Future directions in vascular endothelial growth factor-targeted therapy for metastatic colorectal cancer.

Bevacizumab, the first approved vascular endothelial growth factor (VEGF)-targeted agent for metastatic colorectal cancer, continues to be developed in phase III trials in other tumor types. Its use is being explored not only in advanced disease, but also in earlier-stage disease in the adjuvant setting. Preclinical and clinical research is also addressing several potential strategies for maximizing the benefits of bevacizumab and other VEGF-targeted agents, including (1) dual inhibition of VEGF and platelet-derived growth factor signaling to target both the endothelial and the pericyte components of tumor vasculature; (2) combining VEGF-targeted agents with other targeted agents, such as inhibitors of HER2 or epidermal growth factor receptor signaling, which affect several angiogenic pathways; and (3) combining VEGF-targeted agents with low-dose, metronomic chemotherapy. The optimal dose and schedule of VEGF-targeted agents is another unanswered question. Further investigation of the mechanism of action and vascular effects of VEGF-targeted agents in humans will help to address these questions. Mechanistic studies in humans will be aided by the development and validation of surrogate clinical end points such as noninvasive assessment of hemodynamics and vascular changes within tumors, using imaging studies.