General Surgery and Liver Transplantation Unit, University of Milan, Istituto Nazionale Tumori (National Cancer Institute), Istituto di Ricovero e Cura a Carattere Scientifico Foundation, Milan, Italy.
General Surgery and Liver Transplantation Unit, University of Milan, Istituto Nazionale Tumori (National Cancer Institute), Istituto di Ricovero e Cura a Carattere Scientifico Foundation, Milan, Italy.
Gastroenterology. 2018 Jan;154(1):128-139. doi: 10.1053/j.gastro.2017.09.025. Epub 2017 Oct 5.
BACKGROUND & AIMS: Outcomes of liver transplantation for hepatocellular carcinoma (HCC) are determined by cancer-related and non-related events. Treatments for hepatitis C virus infection have reduced non-cancer events among patients receiving liver transplants, so reducing HCC-related death might be an actionable end point. We performed a competing-risk analysis to evaluate factors associated with survival of patients with HCC and developed a prognostic model based on features of HCC patients before liver transplantation.
We performed multivariable competing-risk regression analysis to identify factors associated with HCC-specific death of patients who underwent liver transplantation. The training set comprised 1018 patients who underwent liver transplantation for HCC from January 2000 through December 2013 at 3 tertiary centers in Italy. The validation set comprised 341 consecutive patients who underwent liver transplantation for HCC during the same period at the Liver Cancer Institute in Shanghai, China. We collected pretransplantation data on etiology of liver disease, number and size of tumors, patient level of α-fetoprotein (AFP), model for end-stage liver disease score, tumor stage, numbers and types of treatment, response to treatments, tumor grade, microvascular invasion, dates, and causes of death. Death was defined as HCC-specific when related to HCC recurrence after transplantation, disseminated extra- and/or intrahepatic tumor relapse and worsened liver function in presence of tumor spread. The cumulative incidence of death was segregated for hepatitis C virus status.
In the competing-risk regression, the sum of tumor number and size and of log level of AFP were significantly associated with HCC-specific death (P < .001), returning an average c-statistic of 0.780 (95% confidence interval, 0.763-0.798). Five-year cumulative incidence of non-HCC-related death was 8.6% in HCV-negative patients and 18.1% in HCV-positive patients. For patients with HCC to have a 70% chance of HCC-specific survival 5 years after transplantation, their level of AFP should be <200 ng/mL and the sum of number and size of tumors (in centimeters) should not exceed 7; if the level of AFP was 200-400 ng/mL, the sum of the number and size of tumors should be ≤5; if their level of AFP was 400-1000 ng/mL, the sum of the number and size of tumors should be ≤4. In the validation set, the model identified patients who survived 5 years after liver transplantation with 0.721 accuracy (95% confidence interval, 0.648%-0.793%). Our model, based on patients' level of AFP and HCC number and size, outperformed the Milan; University of California, San Francisco; Shanghai-Fudan; Up-to-7 criteria (P < .001); and AFP French model (P = .044) to predict which patients will survive for 5 years after liver transplantation.
We developed a model based on level of AFP, tumor size, and tumor number, to determine risk of death from HCC-related factors after liver transplantation. This model might be used to select end points and refine selection criteria for liver transplantation for patients with HCC. To predict 5-year survival and risk of HCC-related death using an online calculator, please see www.hcc-olt-metroticket.org/. ClinicalTrials.gov ID NCT02898415.
肝移植治疗肝细胞癌（HCC）的结果取决于与癌症相关和非相关的事件。丙型肝炎病毒感染的治疗降低了接受肝移植患者的非癌症事件发生率，因此降低 HCC 相关死亡率可能是一个可行的终点。我们进行了竞争风险分析，以评估与 HCC 患者生存相关的因素，并基于 HCC 患者肝移植前的特征开发了一个预后模型。
我们进行了多变量竞争风险回归分析，以确定接受肝移植的 HCC 患者 HCC 特异性死亡的相关因素。训练集包括意大利 3 个三级中心 2000 年 1 月至 2013 年 12 月期间接受肝移植治疗 HCC 的 1018 例患者。验证集包括中国上海肝癌研究所同期接受肝移植治疗 HCC 的 341 例连续患者。我们收集了移植前关于肝脏疾病病因、肿瘤数量和大小、患者甲胎蛋白（AFP）水平、终末期肝病模型评分、肿瘤分期、治疗次数和类型、治疗反应、肿瘤分级、微血管侵犯、死亡日期和原因等数据。当死亡与移植后 HCC 复发、播散性肝内和/或肝外肿瘤复发以及肿瘤播散时肝功能恶化相关时，定义为 HCC 特异性死亡。根据丙型肝炎病毒状态对 HCC 特异性死亡的累积发生率进行了分离。
在竞争风险回归中，肿瘤数量和大小的总和以及 AFP 对数水平与 HCC 特异性死亡显著相关（P <.001），平均 C 统计量为 0.780（95%置信区间，0.763-0.798）。丙型肝炎病毒阴性患者的非 HCC 相关死亡 5 年累积发生率为 8.6%，丙型肝炎病毒阳性患者为 18.1%。对于 HCC 患者，要使其在移植后 5 年内有 70%的 HCC 特异性生存率，其 AFP 水平应<200ng/ml，肿瘤数量和大小的总和不应超过 7cm；如果 AFP 水平为 200-400ng/ml，则肿瘤数量和大小的总和应≤5cm；如果 AFP 水平为 400-1000ng/ml，则肿瘤数量和大小的总和应≤4cm。在验证集中，该模型以 0.721 的准确率（95%置信区间，0.648%-0.793%）识别出存活 5 年以上的肝移植患者。我们的模型基于 AFP 水平和 HCC 数量和大小，优于米兰标准、加州大学旧金山分校标准、上海复旦大学标准、Up-to-7 标准（P <.001）；优于 AFP 法国模型（P <.001），用于预测哪些患者将在肝移植后存活 5 年。
我们开发了一个基于 AFP 水平、肿瘤大小和肿瘤数量的模型，以确定肝移植后与 HCC 相关因素相关的死亡风险。该模型可用于选择 HCC 患者肝移植的终点和改进选择标准。要使用在线计算器预测 5 年生存率和 HCC 相关死亡风险，请访问 www.hcc-olt-metroticket.org/。临床试验注册：NCT02898415。
