Session Item

Preclinical studies have shown a preferential normal tissue sparing effect of FLASH radiotherapy with ultra-high dose rates. In a previous proton FLASH study of an acute damage mouse model, we demonstrated that 44-58% higher dose was needed to obtain the same biological response with FLASH (80Gy/s field dose rate, no repainting) as compared to a conventional dose rate (0.4Gy/s field dose rate, repainting used to spread the dose delivery in a point over the entire field duration). This study investigates the biological response of dose rates in between these two extremes.

The right hind limbs of non-anaesthetized CDF1 mice were irradiated in the entrance plateau of a PBS proton beam. The dose was 39.3Gy for all irradiations. The mice were divided into 15 groups. One group was treated with a 244MeV beam using 0.4Gy/s field dose rate and repainting. The remaining 14 groups were treated with 250MeV and field dose rates of 0.7, 2, 5.5, 20, 40, 60 or 80Gy/s using either repainting or no repainting. For a given field dose rate, the two groups with and without repainting had the same field duration and distribution of instantaneous dose rates, but with repainting the dose delivery to a given point was spread more evenly over the entire field duration. In total, 195 mice were irradiated in three separate experiments with 6-25 mice per group. The endpoints were skin toxicity of different levels up to 25 days after irradiation. Differences in response with and without repainting were modeled by calculating an oxygen enhancement ratio (OER) weighted biological dose using a simple oxygen depletion model [Petersson et al. IJROPB 2020, using Oenv=0.4%, g=0.3/Gy, lambda=3/s, K=1%, m=3].

The skin toxicity occurrence gradually decreased from 100% to 0% with increasing dose rate (Fig 1, left). The field dose rate to induce response in 50% of the animals (MDR50) depended on the skin toxicity level. Lower toxicity levels had MDR50 above 20Gy/s while higher toxicity levels showed a FLASH effect already at 0.7-2Gy/s (Fig 1, left). Repainting in general resulted in higher toxicity than no repainting for the same field dose rate, demonstrating a clear loss of FLASH effect with repainting (Fig 1, left). This may be explained by a higher biological dose caused by a higher OER for repainting (Fig 2). The OER-weighted biological dose gave similar dose response curves with and without repainting (Fig 1, right), indicating that oxygen depletion may explain the observed differences.

There was no common lower dose rate threshold for the FLASH effect across the skin toxicity levels. The appearance of a FLASH effect varied for different skin toxicity levels, which are characterized by varying dose sensitivity. Conclusions on a lower FLASH dose rate threshold can therefore be influenced by the dose sensitivity of the used endpoint. The ability of the biological dose to explain the higher toxicity with repainting supports that oxygen depletion may play a role in the FLASH effect.