Split-Dose FLASH irradiation to investigate the clinical feasibility of multifield treatments.

Abstract

The "FLASH effect", a phenomenon in which radiation-induced toxicity is diminished in healthy tissues when treated at ultra-high dose rates, has been demonstrated in several experimental models. We aim to evaluate the impact of split doses, the time interval between splits, and the effect of dose rate variations below and above the 40 Gy/s threshold. Mice received 16 Gy pelvic radiation with a scattering beam or a scanning beam. The conventional dose rate (CONV) was set at 0.5-1 Gy/s, while the FLASH effect was observed at dose rates ranging from 20 to 120 Gy/s. The mice were irradiated with a single dose or with a split-dose regime (1 or 2 splits) with pauses between treatments of either 30 seconds or 2 minutes. The endpoint was survival. The hazard ratio of a single irradiation in FLASH mode vs CONV was 0.31, confirming the presence of the FLASH effect. A split dose with a single 30-second or 2-minute pause reduced overall survival, with hazard ratios of 0.53 and 0.56, respectively. However, survival was still higher compared to CONV. Two 2-minute pauses were not significantly worse than one 2-minute pause. The lowest dose rate at which a FLASH effect was detected was 20 Gy/s; no benefit was observed for dose rates above 60 Gy/s. For the endpoint of 50% survival rate, the FLASH modification factor is 0.91 and 0.96 for irradiations without and with 1 or 2 pauses, respectively. The FLASH effect is attenuated by the introduction of a split-dose regimen. In the clinical implementation of FLASH, the benefit of multiple fields should be weighed against a reduction of the FLASH effect. For our endpoint, the minimum dose rate for FLASH is 20 Gy/s, while an increase from 60 Gy/s to 120 Gy/s is not beneficial.