FLASH effect is diminished by daily fractionation of electron RT in mouse skin

Objective.While FLASH radiotherapy is known to reduce skin damagein vivofrom ultra-high dose rate (UHDR) irradiation relative to conventional dose rates (CDR), it is not clear whether this sparing is preserved when delivered as fractionated. This study was designed to directly assess whether three daily fractions would maintain the sparing effects in murine leg models and preserve the murine skin sparing with single fraction treatments.Approach.C57Bl/6j female mice were irradiated with 9 MeV UHDR and CDR beams from a FLASH-capable Mobetron system, in a dose escalation study with doses ranging from single dose 22-30 Gy in a single fraction to three daily fractions of 10-16 Gy. The biological responses were scored by a visual skin damage response rubric using up to 5 blinded observers, and a leg contracture assay as a secondary measure of damage.Main results.There was a monotonic dose response in all treatment groups with irradiation dose, with skin damage onset at 9-10 d. In the single dose group a significant FLASH sparing was seen with a FLASH modifying factor (FMF) of approximately 0.73. Similarly in the single dose groups there were significant leg contracture differences between UHDR and CDR groups after 12-15 d. In comparison, there was no significant skin damage sparing between UHDR and CDR in the three daily fraction dose groups, and reduced sparing in the leg contracture assay.Significance.The results of this murine study show a significant reduction of the FLASH effect when the dose is split into three fractions of 10-16 Gy each, whereas there were substantial FLASH sparing effects noted for the single fractions of 22-30 Gy, showing a FMF of ∼0.73. These observations provide the data needed to optimize FLASH sparing experiments in further translational studies.