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Preclinical studies indicate a normal tissue sparing effect using ultra-high dose rate (FLASH) radiation with comparable tumor response. This differential response is promising in order to obtain improved clinical outcome. Most data so far are based on electron beams with limited utility for patient treatments. We have previously conducted an in vivo study validating the effect of PBS proton FLASH on acute skin toxicity, and demonstrated that a 44-58% higher dose was needed to obtain the same biological response when using proton FLASH. The aim of the present study was to investigate both tumor response and normal tissue toxicity in the same mouse model and set-up.Preclinical studies indicate a normal tissue sparing effect using ultra-high dose rate (FLASH) radiation with comparable tumor response. This differential response is promising in order to obtain improved clinical outcome. Most data so far are based on electron beams with limited utility for patient treatments. We have previously conducted an in vivo study validating the effect of PBS proton FLASH on acute skin toxicity, and demonstrated that a 44-58% higher dose was needed to obtain the same biological response when using proton FLASH. The aim of the present study was to investigate both tumor response and normal tissue toxicity in the same mouse model and set-up.

The right hind limbs of non-anaesthetized CDF1 mice were irradiated in a single fraction in the entrance plateau of a scanning proton pencil beam using either CONV dose rate (0.35-0.40 Gy/s field dose rate, 244 MeV) or FLASH (79-85Gy/s field dose rate, 250 MeV). The delivered fields were 2cm x 3cm to ensure a homogeneous dose across the whole mouse leg. The study included 153 mice with a C3H mouse mammary carcinoma subcutaneously implanted in the foot, irradiated in four separate experiments, with 8-12 mice pr dose point, irradiated with physical doses of 40-60Gy. The endpoints were tumor control assessed as no recurrent tumor at 90 days after treatment and the level of acute moist desquamation to the skin of the foot within 25 days post irradiation.

Full dose response curves for tumor control for both CONV and FLASH dose rates demonstrated similar tumor response between the two treatments. The TCD₅₀ values with 95% confidence interval was 49.14 (46.95-51.43) Gy for CONV dose rate, and 50.76 (48.01-53.67) Gy for FLASH dose rate (Fig 1). The acute skin damage was assessed in the same mice, and showed distinct normal tissue sparing effect of proton FLASH. Due to the high number of mice with skin toxicity in the CONV treated group, it was not possible to fit a dose response curve. MDD₅₀ for the FLASH treated mice was 51.57 (49.22-54.03) Gy (Fig 2).

In the current study we investigated the effect on tumor control and showed no differences in the dose response curves between the two modalities. Furthermore, acute skin damage results from the mice in the tumor control study are consistent with our previous data.