Whole abdominal pencil beam scanned proton FLASH increases acute lethality.

Ultra-high dose-rate FLASH radiotherapy (RT) has emerged as a modality which promises to reduce normal tissue toxicity while maintaining tumor control. Previous studies of gastrointestinal toxicity using passively scattered FLASH proton therapy (PRT) have, however, yielded mixed results, suggesting that the requirements for gastrointestinal sparing by FLASH are an open question. Furthermore, the more clinically relevant pencil beam scanned (PBS) FLASH PRT has not yet been assessed in this context, despite differences in the spatiotemporal dose-rate distributions compared to passively scattered PRT. Here, we provide the first report on the effects of PBS FLASH PRT on acute gastrointestinal injury in mice after whole abdominal irradiation. Whole abdominal irradiation was performed on C57BL/6J mice using the entrance channel of the Bragg curve of a 250 MeV PBS proton beam at field-averaged dose-rates of 0.6 Gy/s for conventional (CONV) and 80-100 Gy/s for FLASH PRT. A 2D strip ionization chamber array was used to measure the dose and dose rate for each mouse. Survival was assessed at 14 Gy. Intestines were harvested and processed as Swiss rolls for analysis using a novel artificial intelligence (AI)-based crypt assay to quantify crypt regeneration 4 days post-irradiation. Survival was significantly reduced following 14 Gy FLASH PRT compared to CONV (P<0.001). Our AI-based crypt assays demonstrated no significant difference in intestinal crypts/cm or crypt depth between groups 4 days post-irradiation. Furthermore, we found no significant difference in EdU Overall, our data demonstrate significantly impaired survival following abdominal PBS FLASH PRT without apparent differences in intestinal histology 4 days post-irradiation.

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Copyright © 2024. Published by Elsevier Inc.

Déclaration de conflit d'intérêts

Conflict of Interest Statement C.G. is the co-founder of BioConvergent Health and serves on an advisory board for the Focused Ultrasound Foundation. C.G., C.B.S., W.A.T., and C.V. have received research support from Varian Medical Systems. W.A.T. receives research support from Accuray Inc and Oncospace. The other authors declare no potential conflicts of interest.