Optimization of MeV FLASH radiotherapy for normal tissue preservation

摘要 放射治疗(RT)有效性的显著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 与相同总剂量的常规辐射相比，减少了(‘闪光’效应)。Flash RT交付 对脑、结肠、肺和皮肤等正常组织的形态和功能损害有所减少。 尽管仍有重要的研究，但早期迹象表明，正常组织的节约率可能高达 在某些剂量水平下为50%。如果在翻译中得到证实，这一效果将是RT最显著的改进 自治疗计划问世以来的治疗比率。虽然这一结果的耐人寻味的机制 据推测，它们仍然只是有理有据的推测，因为缺乏直接的体内物理数据-- 化学机制包括氧气耗竭和自由基物种改变。达特茅斯已经创造了 临床委托的直线加速器上的第一个可逆MeV闪光光束&GT；100GY/S治疗患者 Bed，并建立了一个开源治疗规划系统的原型，扩大了研究渠道。此外， 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 氧气瞬变。利用初步数据提出的研究中解决的关键技术障碍是：1) 在临床委托的直线加速器内转换为UHDR辐照器的演示，2)验证PER。 脉冲和每分数剂量率，3)氧瞬变的直接活体观察，4)直接测量 自由基物种在体外的变化，以及5)获得功能组织分析以及遗传和蛋白质组学 化验。单脉冲和单分数剂量率将通过高帧速率成像进行量化。另外， 体内的氧气变化将通过两种独立的方法进行量化，以进行共同验证，包括电子 顺磁共振血氧仪和光致发光血氧仪。产生的自由基物种变化 也将通过系统的体外分析来评估暂时性低氧引起的，以及与 检查功能、蛋白质组和DNA损伤。使正常组织最小化的闪光条件 固定剂量的损害将根据这一基线数据确定。这项工作是临床前的，但可以很容易地 适应正在进行的NIH赞助的自发性犬癌研究，与未来的大型动物和 人类第一个翻译。多个达特茅斯中心合作发起并支持这一闪光计划。 综上所述，这一生物工程研究项目将推动高剂量率辐射技术的发展。 使用由我们的3个研究小组独家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拟议人工翻译。该队 在辐射物理、体内分子测量和辐射遗传学方面拥有领先的专业知识 免疫分子生物学和病理学。这项工作得到了国际社会的外部咨询委员会的支持 专家闪光灯顾问，以及内部放射肿瘤学咨询小组。

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.