Clinical implications of antiangiogenic therapies

The improved survival associated with adding the anti-vascular endothelial growth factor (VEGF) monoclonal antibody bevacizumab (Avastin) to chemotherapy for the treatment of patients with metastatic colorectal cancer demonstrates the importance of targeting collateral cells involved in tumor growth, progression, and metastatic spread. Based on the Gompertzian model of tumor growth, adding anti-VEGF agents to standard chemotherapy may be especially effective in early stages of cancer. By improving chemotherapy delivery to the tumor and inhibiting regrowth between treatment cycles, anti-VEGF agents may alter the growth pattern of a tumor such that it is more susceptible to eradication. These concepts also suggest that anti-VEGF agents could enhance the effectiveness of chemotherapy given conventionally or in a dose-dense fashion. As such, it is possible that the effectiveness of chemotherapy could be maintained or improved, even at lower cumulative doses, which may improve its tolerability. Additionally, the effects of anti-VEGF agents on metronomic chemotherapy, which is reported to have antiangiogenic properties on its own, warrant further evaluation. Preclinical data demonstrate that cytostatic angiogenesis inhibitors are potent complementary agents to metronomic chemotherapy, producing sustained complete regressions in some models of human cancer. Dose-dense and metronomic chemotherapy have in common a shortened dosing interval and resultant increased and/or prolonged exposure of tumor cells to chemotherapy in vivo. Optimizing the use of anti-VEGF agents in the clinic demands further investigation of the most appropriate way to combine them with chemotherapy, particularly regimens designed to exploit known tumor growth patterns and those designed to target the endothelial cells involved in neovascularization with multiple agents.