Optimizing localized therapy for primary liver cancer: a clinical trial and model

优化原发性肝癌的局部治疗：临床试验和模型

• 批准号: 8532650
• 负责人: Rebecca Anne Miksad
• 金额: $ 16.96万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-28 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8532650
• 关键词: Ablation; Advanced Malignant Neoplasm; Angiogenesis Inhibitors; Animals; Area; Award; BAY 54-9085; Balloon Occlusion; Blood; Blood flow; Caliber; Calibration; Characteristics; Chemoembolization; Cirrhosis; Clinical; Clinical Trials; Clinical Trials Design; Computer Simulation; Data; Databases; Development; Drops; Effectiveness; Eligibility Determination; Ethanol; Evaluation; Excision; Future; Goals; Growth; Heating; Hepatitis C; Hepatitis C virus; Human; Image; Incidence; Injection of therapeutic agent; Knowledge; Literature; Liver; Liver Dysfunction; Local Therapy; Magnetic Resonance Imaging; Malignant Neoplasms; Malignant neoplasm of liver; Mathematics; Measures; Mentors; Methods; Modeling; Morbidity - disease rate; Natural History; Operative Surgical Procedures; Oral; Outcome; Patients; Phase; Placebos; Radiofrequency Interstitial Ablation; Randomized Controlled Trials; Research; Research Personnel; Risk; Sample Size; Spin Labels; Stratification Factors; Techniques; Testing; Time; Training; United States; Variant; Waiting Lists; Work; X-Ray Computed Tomography; arm; base; cancer care; career; comparative trial; design; experience; improved; liver function; liver transplantation; markov model; meetings; mortality; novel; outcome forecast; patient oriented; prospective; skills; statistics; therapy development; tumor

PROJECT SUMMARY/ABSTRACT The overall goal of the proposed research is to improve survival for hepatocellular (liver) cancer (HCC) and to support the continued development of the candidate into an independent investigator. With an average five year survival of 12%, the prognosis of HCC is poor and, in contrast to most cancers in the United States, mortality is increasing. Unfortunately, liver resection is often not possible due to liver dysfunction from cirrhosis. Orthotopic liver transplant (OLT) improves survival for HCC patients meeting the Milan criteria. However, there is a national liver donor shortage and more than 20% of candidates lose OLT eligibility (and the chance for cure) while waiting, usually due to HCC progression. Liver-directed therapies attempt to cure patients or "bridge" them until OLT but are suboptimal for HCC >3cm. In addition, evaluation of long-term efficacy is constrained by few prospective trials. For HCC greater than 3cm in size, successful liver directed treatment with radiofrequency ablation (RFA) is limited by the heat sink effect of blood flow. Invasive occlusion of liver blood flow improves RFA efficacy, but adds morbidity and mortality risks. Thus, there is a critical unmet clinical need. Antiangiogenic agents, such as sorafenib, reduce tumor blood flow and improve RFA efficacy in animals. This approach has not yet been tested in humans. This proposal hypothesizes that sorafenib reduces HCC blood flow and improves RFA efficacy and that liver directed therapies with better local control also improve survival for HCC tumors greater than 3cm in size. The proposed research will test these hypotheses with three methods that integrate the strengths of clinical trial and modeling approaches. A Phase II randomized, controlled trial will determine the effect of sorafenib on RFA efficacy for HCC greater than 3cm in size (AIM 1). The size of the ablation zone and the change in tumor blood flow after sorafenib will be measured on radiologic images. In addition, a computer model will be built to analyze the long-term consequences of single and combination (concurrent and sequential) liver-directed therapy for HCC >3cm (AIM 2). National OLT data, an institutional HCC database, and the literature will inform model parameters and model calibration. The effect of each liver directed strategy on overall survival (OS) and OLT wait list drop out will be determined. Results form extensive sensitivity analysis will help inform the development of future HCC trials (AIM 3). Because there is minimal long-term efficacy data for existing liver-directed strategies, the proposed research will advance knowledge about antiangiogenic therapy and RFA in HCC and will add to our understanding of appropriate HCC management and HCC trial design issues. The candidate's immediate career goal is to advance the field of HCC treatment through efficient identification and development of therapies that optimize long-term patient outcomes. The candidate's long- term academic career goal is to found and direct an academic research center of investigators who integrate clinical trial and outcomes modeling research in order to advance cancer care and clinical trials. In order to achieve these research and career goals, the candidate is supported by mentors with expertise in the key areas of the proposed research. In addition to frequent research discussion with mentors, the candidate will pursue additional advanced training through advanced clinical trial, mathematics, statistics and modeling coursework. In summary, with the support of the K23 Patient Oriented Mentored Research Award, the candidate will achieve the specific aims of the research, advance the field of HCC treatment and will gain the skills and experience necessary to become a leading independent investigator.

项目摘要/摘要 拟议研究的总体目标是提高肝细胞（肝）癌（HCC）和 支持候选人持续发展为独立调查员。平均五个 年份的生存率为12％，HCC的预后很差，与美国大多数癌症相反， 死亡率正在增加。不幸的是，由于肝硬化引起的肝功能障碍，通常无法切除肝脏。 原位肝移植（OLT）可改善符合米兰标准的HCC患者的生存率。但是，那里 是国家肝脏供体短缺，超过20％的候选人失去了OLT资格（也是有机会 治愈）等待时，通常是由于HCC的进展。 肝脏定向疗法试图治愈患者或“桥接”他们直到OLT，但对于HCC而言是最佳的 > 3cm。此外，长期疗效的评估受到很少的前瞻性试验的限制。对于HCC更大 比3厘米的大小，成功的肝脏射频消融（RFA）受到热量的限制 血流的下沉作用。肝血流的侵入性阻塞可提高RFA功效，但增加了发病率和 死亡率风险。因此，有一个迫切的未满足临床需求。抗血管生成剂，例如索拉非尼，降低了 肿瘤血流并提高动物的RFA功效。这种方法尚未在人类中进行测试。这 提案假设索拉非尼降低了HCC的血流并提高RFA功效，并且肝脏 具有更好局部控制的定向疗法还可以改善大于3厘米的HCC肿瘤的生存率。 拟议的研究将使用三种整合临床优势的方法来检验这些假设 试验和建模方法。 II期随机对照试验将确定索拉非尼对 HCC的RFA功效大于3厘米（AIM 1）。消融区的大小和肿瘤的变化 索拉非尼后的血流将在放射学图像上测量。此外，将建立计算机模型 分析单一和组合（并发和顺序）肝脏的长期后果 HCC> 3cm的治疗（AIM 2）。国家OLT数据，机构HCC数据库，文献将告知 模型参数和模型校准。每个肝脏的策略对总体生存（OS）和 OLT等待列表辍学将被确定。结果表现出广泛的敏感性分析将有助于告知 开发未来的HCC试验（AIM 3）。 由于现有的肝脏指导策略的长期疗效数据最少，因此拟议的研究 将促进HCC中有关抗血管生成疗法和RFA的知识，并将增加我们对 适当的HCC管理和HCC试验设计问题。 候选人的直接职业目标是通过高效提高HCC治疗领域 鉴定和开发优化长期患者预后的疗法。候选人的长期 学术职业目标是建立并指导一个整合的研究中心 为了推进癌症护理和临床试验，临床试验和结果建模研究。为了 实现这些研究和职业目标，候选人得到了关键专业知识的导师的支持 拟议研究的领域。除了与导师进行频繁的研究讨论外，候选人还将 通过高级临床试验，数学，统计和建模进行其他高级培训 课程。 总而言之，在K23面向患者的指导研究奖的支持下，候选人将 实现研究的具体目标，推进HCC治疗领域，并将获得技能和 成为领先的独立调查员所必需的经验。

项目成果

Phase 1/2 study of everolimus in advanced hepatocellular carcinoma.

• DOI: 10.1002/cncr.26165
• 发表时间: 2011-11-15
• 期刊: Cancer
• 影响因子: 6.2
• 作者: Zhu AX;Abrams TA;Miksad R;Blaszkowsky LS;Meyerhardt JA;Zheng H;Muzikansky A;Clark JW;Kwak EL;Schrag D;Jors KR;Fuchs CS;Iafrate AJ;Borger DR;Ryan DP
• 通讯作者: Ryan DP

When a decision must be made: role of computer modeling in clinical cancer research.

何时必须做出决定：计算机建模在临床癌症研究中的作用。

• DOI: 10.1200/jco.2011.37.8604
• 发表时间: 2011
• 期刊: Journal of clinical oncology : official journal of the American Society of Clinical Oncology
• 作者: Miksad,RebeccaA

Recommendations for liver transplantation for hepatocellular carcinoma: an international consensus conference report.

• DOI: 10.1016/s1470-2045(11)70175-9
• 发表时间: 2012-01
• 期刊: LANCET ONCOLOGY
• 影响因子: 51.1
• 作者: Clavien, Pierre-Alain;Lesurtel, Mickael;Bossuyt, Patrick M. M.;Gores, Gregory J.;Langer, Bernard;Perrier, Arnaud
• 通讯作者: Perrier, Arnaud

Imbalance and gait disturbance from tyrosine kinase inhibition in hepatocellular cancer.

• DOI: 10.1007/s12029-009-9086-7
• 发表时间: 2009
• 期刊: Journal of gastrointestinal cancer
• 影响因子: 1.6
• 作者: Miksad RA;Lai KC;Stein MC;Healy ME;Rojas R;Krajewski KM;Zhu AX
• 通讯作者: Zhu AX

What is the role of adjuvant therapy after liver transplantation for hepatocellular carcinoma?

• DOI: 10.1002/lt.22367
• 发表时间: 2011-10
• 期刊: LIVER TRANSPLANTATION
• 影响因子: 4.6
• 作者: Duvoux, Christophe;Kiuchi, Tetsuya;Pestalozzi, Bernhard;Busuttil, Ronald;Miksad, Rebecca
• 通讯作者: Miksad, Rebecca