Assessment of Flash Radiotherapy to Spare Late-Responding Tissue Toxicity Using a Rat Spinal Cord Model
Abstract
Purpose
FLASH radiotherapy delivers curative dose to tumor at ultra-high dose rates (UHDR,>40Gy/s) while mitigating normal tissue toxicity. However, data on late-responding tissues are limited, halting its safe clinical translation. Owing to its steep dose–response and clinical relevance, spinal cord is an ideal model for investigating whether FLASH mitigates late toxicity. We present the first dose-response study of the rat spinal cord under UHDR, informing FLASH translation.
Methods
The C1–T2 rat spinal cord was irradiated in a single-fraction 18MeV 14.7–30.6Gy at UHDR and 16–24Gy conventional dose rate (CONV). A posterior–anterior beam and 2×2/2×1cm² field sizes provided uniform coverage of the ~2cm spinal segment. Rats were anesthetized with isoflurane carried by oxygen or medical air. Paresis incidence was monitored for 7 months to establish dose-response relationships quantified by ED50(dose leading to paresis in 50% of rats) as function of dose rate and anesthesia gas. The response curve and latent time were used to evaluate whether FLASH increases cord tolerance.
Results
No significant difference in the dose–response was observed between groups inhaling medical air or oxygen under CONV. However, under UHDR, the response curve was shifted toward higher doses by 1.3Gy for medical air group, compared with the oxygen group. Under medical air, FLASH increased the ED50 by 0.9Gy and ED80 by 1.4Gy compared with CONV irradiation (p<0.1). Although this increase was modest, owing to the steep dose-response, FLASH reduced the probability of paresis by up to 37% at 21.8 Gy. The latency to paresis onset was longer in FLASH-treated animals than in CONV-treated animals.
Conclusion
We generated critical dose-related toxicity data for the spinal cord following single-fraction irradiation. Although the results are promising, particularly for vertebral metastasis re-irradiation scenarios, single-dose irradiation remains highly toxic, underscoring the need for hypofractionation studies to further investigate FLASH-mediated sparing of late toxicity.