The toxicity of anti-VEGF agents when coupled with standard chemotherapeutics.

Bevacizumab (Avastin®, Genentech, CA) was granted accelerated approval by the FDA for metastatic breast cancer in 2008. This occurred after the initial clinical trial, E2100, demonstrated an improvement in progression-free survival (PFS) and overall survival (OS) with the addition of bevacizumab to a standard chemotherapy. Unfortunately, the approval was rescinded in 2011 when two subsequent trials, AVADO and RIBBON-1, failed to show survival benefit. We compare and analyze the landmark trials E2100, AVADO and RIBBON-1, and suggest that the present-day clinical trial model may not be suited for the investigation of targeted therapies such as bevacizumab. The existing clinical trial model does not allow for modification of chemotherapeutic doses in a manner that maximizes the effect of biologic response modifiers and does not account for its "chemosensitizing" effect. The E2100, AVADO, and RIBBON-1 trials differed in the type and dose of chemotherapy, the dose and frequency of bevacizumab, and in the trial design, making it difficult to effectively compare and evaluate the results. The efficacy of combining bevacizumab with a maximum tolerated dose (MTD) of chemotherapy is also discussed in view of the observation that increased tumor response did not translate to an increase in survival. We suggest that even though angiogenesis inhibitors are non-toxic as monotherapies, they increase the toxicity of standard chemotherapy, and consequently a re-design of the now classic clinical trial model should be considered. Modifying the existing clinical trial model will lead to a more accurate evaluation of the safety and efficacy of bevacizumab and other biological agents in treating metastatic cancer.