TOTAL ABDOMINAL ULTRA-RAPID FLASH IRRADIATION DEMONSTRATES DECREASED GASTROINTESTINAL TOXICITY COMPARED TO CONVENTIONAL TOTAL ABDOMINAL IRRADIATION IN MICE

OBJECTIVE: Ovarian cancer is the most common cause of gynecologic cancer-related death in the United States. The majority of patients diagnosed with ovarian cancer present with stage III or IV disease in which the tumor has disseminated beyond the ovaries and pelvic organs to the peritoneum and mesothelial lining of abdominal organs. Despite advances in ovarian cancer treatments including maximal cytoreductive surgery, chemotherapy and checkpoint-blockade immunotherapy, recurrence is common and prognosis remains poor. Ovarian cancer is a radiosensitive tumor; however, use of total abdominal irradiation (TAI) has fallen out of favor in the past 15 years due to high toxicity, particularly of the gastrointestinal (GI) tract. In prior studies, ultra-rapid FLASH radiation spares normal tissues, such as the lung and skin, from toxic effects of radiation. This suggests that FLASH may be an effective strategy to reduce complications of radiotherapy while maintaining antitumor control. We developed a FLASH irradiation system for mice using a linear accelerator that generates 16 MeV electrons at a high beam current and delivers large doses of radiation in a single beam in 40 Gy/second. Our objective is to develop a method for delivering TAI using FLASH and assess toxicity. METHODS: Female C57BL/6 mice received TAI using FLASH and conventional (CONV) radiation in increasing doses: 8.5 Gy, 10.5 Gy and 12 Gy. Normal tissue toxicity was determined by measuring total body weights, stool counts, histological analysis, and survival. RESULTS: Seven cohorts of mice were analyzed: five unirradiated controls, eight received 8.5Gy, five received 10.5Gy and five received 12 Gy of either TAI-FLASH or TAI-CONV. Stool counts were unchanged from controls in TAI-FLASH mice 5 days post-irradiation at all doses. In the TAI-CONV cohort, a 50% stool quantity decrease was noted after 8.5Gy and a 63% stool quantity decrease was noted after 12Gy at 5 days post-TAI. Histological analysis of the duodenum post-irradiation demonstrated that TAI-FLASH has a protective effect on the mucosal architecture. Weights remained unchanged across all groups. The survival analysis was most notable for all of the TAI-CONV mice having died by day 9 whereas all of the TAI-FLASH mice survived. CONCLUSIONS: These data demonstrate FLASH protects against death from TAI and improves the epithelial integrity of the lower GI tract following TAI compared to conventional radiation in a preclinical model. Our discovery that FLASH is a safe strategy to deliver effective doses of total abdominal radiation potentially identifies a new opportunity to utilize TAI-FLASH for treatment of ovarian peritoneal metastases. Citation Format: Karen Levy MD, Joshua Eggold BA, Marjan Rafat PhD, Emil Schuler PhD, Hussein Shehade PhD, Daniel Fregoso BS, Jose Vilches-Moure DVM PhD, Albert Koong MD PhD, Peter Maxim PhD MSc, Billy W Loo MD PhD, Erinn Rankin PhD. TOTAL ABDOMINAL ULTRA-RAPID FLASH IRRADIATION DEMONSTRATES DECREASED GASTROINTESTINAL TOXICITY COMPARED TO CONVENTIONAL TOTAL ABDOMINAL IRRADIATION IN MICE [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr AP25.