Preclinical optimization of ultra-high dose rate (FLASH) radiotherapy parameters for translational relevance

项目摘要 超高剂量率放射治疗可能成为癌症的突破性治疗选择 病人。以超高辐射剂量率为靶点的癌症会产生闪光效应，其中控制 肿瘤生长维持与常规(Conv)放射剂量率相似，但正常组织毒性 显著减少。尽管闪光照射已被证明能引起强烈的、可重复的反应 跨越许多不同的器官系统(例如，脑、肺、胃肠道、皮肤)跨越多个物种， 一些研究表明，超高剂量率辐射对人体健康没有影响或有害 正常组织。这种差异尚不清楚；然而，它可能源于物理辐射中的不一致。 束流和分馏参数。此外，尽管之前的研究表明，要么没有变化，要么 与常规剂量率照射相比，闪光照射改善了肿瘤反应，未见研究 在评估肿瘤反应时，已经超越了简单的肿瘤生长延迟。更相关的分析 临床前肿瘤对放射治疗的反应是肿瘤控制(TCD50)试验，到目前为止，还没有进行比较 在闪光和转换剂量率照射上所需剂量治愈50%的肿瘤(TCD50 已执行。缺乏对辐射类型的比较，物理辐射束之间缺乏一致性 参数和分割，以及在以前的闪光灯中缺乏准确的肿瘤控制测量 辐射研究为开展这项严谨、高通量、多机构的研究提供了动力 闪光效果重现性的确凿证据。这个提议的项目将检验这样一个假设： 有一组最优的物理光束参数可以最大化闪光效果，并且在 相同的剂量参数和相同的物理剂量，闪光效应的剂量响应将是相同的 不同的辐射类型。为了检验这一假设，目标1将侧重于确定辐射类型 (例如，电子、光子和光子)改变腹部闪光介导的正常组织保留效果， 对不同辐射类型的相似反应的期望。为了优化物理光束和 最大限度地降低正常组织毒性的分级参数、物理射线参数(例如，平均剂量 速率、每脉冲剂量、脉冲持续时间、总给药时间、预充量和氧分压)以及 将系统地改变和测试分馏(目标2)。目标3将专注于建立治疗性 闪光剂量率照射对三种不同来源的同种异位肿瘤的相似控制作用 使用更相关的TCD50检测的癌细胞株。这个项目的首要目标是尽量减少 对于所有接受放射治疗的癌症患者来说，这将不可避免地提高生活质量。预防 放射治疗对癌症患者的治疗后效果，使个人可以活得更长，更多 充实生活与国家癌症研究所的使命是直接一致的。

Project Summary Radiation therapy delivered at ultra-high dose rates may be becoming a breakthrough treatment option for cancer patients. Targeting cancers with ultra-high radiation dose rates produces a FLASH effect, wherein control of tumor growth is maintained similarly to conventional (CONV) radiation dose rates, but normal tissue toxicity is significantly reduced. Although FLASH irradiation has been shown to evoke strong, reproducible responses across many different organ systems (e.g., brain, lungs, gastrointestinal [GI] tract, skin) across multiple species, some studies have shown that ultra-high-dose rate irradiation to have either no effect or detrimental effects on normal tissue. This discrepancy is not clear; however, it likely stems from inconsistency in the physical radiation beam and fractionation parameters. Furthermore, although previous studies have shown either no change in or improved tumor responses from FLASH irradiation as compared with CONV dose rate irradiation, no studies have looked beyond simple tumor growth delay when evaluating tumor responses. A more relevant analysis for preclinical tumor responses to radiotherapy is the Tumor Control (TCD50) assay, and to date, no comparisons between FLASH and CONV dose rate irradiation on the dose required to cure 50% of tumors (TCD50) have been performed. The lack of comparisons of radiation types, the lack of consistency between physical radiation beam parameters and fractionation, and the lack of accurate measurements of tumor control in previous FLASH irradiation studies provides impetus to conduct this rigorous, high throughput, multi-institutional study to provide confirmatory evidence of the reproducibility of FLASH effects. This proposed project will test the hypothesis that there is an optimal set of physical beam parameters that will maximize the FLASH effect, and that under the same dose parameters and the same physical dose, the FLASH effect dose response will be the same between different radiation types. In order to test the hypothesis, Aim 1 will focus on determining whether radiation type (e.g., electrons, photons, and photons) alters abdominal FLASH-mediated normal tissue-sparing effects, with the expectation of similar responses to the different radiation types. In order to optimize the physical beam and fractionation parameters to maximally reduce normal tissue toxicity, physical beam parameters (e.g., mean dose rate, dose per pulse, pulse duration, overall delivery time, priming dose, and oxygen tension) as well as fractionation will be systematically changed and tested (Aim 2). Aim 3 will focus on establishing the therapeutic effects of FLASH dose rate irradiation mediate similar control of syngeneic, heterotopic tumors of three different cancer cell lines using the more relevant TCD50 assay. The overarching goal of this project is to minimize side effects for all cancer patients receiving radiation therapy, which will inevitably improve quality of life. Preventing the post-treatment effects of radiation therapy in cancer patients so that individuals can live longer, and more fulfilling lives is in direct alignment with the mission of the National Cancer Institute.