Abdominal FLASH irradiation reduces radiation-induced gastrointestinal toxicity for the treatment of ovarian cancer in mice

AUTHORS

Levy KKaren , Natarajan SSuchitra , Wang JJinghui , Chow SStephanie , Eggold JTJoshua T , Loo PEPhoebe E , Manjappa RRakesh , Melemenidis SStavros , Lartey FMFrederick M , Schüler EEmil , Skinner LLawrie , Rafat MMarjan , Ko RRyan , Kim AAnna , H Al-Rawi DDuaa , von Eyben RRie , Dorigo OOliver , Casey KMKerriann M , Graves EEEdward E , Bush KKarl , Yu ASAmy S , Koong ACAlbert C , Maxim PGPeter G , Loo BWBilly W , Rankin EBErinn B . Scientific reports. 2020 12 10; 10(1). 21600

PMID: 33303827[PubMed].

ABSTRACT

Radiation therapy is the most effective cytotoxic therapy for localized tumors. However, normal tissue toxicity limits the radiation dose and the curative potential of radiation therapy when treating larger target volumes. In particular, the highly radiosensitive intestine limits the use of radiation for patients with intra-abdominal tumors. In metastatic ovarian cancer, total abdominal irradiation (TAI) was used as an effective postsurgical adjuvant therapy in the management of abdominal metastases. However, TAI fell out of favor due to high toxicity of the intestine. Here we utilized an innovative preclinical irradiation platform to compare the safety and efficacy of TAI ultra-high dose rate FLASH irradiation to conventional dose rate (CONV) irradiation in mice. We demonstrate that single high dose TAI-FLASH produced less mortality from gastrointestinal syndrome, spared gut function and epithelial integrity, and spared cell death in crypt base columnar cells compared to TAI-CONV irradiation. Importantly, TAI-FLASH and TAI-CONV irradiation had similar efficacy in reducing tumor burden while improving intestinal function in a preclinical model of ovarian cancer metastasis. These findings suggest that FLASH irradiation may be an effective strategy to enhance the therapeutic index of abdominal radiotherapy, with potential application to metastatic ovarian cancer.