Abstract 1820: Investigating whether FLASH radiotherapy spares late-responding organs using a rat spinal cord model

Abstract Purpose: FLASH radiotherapy (FLASH-RT) delivers curative dose to tumors at ultra-high dose rates (UHDR, >40 Gy/s) while offering normal tissue protection via the FLASH effect. Most supporting evidence relies on acute toxicity, but data on late-responding tissues are limited. Inadequate understanding of dose-response relationships has led to severe late toxicity, such as bone necrosis, halting a FLASH trial in cats. To establish FLASH-RT as a clinical modality, determining the dose-response for late-responding organs is essential. The spinal cord, with its steep dose-response curve and risk of myelopathy, serves as an ideal model. This study investigates whether FLASH-RT mitigates late toxicity using the rat spinal cord, a critical step for clinical translation. Methods: The cervical-thoracic spine (C1-T2) of rats was irradiated with an 18 MeV LINAC-based FLASH beam with a posterior-anterior 2×1cm2 field in a single fraction. A pulse control and monitoring system was developed to ensure precise delivery at single-pulse resolution required to establish the dose response curve. A scintillation detector was placed within the C1-T2 region of a rat carcass for validating Monte Carlo (MC) dose calculations. A custom immobilization device, combined with portable X-ray imaging, was used for precise C1-T2 localization for irradiation. An ion chamber was placed beneath the electron cone to monitor Bremsstrahlung as the surrogate for real-time UHDR output measurement. Dose groups were based on the reported median effective dose (ED50) for conventional dose rate (CONV) treatments (20.4-21.5 Gy) and dose-modifying factors (DMF) for FLASH (1-1.4). Sprague Dawley rats were irradiated with FLASH doses ranging from 15.3 to 28.4 Gy. The dose-related paresis incidence was assessed over a 7-month follow-up period to determine the dose-response curve and whether FLASH enhances spinal cord tolerance compared to CONV-RT. Results: MC calculations demonstrated that the 18 MeV FLASH achieved profile non-uniformity of <5% along the 12 mm length of the C1-T2, effectively mitigating the dose-volume effect, and was reproducible across animals. The dose rate achieved 390 Gy/s, exceeding the threshold of 40 Gy/s. Radiation-induced skin damage healed spontaneously by 10 weeks post-irradiation. The animals showed steady weight gain after irradiation, suggesting that no significant radiation-induced esophagitis was observed. Preliminary results indicated that 3 out of 8 rats in both 21.8 and 28.4 Gy FLASH groups exhibited paralysis. The data collection is still ongoing, and the full dose-response curves for both UHDR and CONV irradiation will be established. Conclusions: Our project addresses a critical knowledge gap in FLASH-RT by elucidating the FLASH dose-response relationships for a key late-responding organ, the spinal cord. The findings will have significant implications for the use of FLASH-RT in clinical setting. Citation Format: Banghao Zhou, Lixiang Guo, Yi-Chun Tsai, Albert van der Kogel, John Wong, Iulian Iordachita, Rongxiao Zhang, Varghese Anto Chirayath, Robert Timmerman, Weiguo Lu, Kai Jiang, Chul Ahn, Paul Medin, Ken Kang-Hsin Wang. Investigating whether FLASH radiotherapy spares late-responding organs using a rat spinal cord model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1820.