Emerging evidence indicates that SDRT, such as used in this study, may provide therapeutic benefit to some human tumors, even to those considered resistant to conventional fractionated radiotherapy schemes and chemotherapy. Early clinical studies demonstrated that 24 Gy SDRT alone can locally cure >90% of human cancer regardless of tumor type or size, however this curative effect can be acquired only in cases where normal tissues could be completely avoided [4, 28, 29]. Thus, SDRT use is limited in many clinical settings by close proximity of the tumor to critical normal tissue. According to this principle, the critical dose limitation toxicity for SDRT in multiple clinical settings appears to generally be within the range of 14–16 Gy. Therefore, the challenge is to improve tumor response to lower doses of SDRT, and radiosensitization via temporally constrained use of anti-VEGFR agents may be the answer. Prior work demonstrated that bursts of free radical species, generated by waves of hypoxia/reoxygenation occurring after each radiation exposure, lead to induction of hypoxia-inducible factor-1α (HIF-1α) activity . The up-regulation of HIF-1α elevates overexpression of VEGF and other pro-angiogenic factors, which protect tumor endothelium and confer radioresistance . A recent report from a group at MSKCC showed that a hypoxia-activated chemotherapeutic TH-302 combined with VEGF-A inhibition and RT, an exploratory tri-modality therapy, dramatically enhanced tumor response in preclinical models of sarcoma via increasing DNA damage and apoptosis in endothelial cells and decreasing HIF-1α activity . These results indicate that an anti-VEGF approach may improve the radiosensitization and increase local tumor response. Consistent with our previous publications, our current results further provide direct and clear evidence that anti-VEGF treatment synergistically improved tumor response through radiosensitization.