Microbubble Cavitation for Improving Hepatocellular Carcinoma Radioembolization

微泡空化改善肝细胞癌放射栓塞

• 批准号: 10530640
• 负责人: Kevin Anton
• 金额: $ 11.14万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-11 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10530640
• 关键词: 90Y; Adverse event; Aftercare; Apoptosis; Back; Blood Vessels; Bolus Infusion; Cancer Etiology; Catheters; Chemoembolization; Clinical; Clinical Trials; Consent; Contrast Media; Data; Disease Progression; Dose; Early identification; Evaluation; Fetal Proteins; Glass; Hour; Image; Incidence; Injections; Liver; Liver neoplasms; Magnetic Resonance Imaging; Malignant - descriptor; Measures; Metastatic Neoplasm to the Liver; Microbubbles; Monitor; Nude Rats; Output; Patient Schedules; Patient-Focused Outcomes; Patients; Perfusion; Physiologic pulse; Prediction of Response to Therapy; Primary carcinoma of the liver cells; Progression-Free Survivals; Property; Radiation; Radiation therapy; Radioactive; Radioembolization; Radioisotopes; Radiosensitization; Randomized; Recovery; Reperfusion Therapy; Reporting; Retreatment; Safety; Schedule; Solid Neoplasm; Source; Techniques; Testing; Therapeutic; Therapeutic Effect; Therapeutic Embolization; Time; Tissues; Vascular Endothelial Cell; Vascular Permeabilities; Yttrium; blood fractionation; blood perfusion; contrast enhanced; contrast imaging; dosage; effective therapy; experimental group; first-in-human; follow-up; improved; liver cancer model; liver function; local drug delivery; mortality; nuclear imaging; randomized, clinical trials; response; safety and feasibility; tool; treatment response; treatment strategy; tumor; tumor vascular supply; ultrasound

The use of radioembolization has been shown to be successful for the treatment and downstaging of hepatocellular carcinoma (HCC) as well as liver metastases, and advantages over traditional chemoembolizaion have been reported. The local beta emissions from this technique have been shown to provide therapeutic effect within the tumor. Dosages range from 110-150 Gy, but radiation delivered to malignant tissue is dependent on distance from the yttrium source. Radiotherapy is only effective in treating HCC in doses above 50 Gy. Consequently, treatment response after radioembolization is between 25-60% when based on response criteria in solid tumors (mRECIST). We propose to use ultrasound-triggered microbubble destruction (UTMD) to improve radioembolization of HCC. This technique uses commercial ultrasound contrast agents, whose ultrasound triggered cavitation results in a variety of well documented bioeffects. Localized microbubble cavitation has been shown to sensitize malignant tissue to radiotherapy by inducing vascular endothelial-cell apoptosis. Thus, localized UTMD after radioembolization of HCC may potentially improve tumor response by selectively sensitizing malignant tissue to radiotherapy. In addition, the rate of contrast reperfusion after a destructive pulse can be quantified and used to estimate blood perfusion and fractional vascularity. Changes in fractional vascularity and perfusion may be a potential earlier indicator of treatment response, thereby enabling earlier retreatment in non-responding patients. We propose a clinical trial using localized microbubble cavitation followed by imaging of contrast washing back into the tumor (termed reperfusion) to improve patient outcomes and predict treatment response earlier than the current clinical standards. Patients scheduled for radioembolization of HCC will be randomized to receive radioembolization alone or radioembolization in combination with a contrast ultrasound exam 2-4 hours and 7 and 14 days post radioembolization. A flash destruction-replenishment technique will be used to induce microbubble cavitation at multiple planes within the tumor vasculature. Tumoral response, safety, radioactive bead distribution, liver function, and alpha fetal protein, will then be evaluated and compared between groups. As a secondary aim, tumor perfusion will be quantified in the experimental group based on the rate of contrast agent reperfusion following each destructive ultrasound pulse. Patients will then be stratified according to mRECIST criteria 3-4 months post treatment based on their clinically scheduled follow-up MRI/CT study. Microbubble-derived tumor reperfusion rate will be compared between groups to determine if treatment response can be predicted 7-14 days post therapy. Once validated, this technique is expected to improve patient outcomes by selectively sensitizing malignant tissue to radiotherapy, and by enabling alternative forms of treatment through earlier identification of patients not responding to therapy.

放射栓塞的使用已被证明可以成功治疗和降期 肝细胞癌（HCC）以及肝转移，以及相对于传统化疗栓塞的优势 已被报道。该技术的局部 β 发射已被证明可以提供治疗效果 肿瘤内。剂量范围为 110-150 Gy，但传递到恶性组织的辐射取决于 距钇源的距离。放射治疗仅在剂量超过 50 Gy 时才能有效治疗 HCC。 因此，根据反应标准，放射栓塞后的治疗反应在 25-60% 之间 实体瘤（mRECIST）。我们建议使用超声波触发微泡破坏（UTMD）来改善 HCC 放射栓塞术。该技术使用商业超声造影剂，其超声造影剂 引发的空化会导致各种有据可查的生物效应。局部微泡空化 研究表明，通过诱导血管内皮细胞凋亡，使恶性组织对放射治疗敏感。因此， HCC 放射栓塞术后局部 UTMD 可能通过选择性地改善肿瘤反应 使恶性组织对放射治疗敏感。此外，破坏性脉冲后造影剂再灌注率 可以量化并用于估计血液灌注和血管分布分数。分数的变化 血管分布和灌注可能是治疗反应的潜在早期指标，从而能够更早地 对无反应的患者进行再治疗。 我们建议进行一项临床试验，使用局部微泡空化，然后进行对比清洗成像 回到肿瘤（称为再灌注）以改善患者预后并更早预测治疗反应 高于现行临床标准。计划接受放射栓塞治疗的 HCC 患者将被随机分配至 单独接受放射栓塞或放射栓塞结合超声造影检查 2-4 小时 以及放射栓塞术后7天和14天。将使用闪光破坏补充技术来诱导 肿瘤脉管系统内多个平面的微泡空化。肿瘤反应、安全性、放射性 然后将评估珠子分布、肝功能和甲胎蛋白，并在各组之间进行比较。 作为次要目标，实验组中的肿瘤灌注将根据对比率进行量化 每个破坏性超声脉冲后药剂再灌注。然后将根据以下情况对患者进行分层： 治疗后 3-4 个月的 mRECIST 标准基于临床安排的随访 MRI/CT 研究。 将比较各组之间微泡衍生的肿瘤再灌注率，以确定治疗反应是否有效 可以在治疗后 7-14 天进行预测。一旦经过验证，该技术有望改善患者的治疗结果 通过选择性地使恶性组织对放射治疗敏感，并通过以下方式实现替代治疗形式 及早识别对治疗无反应的患者。