Adding bevacizumab to chemotherapy for patients with platinum-resistant ovarian cancer extends progression-free survival (PFS) and overall response rate, suggesting its addition as an option for this difficult patient population, according to results of the AURELIA (Avastin Use in Platinum-Resistant Epithelial Ovarian Cancer) trial. Overall survival (OS) was not significantly affected, however.
In the Phase III open-label study, 361 patients were randomly assigned to chemotherapy alone (CT) or chemotherapy plus bevacizumab (Avastin, Genentech; BEV-CT. All patients had histologically confirmed epithelial ovarian, fallopian tube, or primary peritoneal cancer that had progressed within six months of completing four or more cycles of platinum-based therapy.
Treating clinicians selected their preferred single-agent CT (pegylated liposomal doxorubicin, paclitaxel or topotecan); half of the patients in the study were assigned to CT alone and the rest to BEV-CT. The bevacizumab dose was 10 mg/kg IV every two weeks or 15 mg/kg every three weeks.
Median PFS in the CT arm was 3.4 months (95% confidence interval [CI], 2.2-3.7) and 6.7 months in the BEV-CT group (95% CI, 5.7-7.9). Objective response rate (ORR), evaluated by RECIST (Response Evaluation Criteria In Solid Tumors) and/or GCIG (Gynecologic Cancer Intergroup) cancer antigen (CA)-125 criteria, was 12.6% with CT and 30.9% with BEV-CT (18.3 percentage point difference [95% CI, 9.6-27.0] ). OS was not statistically significant: The study was not powered enough, and the large (40%) crossover from CT to BEV-CT made a determination impossible. Median OS was 13.3 months (95% CI, 11.9-16.4) in the CT group and 16.6 months (95% CI, 13.7-19) in the BEV-CT group.
Eric Pujade-Lauraine of the Université Paris Descartes and his colleagues published the results in the Journal of Clinical Oncology (2014;32:1302-1308, PMID: 24637997). Adverse events (AEs) reported in previous bevacizumab trials (grade 2 or higher hypertension and proteinuria) were also reported here. Hand–foot syndrome and peripheral sensory neuropathy were similar in both groups; these AEs may be related to the longer chemotherapy exposure in the BEV-CT group rather than bevacizumab-related exacerbation of the symptoms. Overall, AEs of interest were reported in 40.3% of the CT group and 57.0% of the BEV-CT group.
Floor Backes, MD|
Assistant Professor and Gynecologic Oncologist
The Ohio State University
Comprehensive Cancer Center–
Arthur G. James Cancer Hospital and
Richard J. Solove Research Institute
The AURELIA study is the fourth largest randomized trial of bevacizumab in ovarian cancer, the second randomized trial in recurrent ovarian cancer, and the first in platinum-resistant disease. The authors found that the addition of bevacizumab to weekly paclitaxel, weekly topotecan or monthly pegylated liposomal doxorubicin prolonged PFS by approximately three months, without a significant increase in toxicity. The improvement in PFS in this study is similar to those seen in the other randomized comparisons. Despite a moderate increase in PFS, bevacizumab has not yet been approved for treatment of ovarian cancer in the United States, but it has been approved in Europe. Although three to four months may seem to be a small increase, patients with platinum-resistant ovarian cancer have limited options and PFS is relatively short. In this particular population, a near doubling of PFS (3.4 to 6.7 months) with a median duration of therapy of three versus six cycles could be considered a significant improvement.
Furthermore, there is ongoing debate over what should be considered the appropriate end points for trials in patients with recurrent disease who are receiving palliative chemotherapy. This is further heightened by the development and use of targeted agents, which do not always demonstrate similar response patterns as cytotoxic agents, although the target is inhibited or otherwise affected. PFS and ORR may reflect a particular therapy’s efficacy more precisely, but one of the goals remains improvement in OS. Quality of life has become a standard secondary outcome, and other patient-reported outcomes are being collected. In this study, the authors found that of the 113 patients with ascites at baseline, only 2% underwent a paracentesis after starting therapy with bevacizumab compared with 17% of those who received chemotherapy alone. In a disease where abdominal symptoms such as bloating, distention and discomfort affect quality of life, improvements in patient-reported outcomes can be considered additional, important measures of clinical benefit. However, to what degree a fairly subjective measure such as patient-reported outcomes should drive trial design and drug approval remains a topic of further investigation and debate.
Similar to previous studies, the addition of bevacizumab to cytotoxic chemotherapy did not improve OS. In this trial, 40% of the patients who received chemotherapy alone proceeded to receive single-agent bevacizumab after progression. This may have obscured the interpretation of true survival benefit, but also poses the question whether adding bevacizumab to chemotherapy versus sequencing it is the best approach. Given the improvement in ORR of 11.8% with chemotherapy alone compared with 27.3% with bevacizumab using RECIST (11.6% vs. 31.8% using GCIG CA-125 criteria), combination therapy seems to be a reasonable option. Fortunately, most of the toxicity that was seen involved hypertension, but the increased risk for bowel perforation (2.2% vs 0%) also should be discussed with the patient.
In conclusion, the addition of bevacizumab to standard therapy for recurrent platinum-resistant ovarian cancer is a reasonable treatment option. The PFS benefit of three months may be the greatest in the subset of patients with abdominal symptoms caused by ascites, in whom a decrease in the need for paracentesis was also seen.
Dr. Backes reported no relevant financial disclosures.