Novel Point-of-Care Tool to Predict Response to Sorafenib in Hepatocellular Carcinoma

预测肝细胞癌索拉非尼反应的新型护理点工具

• 批准号: 9015986
• 负责人: Ahmed Kaseb
• 金额: $ 17.4万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-12-01 至 2017-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9015986
• 关键词: Adopted; Adverse event; American; Ascites; BAY 54-9085; Bilirubin; Biological Assay; Biological Markers; Blinded; Budgets; Cancer Etiology; Cessation of life; Child; Cirrhosis; Clinical; Clinical Trials; Clinical assessments; Consensus; Development; Diagnosis; Doppler Ultrasound; Double-Blind Method; Encephalopathies; Goals; Grant; Guidelines; Healthcare; Hepatic; Hepatic Encephalopathy; Image; Individual; Insulin-Like Growth Factor I; Intervention; Laboratories; Lead; Liver; Liver Failure; Liver diseases; Measurement; Measures; Medical; Outcome; Outcome Measure; Paper; Patients; Pharmaceutical Preparations; Plasma; Primary carcinoma of the liver cells; Prothrombin time assay; Publishing; Reporting; Resources; Scanning; Selection Criteria; Serum Albumin; Severities; Staging; Staging System; Stratification; System; Systemic Therapy; Testing; Texas; Therapeutic Trials; Time; Training; United States National Institutes of Health; Validation; base; chronic liver disease; clinical practice; cohort; cost; design; disorder risk; improved; innovation; men; novel; outcome forecast; outcome prediction; patient stratification; personalized therapeutic; point of care; predicting response; prognostic; prospective; public health relevance; response; survival outcome; survival prediction; systemic toxicity; tool; treatment effect; tumor progression

 DESCRIPTION (provided by applicant): Since the majority of hepatocellular carcinoma (HCC) patients suffer from a co-existing predisposing chronic liver disease (CLD), risk stratification of HCC patients is defined as the ability to predict outcomes from a given intervention (such as systemic therapy) by arranging patients according to the severity of their underlying liver disease. Child-Pugh (CP) score is the current standard tool for assessing the underlying CLD status in clinical practice and stratifying patients in HCC therapeutic trials. Moreover, it is an essential parameter in most currently used HCC staging systems. Multiple expert panels consensus statements concluded that patients with HCC must have a CP score of A to be considered for systemic therapies in practice or in clinical trials. This selection criterion facilitates assessment of the effect of treatment without the confounding issues of liver failure and death as a result of underlying CLD. CP score uses five variables: three objective laboratory-based (serum albumin, prothrombin time, bilirubin), in addition to two subjective clinical parameters (hepatic encephalopathy and ascites). The last two parameters are clinically difficult to grade and may vary in severity in response to medical therapies. Therefore, CP fails to accurately provide confident prediction of survival and treatment adverse events in HCC patients. Thus, major refinement of the CP score is critically needed. Circulating levels of insulin-like growth factor-1 (IGF-1) decrease sharply in patients with CLD including cirrhosis and HCC, because the liver is responsible for synthesis of most of the circulating IGF-1. Most recently, we published (Kaseb et al, JNCI 2014) a paper describing the development and validation of an innovative plasma IGF score by replacing clinical assessment of ascites and encephalopathy in the CP score with the objectively quantified plasma IGF-1. Notably, a significant number of HCC patients with old CP-A class were reclassified into CP-B (26% in the testing set, and 46% in the validation set). Patients categorized as old A/new B had a significantly poorer OS than did patients categorized as old A/new A in both the training and validation cohorts (P = 0.026 and <0.001, respectively). A major advantage to the use of plasma IGF-1 is being a well-characterized existing plasma assay that is ready for implementation. We hypothesize that among patients with "old CP-A" class HCC treated with sorafenib, those who are reclassified as "new CP-B" will have shorter overall survival and time-to-tumor-progression and a higher rate of adverse events than will those reclassified as "new CP-A." We will test this hypothesis by conducting a prospective double- blinded biomarker study to compare the prognostic stratification ability of the conventional 'old' Child-Pugh score to the 'new' IGF score in 100 HCC patients (all Child-Pugh A) to be treated with sorafenib systemic therapy. Thus, our study is designed to reveal the potential superiority of the new score over the old CP.

 描述（由申请人提供）：由于大多数肝细胞癌（HCC）患者患有共存的易患慢性肝病（CLD）， HCC患者被定义为通过根据其基础肝脏疾病的严重程度安排患者来预测给定干预（如全身治疗）的结果的能力。Child-Pugh（CP）评分是目前在临床实践中评估潜在CLD状态和在HCC治疗试验中对患者进行分层的标准工具。此外，它是大多数目前使用的HCC分期系统中的重要参数。多个专家小组的共识声明得出结论，HCC患者的CP评分必须为A，才能在实践或临床试验中考虑进行全身治疗。该选择标准有助于评估治疗效果，而不会出现基础CLD导致的肝功能衰竭和死亡的混杂问题。CP评分使用五个变量：三个基于实验室的客观参数（血清白蛋白、凝血酶原时间、胆红素），以及两个主观临床参数（肝性脑病和腹水）。最后两个参数在临床上难以分级，并且严重程度可能因药物治疗而异。因此，CP不能准确地提供对HCC患者的生存和治疗不良事件的可靠预测。因此，CP评分的主要改进是迫切需要的。循环中胰岛素样生长因子-1（IGF-1）的水平在CLD（包括肝硬化和HCC）患者中急剧下降，因为肝脏负责合成大部分循环中的IGF-1。最近，我们发表了一篇论文（Kaseb et al，JNCI 2014），描述了通过用客观定量的血浆IGF-1替代CP评分中腹水和脑病的临床评估，开发和验证了一种创新的血浆IGF评分。值得注意的是，大量具有旧CP-A分类的HCC患者被重新分类为CP-B（测试集中为26%，验证集中为46%）。在训练组和验证组中，归类为旧A/新B的患者的OS显著低于归类为旧A/新A的患者（分别为P = 0.026和<0.001）。使用血浆IGF-1的一个主要优点是现有的血浆测定法已充分表征，可随时实施。我们假设，在接受索拉非尼治疗的“老CP-A”类HCC患者中，重新分类为“新CP-B”的患者的总生存期和肿瘤进展时间较短，不良事件发生率高于重新分类为“新CP-A”的患者。“我们将通过进行一项前瞻性双盲生物标志物研究来测试这一假设，以比较传统的”旧“Child-Pugh评分与”新“IGF评分的预后分层能力。 100例HCC患者（均为Child-Pugh A级）接受索拉非尼全身治疗。因此，我们的研究旨在揭示新评分相对于旧CP的潜在优势。