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

超高剂量率 (FLASH) 放疗参数的临床前优化以实现转化相关性

• 批准号: 10518349
• 负责人: Emil Schueler
• 金额: $ 67.9万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10518349
• 关键词: Abdomen; Aftercare; Biological; Biological Assay; Brain; Cancer Center; Cancer Patient; Cancer cell line; Clinic; Clinical; Consensus; Data; Dependence; Dose; Dose Fractionation; Dose-Rate; Electrons; Ensure; Environmental Risk Factor; Evaluation; Foundations; Fractionation; Frequencies; Gastrointestinal tract structure; Goals; Immune system; Individual; Linear Energy Transfer; Lung; Malignant Neoplasms; Measurement; Measures; Mediating; Methods; Mission; Modality; Modeling; Mus; National Cancer Institute; Normal tissue morphology; Oxygen; Photons; Physiologic pulse; Play; Primary Neoplasm; Probability; Protons; Quality of life; Radiation; Radiation Dose Unit; Radiation therapy; Reporting; Reproducibility; Resources; Role; Sampling; Schedule; Skin; Testing; Therapeutic Effect; Time; Tissues; Toxic effect; Translations; Tumor Tissue; Universities; Width; base; beamline; biological systems; body system; clinical translation; clinically relevant; expectation; gastrointestinal; immune system function; improved; in vivo; inter-institutional; irradiation; pre-clinical; preclinical study; preservation; prevent; proton beam; radiation effect; response; side effect; stem; subcutaneous; tissue injury; tumor; tumor growth; tumor microenvironment

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.

项目概要 超高剂量率的放射治疗可能成为癌症的突破性治疗选择 患者。以超高辐射剂量率靶向癌症会产生 FLASH 效应，其中控制 肿瘤生长的维持与传统 (CONV) 辐射剂量率类似，但正常组织毒性是 显着减少。尽管闪光照射已被证明可以引起强烈的、可重复的反应 跨越多个物种的许多不同器官系统（例如大脑、肺、胃肠道、皮肤）， 一些研究表明，超高剂量率照射对人体要么没有影响，要么有有害影响 正常组织。这种差异并不明显；然而，这可能源于物理辐射的不一致 光束和分级参数。此外，尽管之前的研究表明要么没有变化，要么 与 CONV 剂量率照射相比，FLASH 照射改善肿瘤反应，无研究 在评估肿瘤反应时，我们不仅仅着眼于简单的肿瘤生长延迟。更相关的分析 临床前肿瘤对放疗的反应是肿瘤控制（TCD50）测定，迄今为止，没有比较 FLASH 和 CONV 剂量率照射对治愈 50% 肿瘤所需的剂量 (TCD50) 进行了比较 执行。缺乏辐射类型的比较，物理辐射束之间缺乏一致性 之前的FLASH中缺乏对肿瘤控制的精确测量 辐照研究为开展这项严格、高通量、多机构研究提供了动力，以提供 FLASH 效果可重复性的确证证据。该拟议项目将检验以下假设： 有一组最佳的物理光束参数可以最大化 FLASH 效果，并且在 相同的剂量参数和相同的物理剂量，FLASH效应剂量反应将是相同的 不同的辐射类型。为了检验假设，目标 1 将重点确定辐射类型是否 （例如，电子、光子和光子）改变腹部 FLASH 介导的正常组织保护效应， 对不同辐射类型的相似反应的预期。为了优化物理光束和 最大程度降低正常组织毒性的分级参数、物理束参数（例如平均剂量 率、每次脉冲剂量、脉冲持续时间、总输送时间、预充剂量和氧张力）以及 将系统地改变和测试分馏（目标 2）。目标 3 将侧重于建立治疗方法 FLASH剂量率照射对三种不同的同基因、异位肿瘤的相似控制作用 使用更相关的 TCD50 测定的癌细胞系。该项目的总体目标是最大限度地减少副作用 对所有接受放射治疗的癌症患者都有影响，这将不可避免地提高生活质量。预防 癌症患者放射治疗的治疗后效果，使个人可以活得更长，等等 充实的生活与国家癌症研究所的使命直接一致。