Towards Clinical Translation: Establishing Optimal Dose and Dose-Rate Parameters for the FLASH Skin-Sparing Effect

Purpose FLASH radiotherapy (FLASH-RT) has been reported to spare skin from acute radiation toxicity. However, systematic quantification is needed to determine the dose and dose-rate thresholds necessary for optimal radioprotection in FLASH radiotherapy. Materials and Methods The hind limbs of male C57BL/6J mice were irradiated with a single-fraction dose (18-24 Gy) delivered using either FLASH-RT (ultrahigh dose rate: 250 Gy/s) or conventional radiotherapy (CONV-RT: 0.1 Gy/s) in the dose optimization experiment. Subsequent studies included a dose-rate optimization trial comparing FLASH-RT (40-400 Gy/s) with CONV-RT at 20 Gy; the antitumor efficacy of a single 20 Gy dose delivered via FLASH-RT (300 Gy/s) was compared with that of CONV-RT; and an assessment of the reirradiation response using FLASH-RT (400 Gy/s) or CONV-RT at 20 Gy following a prior hypofractionated CONV-RT regimen (9 Gy × 4). Skin injury scores, tumor volume, and body weight were monitored longitudinally for up to 30 days after irradiation or until the experimental endpoint was reached. Tumor weight and lung metastasis nodules were measured at the endpoint. Results Dry desquamation, alopecia, moist desquamation, hemorrhage, full-thickness necrosis, and ulceration were observed more frequently in the CONV-RT group than in the FLASH-RT group. Compared with CONV-RT, FLASH-RT resulted in significantly lower acute skin injury scores at doses ≤22 Gy (18 Gy, 20 Gy, 22 Gy, P < 0.001), but this protective effect was absent at doses ≥24 Gy. Dose-rate optimization (40-400 Gy/s) delivering a 20 Gy dose revealed that acute skin injury scores were significantly reduced only at the higher dose-rates (≥300 Gy/s, compared with CONV-RT, P < 0.001), whereas no significant reduction was observed at the lower dose-rates (≤200 Gy/s, P ≥ 0.05). No additional benefit was detected between 300 Gy/s and 400 Gy/s. Although 250 Gy/s provided significant radioprotection compared with CONV-RT ( P < 0.01), it was not the minimal rate required for maximal protection, as evidenced by a significantly better outcome at 300 Gy/s at 24 days ( P = 0.0296). Finally, in B16/F10 cell-transplanted mouse models, FLASH-RT (300 and 400 Gy/s) achieved tumor control equivalent to that of CONV-RT while also reducing lung metastasis nodules and significantly mitigating acute skin toxicity ( P < 0.001) during reirradiation. Conclusions In this study, a dual-threshold framework was established to guide the clinical implementation of FLASH radiotherapy: a dose ceiling below 24 Gy to preserve the skin-sparing effect and a dose-rate threshold exceeding 200 Gy/s for efficacy, with further optimization achieved at rates above 250 Gy/s. These findings provide ​guidelines for minimizing radiotherapy-induced acute skin toxicity while maintaining comparable antitumor efficacy, thereby outlining a translatable pathway towards the clinical translation of FLASH-RT.