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经肝动脉化疗栓塞术治疗伴门静脉癌栓肝细胞癌的效果及预后评价模型分析
DOI: 10.3969/j.issn.1001-5256.2021.03.021
利益冲突声明：本研究不存在研究者、伦理委员会成员、受试者监护人以及与公开研究成果有关的利益冲突，特此声明。
作者贡献声明：杨乔怡、王哲轩、夏冬东、白苇提出研究思路；韩国宏负责课题设计，指导撰写文章；杨乔怡、王恩鑫、王哲轩、夏冬东、白苇、李小梅参与收集数据，数据筛选和数据分析；杨乔怡负责撰写论文。
Clinical effect of transcatheter arterial chemoembolization in treatment of patients with hepatocellular carcinoma and portal vein tumor thrombus and an analysis of prognostic evaluation models
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摘要:
目的 探讨肝细胞癌(HCC)合并门静脉癌栓患者采用经肝动脉化疗栓塞术(TACE)治疗的效果，并评估现有肝癌预后评价模型的指导价值。 方法 筛选2010年1月—2016年5月在全国24家三级医院行TACE治疗的HCC患者，最终共纳入266例合并门静脉癌栓的HCC患者进行回顾性分析。采用Kaplan-Meier法绘制生存曲线，并采用log-rank法进行比较；采用Cox回归分析进行单因素和多因素分析，建立Cox回归模型；计算HAP评分、mHAP评分、mHAP2评分、mHAP3评分及6&12标准的受试者工作特征曲线下面积(AUC)和C指数，比较各种模型的预测性能。 结果 所纳入患者中位生存时间为9.867个月，根据Child-Pugh分级，Child-Pugh A级患者中位生存时间为10.067个月，明显长于Child-Pugh B级患者的5.967个月(χ2=5.181，P=0.023)。AFP≤800 ng/ml的患者中位生存时间13.10个月，而AFP＞800/ml的患者中位生存时间8.13个月，差异有统计学意义(χ2=8.643，P=0.003)。单因素分析结果显示肿瘤数目、肿瘤直径、总胆红素、血清白蛋白、AST、ALT与患者的生存有关(P值均＜0.05)。多因素分析结果显示肿瘤数目(HR=1.186，95%CI：1.058~1.329，P＜0.05)、肿瘤直径(HR=1.047，95%CI：1.001~1.095，P＜0.05)是影响患者生存的独立影响因素。6&12标准的1年、2年、3年AUC分别为0.651、0.655、0.641，高于其他模型，而6&12标准和新建模型的C指数分别为0.577和0.579，高于其他模型。 结论 在AFP水平较低、肝功能良好的HCC合并门静脉癌栓患者中，TACE是安全有效的。肿瘤直径和肿瘤数目为筛选合适的患者行TACE治疗提供了可靠依据。现有的原发性肝癌TACE治疗的预后评价模型中，6&12标准具有较好的预测能力。 Abstract:Objective To investigate the clinical effect of transcatheter arterial chemoembolization (TACE) in the treatment of patients with hepatocellular carcinoma (HCC) and portal vein tumor thrombus and the value of existing prognostic evaluation models for HCC. Methods Screening was performed for HCC patients who underwent TACE in 24 tertiary hospitals in China from January 2010 to May 2016, and finally 266 HCC patients with portal vein tumor thrombus were included for retrospective analysis. The Kaplan-Meier method was used to plot survival curves and the log-rank test was used for comparison; a Cox regression analysis was used to perform univariate and multivariate analyses and establish a Cox regression model; area under the ROC curve (AUC) and C-index were calculated for HAP score, mHAP score, mHAP2 score, mHAP3 score, and 6&12 criteria to compare their prediction performance. Results The median survival time was 9.867 months for all patients, and according to Child-Pugh class, the patients with Child-Pugh class A HCC had a significantly longer median survival time than those with Child-Pugh class B HCC (10.067 months vs 5.967 months, χ2=5.181, P=0.023). The patients with alpha-fetoprotein (AFP) ≤800 ng/ml had a significantly longer median survival time than those with AFP > 800 ng/ml (13.10 months vs 8.13 months, χ2=8.643, P=0.003). The univariate analysis showed that number of tumors, tumor diameter, total bilirubin, serum albumin, alanine aminotransferase (AST), and alanine aminotransferase (ALT) were associated with the survival of patients (all P < 0.05), and the multivariate analysis showed that number of tumors (hazard ratio [HR]=1.186, 95% confidence interval [CI]: 1.058-1.329, P < 0.05) and tumor diameter (HR=1.047, 95% CI: 1.001-1.095, P < 0.05) were independent influencing factors for the survival of patients. The 1-, 2-, and 3-year AUCs of 6&12 criteria were 0.651, 0.655, and 0.641, respectively, which were higher than those of the other models; 6&12 criteria and the new model had a C-index of 0.577 and 0.579, respectively, which were higher than C-index of the other models. Conclusion TACE is safe and effective in HCC patients with portal vein tumor thrombus who have a low AFP level and good liver function. Tumor diameter and number of tumors provide a reliable basis for screening out the patients suitable for TACE. Among the existing prognostic evaluation models for primary liver cancer, 6&12 criteria have a better predictive capability than the other models. -
表 1 266例患者TACE术前基线资料
指标 数值 年龄(岁) 53.0±11.6 性别(男/女，例) 227/39 病因学(乙型肝炎/其他，例) 253/13 肿瘤大小[例(%)] ≤3 cm 7(2.65) ＞3 cm且≤7 cm 55(20.83) ＞7 cm且≤10 cm 78(29.50) ＞10 cm 124(46.97) 肿瘤数目[例(%)] 1个 119(44.74) 2~3个 92(34.59) 4~5个 35(13.16) 6~10个 8(3.00) ＞10个 12(4.51) AFP[例(%)] ≤1000 ng/ml 133(50.57) ＞1000 ng/ml 130(49.43) 国际标准化比值 1.08±0.13 白细胞(×109/L) 5.98±2.03 血小板(×109/L) 189.06±83.13 血清白蛋白(mg/dl) 38.37±4.88 血清胆红素(μmol/L) 19.34±12.60 AST(U/L) 80.25±46.74 ALT(U/L) 56.51±37.16 尿素氮(mg/dl) 5.27±1.94 肌酐(μmol/L) 71.94±21.5 Child-Pugh分级(A/B，例) 256/10 
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表 2 Cox回归单因素多因素分析结果
变量 单因素分析 多因素分析 HR(95%CI) P值 HR(95%CI) P值 性别 1.055(0.719~1.549) 0.783 病因学 0.633(0.323~1.239) 0.182 肿瘤直径 1.052(1.015~1.090) 0.005 1.047(1.001~1.095) 0.043 肿瘤数目 1.138(1.033~1.253) 0.009 1.186(1.058~1.329) 0.003 AFP(ng/ml) 1.000(1.000~1.000) 0.674 白细胞(109/L) 1.049(0.966~1.139) 0.253 血小板(109/L) 1.000(0.998~1.002) 0.957 国际标准化比值 2.740(0.908~8.272) 0.074 ALT(U/L) 1.005(1.000~1.009) 0.029 1.002(0.997~1.006) 0.567 AST(U/L) 1.003(1.000~1.006) 0.033 1.001(0.996~1.008) 0.571 血清白蛋白(mg/dl) 0.970(0.942~1.000) 0.048 0.965(0.929~1.003) 0.069 总胆红素(μmol/L) 1.010(1.000~1.019) 0.039 1.005(0.994~1.017) 0.371 尿素氮(mg/dl) 0.905(0.815~1.005) 0.061 肌酐(μmol/L) 1.000(0.994~1.007) 0.906
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表 3 现有预后评价模型的比较
预后模型 C指数 LR 时间依赖AUC 1年AUC 2年AUC 3年AUC HAP 0.572±0.02 10.06 0.588±0.036 0.621±0.048 0.549±0.082 mHAP 0.552±0.021 4.23 0.565±0.035 0.573±0.053 0.510±0.088 mHAP2 0.563±0.019 8.92 0.587±0.033 0.597±0.049 0.552±0.075 mHAP3 0.568±0.023 10.36 0.597±0.036 0.653±0.048 0.635±0.079 6&12标准 0.577±0.022 12.96 0.651±0.035 0.655±0.048 0.641±0.068 新建模型 0.579±0.023 14.45 0.665±0.035 0.645±0.046 0.599±0.066 注：LR，似然比。
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