FLASH irradiation enhances the therapeutic index of abdominal radiotherapy in mice

Levy, K.; Natarajan, S.; Wang, J.; Chow, S.; Eggold, J.; Loo, P.; Manjappa, R.; Lartey, F. M.; Schüler, E.; Skinner, L.; Rafat, M.; Ko, R.; Kim, A.; Al Rawi, D.; von Eyben, R.; Dorigo, O.; Casey, K. M.; Graves, E. E.; Bush, K.; Yu, A. S.; Koong, A. C.; Maxim, P. G.; Loo, B. W.; Rankin, E. B.

doi:10.1101/2019.12.12.873414

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bioRxiv · 10.1101/2019.12.12.873414

FLASH irradiation enhances the therapeutic index of abdominal radiotherapy in mice

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Abstract

Peritoneal metastases are the leading cause of morbidity and mortality in ovarian cancer. Despite current surgery, chemotherapy and targeted therapies, the majority of patients diagnosed with advanced epithelial ovarian cancer develop recurrent disease and overall survival rates remain poor. It is known that ovarian cancer is a radiosensitive tumor. Historically, total abdominal irradiation (TAI) was used as an effective postsurgical adjuvant therapy in the management of chemotherapy sensitive and resistant ovarian cancer. However, TAI fell out of favor due to high toxicity, particularly of the gastrointestinal tract. We have developed a preclinical irradiation platform that allows for total abdominal ultrahigh dose rate FLASH irradiation. We demonstrate that TAI-FLASH reduces radiation-induced intestinal injury in both healthy and tumor-bearing mice compared to conventional dose rate (CONV) irradiation. Single high dose TAI-FLASH reduced mortality from gastrointestinal syndrome, spared gut function and epithelial integrity, and decreased cell death in crypt base columnar cells. Importantly, FLASH and CONV irradiation had similar efficacy in the reduction of ovarian cancer peritoneal metastases. These findings suggest that FLASH irradiation may be an effective strategy to enhance the therapeutic index of radiotherapy for the treatment of metastatic ovarian cancer in women.

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Levy, K., Natarajan, S., Wang, J., Chow, S., Eggold, J., Loo, P., Manjappa, R., Lartey, F. M., Schüler, E., Skinner, L., Rafat, M., Ko, R., Kim, A., Al Rawi, D., von Eyben, R., Dorigo, O., Casey, K. M., Graves, E. E., Bush, K., Yu, A. S., Koong, A. C., Maxim, P. G., Loo, B. W., Rankin, E. B.. 2019-12-12. FLASH irradiation enhances the therapeutic index of abdominal radiotherapy in mice. https://doi.org/10.1101/2019.12.12.873414

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