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.

项目摘要 以超高剂量率提供的放射疗法可能已成为癌症的突破性治疗选择 患者。具有超高辐射剂量率的靶向癌症会产生闪光效应，其中控制 肿瘤的生长与常规（CORS）辐射剂量率相似，但正常的组织毒性为 大幅减少。尽管闪光照射已被证明可以唤起强烈的响应 在许多不同的器官系统（例如，大脑，肺，胃肠道[GI]，皮肤）中，多种物种， 一些研究表明，超高剂量率照射对 正常组织。这种差异尚不清楚。但是，它可能源于物理辐射的不一致 梁和分级参数。此外，尽管以前的研究表明没有变化或 与Cons剂量率照射相比，闪光照射的肿瘤反应改善了，无研究 评估肿瘤反应时，看起来超出了简单的肿瘤生长延迟。更相关的分析 临床前肿瘤对放射疗法的反应是肿瘤对照（TCD50）测定，迄今为止，没有比较 在治愈50％的肿瘤所需剂量上的闪光剂量率照射（TCD50）之间 执行。缺乏辐射类型的比较，物理辐射束之间缺乏一致性 参数和分馏，以及先前闪光灯中缺乏对肿瘤控制的精确测量 辐照研究提供了进行这项严格，高通量，多机构研究的动力，以提供 闪光效应可重复性的确认证据。这个拟议的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闪光效应 相同的剂量参数和相同的物理剂量，闪光效应剂量响应之间的相同 不同的辐射类型。为了检验假设，AIM 1将专注于确定辐射是否类型 （例如，电子，光子和光子）改变腹部闪光介导的正常组织比较效应，并具有 对不同辐射类型的相似反应的期望。为了优化物理光束， 分馏参数可最大程度降低正常组织毒性，物理束参数（例如，平均剂量 速率，每脉冲剂量，脉搏持续时间，整体递送时间，启动剂量和氧张力）以及 分馏将被系统地更改和测试（AIM 2）。 AIM 3将专注于建立治疗性 闪光剂量辐射的作用介导了三种不同的合成性，异位肿瘤的相似控制 使用更相关的TCD50测定法。该项目的总体目标是最大程度地减少一方 对所有接受放射治疗的癌症患者的影响，这将不可避免地改善生活质量。预防 放射治疗对癌症患者的治疗后作用，以便个人可以寿命更长，更多 实现生活与国家癌症研究所的任务直接保持一致。