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. 2025 Apr:205:110744.
doi: 10.1016/j.radonc.2025.110744. Epub 2025 Jan 27.

FLASH proton reirradiation, with or without hypofractionation, reduces chronic toxicity in the normal murine intestine, skin, and bone

Ioannis I Verginadis  1 , Anastasia Velalopoulou  1 , Michele M Kim  1 , Kyle Kim  1 , Ioannis Paraskevaidis  1 , Brett Bell  2 , Seyyedeh Azar Oliaei Motlagh  1 , Antoneta Karaj  3 , Esha Banerjee  4 , Giovanni Finesso  4 , Charles-Antoine Assenmacher  4 , Enrico Radaelli  4 , Jiawei Lu  5 , Yuewei Lin  5 , Mary E Putt  3 , Eric S Diffenderfer  1 , Chandan Guha  2 , Ling Qin  5 , James M Metz  1 , Amit Maity  1 , Keith A Cengel  1 , Constantinos Koumenis  1 , Theresa M Busch  6
Affiliations

FLASH proton reirradiation, with or without hypofractionation, reduces chronic toxicity in the normal murine intestine, skin, and bone

Ioannis I Verginadis et al. Radiother Oncol. 2025 Apr.

Abstract

Background and purpose: The normal tissue sparing afforded by FLASH radiotherapy is being intensely investigated for potential clinical translation. Here, we studied the effects of FLASH proton radiotherapy (F-PRT) in the reirradiation setting, with or without hypofractionation. Chronic toxicities in three murine models of normal tissue toxicity including the intestine, skin, and bone were investigated.

Materials and methods: In studies of the intestine, single-dose irradiation was performed with 12 Gy of standard proton RT (S-PRT), followed by a second dose of 12 Gy of F-PRT or S-PRT. Additionally, a hypofractionation scheme was applied in the reirradiation setting (3 x 6.4 Gy of F-PRT or S-PRT, given every 48 hrs). In studies of skin/bone of the murine leg, 15 Gy of S-PRT was followed by hypofractionated reirradiation with F-PRT or S-PRT (3 x 11 Gy).

Results: Compared to reirradiation with S-PRT, F-PRT induced less intestinal fibrosis and collagen deposition that was accompanied by significantly increased survival rate, demonstrating its protective effects on intestinal tissues in the reirradiation setting. In previously irradiated leg tissues, reirradiation with hypofractionated F-PRT created transient dermatitis that fully resolved in contrast to reirradiation with hypofractionated S-PRT. Lymphedema was also alleviated after a second course of radiation with F-PRT, along with significant reductions in the accumulation of fibrous connective tissue in the skin, compared to mice reirradiated with S-PRT. The delivery of a second course of fractionated S-PRT induced tibial fractures in 83.3% of the mice, whereas only 20% of mice reirradiated with F-PRT presented with fractures.

Conclusion: These studies provide the first evidence of the sparing effects of F-PRT in the setting of hypofractionated reirradiation. The results support FLASH as highly relevant to the reirradiation regimen where it exhibits significant potential to minimize chronic complications for patients undergoing RT.

Keywords: Bone; FLASH; Fibrosis; Intestine; Proton; Reirradiation; Skin.

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Conflict of interest statement

Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [Ioannis I. Verginadis reports consulting fees from Mevion Medical Systems, honoraria from University of Arkansas and support for attending FRPT, outside the submitted work. Michele M. Kim reports honoraria from IBA, outside the submitted work. James M. Metz reports honoraria and support for attending meetings from IBA and Varian Medical Systems, outside the submitted work. Keith A. Cengel reports honoraria from Ion Beam Associates, co-investor on a patent, Vice-Chair at UPenn Abramson Cancer Center DSMC, and equity from Simphotek, Inc outside the submitted work. Constantinos Koumenis reports honoraria from MDACC, Dartmouth University, Duke University and support for attending AACR, outside the submitted work. He is also the scientific founder and majority stock option holder at Veltion Therapeutics, LLC. Theresa M. Busch reports equity from Simphotek, Inc outside of the submitted work. All other authors report nothing to disclose].

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