Breathing-phase selection for gated proton therapy in lung cancer towards temporally targeted ultra-high dose rate delivery

Background and purpose Ultra-high dose rate (UHDR) irradiation has been demonstrated to reduce normal tissue damage compared to conventional dose rates, while maintaining tumor response (FLASH-effect). UHDR could potentially freeze intra-fraction breathing motion, enabling margin reduction for moving tumors when accurately timed. Targeting the optimal breathing-phase could reduce organ-at-risk (OAR) dose and side effects. In this treatment planning study, the optimal phase(s) for UHDR proton therapy were identified and potential benefits were evaluated.Materials and methods Twenty lung cancer patients, previously treated with 66 GyE/24 or 60 GyE/30 fractions, were included. Four-dimensional computed tomography (4D-CT) scans with clinical target and OAR delineations were used to create new treatment plans for individual 4D-CT phases, one-phase plans (OPP) and multiple-phase plans (MPP). Clinically relevant dose-volume parameters and normal tissue complication probabilities (NTCP) were evaluated.Results Phase-targeted proton therapy (PTPT) significantly reduced OAR dose. The largest reductions were achieved with OPP, while MPP showed smaller reductions. With OPP, mean lung dose (mean: -0.7 GyE, range: -1.7 to 0.3 GyE), mean heart dose (mean: -0.4 GyE, range: -1.4 to 0.5 GyE), and mean esophagus dose (mean: -0.9 GyE, range: -6.0 to 0 GyE) were reduced, with most reductions in the 0%, 40%, and 70% phases, respectively. NTCP values indicated reduced complication probabilities across all phases, with additional gains for optimal phases.Conclusions With PTPT, OAR dose may be reduced with potential clinical benefit across all phases. The optimal phase depended on the endpoint, suggesting patient-specific phase targeting could further improve outcomes. Future research should address phase targetability, residual variation and required robustness.