1105 - The Sparing Effect of FLASH Radiotherapy on Intestinal Tissue in Mice Using Conventional Fractionation

Purpose/Objective(s): FLASH radiotherapy (FLASH-RT) has shown remarkable potential in reducing normal tissue toxicity while preserving tumor control. Despite its promise, most preclinical studies have focused on single-dose irradiation, leaving critical gaps in our understanding of the FLASH effect under fractionated conditions. Specifically, it remains unclear whether FLASH-RT can maintain its tissue-sparing benefits during multi-angle irradiation with gantry rotation, which is commonly used in clinical practice. This study aims to address these gaps by investigating the FLASH effect on intestinal tissues following fractionated whole-abdomen irradiation.

Materials/Methods: C57BL/6 mice were subjected to fractionated whole-abdominal irradiation using FLASH-RT or conventional dose-rate radiotherapy (CONV-RT). FLASH-RT was delivered using electron beams at a dose rate of =550 Gy/s. Fractionated dose regimens were designed to deliver single doses ranging from 2.2 Gy to 4 Gy per fraction, with 1-minute intervals between fractions. Survival, body weight, and intestinal crypt regeneration were evaluated to assess intestinal toxicity and persistence of the FLASH intestine-sparing effect under fractionation. Irradiation parameters such as the total dose, pulse dose, dose rate, and pulse frequency were varied.

Results: Fractionated FLASH irradiation resulted in outcomes superior to those of CONV irradiation. Survival rates were significantly higher following FLASH-RT at 11 Gy in five fractions (2.2Gy per fraction) than after CONV-RT at 11 Gy. And the survival rates among FLASH mice in the one-, two-, and five-fraction groups were not significantly different. To ensure robust comparisons and account for potential confounding variables, we systematically evaluated various irradiation parameters, including total doses (9, 10, and 12 Gy), mean dose rates (550-784 Gy/s), pulse doses (1.25-3 Gy/pulse), and frequencies (250-560 Hz). Across a wide range of irradiation parameters, FLASH-RT consistently yielded superior survival outcomes compared to CONV-RT, with efficacy comparable to that of single-fraction FLASH irradiation. Similarly, body weight recovery was better with FLASH-RT at 8 Gy in two fractions than with CONV-RT at 8 Gy, and intestinal crypt regeneration was greater with FLASH-RT at 12 Gy in four fractions than with CONV-RT at 12 Gy. These findings suggested that the intestinal FLASH effect occurs at dose thresholds as low as 2.2–4 Gy.

Conclusion: This study demonstrates that FLASH-RT retains its robust tissue-sparing effects on intestinal toxicity under conventional fractionation regimens, with no compromise in efficacy compared to single-dose irradiation. These findings suggest that multibeam irradiation can be employed in abdominal and pelvic FLASH-RT to achieve good dose conformity. By demonstrating a low dose threshold for the intestinal FLASH effect, our findings indicate its applicability in both hypofractionated and conventional fractionated regimens.