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

Karen Levy,Amy S Yu,Emil Schüler,Duaa H Al-Rawi,Anna Kim,Stephanie Chow,Stavros Melemenidis,Joshua T Eggold,Rakesh Manjappa,Phoebe Loo ,Frederick M Lartey,Marjan Rafat,Lawrie Skinner,Rie Von Eyben,Karl Bush,Albert C Koong,Billy W Loo,Edward E Graves,Peter G Maxim,Suchitra Natarajan,Ryan B Ko ,Oliver Dorigo,Kerriann M Casey,Jinghui Wang,Erinn B Rankin

doi:10.1038/s41598-020-78017-7

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.

Highlights

Radiation therapy is the most effective cytotoxic therapy for localized tumors
These findings demonstrate that FLASH irradiation produces less radiation-induced lethal injury
Our findings have important clinical implications for the treatment of metastatic ovarian cancer. We demonstrate that both FLASH and conventional dose rate (CONV) irradiation have similar tumor control efficacy in a preclinical model of ovarian cancer metastasis

Summary

Introduction

Radiation therapy is the most effective cytotoxic therapy for localized tumors. normal tissue toxicity limits the radiation dose and the curative potential of radiation therapy when treating larger target volumes. 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. Ultra-high dose rate FLASH irradiation is emerging as a new strategy to reduce radiation-induced normal tissue toxicity and enhance the therapeutic index of radiation therapy. In preclinical models of lung cancer, FLASH achieves similar tumor control as CONV irradiation[10] These findings demonstrated localized FLASH irradiation of the lung, skin, or brain could reduce radiation induced toxicities. Our findings identify a potential strategy to enhance the therapeutic index of abdominal irradiation for metastatic ovarian cancer

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