Assessing FLASH irradiation for late-responding tissue protection: A translational approach to re-irradiation of spinal metastases - PROJECT SUMMARY. The effectiveness of radiotherapy (RT) is often constrained by normal tissue toxicity. Currently, toxicity is mitigated through fractionation and high-precision delivery techniques, yet radiation-induced damage to normal tissues remains a major barrier. FLASH-RT, characterized by ultra-high dose rate (UHDR, >40 Gy/s), offers transformative potential to mitigate normal tissue toxicity without compromising tumor control. While preclinical studies highlight FLASH’s benefits in reducing acute toxicity, its effects on sparing late-responding tissues remain largely unexamined. The spinal cord, constituting the most critical late-responding organ, has a well described steep dose-response curve. Radiation exceeding its tolerance increases the risk of myelopathy, leading to paresis, which is easily discerned. Its clinical relevance and dose limiting nature make the spinal cord an ideal model to investigate whether FLASH can reduce late toxicity. The impact of potential FLASH sparing on late responding tissues is further heightened in the context of re-irradiation, where cumulative radiation exposure poses enhanced risks. In the U.S., >120,000 vertebral metastases occur annually, requiring palliative RT to provide pain relief and local control. However, symptoms frequently recur after initial RT, necessitating re-irradiation. The re-irradiation of vertebral metastases poses unique challenges, as the radiation dose to targets near the spinal cord is severely limited by the cord’s radiation tolerance. FLASH-RT has the potential to overcome these constraints by enabling higher cumulative doses and improved tumor control without increasing spinal cord toxicity, thereby addressing an urgent clinical need. We hypothesize FLASH-RT will enhance spinal cord tolerance in both de novo and re-irradiation settings, thereby advancing RT in vertebral tumor management. Rats have been widely used to study radiationinduced spinal cord injury, showing syndromes that resemble those seen in humans. The proposed studies require animal model because late spinal cord toxicity-including microvascular injury, immune responses, and functional outcomes such as paresis-cannot be adequately replicated in vitro or through computational modeling alone. The rat spinal cord model is uniquely suited for these studies due to its well-characterized dose-response relationships, reproducible functional endpoints, and strong translational relevance to human radiation-induced myelopathy, thereby supporting NIH’s mission to reduce treatment-related toxicity and improve cancer outcomes. Leveraging this rat model, our aims are designed to test the hypothesis by determining if FLASH-RT increases spinal cord tolerance compared to CONV-RT, investigating the underlying mechanisms of FLASH effect in response to spinal cord irradiation, and facilitating clinical translation. Aim 1: Assess if FLASH-RT enhances spinal cord tolerance in hypofractionation and re-irradiation, and evaluate its efficacy for tumor control and dose escalation in re-irradiation. Aim 2: Develop a novel physicochemical model integrated with vascular and immune assays to elucidate FLASH mechanisms mitigating spinal cord toxicity and to identify optimal dosimetric parameters. Aim 3: Integrate preclinical findings into proton FLASH planning for spinal metastases irradiation. IMPACT: This proposal will generate critical dose-related toxicity data for the spinal cord, providing insights into FLASH’s ability in mitigating late responding tissue injury. These results will deepen our mechanistic understanding of FLASH and determine its clinical applicability. Moreover, translating these preclinical findings into proton FLASHRT will support clinical trials, optimizing FLASH-RT for hypofractionation and re-irradiation, ultimately expanding radiation therapy options for cancer patients.
