A Cochrane Review of bevacizumab in metastatic breast cancer has found the medication helpful in prolonging progression-free survival and boosting response rates in both first and second-line treatment with certain types of chemotherapy.
However, the same review, published July 10 (doi:10.1002/14651858.CD008941.pub2) found no evidence of improvement in overall survival or quality of life associated with bevacizumab (Avastin), a vascular endothelial growth factor inhibitor whose use in metastatic breast cancer remains controversial.
The findings of improved progression-free survival without gains in overall are consistent with previous published systematic reviews and meta-analyses. The Cochrane Review, led by Dr. Anna Dorothea Wagner of the Centre Hospitalier Universitaire Vaudois in Lausanne (Switzerland) incorporates more trials, more individual patient data, and evidence from the most recent published trial of bevacizumab in breast cancer (Lancet Oncology 2011;12,4:369-76).
"Overall, the clinical value of bevacizumab in metastatic breast cancer can at best be considered as modest," the authors concluded.
In an interview about the Cochrane Review, oncologist Robert W. Carlson of Stanford (Calif.) University called the findings "very reassuring." Dr. Carlson, chair of the National Comprehensive Cancer Network (NCCN) panel that has maintained its endorsement of a bevacizumab and paclitaxel combination despite the Food and Drug Administration’s removal of bevacizumab’s breast cancer indication in November 2011, said that the "objective, independent, thorough look at the data comes up with the same conclusions that I think we already knew."
While the FDA revoked bevacizumab’s breast cancer indication in part because of a lack of evidence for an overall survival gain, the European Medicines Agency continues to recommend bevacizumab in combination with paclitaxel for first-line treatment or with capecitabine for the first-line treatment in patients for whom treatment with taxanes or anthracyclines are inappropriate.
"The question remains whether ... bevacizumab should be available for women with breast cancer. It’s interesting how different people can look at the same conclusions and make different inferences. And that’s really what this study highlights," Dr. Carlson said.
For their research, Dr. Wagner and her colleagues looked at published results from seven randomized controlled trials using bevacizumab and various chemotherapy regimen plus data from one registry and five ongoing studies. For some trials, investigators supplied Dr. Wagner and her colleagues with individual patient data. In all, 4,032 women were included in the analysis of progression-free survival (the trials’ primary end point), and 3,841 in analysis of overall survival.
In first-line chemotherapy progression-free survival was seen as significantly better in the bevacizumab trial arms than in the chemotherapy-only arms (hazard ratio, 0.67; 95% confidence interval, 0.61-0.73). For second-line treatment, a smaller but significant benefit was seen associated with bevacizumab (HR, 0.85; 95% CI, 0.73-0.98). Overall survival did not differ significantly in either first-line (HR, 0.93; 95% CI, 0.84-1.04) or second-line treatment (HR, 0.98; 95% CI, 0.83-1.16).
Patients with previous taxane chemotherapy and with hormone receptor–negative status saw significantly greater progression-free survival benefit, the study found. Quality of life data were available for only two trials and did not show a benefit for bevacizumab. Treatment deaths were lower among patients treated with bevacizumab (odds ratio, 0.60; 95% CI, 0.36-0.99), although serious adverse events were higher (OR, 1.41; 95% CI, 1.13-1.75).
Dr. Wagner and her colleagues wrote in their analysis that their findings had more implications for research priorities than for clinical practice, except to say that, in theory, "patients with a large tumor burden, at risk for local complications but without risk factors for thromboembolic or bleeding complications" should be likelier to benefit.
"If the administration of bevacizumab is considered, the combination with paclitaxel weekly, administered as first-line treatment, should be preferred," the authors said.
"Validated clinical or laboratory markers, which permit a selection of patients most likely to benefit from bevacizumab, are highly warranted," the paper concludes.
Dr. Carlson said that in the decision to use bevacizumab, in the absence of validated clinical markers predicting benefit, "relates to how important you think it is to get a response sooner rather than later, and what kind of risk do you place on the very bad but rare serious side effects – bowel perforation or thrombosis. The challenge is can you identify who those people are prospectively. I wish I could."
Although the NCCN breast cancer guideline still states that bevacizumab should remain an option, "it's not necessarily preferred," Dr Carlson said, adding that he has not prescribed bevacizumab outside a clinical trial for at least 2 years. "While my panel believes it should be available, most of us are not using it."
Dr. Wagner and her colleagues’ study was funded by the Martin Luther University Halle-Wittenberg (Germany) and the German government. One of Dr. Wagner’s coauthors, Dr. Christoph Thomssen, reported an advisory role with and funding from Roche, the parent company of Genentech. Dr. Carlson has received research funding in the past from Genentech but is not doing so currently.