A New Lab Based Algorithm for HCC Surveillance in Patients with Cirrhosis

描述(申请人提供)：肝细胞癌是美国癌症相关死亡人数上升最快的原因。存活率令人沮丧，除非是在相对较少的病例中，这些病例被早期发现并接受潜在的根治治疗。因此，建议对肝硬变患者定期监测肝细胞癌。血清甲胎蛋白(AFP)已被广泛用作肝细胞癌的标志物，但其在肝细胞癌监测中的作用普遍较低。然而，AFP的检测特征受肝脏疾病的严重程度和活动性的影响，这部分反映在血清AST、ALT、胆红素、血小板等水平上。将这些因素中的一些因素纳入调整后的基于AFP的算法中，可能会提高其在检测肝细胞癌中的预测价值。我们的初步预测Logistic模型将AFP、年龄、ALT和总胆红素作为连续的非线性变量和交互作用项(AFP*ALT、AFP*胆红素)，发现在AFP检测后的6个月内，与单独使用AFP相比，预测肝细胞癌的发生有显著改善。这项研究已被《胃肠病学》杂志接受发表。这项拟议的研究将通过使用具有更长随访时间和更多肝细胞癌病例的更新派生数据集来优化这一有希望的初步算法的预测效用，在来自退伍军人事务部(VA)和北加州凯撒永久医院(KPNC)的两个独立队列中验证和改进该算法，并与KPNC基于肝脏超声和AFP的筛查相比较，评估其在检测早期肝细胞癌方面的临床应用价值。目标1(调整后的AFP算法的推导)：为了最大限度地提高我们的基于AFP的初步模型(调整后的AFP)在预测肝细胞癌发生中的预测价值，并在一个庞大的派生数据集中估计肝硬变和丙型肝炎感染患者的“阳性或异常”结果的临界值。目的2(外部验证)：测试我们调整后的AFP模型在预测因各种原因引起的肝硬变患者的两个外部队列中发生肝细胞癌的风险。目的3(临床实用性测试)：与标准血清AFP检测加或不加肝脏超声筛查(US)相比，检测调整后的AFP算法在提高早期肝癌检测方面的临床应用价值。鉴于AFP检测的广泛性、实验室标准化水平高、成本低，以及缺乏有前景的和容易获得的新生物标志物，我们相信调整后的AFP算法可能会立即对临床实践产生实用和影响。

DESCRIPTION (provided by applicant): Hepatocellular carcinoma (HCC) is the fastest rising cause of cancer related deaths in the United States. Survival is dismal except in a relatively small number of cases that are detected early and subjected to potentially curative treatment. Therefore, periodic surveillance for HCC has been recommended in patients with liver cirrhosis. Serum alpha-fetoprotein (AFP) has been extensively used as a marker for HCC detection, but its performance in the surveillance for HCC has been generally low. However, AFP test characteristics are influenced by severity and activity of liver disease that are partly reflected n serum levels of AST, ALT, bilirubin, platelets, etc. Incorporating some of these factors into an adjusted AFP-based algorithm may improve its predictive value in detecting HCC. Our preliminary predictive logistic model with AFP, age, ALT, and total bilirubin as continuous non-linear variables and interaction terms (AFP*ALT, AFP*bilirubin) found marked improvement in predicting HCC occurrence in the 6 months following an AFP test compared to AFP alone. This work has been accepted for publication in Gastroenterology. The proposed study will optimize the predictive utility of this promising yet preliminary algorithm by using an updated derivation dataset with longer follow up and more HCC cases, validate and refine the algorithm in two independent cohorts of HCV- and non HCV- related cirrhosis patients from the Department of Veterans Affairs (VA) and Kaiser Permanente Northern California (KPNC), and evaluate its clinical utility in detecting early HCC in comparison to liver ultrasound- and AFP -based screening at KPNC. Aim 1 (DERIVATION OF THE ADJUSTED AFP ALGORITHM): To maximize the predictive value of our preliminary AFP based model (adjusted AFP) in predicting the occurrence of HCC and estimate cutoffs for "positive or abnormal" results in a large derivation dataset of patients with cirrhosis and hepatitis C infection. Aim 2 (EXTERNAL VALIDATION): To test the use of our adjusted AFP model in predicting the risk of HCC in two external cohorts of patients with cirrhosis due to various etiologies. Aim 3 (TESTING OF CLINICAL UTILITY): To examine the clinical utility of the adjusted AFP algorithm in improving early HCC detection compared to standard serum AFP test with or without liver ultrasound screening (US) test. Given the wide availability of AFP tests, their high level of lab standardization, low cost, and the absence of promising and readily available new biomarkers, we believe that an adjusted AFP based algorithm may have an immediate utility and impact on clinical practice.