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

通过集成 PET、EPR 和 MR 成像改进缺氧肿瘤区域的放射治疗 - 重新提交 01

• 批准号: 9897365
• 负责人: Chin-Tu Chen
• 金额: $ 62.33万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9897365
• 关键词: 3-Dimensional; 3D Print; Affect; Animals; Behavior; Biochemical; Biological; Blood Vessels; Breast Carcinoma; Cervix Uteri; Chemicals; Clinical; Data; Data Correlations; Defect; Dependence; Dose; Effectiveness; Electrodes; Electron Spin Resonance Spectroscopy; France; Gold; Head and neck structure; Human; Hypoxia; Image; Inbred C3H Mice; Kinetics; Magnetic Resonance; Magnetic Resonance Imaging; Malignant Neoplasms; Maps; Measurement; Measures; Methodology; Methods; Misonidazole; Multimodal Imaging; Mus; Organ; Outcome; Oxygen; Paper; Partial Pressure; Patients; Perfusion; Peripheral; Phase II Clinical Trials; Physiological; Positron-Emission Tomography; Precision therapeutics; Predictive Value; Protocols documentation; Publications; Radiation; Radiation Dose Unit; Radiation therapy; Randomized; Reporting; Research Project Grants; Resistance; Source; Standardization; Statistical Methods; Structure; Time; Tissues; Translations; Treatment outcome; Tumor Volume; Validation; Work; base; clinical practice; clinically relevant; contrast enhanced; experimental study; fibrosarcoma; human imaging; image guided; image guided radiation therapy; imaging approach; imaging modality; imaging system; improved; interest; mouse model; multimodality; novel; parametric imaging; physiologic model; pre-clinical; preclinical study; predictive modeling; quantitative imaging; radiation delivery; radiation effect; radiotracer; sarcoma; therapy outcome; tool; tumor; tumor hypoxia; tumor microenvironment; uptake

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.

一个多世纪以来，人们就知道缺氧对放射治疗的抵抗力。然而，有效的图像引导 一直缺乏针对耐药缺氧肿瘤区域的方法。最新公布的结果 法国的一项 II 期临床试验表明，使用 18F-氟- 米索硝唑（FMISO）用于定义低氧肿瘤靶向的感兴趣区域（ROI）被证明是失败的 改善肿瘤控制和治疗结果。该拟议研究项目的长期目标是 开发新颖的集成多模态成像方法，以有效引导辐射输送 显着提高耐药缺氧肿瘤区域的治疗精度和治疗效果。我们最近的 使用绝对 pO2 的电子顺磁共振 (EPR) 图像 (EPRI) 进行动物研究 证明用额外的辐射剂量（即增加剂量）瞄准肿瘤的缺氧区域 绘画）可增加肿瘤治愈率。这涉及新型 3D 快速打印辐射块和保形动物 辐射。通过比较所有肿瘤的均匀辐射剂量，我们显示了肿瘤治愈的改善 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治疗 (1) 由 EPR pO2 图像确定的所有缺氧肿瘤体积 (pO2 < 10 torr) 或 (2)等体积剂量增强肿瘤的氧合效果。结果表明，治疗（1）提供了 明显更好的结果，包括使重要器官免受高剂量辐射造成的损害。这 表明 EPR pO2 图像有可能指导改进缺氧肿瘤的放射治疗。 不幸的是，EPR 图像目前无法在临床实践中常规使用。我们假设 使用 EPRI pO2 图像作为黄金标准，新颖的定量缺氧参数成像方法 可以建立基于 PET-FMISO 数据的分析，结合其他数据的考虑和关联 临床可用的缺氧相关成像方法，例如动态对比增强磁共振 成像 (DCE-MRI) 和碘巴醇抗磁性化学交换饱和转移 (Idia-CEST 或 ICEST）pH MRI。这些临床上可用的 MRI 研究将明确缺氧肿瘤区域的定义 更有效的放射增强治疗可改善治疗结果。我们首先将追求以下目标 动物研究的具体目标：（1）实施和验证新型定量多模态 PET/MR/EPR 成像方法； (2) 开发统计方法，通过以下方式导出修改后的参数图像： 整合多模态 PET 和 MRI 数据以模拟 EPR 图像； （三）聘用已设立的 目标 (2) 中开发的方法用于验证对缺氧肿瘤提供改进的精确放射治疗 使用多模态参数成像获得更好的治疗结果。