse events in each arm. Bevacizumab treatment led to higher rates of fistula (3% vs 0%), hypertension (25% vs 2%), thrombosis/embolism (9% vs 2%), and grades 3 or higher GI bleeding (4% vs 1%), but all of the side effects were expected. “No new or unexpected adverse events were reported,” Dr. Tewari commented.
Patient-reported quality-of-life measures of well-being and function on the Functional Assessment of Cancer Therapy Cervical Cancer Scale (FACT-Cx) showed no meaningful differences between the two groups. A difference of 4 points or more on the quality-of-life scale is considered clinically meaningful, he said, but patients in the bevacizumab-containing arms differed from those on the chemotherapy-alone arm by an average of only about 1 point.
Dr. Tewari said that cost is a major problem with bevacizumab. The authors plan to do a cost-effectiveness analysis of this trial. “We can demonstrate that antiangiogenic agents improve survival. This opens the door for studies of other antiangiogenic agents, which may be less expensive,” he said at an official press conference.
Expert consensus is that the study will affect treatment decisions. “A reduction in death is the gold standard. We need to review the full published study, but ultimately this should be practice-changing,” said Carol Aghajanian, MD, Chief of the Gynecologic Medical Oncology Service at Memorial Sloan-Kettering Cancer Center in New York. ■
Disclosure: Dr. Tewari reported no potential conflicts of interest.
1. Tewari KS, Sill M, Long HJ, et al: Incorporation of bevacizumab in the treatment of recurrent and metastatic cervical cancer: A phase III randomized trial of the Gynecologic Oncology Group. ASCO Annual Meeting. Abstract 3. Presented June 2, 2013.
Formal discussant Gottfried Konecny, MD, Associate Professor of Medicine, David Geffen School of Medicine at UCLA, also viewed the study as a game changer. He cited the strengths of the study, including its design, randomization with stratification, P values adjusted for multiple testing, and the...