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.