Investigating the therapeutic potential of FLASH radiotherapy - a treatment planning study.

PURPOSE/BACKGROUND: Ultra-high dose rate radiotherapy (RT) has shown potential for differential normal tissue (NT) sparing (a phenomenon termed the "FLASH effect"), particularly for larger fraction doses (>5 Gy). However, transitioning to hypofractionation may increase late-reacting NT toxicity, counteracting the FLASH effect. This study evaluates whether FLASH-RT can provide netsparing for organs at risk (OARs) and NT within the PTV under the assumption of standard-of-care dose-conformity. MATERIAL/METHODS: Five patients per tumor-site (breast, head-and-neck, prostate, and glioblastoma) were analyzed. Using the Linear-Quadratic model, dose-distributions with higher dose per fraction were derived from standard schedules while maintaining tumor control efficacy. FLASH-modified dose-distributions were simulated voxel-by-voxel using logistic regression-based dose-modifying factors modeled from preclinical data. These plans were converted to standard fractionation equivalents for radiobiological comparisons of NT damage. Netsparing was defined as the difference in OAR dose-volume histogram parameters between standard and FLASH-modified plans, normalized to the prescribed dose. Commonly used α/β-ratios for tumors and late-reacting NT were applied. RESULTS: The netsparing for OARs and PTV varied strongly by tumor location. Breast and prostate cases showed positive netsparing, indicating that the FLASH effect outweighed increased toxicity. Even under a conservative scenario (higher α/βT vs. α/βNT), most OARs showed positive netsparing. In glioblastoma and head-and-neck cases, no netsparing was observed, indicating increased toxicity even with FLASH induced NT-sparing. CONCLUSION: FLASH-RT appears to be beneficial for tumor sites where α/βT ≲ α/βNT, such as breast and prostate. However, not all tumor sites may benefit from FLASH-RT, highlighting the need for site-specific consideration for FLASH-RT implementation.