Lung Functional Avoidance Radiotherapy Using Hyperpolarized Xenon MRI

摘要 肺癌放射治疗的定制3D计划为肿瘤提供致命剂量 避免重要的结构(脊柱)和器官(食道、心脏、肺)，因为 功能肺的辐射剂量与急性放射性肺炎和慢性放射性肺炎有关 放射性纤维化，研究人员寻求将剂量优先从肺区域转移到 最高性能。已经研究了几种肺功能成像方式(通风- SPECT和PET，4DCT，超极化3He)。这些研究表明，区域 通风不是最佳的生物标志物。所需要的是一种高分辨率成像模式， 对于屏气困难的患者来说是可以耐受的，这描绘了全肺的区域 功能保证保留，并确定其功能已不可挽回地消失的区域。 超极化氙气-129(HXE)磁共振成像提供了几种肺功能的非常详细的地图 特点。它在组织中的溶解性和对血红蛋白的亲和力使其可以用作示踪剂。 对于气体交换动力学，我们称之为“区域DLCO”。到目前为止，HXE成像方式 需要长时间的屏气，这是肺部受损的患者不能很好地耐受的。我们 开发了一种HXE评估技术，可以探测几个肺功能特征， 包括与红细胞之间的气体交换，以及自然的潮气呼吸方案。我们的 工业团队开发了一种自动氙气超极化器，可提供所需的多升 偏振率接近50%的体积，使这一协议成为常规。 我们提出了一项将HXE MRI应用于功能回避计划优化的翻译研究 最大限度地减少肺癌患者的纤维化。为了使统计意义最大化，我们将 患者队列选择具有显著异质性的患者：一半的初治肺癌患者 Gold期3+肺气肿合并症和一半接受第二(原)肺放射治疗 癌症。地图将划定三个功能区：全功能，通风和燃气并存 交换到RBC(对于避免特别重要)，即功能不可挽回地缺失的地区 (减少回避)，以及功能可能存在或可恢复的其他区域(正常 回避)。在第一年，我们进行了一项开放标签试验，以优化功能成像方案 升级了硬件。有了IRB和DSMB的批准，我们的第二阶段临床试验将招募70人 患者：一半接受标准治疗，一半接受HXE MRI指导下的RT。 治疗后6个月的评估包括HXE MRI的变化，用于区域相关性 局部剂量。主要终点将是DLCO的变化，次要终点为呼吸- 与基线相关的生活质量变化，相对于预测的肺活量/DLCO， 肺炎的发生率/严重程度以及HXE-MRI的变化。

SUMMARY Customized 3D planning of radiation therapy for lung cancer delivers a lethal dose to the tumor region while avoiding important structures (spine) and organs (esophagus, heart, lungs) Since radiation dose to functioning lung is associated with acute radiation pneumonitis and chronic radiation fibrosis, researchers seek to shift dosage preferentially away from lung regions with highest function. Several lung functional imaging modalities have been investigated (ventilation- perfusion SPECT and PET, 4DCT, hyperpolarized 3He). These studies indicate that regional ventilation is not the optimal biomarker. What is needed is a high-resolution imaging modality, tolerable to patients who have difficulty holding their breath, that delineates regions of full lung function warranting preservation, and also identifies regions whose function is irrevocably gone. Hyperpolarized xenon-129 (HXe) MRI provides highly detailed maps of several lung functional characteristics. Its solubility in tissues and affinity for hemoglobin allow it to be used as a tracer for gas exchange kinetics, a so-called “regional DLCO”. Up until now, HXe imaging modalities required long breath holds, which are not well tolerated by lung-compromised patients. We developed an HXe assessment technique that probes several lung function characteristics, including gas exchange to/from red blood cells, with a natural tidal-breathing protocol. Our industrial team developed an automated xenon hyperpolarizer that delivers the required multi-liter volumes at polarizations that approach 50%, enabling this protocol to become routine. We propose a translational study applying HXe MRI to functional avoidance plan optimization to minimize fibrosis in lung cancer patients. To maximize statistical significance, we stratify the patient cohort selecting patients with significant heterogeneity: half with de novo lung cancer with GOLD stage 3+ emphysema comorbidity and half receiving RT for their second (primary) lung cancer. Maps will delineate three functional regions: full function with both ventilation and gas exchange to RBCs (extra importance for avoidance), regions where function is irrevocably absent (reduced avoidance), and other regions where function may be present or recoverable (normal avoidance). In year 1 we conduct an open-label trial to optimize the functional imaging protocols with upgraded hardware. With IRB and DSMB approval, our Phase 2 clinical trial will enroll 70 patients: half receiving standard-of-care treatment and half undergoing RT guided by HXe MRI. Six-month post-treatment assessments include changes in HXe MRI, for regional correlation with local dose. Primary endpoint will be change in DLCO, with secondary endpoints of breathing- related quality of life change from baseline, spirometry/DLCO relative to predicted, incidence/severity of pneumonitis, and change in HXe-MRI.