Optimization of MeV FLASH radiotherapy for normal tissue preservation

摘要 放射治疗（RT）的有效性的显着改善现在似乎是可能的，因为最近的 使用超高剂量率（UHDR）的令人兴奋的研究结果表明，正常组织损伤可以 减少（“闪光”效应），与相同总剂量的常规辐射相比。FLASH RT交付 显示出对正常组织如脑、结肠、肺和皮肤的形态和功能损伤减少。 虽然重要的研究仍然存在，但早期迹象表明，正常组织的保留效果可能高达 在某些剂量水平下为50%。如果在翻译中得到证实，这种效果将是RT中最显著的改进 自治疗计划出现以来，治疗率一直在下降。虽然这一结果的有趣机制一直是 假设，他们仍然只是合理的推测，因为缺乏直接的体内数据的物理， 化学机制包括氧消耗和自由基物种改变。达特茅斯创造了 临床调试的直线加速器上的第一个可逆MeV FLASH束，在患者治疗时具有>100戈伊/s 床，并建立了一个开源的治疗计划系统，扩大了研究的访问。另夕h 该团队发明了独特的技术能力，可以直接测量最高剂量率和体内组织 氧瞬变在初步数据的基础上，本研究解决的关键技术障碍有：1） 在临床调试的直线加速器内转换为UHDR辐照器的演示，2）验证 脉冲和每部分剂量率，3）直接体内观察氧瞬变，4）直接测量 体外自由基种类变化，以及5）获得功能组织测定以及遗传和蛋白质组学 测定。单脉冲和单次剂量率将通过高帧率成像进行量化。此外，本发明还 体内氧变化将通过两种独立的方法进行定量，包括电子 顺磁共振血氧测定法和光学发光血氧测定法。产生的自由基种类变化 还将通过系统的体外分析评估短暂缺氧的可能性， 功能、蛋白质组学和DNA损伤检查。最小化正常组织的闪光光束条件 将使用该基线数据确定固定剂量的损伤。这项工作是临床前的，但可以很容易地 适用于正在进行的NIH申办的自发性犬癌研究，与未来的大型动物相关， 第一次人工翻译多个达特茅斯中心合作发起并支持该FLASH计划。 总的来说，这个生物工程研究项目将推进高剂量率辐射的最新技术水平 使用我们3个研究小组独特开发的工具进行治疗，项目结果将 建立所需的基础科学，以支持这一开创性领域的人类翻译。球队 在辐射物理学、体内分子测量和辐射遗传学方面具有领先的专业知识， 免疫分子生物学和病理学。这项工作得到了一个国际咨询委员会的支持。 专家FLASH顾问，以及一个内部放射肿瘤咨询小组。

ABSTRACT Significant improvement in the effectiveness of radiation therapy (RT) now seems possible because of recent exciting research results using ultra-high dose rates (UHDR), indicating that normal tissue damage can be reduced (the `FLASH' effect), compared to conventional radiation for the same total dose. FLASH RT delivery has shown reduced morphological and functional damage to normal tissues such as brain, colon, lung, and skin. Although significant research remains, early indications are that the normal tissue sparing effect may as high 50% at some dose levels. If proven in translation, this effect would be the most significant improvement in RT therapeutic ratio since the advent of treatment planning. While intriguing mechanisms for this result have been postulated, they remain only well-reasoned speculations because of a lack of direct in vivo data on the physico- chemical mechanisms including oxygen depletion and free radical species alterations. Dartmouth has created the first reversible MeV FLASH beam on a clinically commissioned linac with >100 Gy/s at the patient treatment bed, and prototyped an open-source treatment planning system, expanding research access. Additionally, the team has invented unique technological capabilities to directly measure the highest dose rates and in vivo tissue oxygen transients. The key technological barriers solved in the proposed research with preliminary data are: 1) demonstration of conversion to a UHDR irradiator within a clinically commissioned linac, 2) verification of per- pulse and per-fraction dose rates, 3) direct in vivo observation of oxygen transients, 4) direct measurements of free radical species changes in vitro, and 5) access to functional tissue assays and genetic and proteomic assays. Single-pulse and single-fraction dose rates will be quantified by high frame rate imaging. Additionally, the in vivo oxygen changes will be quantified by two independent methods for co-validation, including electron paramagnetic resonance oximetry and optical luminescence oximetry. Free radical species changes produced from transient hypoxia will also be assessed through systematic in vitro analyses, and the potential linkages to functional, proteomic and DNA damage examined. The FLASH beam conditions that minimize normal tissue damage for a fixed dose will be established with this baseline data. The work is pre-clinical but can be readily adapted to ongoing NIH sponsored spontaneous canine cancer studies has relevance to future large animal and first-in-human translation. Multiple Dartmouth centers partnered to initiate and support this FLASH program. Taken altogether, this bioengineering research project will advance the state of the art in high dose rate radiation therapy using tools that have been uniquely developed by our 3 research groups, and the project results will build the basic science needed to support proposed human translation of this ground-breaking field. The team has leading expertise in radiation physics, in vivo molecular measurement, and radiation genetics and immunomolecular biology and pathology. The work is supported by an External Advisory Board of international expert FLASH consultants, as well as an internal Radiation Oncology Advisory Group.