In vivo validation and tissue sparing factor for acute damage of pencil beam scanning proton FLASH

Background and purpose: Preclinical studies indicate a normal tissue sparing effect using ultra-high dose rate (FLASH) radiation with comparable tumor response. Most data so far are based on electron beams with limited utility for human treatments. This study validates the effect of proton FLASH delivered with pencil beam scanning (PBS) in a mouse leg model of acute skin damage and quantifies the normal tissue sparing factor, the FLASH factor, through full dose response curves. Materials and methods: The right hind limb of CDF1 mice was irradiated with a single fraction of proton PBS in the entrance plateau of either a 244 MeV conventional dose rate field or a 250 MeV FLASH field. In total, 301 mice were irradiated in four separate experiments, with 7–21 mice per dose point. The endpoints were the level of acute moist desquamation to the skin of the foot within 25 days post irradiation. Results: The field duration and field dose rate were 61–107 s and 0.35–0.40 Gy/s for conventional dose rate and 0.35–0.73 s and 65–92 Gy/s for FLASH. Full dose response curves for five levels of acute skin damage for both conventional and FLASH dose rate revealed a distinct normal tissue sparing effect with FLASH: across all scoring levels, a 44–58% higher dose was required to give the same biological response with FLASH as compared to the conventional dose rate. Conclusions: The normal tissue sparing effect of PBS proton FLASH was validated. The FLASH factor was quantified through full dose response curves.