Preclinical testing of ultra-rapid FLASH total abdominal irradiation demonstrates survival benefit and decreased gastrointestinal toxicity compared to conventional external beam radiation.

Abstract

3092 Background: Total abdominal irradiation (TAI) is not widely used in the treatment of ovarian cancer due to high abdominopelvic toxicity. Ultra-rapid FLASH irradiation has been shown to spare the lung, skin and brain from radiation toxicity in preclinical models. Conventional radiotherapy delivers a dose-rate of 3-4 Gy/minute, while our small animal FLASH system uses a linear accelerator to generate a dose-rate of 200 Gy/second. Our data demonstrates that use of FLASH-TAI in a preclinical model protects against death from irradiation and confers gastrointestinal (GI) protection when compared to conventional external beam irradiation. Ongoing studies are evaluating the potential for tumor control in an ID8 mouse model of ovarian cancer. Methods: Female C57BL/6 mice received TAI using FLASH and conventional (CONV) radiation at increasing doses: 8.5 Gy, 10.5 Gy and 12 Gy. Unirradiated controls and irradiated cohorts were analyzed at 5-days and 12 months post-irradiation. Normal tissue toxicity was determined by measuring total body weights, stool counts, laboratory analysis, histological analysis, immunohistochemistry, immunofluorescence microscopy and survival. Results: Solid stool production was preserved in FLASH mice, whereas a 50-63% decrease was observed in the CONV cohorts. Histology demonstrated that FLASH preserves small intestinal architecture. TUNEL analysis demonstrated an increase in apoptosis throughout the small intestine of only the CONV cohort. Exploratory necropsy of all surviving cohorts at 12 months post-irradiation was notable for secondary transmural proximal duodenal adenocarcinomas within the radiation field in 25% of only the aged CONV cohorts. There was no laboratory evidence of long-term hematopoietic, liver or kidney toxicity at 12 months. Survival analysis was notable for death of all 12 Gy CONV mice by 9 days post-irradiation whereas 75% of the 12 Gy FLASH mice were alive at 11 months. Conclusions: FLASH protects against death from TAI, improves small intestine epithelial integrity following TAI, protects against radiation-induced apoptosis and may protect from secondary gastrointestinal tumors in the radiation field. Our discovery that FLASH is a safe strategy to deliver effective doses of total abdominal radiation potentially identifies a new opportunity to utilize FLASH-TAI for treatment of ovarian peritoneal metastases.