Prognosis of Patients with Hepatocellular Carcinoma. Validation and Ranking of Established Staging-Systems in a Large Western HCC-Cohort

BackgroundHCC is diagnosed in approximately half a million people per year, worldwide. Staging is a more complex issue than in most other cancer entities and, mainly due to unique geographic characteristics of the disease, no universally accepted staging system exists to date. Focusing on survival rates we analyzed demographic, etiological, clinical, laboratory and tumor characteristics of HCC-patients in our institution and applied the common staging systems. Furthermore we aimed at identifying the most suitable of the current staging systems for predicting survival. Methodology/Principal FindingsOverall, 405 patients with HCC were identified from an electronic medical record database. The following seven staging systems were applied and ranked according to their ability to predict survival by using the Akaike information criterion (AIC) and the concordance-index (c-index): BCLC, CLIP, GETCH, JIS, Okuda, TNM and Child-Pugh. Separately, every single variable of each staging system was tested for prognostic meaning in uni- and multivariate analysis. Alcoholic cirrhosis (44.4%) was the leading etiological factor followed by viral hepatitis C (18.8%). Median survival was 18.1 months (95%-CI: 15.2–22.2). Ascites, bilirubin, alkaline phosphatase, AFP, number of tumor nodes and the BCLC tumor extension remained independent prognostic factors in multivariate analysis. Overall, all of the tested staging systems showed a reasonable discriminatory ability. CLIP (closely followed by JIS) was the top-ranked score in terms of prognostic capability with the best values of the AIC and c-index (AIC 2286, c-index 0.71), surpassing other established staging systems like BCLC (AIC 2343, c-index 0.66). The unidimensional scores TNM (AIC 2342, c-index 0.64) and Child-Pugh (AIC 2369, c-index 0.63) performed in an inferior fashion. Conclusions/SignificanceCompared with six other staging systems, the CLIP-score was identified as the most suitable staging system for predicting prognosis in a large German cohort of predominantly non-surgical HCC-patients.

背景：肝细胞癌（Hepatocellular Carcinoma, HCC）在全球范围内每年约有50万新增确诊病例。其分期相较于多数其他癌种更为复杂，且由于该疾病独特的地域发病特征，目前尚无全球通用的分期标准。本研究以患者生存率为核心分析目标，对本医疗机构收治的HCC患者的人口学、病因学、临床、实验室检查及肿瘤相关特征进行了回顾性分析，并应用了当前主流的肝癌分期系统；此外，本研究旨在筛选出当前最适用于预测患者生存结局的分期系统。

研究方法与主要结果：本研究从电子病历数据库中筛选出405例HCC患者。研究应用了7种主流分期系统，并通过赤池信息准则（Akaike Information Criterion, AIC）与一致性指数（Concordance Index, c-index）对各系统的生存预测能力进行排序，分别为巴塞罗那临床肝癌分期（Barcelona Clinic Liver Cancer, BCLC）、意大利肝癌项目分期（Cancer of the Liver Italian Program, CLIP）、GETCH分期、日本综合分期系统（Japan Integrated Staging, JIS）、奥田分期（Okuda staging）、TNM分期系统（TNM Staging System, TNM）及Child-Pugh分级（Child-Pugh Classification, Child-Pugh）。同时，本研究对每个分期系统中的各项指标分别开展单因素及多因素预后分析，以评估其预后价值。
病因学分析显示，酒精性肝硬化（44.4%）为最主要的致病因素，其次为丙型病毒性肝炎（18.8%）。患者中位生存期为18.1个月（95%置信区间：15.2~22.2个月）。多因素分析结果表明，腹水、胆红素水平、碱性磷酸酶、甲胎蛋白（Alpha-fetoprotein, AFP）、肿瘤结节数量及BCLC分期的肿瘤侵犯范围均为独立预后因素。
总体而言，所有受试分期系统均具备一定的预后区分能力。其中CLIP分期（紧随其后的为JIS系统）在预后评估能力上表现最优，其AIC与c-index数值最佳（AIC=2286，c-index=0.71），优于BCLC分期（AIC=2343，c-index=0.66）等其他公认分期系统；单维度评分系统如TNM分期（AIC=2342，c-index=0.64）与Child-Pugh分级（AIC=2369，c-index=0.63）的表现相对逊色。

结论与意义：相较于其他6种分期系统，在本项纳入大量以非手术治疗为主的德国HCC患者队列的研究中，CLIP分期被证实为最适用于预测患者预后的分期系统。