Improved Radiation Therapy of Hypoxic Tumor Regions by Integrated PET, EPR, and MR Imaging - Resubmission 01

世纪以来，人们就知道放射治疗的低抵抗性。然而，有效的图像引导 缺乏靶向耐缺氧肿瘤区域的方法。最近发表的一项研究结果显示， 来自法国的II期临床试验表明，使用18F-氟- 米索咪唑（FMISO）定义缺氧肿瘤靶向的感兴趣区域（ROI）， 改善肿瘤控制和治疗结果。这项拟议研究项目的长期目标是 开发新的集成多模态成像方法，以有效引导辐射输送， 显著提高了耐缺氧肿瘤区域的治疗精度和治疗效果。我们最近 在动物研究中，使用绝对pO 2的电子顺磁共振（EPR）图像（EPRI）， 证明了用额外的放射剂量靶向肿瘤的缺氧区域（即，剂量加强 绘画）增加肿瘤治愈。这涉及新型3D快速打印辐射块和适形动物 辐射我们通过比较所有肿瘤的均匀放射剂量， 足以治愈15%的肿瘤（在单独的实验中确定），然后随机接受额外的 （1）通过EPR pO 2图像确定的所有缺氧肿瘤体积（pO 2 < 10 μ g）或 (2)等体积剂量增加到更好的氧合肿瘤。结果表明，处理（1）提供了一个 结果明显更好，包括保护重要器官免受高剂量辐射造成的损害。这 表明EPR pO 2图像有可能指导低氧肿瘤的放射治疗。 遗憾的是，EPR图像目前无法用于临床实践中的常规用途。我们假设 使用EPRI pO 2图像作为金标准， 基于PET-FMISO数据，可以建立，包括考虑和相关的数据，从其他 临床上可用的缺氧相关成像方法 成像（DCE-MRI）和碘帕醇抗磁性化学交换饱和转移（Idia-CEST或 ICEST）pH MRI。这些临床可用的MRI研究将使缺氧肿瘤区域的定义更加清晰， 更有效的辐射增强输送，以改善治疗效果。我们将首先开展以下工作： 动物研究的具体目标：（1）实施和验证新的定量多模态PET/MR/EPR 成像方法;（2）开发统计方法，用于通过以下方式导出修改的参数图像： 整合多模态PET和MRI数据，以模拟EPR图像;（3）采用已建立的 目的（2）中开发的方法，用于验证对低氧肿瘤提供更精确的放射治疗， 使用多模态参数成像实现更好的治疗结果。

Hypoxic resistance to radiation therapy has been known for over a century. However, effective image-guided approaches to target resistant hypoxic tumor regions have been lacking. A recent publication of the results from a Phase II clinical trial in France indicates that positron emission tomography (PET) using 18F-fluoro- misonidazole (FMISO) to define region-of-interest (ROI) for hypoxic tumor targeting was shown to fail in improving tumor control and treatment outcome. The long-term objective of this proposed research project is to develop novel integrated multi-modality imaging approaches to effectively guide radiation delivery for significantly improving therapy precision and treatment outcome of resistant hypoxic tumor regions. Our recent work in animal studies using electron paramagnetic resonance (EPR) images (EPRI) of absolute pO2 has demonstrated that targeting the hypoxic regions of tumors with extra radiation dose (i.e., boost in dose painting) increases tumor cure. This involved novel 3D rapidly printed radiation blocks and conformal animal radiation. We showed improved tumor cure by comparing uniform radiation delivery of the dose to all tumors sufficient to cure 15% of tumors (determined in separate experiments) and then randomized to receive extra doses of radiation to either (1) all hypoxic tumor volumes determined by the EPR pO2 image (pO2 < 10 torr) or (2) equal volume dose boosts to better-oxygenated tumor. The results showed that treatment (1) offered a significantly better outcome, including sparing critical organs from damage caused by high dose radiation. This demonstrates that EPR pO2 images have the potential to guide improved radiation therapy of hypoxic tumors. Unfortunately, EPR images are currently not available for routine uses in clinical practice. We hypothesize that using EPRI pO2 images as the gold standard, novel quantitative hypoxia parametric imaging methodologies based on PET-FMISO data can be established, incorporating consideration and correlation of data from other clinically available hypoxia-related imaging methods such as dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) and Iodopamidol diamagnetic chemical exchange saturation transfer (Idia-CEST or ICEST) pH MRI. These clinically available MRI studies will sharpen the hypoxic tumor region definition for more effective radiation boost delivery in improving treatment outcomes. We will initially pursue the following specific aims in animal studies: (1) Implementing and validating novel quantitative multi-modality PET/MR/EPR imaging methodologies; (2) Developing statistical methodologies for deriving modified parametric images by integrating multi-modality PET and MRI data in order to emulate EPR images; (3) Employing the established methods developed in Aim (2) for validation in delivering improved precision radiotherapy of hypoxic tumors to achieve better treatment outcomes using multi-modality parametric imaging.