Ultra-rapid total abdominal FLASH irradiation in a preclinical model of ovarian cancer.

Abstract

103 Background:Total abdominal irradiation (TAI) is no longer used in the treatment of ovarian cancer due to abdominopelvic toxicity. FLASH irradiation is known to spare the lung, skin and brain from radiation toxicity in preclinical models. Conventional radiotherapy delivers a dose-rate of 2-4 Gy/minute, while our small animal FLASH system uses a linear accelerator to generate a dose-rate of 200 Gy/second. We have demonstrated that FLASH-TAI produces less gastrointestinal (GI) toxicity and death compared to conventional (CONV) radiation in a murine model. Here we present the first data supporting the potential for both tumor control and GI sparing using FLASH-TAI in a syngeneic orthotopic preclinical model of ovarian cancer. Methods: Normal tissue toxicity was assessed through survival, total body weight, solid stool production, complete blood count and histologic analysis. For the tumor model, ID8 ovarian cancer cells were injected intraperitoneally into female C57BL/6mice. Radiation was delivered 10 days post-ID8 injection. Tumor burden was assessed at the time of morbidity. Flow cytometry was used to profile infiltrating immune cells. Results: At 16 Gy, 100% of CONV treated mice demonstrated lethal GI toxicity while 90% of FLASH treated mice recovered to normal bodyweight by day 14. Histologic analysis at 96 hours after 14 Gy FLASH found 3-fold more surviving small intestinal crypts compared to CONV. In the ID8 mice, 14 Gy FLASH spared GI function with a 2-fold higher solid stool production at 5 days post-TAI. Both modalities extended median overall survival in the ID8 model by 5 days and reduced tumor burden by 50% relative to unirradiated controls. Irradiated cohorts also demonstrated a 2-3 fold increase in the number of proliferating CD8+ and CD4+ T cells present in the ascites. Conclusions: Compared to CONV-TAI, FLASH-TAI spares gastrointestinal function, provides equivalent tumor control, and is associated with improved post-radiation recovery and overall survival in an orthotopic preclinical model of ovarian cancer. Our findings suggest an exciting new opportunity to improve the safety of TAI in the treatment of intra-abdominal tumors.