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Abstract
Objectives: FLASH radiotherapy (FLASH-RT), characterized by ultra-high dose rate irradiation (>40 Gy/s), has demonstrated the potential to spare normal tissues while maintaining tumour control. Most proton and electron FLASH studies have focused on whole-organ irradiation, and the normal tissue-sparing effects of high-dose proton FLASH-RT in localized thoracic settings remain unclear.

Methods: A preclinical mouse model was developed to evaluate localized high-dose (60 Gy) proton FLASH irradiation to the left lung using spot-size transmission at FLASH (500 Gy/s) or conventional (2 Gy/s) dose rates. Lung and skin responses were assessed by histology, flow cytometry, and enzyme-linked immunosorbent assays.

Results: FLASH-irradiated lungs exhibited decreased pneumonitis and fibrosis compared to conventional irradiation, with faster resolution of tissue damage. Skin toxicity, including epidermal thickening and dermal fibrosis, was significantly reduced after FLASH-RT. At the molecular level, FLASH-RT reduced oxidative stress and inflammatory injury, demonstrated by lower Nrf2 activation, reduced 8-OHdG levels, and decreased MPO expression. Systemically, FLASH-RT led to lower neutrophil-to-lymphocyte ratios and decreased serum IL-6, TNF-α, and IFN-γ, indicating reduced inflammation.

Conclusions: Our findings provide the first evidence that proton FLASH-RT at ablative dose levels (>60 Gy) confers localized protection against radiation-induced lung and skin injury in a preclinical setting. These results support the potential of high-dose proton FLASH-RT for thoracic application, though further studies are needed to establish dose-response relationships and optimize clinical beam configurations.

Advances in knowledge: High-dose proton FLASH-RT preserves lung and skin, and mitigates oxidative and inflammatory responses, offering insights into mechanisms underlying the FLASH effect.

Affiliations

Sung Eun Lee 1, Heesoon Sheen 1, Yeeun Kim 1, Sungkoo Cho 1, Sung Hwan Ahn 1, Kenzo Sasai 2, Nagaaki Kamiguchi 2, Junichi Inoue 2, Daizo Amano 2, Hee Chul Park 3, Youngyih Han 3 4, Changhoon Choi 1
1Department of Radiation Oncology, Samsung Medical Center, Seoul 06351, Republic of Korea.
2Sumitomo Heavy Industries, Ltd, ThinkPark Tower, Tokyo 141-6025, Japan.
3Department of Radiation Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Republic of Korea.
4Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul 06351, Republic of Korea.