Monitoring the Effects of Anti-angiogenesis on the Radiation Sensitivity of Pancreatic Cancer Xenografts Using Dynamic Contrast-Enhanced CT

Abstract

Purpose To image the intra-tumor vascular physiological status of pancreatic tumors xenografts and their response to anti-angiogenic therapy using Dynamic Contrast-Enhanced CT (DCE-CT), and to identify parameters of vascular physiology associated with tumor X-ray sensitivity following anti-angiogenic therapy. Methods and Materials Nude mice bearing human BxPC-3 pancreatic tumor xenografts were treated with 5Gy of radiation therapy (RT), either a low-dose (40mg/kg) or a high-dose (150mg/kg) of DC101, the anti-VEGF receptor-2 anti-angiogenesis antibody, or with combination of low or high dose DC101 and 5Gy RT (DC101-plus-RT). DCE-CT scans were longitudinally acquired over three week period post-DC101 treatment. Parametric maps of tumor perfusion and fractional plasma volume (Fp) were calculated and their averaged values and histogram distributions evaluated and compared to controls, from which a more homogeneous physiological window was observed 1-week post-DC101. Mice receiving a combination of DC101-plus-RT(5Gy) were imaged baseline prior to receiving DC101 and 1-week after DC101 (prior to RT). Changes in perfusion and Fp were compared with alternation in tumor growth delay for RT and DC101-plus-RT(5Gy) treated tumors. Results Pretreatment with low or high doses of DC101 prior to RT significantly delayed tumor growth by an average 7.9 days compared to RT alone (p≤0.01). The increase in tumor growth delay for the DC101-plus-RT treated tumors was strongly associated with changes in tumor perfusion (ΔP>−15%) compared to RT treated tumors alone (p=0.01). In addition, further analysis revealed a trend linking the tumor’s increased growth delay to its tumor volume-to-DC101 dose ratio. Conclusions DCE-CT is capable of monitoring changes in intra-tumor physiological parameter of tumor perfusion in response to anti-angiogenic therapy of a pancreatic human tumor xenograft that was associated with enhanced radiation response.