Abstract 850: Vascular based strategies for enhancing tumour response to radiation administered in a stereotactic schedule

Abstract

Abstract Background: Various agents that influence tumour vasculature have been shown to be capable of enhancing tumour response to radiation administered as single treatments or in limited fractionated schedules. The aim of this pre-clinical study was to investigate the potential of such agents to improve tumour response to a clinically relevant stereotactic radiation schedule. Material and methods: A C3H mammary carcinoma grown in the right rear foot of female CDF1 mice was used in all experiments. Treatments were performed in restrained non-anaesthetised animals when tumours had reached 200 cubic mm in size. Tumours were locally irradiated (230 kV x-rays) with 3 x 15 Gy (each fraction given with an interval of 2-3 days over a one week period). The vascular based strategies were the drug OXi4503 (10 mg/kg intraperitoneally injected 1 hour after irradiating) or mild temperature hyperthermia (MTH; 41.5 degrees C for 60 minutes starting 4 hours after irradiating). OXi4503 or MTH were given either with each of the 3 x 15 Gy irradiations or only the final 15 Gy treatment. Three days after the final irradiation the tumours were subjected to a clamped top-up dose which involved giving graded radiation doses with the tumour bearing leg clamped for 5 minutes before and during irradiation. The percentage of mice in each treatment group showing local tumour control 90 days after irradiating was recorded and the TCD50 values (radiation dose to control 50% of tumours) estimated from the clamped top-up radiation dose response curves. A Chi-squared test (p<0.05) was used to determine significant differences between TCD50 values. Results: The clamped top-up TCD50 value (with 95% confidence intervals) following 3 x 15 Gy was 30 Gy (23-38). This was significantly reduced to 12 Gy (8-19) if OXi4503 was given with all three 15 Gy irradiations and to the same 12 Gy (6-25) value when injected with only the last radiation treatment. Similar effects were seen with 3 or 1 MTH treatments; the respective TCD50 values being 9 Gy (5-17) and 10 Gy (7-15). Combining OXi4503 with MTH, but only administering them with the final 15 Gy irradiation, gave the greatest enhancement with the TCD50 value being 2 Gy (1-9). Conclusions: Vascular based strategies are very effective at improving the efficacy of radiation given in a stereotactic schedule. Surprisingly, this enhancement was independent of the frequency at which these vascular modifiers were administered. The greatest effect was observed by combining complimentary vascular modifying agents. Supported by grants from the Danish Cancer Society and the Danish Council for Independent Research: Medical Sciences. Citation Format: Michael R. Horsman, Thomas Wittenborn. Vascular based strategies for enhancing tumour response to radiation administered in a stereotactic schedule. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 850. doi:10.1158/1538-7445.AM2014-850