Therefore, this process of vascular normalization could enhance the tumor killing activity of radiation as well as improve drug delivery into the tumor [19]. Although the induction of vascular normalization by anti-angiogenic agents has been supported by preclinical studies [20], it remains a challenge to capture the transient “tumor oxygenation window” for the delivery of radiation. We are commencing

real-time imaging of tumor hypoxia profiles in animals during treatment to help explore optimal strategies for this combined Poziotinib in vitro therapy. In the clinic, several clinical phase I/II studies have been conducted to investigate the safety and efficacy of radiation and bevacizumab in R428 cell line cancer patients.

The first report came from a series of 6 patients with locally advanced rectal carcinoma who were treated in a phase I trial with induction therapy of bevacizumab (5 mg/kg x 1 dose) followed by radiation in combination with bevacizumab and 5-fluorouracil, then surgical resection [21]. This pilot study demonstrated that a single dose of bevacizumab induction lead to a significant decrease in interstitial fluid pressure, tumor blood perfusion, and microvascular density on day 12 [21]. The subsequent phase II trial in the same patient population demonstrated that bevacizumab induction therapy followed by concurrent bevacizumab and chemoradiation appeared safe and active with a 5-year local control Adriamycin and overall survival of 100% [22]. The combination of bevacizumab with radiation was also investigated in early clinical studies in other diseases including pancreatic cancer [23] and head and neck cancer [24], in which bevacizumab was started either prior or concurrently with chemoradiation. Conclusions In conclusion, the current study demonstrates enhanced tumor response when bevacizumab

is combined with radiation. These data support the strategy of blocking the VEGF signaling pathway and Glycogen branching enzyme targeting tumor blood vessels to improve the therapeutic index of radiation. Important questions remain including optimization of modality sequencing to achieve best outcome. Further molecular and genetic knowledge regarding angiogenesis, interaction between radiation and tumor, blood vessels as well as microenvironment are needed. New imaging tools that capture real time changes in tumor oxygenation may provide further guidance regarding optimal sequencing of combined antiangiogenic therapies and radiation. Further studies of anti-angiogenic drugs and irradiation in non-squamous carcinoma lung and squamous carcinoma H&N models are warranted. References 1. Folkman J: Tumor angiogenesis: therapeutic implications. N Engl J Med 1971, 285:1182–6.PubMedCrossRef 2.