KEY POINTS
- This preclinical study randomized mice to standard-dose-rate proton RT, FLASH proton RT, or no irradiation. Single-fraction bilateral whole-eye doses of 15, 24, or 30 Gy were tested; 24 Gy was selected because standard-rate treatment reduced rod a-wave amplitude by 39.5% at one month (P<.001) without causing the complete blindness seen at 30 Gy.
- The comparison used identical proton geometry but markedly different delivery rates: the 24-Gy FLASH exposure was delivered at approximately 116.2 Gy/s, versus 0.58 Gy/s for standard-rate irradiation. Normal-tissue experiments generally included 5 mice/10 eyes per group, with serial assessment by OCT, fundus imaging, electroretinography and blinded histopathology.
- Standard-rate 24-Gy irradiation caused progressive corneal injury beginning with edema at one month, followed by ulceration and eventual perforation by five months. FLASH-treated eyes largely maintained corneal transparency and integrity, with ocular surface area 75,985 ± 22,691 µm² versus 38,714 ± 24,616 µm² after standard-rate irradiation and 92,639 ± 18,462 µm² in controls.
- Retinal function diverged dramatically over time. At five months, standard-rate irradiation reduced maximum rod a-wave amplitude by 76%, rod b-wave by 69%, and cone b-wave by 74% versus controls, all P<.0001; FLASH-treated eyes retained near-normal rod, cone and retinal pigment epithelium responses.
- Histopathology confirmed severe multi-compartment injury after standard-rate irradiation, including grade 3–4 corneal inflammation, stromal loss, perforation, uveal inflammation and retinal disorganization. FLASH substantially reduced these abnormalities, although cataract formation and retinal thinning were not prevented, an important limitation to the apparent ocular-sparing effect.
- In an intraocular B16F10 melanoma model, both 24-Gy regimens significantly reduced tumor burden versus untreated controls after one week (P<.05), with no significant difference between FLASH and standard-rate protons. Histology likewise showed comparable short-term tumor reduction between the irradiated groups.
- Translation remains uncertain: the experiment used whole-eye shoot-through irradiation rather than conformal tumor treatment, only one fraction, murine eyes rather than human anatomy, and tumor follow-up of just 7 days because of rapid B16F10 growth. Whether FLASH sparing persists over clinically used multi-fraction ocular proton schedules remains unknown.
CLINICAL TAKEAWAY
This is a strong proof-of-principle demonstration of a FLASH therapeutic-window effect in one of radiation oncology's most function-sensitive organs: severe late ocular injury was markedly reduced without an obvious short-term tumor-control penalty. It is not yet clinical evidence, and fractionation, conformal delivery and durable melanoma control need validation before extrapolation to ocular proton therapy.
SOURCE
International Journal of Radiation Oncology, Biology, Physics