Proton FLASH: impact of dose rate and split dose on acute skin toxicity in a murine model

Abstract

PurposePreclinical studies have shown a preferential normal tissue sparing effect of FLASH radiotherapy with ultra-high dose rates. The aim of the present study was to use a murine model of acute skin toxicity to investigate the biological effect of varying dose rates, time structure, and of introducing pauses in the dose delivery. Materials and MethodsThe right hind limbs of non-anaesthetized mice were irradiated in the entrance plateau of a PBS proton beam with 39.3 Gy. Experiment 1 with varying field dose rates (0.7- 80 Gy/s) without repainting, Experiment 2 with varying field dose rates (0.37- 80 Gy/s) with repainting, and Experiment 3 where the dose was split into 2, 3, 4 or 6 identical deliveries with 2 minutes pauses. In total 320 mice were included with 6-25 mice per group. The endpoints were skin toxicity of different levels up to 25 days after irradiation. ResultsThe Dose rate50, dose rate to induce response in 50% of the animals, depended on the level of skin toxicity, with the higher toxicity levels displaying a FLASH effect at 0.7-2 Gy/s. Repainting resulted in higher toxicity for the same field dose rate. Splitting the dose into two deliveries reduced the FLASH effect, and for three or more deliveries, the FLASH effect was almost abolished for lower grades of toxicity. ConclusionsThe dose rate that induced a FLASH effect varied for different skin toxicity levels, which are characterized by a differing degree of sensitivity to radiation dosage. Conclusions on a threshold for the dose rate needed to obtain a FLASH effect can therefore be influenced by the dose sensitivity of the used endpoint. Splitting the total dose into more deliveries compromised the FLASH effect. This can have an impact for fractionation as well as for regions where two or more FLASH fields overlap within the same treatment session.