Flexible Tools for Pre-Clinical Studies to Answer Key Questions UnderlyingHeavy-Ion Radiotherapy

总结/摘要 重离子放射治疗（HIRT）不同于其他放射疗法，如X射线和质子， 这些高LET（线性能量转移）辐射在微观尺度上更密集地沉积存款能量。 目前对将HIRT引入美国有浓厚的兴趣，主要是基于 在日本和德国，碳离子放射治疗的存活率非常令人鼓舞， 一些难以治疗的癌症，如胰腺癌、直肠癌和肉瘤。例如，2年生存率为50 据报道，在碳离子和吉西他滨联合化疗后， 胰腺癌，非常令人鼓舞的治疗后时间，当生存率主要是由遥远的 转移因此，有很多讨论认为，HIRT除了对肿瘤产生局部作用外， 也可能诱导长期的系统性抗癌作用。然而，这种现象的基本机制 高LET诱导的长期全身效应尚不清楚，有证据表明，经典的 放射生物学现象是传统X射线放射治疗有效性的基础， 与局部肿瘤控制相关，不是驱动潜在全身疗效的主要现象。 HIRT。相反，这些数据表明，不同的高LET诱导的机制，辐射诱导的长， 范围内的抗癌作用-什么是不知道的是LET依赖这些长期的影响。 在本BRP中，利用放射学研究中心的独特技术和技能， 加速器设施（RARAF）和功能光学成像实验室（LFOI），新的工具将被 研究和了解远距离辐射引起的生物效应，特别是它们的 依赖于。关键的工具将是1）一系列单LET离子束提供空间定义的3-D 曝光，与2）SCAPE（扫描共聚焦对准平面激发）广域3D显微镜集成， 在辐射场内外成像。与此同时，将应用BRP工具来解决 远距离辐射效应的LET依赖性假说。这些研究将包括增加 从肿瘤细胞到体外肿瘤/组织模型再到体内肿瘤模型的复杂性。 为了开发和应用这些技术，一个跨学科的团队已经组装了加速器 来自RARAAF的物理学家和放射生物学家，以及来自LFOI的生物医学工程师，通过 与具有HIRT经验的国际公认的科学家和临床医生持续合作。 除了优化HIRT疗效的主要目标外，了解相关的LET依赖性， HIRT将提供一种确定其使用的最佳离子/离子的途径-这是一个关键成果，反过来将 可能决定HIRT未来在全球范围内的使用，因为HIRT的资本成本主要取决于选择 一种或多种离子。例如，如果HIRT的最佳LET范围可以用氦离子实现， 氦治疗机将比一台> 1.5亿美元的碳离子治疗机更小更便宜。

SUMMARY / ABSTRACT Heavy-ion radiation therapy (HIRT) differs from other radiotherapy modalities such as x rays and protons as these high-LET (Linear Energy Transfer) radiations deposit energy far more densely on a microscopic scale. There is currently strong interest in the introduction of HIRT to the U.S., largely based on the experience of carbon-ion radiotherapy in Japan and Germany, where very encouraging survival rates have been reported for a number of hard-to-treat cancers such as pancreas, rectum and sarcomas. For example, 2-year survival of 50 to 65% has been reported after combined carbon-ion and gemcitabine chemotherapy for locally-advanced pancreatic cancer, remarkably encouraging at a post-treatment time when survival is dominated by distant metastases. Thus there has been much discussion that, as well as producing local effects to the tumor, HIRT may also be inducing long-range systemic anti-cancer effects. However, the underlying mechanisms for such high-LET-induced long-range systemic effects are not understood and there is evidence that the classic radiobiological phenomena underlying the efficacy of conventional x-ray radiotherapy, while still potentially relevant for local tumor control, are not the dominant phenomena driving the potential systemic efficacy of HIRT. Rather the data suggest different high-LET-induced mechanisms underlying radiation-induced long- range anti-cancer effects – and what is not known is the LET dependence of these long-range effects. In this BRP, and leveraging from the unique technologies and skillsets at the Radiological Research Accelerator Facility (RARAF) and the Laboratory for Functional Optical Imaging (LFOI), novel tools will be developed to study and understand long-range radiation-induced biological effects, and particularly their dependence on LET. The key tools will be 1) a series of mono-LET ion beams providing spatially defined 3-D exposures, integrated with 2) SCAPE (Swept Confocally-Aligned Planar Excitation) wide-area 3D microscopy, imaging within and outside the radiation field. In parallel, the BRP tools will be applied to address the central hypothesis of LET dependence of long-range radiation effects. These studies will encompass increasing levels of complexity from tumor cells through in-vitro tumor/tissue models to in-vivo tumor models. To develop and apply these technologies, an interdisciplinary team has been assembled of accelerator physicists and radiobiologists from RARAF, and biomedical engineers from LFOI, enhanced through continuous engagement with internationally recognized scientists and clinicians with experience in HIRT. Apart from the primary goal of optimizing HIRT efficacy, understanding the relevant LET dependencies in HIRT will provide a pathway for determining the optimal ion / ions for its use – a key outcome that in turn will likely determine the future worldwide usage of HIRT, in that the capital cost of HIRT is dominated by the choice of ion or ions to be used. If, for example, the optimal LET range for HIRT could be achieved with helium ions, a helium therapy machine would be far smaller and cheaper than a >$150M carbon-ion machine.