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.

耐低氧放射治疗早在一个世纪前就已为人所知。然而，有效的图像引导 靶向耐缺氧肿瘤区域的方法一直缺乏。最近发表的研究结果 来自法国的一项II期临床试验表明，使用18F-氟化物的正电子发射断层扫描(PET) 米索硝唑(FMISO)为低氧肿瘤靶向定义感兴趣区(ROI)的方法被证明失败 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 开发新的集成多模式成像方法，以有效地指导 显著提高耐缺氧肿瘤区域的治疗精度和治疗结果。我们最近 在动物研究中使用绝对pO2的电子顺磁共振(EPR)图像(EPRI)的工作 证明了用额外的辐射剂量(即增加剂量)来靶向肿瘤的缺氧区 绘画)增加了肿瘤的治愈率。这涉及到新的3D快速打印辐射块和适形动物 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 辐射剂量：(1)由EPR pO2图像确定的所有缺氧性肿瘤体积(pO2和lt；10torr)或 (2)等体积剂量有利于提高肿瘤的氧合能力。结果表明，处理(1)提供了一种 明显更好的结果，包括使关键器官免受高剂量辐射的损害。这 证明EPR pO2图像有可能指导低氧肿瘤的改进放射治疗。 不幸的是，EPR图像目前还不能用于临床实践中的常规使用。我们假设 以EPRI pO2图像为金标准的定量缺氧参数成像新方法 可以建立基于PET-FMISO的数据，纳入对其他数据的考虑和关联 临床可用的低氧相关成像方法，如动态增强磁共振 磁共振成像(DCE-MRI)和碘多巴胺抗磁化学交换饱和转移(IDIA-CEST或 ICEST)pH磁共振。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 在改善治疗结果方面，更有效的放射促进传递。我们将初步实现以下目标 动物研究的具体目标：(1)实施和验证新的定量多模式PET/MR/EPR 成像方法；(2)开发统计方法，通过以下方式得出修改后的参数图像 集成多模式PET和MRI数据以模拟EPR图像；(3)使用已建立的 在AIM(2)中开发的方法，用于验证将改进的低氧肿瘤的精确放射治疗传递到 使用多模式参数成像获得更好的治疗结果。