Carbon ion FLASH irradiation reduces acute skin toxicity compared with conventional dose rate irradiation

FLASH radiotherapy, defined by ultra-high dose rates exceeding 40 Gy/s, has shown potential for widening the therapeutic window due to its demonstrated normal tissue-sparing effects while maintaining tumor control with electrons, photons, and protons. However, limited biological data are available regarding its effects with heavy ions. This study aimed to investigate the biological effects of carbon-ion FLASH irradiation by assessing acute skin reactions in mice. C3H/He mice received irradiation to the right hind limb with 34-58 Gy of carbon-ion pencil beam scanning at the entrance region (dose-averaged LET: 13 keV/µm), delivered at either conventional dose rate (CONV: 0.047-0.051 Gy/s) or ultra-high dose rate (FLASH: 166.7-190.8 Gy/s). Skin reactions were evaluated every other day for up to 5 weeks to monitor early responses. The temporal patterns of skin response were similar between the CONV and FLASH groups. However, FLASH group consistently resulted in lower reaction scores across all doses and time points. Dose-response curve indicated a tissue-sparing effect with FLASH group, requiring approximately 1.5 times higher dose to produce the same biological effect as CONV group. These findings confirm the normal tissue-sparing potential of carbon-ion FLASH irradiation, with the FLASH effect quantitatively demonstrated through dose-response comparisons.