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

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

doi:10.1038/s41598-020-78017-7

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

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

Radiation Oncology

Research output: Contribution to journal › Article › peer-review

118 Scopus citations

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.

Original language	English (US)
Article number	21600
Journal	Scientific reports
Volume	10
Issue number	1
DOIs	https://doi.org/10.1038/s41598-020-78017-7
State	Published - Dec 2020

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Levy, K., Natarajan, S., Wang, J., Chow, S., Eggold, J. T., Loo, P. E., Manjappa, R., Melemenidis, S., Lartey, F. M., Schüler, E., Skinner, L., Rafat, M., Ko, R., Kim, A., H. Al-Rawi, D., von Eyben, R., Dorigo, O., Casey, K. M., Graves, E. E., ... Rankin, E. B. (2020). Abdominal FLASH irradiation reduces radiation-induced gastrointestinal toxicity for the treatment of ovarian cancer in mice. Scientific reports, 10(1), Article 21600. https://doi.org/10.1038/s41598-020-78017-7

Levy, K, Natarajan, S, Wang, J, Chow, S, Eggold, JT, Loo, PE, Manjappa, R, Melemenidis, S, Lartey, FM, Schüler, E, Skinner, L, Rafat, M, Ko, R, Kim, A, H. Al-Rawi, D, von Eyben, R, Dorigo, O, Casey, KM, Graves, EE, Bush, K, Yu, AS, Koong, AC, Maxim, PG, Loo, BW & Rankin, EB 2020, 'Abdominal FLASH irradiation reduces radiation-induced gastrointestinal toxicity for the treatment of ovarian cancer in mice', Scientific reports, vol. 10, no. 1, 21600. https://doi.org/10.1038/s41598-020-78017-7

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

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.",

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

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doi = "10.1038/s41598-020-78017-7",

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AU - Levy, Karen

AU - Natarajan, Suchitra

AU - Wang, Jinghui

AU - Chow, Stephanie

AU - Eggold, Joshua T.

AU - Loo, Phoebe E.

AU - Manjappa, Rakesh

AU - Melemenidis, Stavros

AU - Lartey, Frederick M.

AU - Schüler, Emil

AU - Skinner, Lawrie

AU - Rafat, Marjan

AU - Ko, Ryan

AU - Kim, Anna

AU - H. Al-Rawi, Duaa

AU - von Eyben, Rie

AU - Dorigo, Oliver

AU - Casey, Kerriann M.

AU - Graves, Edward E.

AU - Bush, Karl

AU - Yu, Amy S.

AU - Koong, Albert C.

AU - Maxim, Peter G.

AU - Loo, Billy W.

AU - Rankin, Erinn B.

PY - 2020/12

Y1 - 2020/12

N2 - 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.

AB - 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.

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

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