Targeting angiogenesis in cancer: clinical development of bevacizumab.
The importance of vascular endothelial growth factor (VEGF) as a regulator of normal and tumor blood vessel growth has been increasingly characterized over the past two decades. VEGF increases vascular permeability and has a well established role in stimulating angiogenesis, a prerequisite of tumor growth. Numerous compounds have been developed to counteract the angiogenic effects of VEGF. One such drug, bevacizumab, a humanized anti-VEGF monoclonal antibody, received FDA approval in the US earlier this year. Results obtained from initial trials showed that this drug was generally well tolerated, and combination studies of bevacizumab and chemotherapeutic agents have been completed in patients with breast, prostate, lung, and colorectal cancers. A randomized trial of bevacizumab used in combination with capecitabine for metastatic breast patients showed no overall improvement of progression-free survival. However, this result contrasted greatly with the data obtained for patients with advanced colorectal cancer, where a combination regimen of bevacizumab, 5-fluorouracil, leucovorin and irinotecan demonstrated a significant improvement in response rates and overall survival compared with chemotherapy alone. This review highlights the key clinical trial data with bevacizumab and discusses the reasons for some of the contrasting results seen in different patient studies.