Split-Dose FLASH Irradiation to Investigate the Clinical Feasibility of Multifield Treatments: The Effect of Split...

The "FLASH effect," a phenomenon, in which radiation-induced toxicity is diminished in healthy tissues when treated at ultrahigh dose rates, has been demonstrated in several experimental models. We aimed to evaluate the impact of split doses, the time interval between splits, and the effects of dose-rate variations below and above the 40 Gy/s threshold.

Mice received 16 Gy of pelvic radiation with a scattered or scanning beam. The conventional (CONV) dose rate was set at 0.5 to 1 Gy/s, while the FLASH effect was observed at dose rates ranging from 20 to 120 Gy/s. Mice were irradiated with a single dose or a split-dose regimen (1 or 2 splits), with pauses between treatments of either 30 seconds or 2 minutes. The endpoint was survival.

The hazard ratio for single irradiation in FLASH mode versus CONV radiation 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 than with CONV radiation. 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 at dose rates above 60 Gy/s. For the 50% survival rate endpoint, the FLASH modification factor was 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 the reduction in the FLASH effect. For our endpoint, the minimum dose rate for FLASH is 20 Gy/s, whereas an increase from 60 Gy/s to 120 Gy/s is not beneficial.