Non-invasive, image-based, in-vivo assessment of tumor hypoxia to guide hypoxia-driven adaptive radiation therapy

对肿瘤缺氧进行非侵入性、基于图像的体内评估，以指导缺氧驱动的适应性放射治疗

• 批准号: 10661802
• 负责人: Manus J Donahue
• 金额: $ 15.83万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10661802
• 关键词: Address; Adoption; Adverse event; Anemia; Area; Behavior; Biological Markers; Blood; Blood capillaries; Brain; Brain Neoplasms; Cerebrovascular Circulation; Cerebrum; Clinical; Clinical Trials; Data; Development; Diameter; Diffusion; Dose; Enrollment; Environment; Evaluation; Fractionation; Future; Gases; Goals; Hypoxia; Image; Impairment; In Vitro; Intuition; Ionizing radiation; Lesion; Magnetic Resonance Imaging; Malignant Neoplasms; Measurement; Measures; Metabolic; Metastatic malignant neoplasm to brain; Methodology; Methods; Minor; Modality; Nature; Normal tissue morphology; Oxygen; Participant; Patient Triage; Patients; Persons; Physiological; Positron-Emission Tomography; Prediction of Radiation Response; Predisposition; Procedures; Process; Protocols documentation; Radiation; Radiation Dose Unit; Radiation necrosis; Radiation therapy; Radiosurgery; Recurrent tumor; Reporting; Reproducibility; Risk; Role; Specialized Center; Stimulus; Surface; Technology; Testing; Therapeutic; Time; Tissues; Titrations; Treatment Efficacy; Tumor Markers; Tumor Oxygenation; Tumor Tissue; Validation; Variant; Vascular Diseases; Work; angiogenesis; cerebral blood volume; cerebral hemodynamics; cerebrovascular; clinical biomarkers; clinical implementation; clinical practice; design; effective therapy; efficacy evaluation; hemodynamics; improved; in vivo; insight; metabolic rate; novel; participant enrollment; personalized cancer care; radiation resistance; radiation risk; respiratory; routine screening; sex; standard measure; statistics; tissue oxygenation; treatment planning; tumor; tumor hypoxia

ABSTRACT Stereotactic radiosurgery is an effective treatment modality for brain metastases. In clinical practice, the radiation dose prescribed to a lesion balances risk of tumor recurrence and risk of radiation necrosis, with only minor crude adjustments in dose and fractionation based upon tumor diameter. In vitro studies have established the relevance of tumor hypoxia on tumor recurrence, tumor malignant behavior, and radiation necrosis which suggests that tumor hypoxia may be a valuable predictor of radiation response and a biomarker for adaptive or personalized radiation treatments. However, clinical adoption of tumor hypoxia as a biomarker has been limited due to the invasive nature and inaccessibility of hypoxia evaluation methods. Physiologically, tumor hypoxia results in neo-angiogenesis which elevates regional cerebral blood volume (CBV) and cerebral blood flow (CBF), but contra-intuitively causes decreased oxygen extraction due to elevated capillary transit times (CTT) which restricts diffusion. Magnetic resonance imaging (MRI)-based collective assessment of CBV, CBF, CTT and oxygen extraction fraction (OEF) may provide insight into tumor oxygenation status. MRI-based CBF, CBV and CTT evaluations can be accomplished by implementing well-established dynamic susceptibility contrast MRI. MRI-OEF evaluations are more challenging but work by us and others has demonstrated that this parameter can be quantified non-invasively in vivo using an asymmetric spin echo (ASE) MRI sequence. The overarching objective of this study is to validate an MRI protocol to assess brain tumor hypoxia non- invasively in vivo. Of the above proposed MRI-indicators of tumor hypoxia, we hypothesize that OEF is the parameter most likely to detect tumor hypoxia. To address our objective, we will pursue two aims: Aim (1) to obtain normative values and assess reproducibility and repeatability of MRI-based CBF, CBV, CTT and OEF in healthy participants undergoing both DSC and modified ASE MRI, and Aim (2) to validate regional ASE-MRI derived OEF as a marker for tumor hypoxia in patients with brain metastases. For the latter aim, participants will undergo both MRI and 18F-Fluoromisonidazole Positron Emission Tomography (18F-FMISO-PET) which is a known, sensitive indicator of tissue hypoxia. This work is impactful because validation of a scalable, non- invasive MRI indicator for tumor hypoxia will allow for clinical trials that evaluate the role of hypoxia on both tumor recurrence and radiation necrosis. In addition, the data gathered in this study will allow these trials to be responsibly motivated and designed. The long-term goal is to use these methodologies to elucidate a clinically useful biomarker which may allow for patient- and tumor-specific titrations in radiation treatment plan to optimize the therapeutic ratio in the setting of personalized cancer care.

抽象的 立体定向放射外科手术是治疗脑转移瘤的有效方法。在临床实践中，辐射 对病灶开具的剂量平衡了肿瘤复发的风险和放射性坏死的风险，只有很小的风险 根据肿瘤直径粗略调整剂量和分次。体外研究已确定 肿瘤缺氧与肿瘤复发、肿瘤恶性行为和放射性坏死的相关性 表明肿瘤缺氧可能是放射反应的一个有价值的预测指标，也是适应性或适应性的生物标志物。 个性化放射治疗。然而，肿瘤缺氧作为生物标志物的临床应用受到限制 由于缺氧评估方法的侵入性和难以获得。生理上，肿瘤缺氧 导致新血管生成，从而提高局部脑血容量（CBV）和脑血流量（CBF）， 但与直觉相反的是，由于毛细血管通过时间 (CTT) 增加，导致氧气提取量减少 限制扩散。基于磁共振成像 (MRI) 的 CBV、CBF、CTT 和 氧提取分数（OEF）可以提供对肿瘤氧合状态的深入了解。基于 MRI 的 CBF、CBV 和 CTT 评估可以通过实施完善的动态磁敏感对比 MRI 来完成。 MRI-OEF 评估更具挑战性，但我们和其他人的工作表明该参数可以 使用不对称自旋回波 (ASE) MRI 序列在体内进行非侵入性定量。 本研究的总体目标是验证 MRI 协议来评估脑肿瘤缺氧非 侵入体内。在上述提出的肿瘤缺氧 MRI 指标中，我们假设 OEF 是 最有可能检测肿瘤缺氧的参数。为了实现我们的目标，我们将追求两个目标： 目标 (1) 获得规范值并评估基于 MRI 的 CBF、CBV、CTT 和 OEF 的再现性和可重复性 接受 DSC 和改良 ASE MRI 的健康参与者，目的 (2) 验证区域 ASE-MRI 衍生的 OEF 作为脑转移患者肿瘤缺氧的标志物。对于后一个目标，参与者将 接受 MRI 和 18F-氟罗米索硝唑正电子发射断层扫描 (18F-FMISO-PET)，这是一种 已知的组织缺氧的敏感指标。这项工作具有影响力，因为验证了可扩展的、非 肿瘤缺氧的侵入性 MRI 指标将允许临床试验评估缺氧对肿瘤的影响 肿瘤复发和放射性坏死。此外，本研究中收集的数据将使这些 试验的动机和设计要负责任。长期目标是使用这些方法 阐明一种临床上有用的生物标志物，可以在治疗中进行患者和肿瘤特异性滴定 放射治疗计划，以优化个性化癌症护理环境中的治疗比例。