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脑转移瘤的有效治疗手段。在临床实践中，放射治疗 给病变开的剂量平衡了肿瘤复发的风险和辐射坏死的风险，只有轻微的 基于肿瘤直径的剂量和分割的粗略调整。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关系 提示肿瘤缺氧可能是辐射反应的有价值的预测指标和适应性或非适应性的生物标志物 个性化的放射治疗。然而，临床将肿瘤缺氧作为生物标记物的应用受到限制。 由于低氧评估方法的侵袭性和不可获得性。生理学上，肿瘤缺氧 结果导致局部脑血容量(CBV)和脑血流量(CBF)增加的新生血管生成， 但相反地，由于毛细血管通过时间(CTT)的增加而导致氧摄取率下降 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的评估可以通过实施良好的动态磁化率对比MRI来完成。 MRI-OEF评估更具挑战性，但我们和其他人的工作已经证明，这个参数可以 在体内使用非对称自旋回波(ASE)MRI序列进行非侵入性量化。 这项研究的首要目标是验证一种评估脑肿瘤缺氧的MRI方案。 在体内侵袭性地。在上述提出的肿瘤缺氧的MRI指标中，我们假设OEF是 最有可能检测到肿瘤缺氧的参数。为了达到我们的目标，我们将追求两个目标：目标(1) 获取标准值并评估基于MRI的CBF、CBV、CTT和OEF的重复性和重复性 接受DSC和改良ASE MRI的健康受试者，以及AIM(2)验证局部ASE-MRI 衍生OEF作为脑转移瘤患者肿瘤缺氧的标志。对于后一种目标，参与者将 同时接受MRI和18F-氟异硝唑正电子发射断层扫描(18F-FMISO-PET)，这是一个 已知的，组织缺氧的灵敏指标。这项工作是有影响的，因为验证可伸缩的、非 肿瘤缺氧的侵入性MRI指示器将允许进行临床试验，以评估缺氧在 肿瘤复发和放射性坏死。此外，这项研究收集的数据将使这些 试验要有负责任的动机和设计。长期目标是使用这些方法来 阐明一种临床上有用的生物标志物，它可能允许患者和肿瘤特异性滴定 放射治疗计划，在个性化癌症护理的背景下，优化治疗比例。

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.