FLASH Proton Radiotherapy Preserves Ocular Structure and Function Without Compromising Antitumor Efficacy.

Abstract

To evaluate the protective effects and therapeutic efficacy of FLASH proton therapy (FR) compared with standard dose-rate proton therapy (SR) in a preclinical model of ocular irradiation. Mice received bilateral ocular irradiation with SR (≤1 Gy/s) or FR (>40 Gy/s) at identical doses. Longitudinal ocular structure and function were assessed over five months using spectral-domain optical coherence tomography, confocal scanning laser ophthalmoscopy, electroretinography (ERG), and histopathological analysis. Tumor control was evaluated in an intraocular B16F10 melanoma model using bioluminescence imaging and histopathology. Dose-response studies identified 24 Gy as the optimal dose, producing substantial visual impairment with SR (39.5% reduction in rod a-wave amplitude, p<0.001) without inducing complete blindness. SR induced progressive ocular injury, with significant corneal edema evident by 1 month (p<0.0001), advancing to ulceration by 5 months, whereas FR maintained corneal transparency comparable to non-irradiated controls. Consistent with these findings, TUNEL analysis demonstrated markedly increased corneal apoptosis following SR, whereas FR showed minimal apoptotic activity. ERG analysis revealed profound SR-induced functional deterioration by 5 months, with a 76% reduction in rod a-wave, 69% in rod b-wave, and 74% in cone b-wave amplitudes (all p<0.0001), reflecting extensive photoreceptor and bipolar cell dysfunction. FR eyes retained near-normal responses across retinal layers. Histopathology confirmed severe SR-associated pathology, including corneal perforation, uveal inflammation, and retinal disorganization, whereas FR largely preserved ocular architecture. Importantly, FR maintained short-term antitumor efficacy equivalent to SR, with comparable reductions in tumor burden (both p<0.05 vs. controls; p>0.05 SR vs. FR). FR provides substantial normal tissue protection across multiple ocular compartments while preserving therapeutic efficacy, effectively expanding the therapeutic window for ocular radiotherapy. These findings establish proof-of-principle for clinical translation of FR to improve visual outcomes in patients with ocular and orbital malignancies without compromising tumor control.