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

摘要/摘要 重离子放射治疗(HIRT)不同于其他放射治疗方法，如x射线和质子放射治疗。 这些高LET(线性能量转移)辐射在微观尺度上储存的能量要密集得多。 目前，人们对将Hirt引入美国有很大的兴趣，这主要是基于 日本和德国的碳离子放射治疗，据报道，这两个国家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，两年存活率为50% 据报道，在碳离子和吉西他滨联合化疗后，局部晚期患者的治愈率为65% 胰腺癌，在治疗后生存由远距离控制的情况下，非常令人鼓舞 转移瘤。因此，有很多讨论认为，除了对肿瘤产生局部影响外，Hirt 可能还会产生长期的全身性抗癌效果。然而，这种情况的基本机制 高LET诱导的长期系统效应尚不清楚，有证据表明，经典的 常规X射线放射治疗疗效的放射生物学现象，但仍有可能 与局部肿瘤控制相关，不是驱动潜在全身疗效的主导现象 希尔特。相反，这些数据表明，在辐射诱导的长时间内，高LET诱导的机制不同。 广泛的抗癌作用--而尚不清楚的是这些长期作用的LET依赖性。 在这个BRP中，并利用放射研究的独特技术和技能 加速器设施(RARAF)和功能光学成像实验室(LFOI)，新工具将是 旨在研究和了解远程辐射引起的生物效应，特别是其 依赖于LET。关键工具将是1)提供空间定义的3-D的一系列单重态离子束 曝光，与2)SCAPE(扫描共焦对齐平面激发)广域3D显微镜集成， 辐射场内和场外的成像。同时，将应用预算资源规划工具来处理中央 长程辐射效应的LET依赖性假说。这些研究将包括不断提高的水平 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，加速器组建了一个跨学科的团队。 来自RARAF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接触。 除了优化HIRT疗效的主要目标外，了解相关LET依赖关系 HIRT将提供一条确定其使用的最佳离子的途径--这是一个关键结果，反过来将 可能决定Hirt未来在全球的使用，因为Hirt的资本成本由选择决定 要使用的一个或多个离子的。例如，如果可以用氦离子实现HIRT的最佳LET范围，则 氦治疗机将比一台价值1.5亿美元的碳离子治疗机小得多，也更便宜。

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.