FLASH Proton Radiation Therapy Preserves Ocular Structure and Function Without Compromising Antitumor Efficacy

To evaluate the protective effects and therapeutic efficacy of FLASH proton radiation therapy (FR) compared with standard proton radiation 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 5 months using spectral-domain optical coherence tomography, confocal scanning laser ophthalmoscopy, electroretinography, and histopathologic 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 < .001) without inducing complete blindness. SR-induced progressive ocular injury, with significant corneal edema evident by 1 month (P < .0001), advancing to ulceration by 3 months and complete corneal destruction by 5 months whereas FR maintained corneal transparency comparable to nonirradiated controls. Consistent with these findings, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling analysis demonstrated markedly increased corneal apoptosis following SR, whereas FR showed minimal apoptotic activity. Electroretinography 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 < .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 < .05 vs controls, P > .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 radiation therapy. 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.