Early therapeutic monitoring of response to therapy with serial ultrasound in metastatic RCC

项目摘要 我们提出了一项初步研究，以检测治疗反应早在3周后开始治疗， 应用多普勒超声检测肾转移瘤患者肿瘤血管的变化 癌（mRCC）。迫切需要快速检测对RCC治疗反应的生物标志物，因为 所有患者均对抗血管生成酪氨酸激酶抑制剂（阿西替尼）加抗PD的一线治疗有反应， 1免疫检查点抑制剂（pembrolizumab）。然而所有的病人都忍受着这种组合的副作用 治疗（疲劳、恶心、腹泻和/或肝脏炎症），同时等待计算的标准治疗 断层摄影（CT）成像。目前，需要12周通过测量肿瘤细胞的减少来评估反应。 因为肿瘤大小在12周治疗前通常不会改变。快速检测 对RCC治疗的反应将最大限度地减少无效药物的使用， 治疗，并继续只有有效的治疗。由于RCC治疗靶向血管生成，我们发现， 基于成像的肿瘤血管分布测量，如灌注CT扫描，或新型PET剂F18- 结合血管的FPPRGD 2可以检测mRCC中对治疗的早期反应。但这些要求 静脉注射和去放射科就诊。我们开发了高灵敏度，无对比度， 使用先进的能量多普勒超声进行血管成像，可在肿瘤科床边进行 临床上可对直径小至1 mm的血管进行成像。现在，我们建议使用先进的能量多普勒 超声用于初步研究，以评估肿瘤血管分布的变化，在常规肿瘤学门诊访视期间， 接受联合治疗的患者。我们假设通过测量肿瘤血管分布的变化， 超声可以比肿瘤直径的变化更早地检测对治疗的反应。我们将招收20名 在治疗前、治疗3周后和治疗6周后， 阿昔替尼和帕博利珠单抗的联合治疗。我们的试点研究旨在确定1）功率多普勒 超声波可以检测到早在开始用派姆单抗治疗后3和/或6周的变化， 阿西替尼; 2）如果通过超声检测到的变化与通过标准护理CT扫描测量的反应相关 治疗12周后;以及3）如果在3周或6周时超声与标准12 周结果。我们将使用能量多普勒超声成像来加速对以下反应的检测： 联合阿西替尼+派姆单抗。如果成功，我们可以将我们的方法应用于其他肿瘤， 肿瘤血管分布的变化是对大多数癌症治疗反应的关键机制。

Project Summary We propose a pilot study to detect therapeutic response as early as 3 weeks after initiating therapy, using Doppler ultrasound to measure changes in tumor vascularity in patients with metastatic renal cell carcinoma (mRCC). Biomarkers to rapidly detect response to RCC therapy are urgently needed, because not all patients respond to first line treatment with anti-angiogenesis tyrosine kinase inhibitor (axitinib), plus anti-PD- 1 immune checkpoint inhibitor (pembrolizumab). Yet all patients endure the side effects of this combination treatment (fatigue, nausea, diarrhea, and/or liver inflammation) while awaiting standard of care computed tomography (CT) imaging. Currently, 12 weeks is required to assess response by measuring decreases in tumor diameters with CT because tumor size does not typically change before 12 weeks of therapy. Rapid detection of response to RCC therapy would minimize use of ineffective drugs and allow patients to discontinue ineffective therapies and continue only effective therapy. Because RCC treatments target angiogenesis, we have found that imaging-based measurements of tumor vascularity, such as perfusion CT scans, or novel PET agent F18- FPPRGD2 that binds blood vessels, can detect early response to therapy in mRCC. But these require intravenous injections and visits to the radiology department. We have developed highly sensitive, non-contrast, vascular imaging using advanced power Doppler ultrasound that can be performed at bedside in the oncology clinic to image vessels as small as 1mm in diameter. Now, we propose to use advanced power Doppler ultrasound for a pilot study to assess changes in tumor vascularity, during routine oncology clinic visits for patients receiving combined therapy. We hypothesize that changes in tumor vascularity measured by ultrasound, can detect response to treatment earlier than changes in tumor diameters. We will enroll 20 patients with mRCC, to be evaluated with power Doppler ultrasound before treatment and after 3 weeks and 6 weeks of combined axitinib and pembrolizumab therapy. Our pilot study aims to determine if 1) power Doppler ultrasound can detect changes as early as 3 and/or 6 weeks after initiating therapy with pembrolizumab and axitinib; 2) if changes detected by ultrasound correlate with response measured by standard of care CT scan after 12 weeks of therapy; and 3) if ultrasound at 3 weeks or 6 weeks has better correlation with standard 12 week results. We will use power Doppler ultrasound imaging to accelerate detection of response to combined axitinib + pembrolizumab. If successful, we can apply our approach to additional tumors and drugs, as changes in tumor vascularity are a key mechanism of response to most cancer therapies.