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

摘要 立体定向放射外科是治疗脑转移瘤的有效方法。在临床实践中， 对病变规定的剂量平衡了肿瘤复发的风险和放射性坏死的风险， 根据肿瘤直径粗略调整剂量和分级。体外研究已经建立了 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有价值的预测因子，也是适应性或 个性化的放射治疗然而，肿瘤缺氧作为生物标志物的临床应用受到限制 这是由于缺氧评估方法的侵入性和不可及性。从生理上讲，肿瘤缺氧 导致新血管生成，其升高局部脑血容量（CBV）和脑血流量（CBF）， 但是由于毛细血管通过时间（CTT）升高而相反地导致氧提取减少， 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洞察。基于MRI的CBF、CBV和 CTT评价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序列在体内非侵入性定量。 本研究的总体目标是验证MRI方案，以评估脑肿瘤缺氧非 侵入性地在体内。在上述提出的肿瘤缺氧的MRI指标中，我们假设OEF是 最有可能检测肿瘤缺氧的参数。为达致这个目标，我们会致力达致两个目标： 获得标准值，并评估基于MRI的CBF、CBV、CTT和OEF的再现性和重复性， 接受DSC和改良ASE MRI的健康受试者，目的（2）验证区域ASE-MRI 导出的OEF作为脑转移瘤患者肿瘤缺氧的标志物。为了实现后一个目标，与会者将 接受MRI和18 F-氟咪唑正电子发射断层扫描（18 F-FMISO-PET）， 已知的组织缺氧的敏感指标。这项工作是有影响力的，因为验证一个可扩展的，非 肿瘤缺氧的侵入性MRI指标将允许临床试验评估缺氧对 肿瘤复发和放射性坏死。此外，这项研究中收集的数据将使这些 以负责任的方式激励和设计试验。长期目标是使用这些方法， 阐明了一种临床上有用的生物标志物，其可以允许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。

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.