Microbubble Cavitation for Improving Hepatocellular Carcinoma Radioembolization

微泡空化改善肝细胞癌放射栓塞

• 批准号: 10301005
• 负责人: Kevin Anton
• 金额: $ 44.76万
• 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 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10301005
• 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; Drug Delivery Systems; 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; Randomized Clinical Trials; Recovery; Reperfusion Therapy; Reporting; Retreatment; Safety; Schedule; Solid Neoplasm; Source; Techniques; Testing; Therapeutic; Therapeutic Effect; Therapeutic Embolization; Time; Tissues; Tumor-Derived; Vascular Endothelial Cell; Vascular Permeabilities; Yttrium; base; blood perfusion; contrast enhanced; contrast imaging; dosage; effective therapy; experimental group; first-in-human; follow-up; improved; liver cancer model; liver function; mortality; nuclear imaging; response; safety and feasibility; tool; treatment duration; 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.

放射性栓塞的使用已被证明是成功的治疗和降级， 肝细胞癌（HCC）以及肝转移，以及优于传统的化疗栓塞 已被报道。来自该技术的局部β发射已显示出提供治疗效果 在肿瘤内。剂量范围为110-150戈伊，但传递到恶性组织的辐射取决于 与钇源的距离。放射治疗仅在剂量高于50戈伊时对治疗HCC有效。 因此，根据缓解标准，放射性栓塞后的治疗缓解率在25-60%之间 实体瘤（mRECIST）。我们建议使用超声触发微泡破坏（UTMD）来改善 肝癌的放射性栓塞。该技术使用商业超声造影剂，其超声 触发的空化导致各种有据可查的生物效应。局部微泡空化已经被 显示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，在本发明中， HCC放射性栓塞后局部UTMD可能通过选择性地增强肿瘤反应， 使恶性组织对放疗敏感。此外，破坏性脉冲后对比剂再灌注的速率 可以量化并用于估计血液灌注和部分血管分布。分数变化 血管分布和灌注可能是治疗反应的潜在早期指标， 无应答患者的再治疗。 我们提出了一项临床试验，使用局部微泡空化，然后进行造影剂冲洗成像 返回肿瘤（称为再灌注），以改善患者预后并更早预测治疗反应 目前的临床标准。计划接受HCC放射栓塞治疗的患者将随机分配至 单独接受放射性栓塞或放射性栓塞联合超声造影检查2-4小时 放射栓塞后第7天和第14天。将使用一种闪光破坏-补充技术， 在肿瘤脉管系统内的多个平面处的微泡空化。肿瘤缓解，安全性，放射性 然后评估珠分布、肝功能和α胎儿蛋白，并在组间进行比较。 作为次要目标，将根据对比率对实验组中的肿瘤灌注进行量化 在每次破坏性超声脉冲之后的药剂再灌注。然后将根据以下因素对患者进行分层： 基于临床计划随访MRI/CT研究，治疗后3-4个月符合mRECIST标准。 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 可以在治疗后7-14天预测。一旦得到验证，这项技术有望改善患者的预后 通过选择性地使恶性组织对放射疗法敏感，并通过使替代形式的治疗成为可能， 早期识别对治疗无反应的患者。