# Initial Evaluation of Feasibility and Cutaneous Toxicity of Electron FLASH Radiotherapy Using a Standard-of-Care Fractionation Scheme in a Porcine Skin Model

## TL;DR

This study tested electron FLASH radiotherapy in a pig skin model using a five-fraction regimen and found it feasible but did not observe reduced skin toxicity compared to conventional radiotherapy.

## Contribution

The study is the first to evaluate fractionated FLASH radiotherapy in a large animal model using a clinically relevant workflow.

## Key findings

- FLASH radiotherapy was technically feasible and well tolerated at clinical doses.
- No FLASH-specific normal tissue sparing was observed in the five-fraction regimen.
- Both FLASH and conventional radiotherapy caused similar skin toxicity at higher doses.

## Abstract

FLASH radiotherapy delivers radiation at ultra-high dose rates and has been proposed to reduce normal tissue toxicity compared with conventional dose rate treatment. Because most evidence comes from single-fraction studies, we evaluated a clinically relevant five-fraction regimen in a porcine skin model using a workflow designed to simulate adjuvant treatment for high-risk cutaneous melanoma. Skin injury was assessed by longitudinal clinical grading, objective erythema measurements, and histopathology. Fractionated FLASH radiotherapy was technically feasible and well tolerated at clinical doses, with skin reactions comparable to conventional irradiation. No FLASH normal tissue sparing was observed in this five-fraction setting. These results support the feasibility of fractionated FLASH delivery while motivating further investigation of the biological and physical conditions required to achieve normal tissue sparing.

Background/Objectives: FLASH radiotherapy (RT) has shown potential to reduce normal tissue toxicity compared with conventional (CONV) RT while maintaining tumor control. FLASH RT is characterized by ultra-high dose rate delivery, commonly using mean dose rates ≥ 40 Gy/s and sub-second delivery times. Most preclinical studies have used single-fraction regimens, leaving the feasibility and normal tissue impact of clinically relevant fractionation largely unexplored. We evaluated electron FLASH RT given in a standard five-fraction regimen to a porcine skin model, simulating adjuvant treatment workflow for high-risk cutaneous melanoma. Method: Three Yorkshire–Landrace swine received paired five-fraction electron irradiations to dorsolateral skin using either FLASH RT (mean dose rates 175–246 Gy/s) or CONV RT (8 Gy/min). Radiation was delivered with a 9-MeV electron beam; field diameters of 4, 7, or 10 cm; and doses of 5 × 6, 5 × 7, or 5 × 8 Gy. Dosimetry was validated with several dosimeters and real-time beam monitoring, confirming dose accuracy within 3%. Skin toxicity was assessed over 22–24 weeks using clinical grading, erythema spectrophotometry, and histopathologic evaluation. Results: FLASH RT was well tolerated at 5 × 6 Gy and 5 × 7 Gy, with no significant differences in peak radiation dermatitis, erythema index, or histologic damage compared with CONV RT. At 5 × 8 Gy, both modalities caused unacceptable toxicity, including moist desquamation and necrosis. No volume-dependent effects were observed. Conclusions: Although a FLASH-specific normal tissue sparing effect was not observed, this study demonstrates the technical feasibility and safety of delivering fractionated electron FLASH RT in a large animal model using a clinically relevant workflow. These findings support further investigation of physical beam parameters and biological modifiers, such as tissue oxygenation, and inform the clinical translation of fractionated FLASH RT for cutaneous malignancies.