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

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.

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.

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/β_T vs. α/β_NT), 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.

FLASH-RT appears to be beneficial for tumor sites where α/β_T ≲ α/β_NT, 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.