Hypo-fractionated ultra-high dose rate (FLASH) radiation therapy reduces leg contracture in mouse model

Ultra-high dose rate radiation therapy (FLASH-RT) is a novel method of radiation treatment that has shown to spare normal tissues while maintaining an isoeffective anti-tumor response compared to conventional dose rate (CONV) RT. However, the role of fractionation in FLASH-RT has yet to be determined. The purpose of this study is to evaluate the physiological effects of single- and hypo-fractionated electron FLASH-RT on leg contracture to determine the role of fractionation in differential normal tissue toxicity. Female C57Bl/6 mice were separated into three fractionation groups, each containing three dose groups (n=5/group), and one sham treated control group. The mice were treated to a total biologically effective dose (BED) of 120, 200, or 300 Gy using one, three, or five fractions QOD. The left hindlimb was treated with 9 MeV FLASH-RT and the right hindlimb was treated with 9 MeV CONV-RT. The mean dose rate was 460 Gy/s and the dose per pulse was 3.75 Gy across all groups. A Mann-Whitney test was used to compare the peak hindlimb contraction for each group. With single-fraction RT, FLASH-RT had significantly less peak contracture than CONV-RT at 40 (BED=200Gy, p=0.0079) and 50 Gy (BED=300Gy, p=0.0159). Additionally, the FLASH-RT 5-fraction regimen had significantly less peak contracture than CONV-RT at a BED of 200Gy. Longer follow-up, histological analysis on skin and muscle tissue, and skin toxicity scoring by independent radiation oncologists are currently pending. At the BEDs evaluated, FLASH-RT showed a robust differential effect against CONV-RT at single-fractioned 40 and 50 Gy and at the 5-fraction regimen of 15.6 Gy. While 3- and 5-fraction regimen data is maturing, peak contracture occurs earlier and displays a skin- and superficial tissue-sparing, although further trials are needed for further confirmation. Future trials will include histological analysis on tissue and streamline the qualitative scoring process.