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

 描述(申请人提供)：由于大多数肝细胞癌患者同时患有易患慢性肝病， 肝细胞癌患者被定义为通过根据潜在肝病的严重程度安排患者来预测给定干预(如系统治疗)的结果的能力。Child-Pugh(CP)评分是目前在临床实践中评估潜在的CLD状态和在肝癌治疗试验中对患者进行分层的标准工具。此外，在目前使用的大多数肝细胞癌分期系统中，它是一个必不可少的参数。多个专家小组的共识声明得出结论，在实践或临床试验中，肝细胞癌患者的CP评分必须为A，才能考虑进行系统治疗。这一选择标准有助于评估治疗效果，而不会出现潜在的慢性肝病引起的肝功能衰竭和死亡等令人困惑的问题。CP评分使用五个变量：三个客观实验室基础(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)。后两个参数在临床上很难分级，其严重程度可能因药物治疗的不同而不同。因此，CP不能准确预测肝细胞癌患者的存活率和治疗不良事件。因此，关键是需要对CP分数进行重大改进。在包括肝硬变和肝细胞癌在内的慢性肝病患者中，循环中的胰岛素样生长因子-1(IGF-1)水平急剧下降，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等人，JNCI 2014)，描述了一种创新的血浆IGF评分的开发和验证，用客观量化的血浆IGF-1取代了CP评分中对腹水和脑病的临床评估。值得注意的是，相当数量的具有旧的CP-A级的肝细胞癌患者被重新分类为CP-B(在测试组中占26%，在验证组中占46%)。在训练和验证队列中，被归类为旧A/新B的患者的OS显著低于被归类为旧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，现有的血浆检测方法具有良好的特性，可以随时实施。我们假设，在接受索拉非尼治疗的“旧CP-A”级肝细胞癌患者中，被重新归类为“新CP-B”的患者与被重新归类为“新CP-A”的患者相比，总体生存时间和肿瘤进展时间更短，不良事件发生率更高。我们将通过进行一项前瞻性双盲生物标志物研究来检验这一假设，以比较传统的Child-Pugh评分和新的IGF评分的预后分层能力 100例肝细胞癌患者(均为Child-Pugh A级)接受索拉非尼系统治疗。因此，我们的研究旨在揭示新分数相对于旧的CP分数的潜在优势。

 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.