A Proton Treatment Planning Method for Combining FLASH and Spatially Fractionated Radiation Therapy to Enhance Normal Tissue Protection

Background and purpose: FLASH radiation therapy (FLASH-RT) enhances normal tissue sparing through the ultra-high dose rate irradiation known as the FLASH effect. In proton Bragg peak FLASH-RT this effect is generally limited to high-dose regions in normal tissue close to the target (deep tissue). Spatially Fractionated Radiation Therapy (SFRT) creates distinct spatial dose distributions, consisting of alternating high-dose (“peak”) and low-dose regions (“valley”), to activate various biological mechanisms that improve normal tissue protection, characterized by the peak-to-valley dose ratio (PVDR). Due to proton’s multiple Coulomb scattering, the biological sparing effect of SFRT with high PVDR is primarily seen in normal tissues from the beam entrance to shallow-to-intermediate depths, a few centimeters from the target. With the therapeutic potential of each technique established independently, the combination of FLASH-RT and SFRT could offer a powerful and synergistic approach for improved treatment outcomes. In this work, the treatment planning study is performed to investigate the possibility of a new proton modality SFRT-FLASH that synergizes FLASH-RT and SFRT for enhanced normal tissue protection, i.e., the use of FLASH-RT to enhance the sparing of deep-depth normal tissues and the use of SFRT to enhance the sparing of shallow-to-intermediate-depth normal tissues.Materials and methods: Two SFRT techniques, proton GRID therapy with conventional beam size (pGRID) and proton minibeam radiation therapy (pMBRT), are considered for SFRT-FLASH, i.e., pGRID-FLASH (SB-FLASH) and minibeam-FLASH (MB-FLASH). pGRID utilizes the scissor-beam (SB) method to achieve uniform dose distribution in target. To achieve the FLASH effect’s high-dose (5 Gy) and high-dose-rate (40 Gy/s) thresholds, a single-field-uniform-dose-per-fraction (SFUDPF) delivery strategy is employed. In addition to conventional dose constraints, a dose rate constraint is applied to CTV1cm (an auxiliary organ-at-risk (OAR) structure defined as a 1 cm ring extension of the CTV, excluding the CTV) for each field. The dose and dose rate objectives are jointly optimized during treatment planning.Results: The proposed methods (MB-FLASH and SB-FLASH) were validated in comparison to conventional (CONV), FLASH-RT (FLASH), pMBRT (MB), and pGRID (SB) plans across four clinical cases. Our method achieved both high FLASH effect coverage near the target and high PVDR in shallow-to-intermediate depths. For example, the CTV1cm volume achieved ~60-80% FLASH effect coverage, and intermediate-depth dose planes in the beam-eye-view achieved PVDR values of approximately 2.5-7.Conclusion: We present a novel proton treatment planning approach that achieves the FLASH effect at deep tissue depths while maintaining high PVDR at shallow-to-intermediate depths, enhancing normal tissue protection and advancing the therapeutic potential of proton therapy.