Predicting benefit from anti-angiogenic agents in malignancy

Key Points The addition of anti-angiogenic agents to cytotoxic chemotherapy prolongs patient survival in specific types of cancer. Objective response is a poor estimate of probable benefit from the addition of anti- vascular-endothelial-growth-factor (VEGF) therapy in colorectal cancer. The cost and choice of cancer therapy are increasing dramatically. Therefore, a high likelihood of benefit is needed to justify the use of a targeted anti-angiogenic agent. Anti-angiogenic therapies induce a number of biological and physiological changes in preclinical models of cancer. Similar observations have been reported in human disease, and might function as early indicators of survival benefit. Resistance to anti-VEGF therapy has been noted in human and animal models. Understanding the mechanisms of resistance will be essential when choosing second-line therapies. The optimal biological dose of anti-angiogenic therapy is likely to be lower than the maximum tolerated dose used for cytotoxic chemotherapy. Biomarkers could be needed to guide adequate dose selection and maximize potential benefit. A better understanding of the mechanism of anti-angiogenic therapy is essential to guide the development of biomarkers, drug choice and dosage, and improve survival. Biomarkers used in determining the response to cytotoxic agents are not optimal for predicting benefit from anti-angiogenic drugs. Which anti-angiogenic biomarkers might prove useful for identifying initial drug choice, appropriate dosing, early clinical benefit, emerging resistance and second-line treatments? A high probability of benefit is desirable to justify the choice of anti-angiogenic therapy from an ever-expanding list of expensive new anticancer agents. However, biomarkers of response to cytotoxic agents are not optimal for predicting benefit from anti-angiogenic drugs. This discussion will focus on both preclinical and clinical research to identify biomarkers for anti-angiogenic therapies that can inform dosing, early clinical benefit, initial drug choice, emerging resistance and second-line treatments.