Quantitative Non-Contrast Perfusion using Arterial Spin Labeling for Assessment of Cancer Therapy Response

项目摘要 对癌症生物学理解的最新进展导致癌症数量增加 治疗在人类临床试验中对这些新疗法的评估与高成本和高风险有关。 潜在风险影像学方法可以通过识别以下患者在此评估中发挥重要作用： 对治疗有反应。目前治疗结果的放射学评估主要依赖于 肿瘤大小的变化。这是一个主要的限制因素，因为许多治疗剂的效果在治疗过程中是不稳定的。 在显微镜水平上肿瘤大小的变化之前。其中一个肿瘤特性， 新的癌症治疗方法是肿瘤血管生成（或灌注），这已被证明可以支持肿瘤 增殖和浸润。我们最近开发了定量磁共振成像（MRI） 一种称为动脉自旋标记（ASL）的技术，可以非侵入性地测量肿瘤灌注， 给予外源性造影剂。ASL MRI使用高渗透性的水作为示踪剂，通过磁性 标记动脉血中的水质子并测量它们在感兴趣的组织中的积累。我们 在多项临床试验中使用ASL监测治疗反应，并表明ASL测量 肾肿瘤患者在开始抗血管生成治疗后8天肿瘤灌注降低， 细胞癌（RCC），远早于肿瘤大小的变化。然而，ASL尚未经历一个强大的 并建立严格的验证过程作为定量成像方法。在这个项目中，我们将 验证ASL测量的灌注作为定量成像标记物，以评价患者的治疗反应 脑肿瘤（多形性胶质母细胞瘤，GBM）和转移性RCC，两种已知的高度血管化的肿瘤。 本课题的具体目标是：1）验证ASL测量灌注的可靠性和精确性 在30名正常志愿者的大脑和肾脏中; 2）基于基线（前 40例新诊断GBM患者的治疗）灌注和治疗后灌注的早期变化 接受放化疗治疗;和3）基于基线（治疗前）预测长期结局 40例转移性肾细胞癌患者接受化疗后灌注和治疗后早期灌注变化 抗血管生成疗法。在第一个目标中，我们还将使用新型3D打印技术开发质量控制协议。 灌注体模，目前可在UT西南（UTSW）医学中心获得，用于测量可靠性 和ASL测量流量的精度。在第二和第三个目标中，我们将结合自动化和半自动化， 肿瘤分割和分析的自动化方法，使得这些结果可以在其他地方复制。 目标2和3的患者将从UTSW正在进行的临床试验中招募。为了实现这两个目标，我们将 检验我们的假设，与基线相比，治疗后即刻肿瘤灌注的减少更大 与改善的无进展生存期和总生存期相关。测量ASL的这种早期变化 灌注可以比解剖成像更好地预测肿瘤反应性，从而影响患者 通过改变可能无效和可能有毒的治疗方法，及时进行管理。

Project Summary Recent advances in the understanding of cancer biology have led to an increased number of cancer therapies. The evaluation of these new therapies in human clinical trials is associated with high cost and potential risks. Imaging approaches can play an important role in this evaluation by identifying patients who respond to treatments. The current radiological assessment of treatment outcomes predominantly relies on changes in tumor size. This is a major limiting factor as the effects of many therapeutic agents at the microscopic level precede changes in tumor size. One such tumor property that has been extensively targeted for new cancer therapies is tumor angiogenesis (or perfusion), which has been shown to support tumor proliferation and infiltration. We have recently developed a quantitative magnetic resonance imaging (MRI) technique, called Arterial Spin Labeling (ASL) that can measure tumor perfusion non-invasively and without the administration of exogenous contrast agent. ASL MRI uses highly permeable water as a tracer, by magnetically labeling the water proton in the arterial blood and measuring their accumulation in the tissue of interest. We have used ASL to monitor therapy response in multiple clinical trials and have shown that ASL measured tumor perfusion decreased as early as 8 days after the initiation of antiangiogenic therapy in patients with renal cell carcinoma (RCC), much earlier than the tumor size changes. However, ASL has not undergone a robust and rigorous validation process to be established as a quantitative imaging method. In this project, we will validate ASL measured perfusion as a quantitative imaging marker to evaluate treatment response in patients with brain tumors (glioblastoma multiforme, GBM) and metastatic RCC, two known highly vascularized tumors. The specific aims of the project are: 1) To demonstrate the reliability and precision of ASL measured perfusion in the brain and kidneys of 30 normal volunteers; 2) To predict clinical outcomes based on baseline (pre- treatment) perfusion and early changes in post-treatment perfusion in 40 patients with newly diagnosed GBM undergoing chemoradiation therapy; and 3) To predict long-term outcomes based on baseline (pre-treatment) perfusion and early changes in post-treatment perfusion in 40 patients with metastatic RCC undergoing antiangiogenic therapies. In the first aim, we will also develop quality-control protocols using a novel 3D printed perfusion phantom, currently available at UT Southwestern (UTSW) Medical Center to measure the reliability and precision of ASL measured flow. In the second and third aims, we will incorporate automated and semi- automated methods for tumor segmentation and analysis, such that these results can be replicated elsewhere. The patients for aims 2 and 3 will be recruited from ongoing clinical trials at UTSW. In both these aims, we will test our hypothesis that greater reduction in tumor perfusion immediately after treatment, compared to baseline correlates with improved progression free survival and overall survival. Such early changes in ASL measured perfusion may predict tumor responsiveness better than anatomical imaging, thereby affecting patient management in a timely manner by changing treatments that may be ineffective and potentially toxic.