Fractionation dose optimization facilities the implementation of transmission proton FLASH-RT

<i>Objective.</i>The beam switching time and fractional dose influence the FLASH effect. A single-beam-per-fraction (SBPF) scheme using uniform fractional dose (UFD) has been proposed for FLASH- radiotherapy (FLASH-RT) to eliminate the beam switching time. Based on SBPF schemes, a fractionation dose optimization algorithm is proposed to optimize non-UFD plans to maximize the fractionation effect and dose-dependent FLASH effect.<i>Approach.</i>The UFD plan, containing five 236 MeV transmission proton beams, was optimized for 11 patients with peripheral lung cancer, with each beam delivering a uniform dose of 11 Gy to the target. Meanwhile, the non-UFD plan was optimized using fractionation dose optimization. To compare the two plans, the equivalent dose to 2 Gy (EQD2) for the target and normal tissues was calculated with an<i>α</i>/<i>β</i>ratio of 10 and 3, respectively. Both UFD and non-UFD plans ensured that the target received an EQD2 of 96.3 Gy. To investigate the overall improvement in normal tissue sparing with the non-UFD plan, the FLASH-enhanced EQD2 was calculated.<i>Main results.</i>The fractional doses in non-UFD plans ranged between 5.0 Gy and 24.2 Gy. No significant differences were found in EQD2_2%and EQD2_98%of targets between UFD and non-UFD plans. However, the<i>D</i>_95%of the target in non-UFD plans was significantly reduced by 15.1%. The sparing effect in non-UFD plans was significantly improved. The FLASH-enhanced EQD2_meanin normal tissue and ipsilateral lung was significantly reduced by 3.5% and 10.4%, respectively, in non-UFD plans. The overall improvement is attributed to both the FLASH and fractionation effects.<i>Significance.</i>The fractionation dose optimization can address the limitation of multiple-beam FLASH-RT and utilize the relationship between fractional dose and FLASH effect. Consequently, the non-UFD scheme results in further improvements in normal tissue sparing compared to the UFD scheme, attributed to enhanced fractionation and FLASH effects.