Combining angiogenesis inhibition and radiotherapy: a double-edged sword

A large number of patients that undergo radiotherapy develop local failure. To improve the efficacy of treatment, there is an increasing interest in combining radiotherapy with novel targeted therapies. Inhibiting the growth of new tumor blood vessels, i.e. tumor angiogenesis, is such a targeted therapy. Growing tumors induce angiogenesis to ensure an adequate delivery of oxygen and nutrients and several angiostatic drugs have been approved for the treatment of cancer patients. Both pre-clinical and clinical studies have shown that radiotherapy can influence tumor angiogenesis and that angiogenesis inhibition can potentiate the effect of radiotherapy. Therefore, the combination of angiogenesis inhibition and radiotherapy holds a promising future in cancer treatment. However, the radiosensitizing effects of angiogenesis inhibition are transient and recent findings indicate that the effects of irradiation on angiogenesis depend on the dose and treatment schedule. This raises questions regarding the scheduling of both treatment modalities in order to achieve the optimal treatment efficacy with minimal toxicity. In this review the opportunities and pitfalls of combining angiostatic agents with radiotherapy are discussed. The lessons learned from (pre)clinical studies are summarized with an emphasis on scheduling and dosing of the combination therapy. Finally, the opportunities of ongoing clinical studies are discussed and opportunities to improve the combination of angiostatic drugs with radiotherapy are presented.