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中华移植杂志(电子版) ›› 2023, Vol. 17 ›› Issue (06) : 362 -371. doi: 10.3877/cma.j.issn.1674-3903.2023.06.008

荟萃分析

肝癌肝移植术后免疫抑制方案的网状荟萃分析
张琳成1, 詹启帆1, 赵禹迪2, 邵初晓3, 凌孙彬4, 徐骁5,†()   
  1. 1. 310058　杭州，浙江大学医学院；310006　杭州，浙江省肿瘤融合研究与智能医学重点实验室
    2. 310058　杭州，浙江中医药大学第四临床医学院
    3. 323000　丽水市人民医院肝胆胰外科
    4. 310058　杭州，浙江中医药大学第四临床医学院；310003　杭州市第一人民医院肝胆胰外科
    5. 310058　杭州，浙江大学医学院；310006　杭州，浙江省肿瘤融合研究与智能医学重点实验室；310003　杭州，卫生部多器官联合移植研究重点实验室
  • 收稿日期:2023-09-12 出版日期:2023-12-25
  • 通信作者: 徐骁
  • 基金资助:
    国家自然科学基金项目(92159202，82273270，32171368); 国家科技重大专项(2017ZX10203205)

Efficacy evaluation of immunosuppressive regimen after liver transplantation for hepatocellular carcinoma: a network analysis

Lincheng Zhang1, Qifan Zhan1, Yudi Zhao2, Chuxiao Shao3, Sunbin Ling4, Xiao Xu5,†()   

  1. 1. Zhejiang University School of Medicine, Hangzhou 310058, China; Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou 310006, China
    2. Fourth Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou 310058, China
    3. Department of Hepatobiliary and Pancreatic Surgery, Lishui People′s Hospital, Lishui 323000, China
    4. Fourth Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou 310058, China; Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People′s Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
    5. Zhejiang University School of Medicine, Hangzhou 310058, China; Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou 310006, China; NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou 310003, China
  • Received:2023-09-12 Published:2023-12-25
  • Corresponding author: Xiao Xu
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引用本文：

张琳成, 詹启帆, 赵禹迪, 邵初晓, 凌孙彬, 徐骁. 肝癌肝移植术后免疫抑制方案的网状荟萃分析[J]. 中华移植杂志(电子版), 2023, 17(06): 362-371.

Lincheng Zhang, Qifan Zhan, Yudi Zhao, Chuxiao Shao, Sunbin Ling, Xiao Xu. Efficacy evaluation of immunosuppressive regimen after liver transplantation for hepatocellular carcinoma: a network analysis[J]. Chinese Journal of Transplantation(Electronic Edition), 2023, 17(06): 362-371.

目的

评价肝细胞癌(以下简称肝癌)肝移植术后不同免疫抑制方案的疗效。

方法

计算机检索PubMed、Medline、Scopus、EMbase、Cochrane Library和中国知网数据库。检索年限为数据库建库时间至2023年8月31日。主要观察指标为移植术后不同时间总体生存率和无复发生存率。利用Cochrane偏倚风险评估工具5.1.0对纳入的研究进行偏倚风险评价。使用R软件基于贝叶斯随机效应一致性模型进行网状荟萃分析。二分类变量结局指标采用比值比(OR)计算，连续变量结局指标采用均数差(MD)计算，均以效应值及95%可信区间(CI)表示。采用I2统计量评价研究间异质性。采用规模缩减因子判断模型收敛性，并绘制Brooks-Gelman-Rubin诊断图。P<0.05为差异有统计学意义。

结果

最终纳入27篇，其中随机对照试验8项、前瞻性队列研究1项、回顾性队列研究18项，共11 410例肝癌肝移植受者。与CNI组和西罗莫司组相比，依维莫司组受者血管侵犯率更高(OR＝0.45, 95%CI：0.30～0.71; OR＝2.20, 95%CI：1.24～3.77)。与接受以依维莫司为基础免疫抑制方案的肝移植受者相比，接受CNI受者移植后2年(OR：0.44, 95%CI：0.21～0.86)、3年(OR：0.49, 95%CI：0.25～0.94)、4年(OR：0.21, 95%CI：0.10～0.43)、5年(OR：0.20, 95%CI：0.07～0.58)和6年(OR：0.18, 95%CI：0.07～0.50)总体生存率更低；与接受以西罗莫司为基础免疫抑制方案受者相比，接受CNI的受者移植后1年(OR：0.41, 95%CI：0.24～0.66)、2年(OR：0.54, 95%CI：0.33～0.88)、3年(OR：0.66, 95%CI：0.44～0.99)、4年(OR：0.42, 95%CI：0.28～0.60)、5年(OR：0.59, 95%CI：0.38～0.90)、6年(OR：0.51, 95%CI：0.28～0.82)、7年(OR：0.49, 95%CI：0.27～0.84)总体生存率更低。与接受以西罗莫司为基础免疫抑制方案的肝移植受者相比，接受CNI的受者移植后1年(OR：0.43, 95%CI：0.23～0.77)、2年(OR：0.57, 95%CI：0.34～0.95)、3年(OR：0.56, 95%CI：0.34～0.92)和4年(OR：0.47, 95%CI：0.21～0.92)无复发生存率均更低。

结论

相较于以CNI为基础的免疫抑制方案，术后使用以哺乳动物雷帕霉素靶蛋白抑制剂为基础的免疫抑制方案的肝癌肝移植受者预后更佳。

关键词: 肝细胞癌, 肝移植, 免疫抑制方案, 西罗莫司, 依维莫司, 钙调磷酸酶抑制剂
Objective

To evaluate the efficacy of different immunosuppressive regimens after liver transplantation for hepatocellular carcinoma.

Methods

PubMed, Medline, Scopus, EMbase, Cochrane Library and China National Knowledge Infrastructure databases were searched. The search period was from the establishment of the database to August 31, 2023. The main observation indexes were overall survival rate and recurrence-free survival rate at different time after liver transplantation. The Cochrane bias risk assessment tool 5.1.0 was used to evaluate the bias risk of the included studies. R software was used for network meta-analysis based on Bayesian random effect consistency model. The outcome indicators of dichotomous variables were calculated by odds ratio (OR), and the outcome indicators of continuous variables were calculated by mean difference (MD), which were expressed by effect value and 95% confidence interval (CI). The I2 statistic was used to evaluate the heterogeneity between studies. The potiential scale reduction factor was used to judge the convergence of the model, and the Brooks-Gelman-Rubin diagnostic diagram was drawn. P<0.05 was considered statistically significant.

Results

Finally, 27 articles were included, including 8 randomized controlled trials, 1 prospective cohort study and 18 retrospective cohort studies. A total of 11 410 liver transplantation recipients with hepatocellular carcinoma were included. Compared with CNI group and sirolimus group, the rate of vascular invasion in everolimus group was higher (OR = 0.45, 95 %CI: 0.30-0.71; OR = 2.20, 95%CI: 1.24-3.77). Compared with liver transplant recipients receiving everolimus-based immunosuppressive regimen, recipients receiving CNI had lower overall survival rates at 2 years (OR: 0.44, 95%CI: 0.21-0.86), 3 years (OR: 0.49, 95%CI: 0.25-0.94), 4 years (OR: 0.21, 95%CI: 0.10-0.43), 5 years (OR: 0.20, 95%CI: 0.07-0.58) and 6 years (OR: 0.18, 95%CI: 0.07-0.50) after transplantation. Compared with liver transplant recipients receiving sirolimus-based immunosuppressive regimen, recipients receiving CNI had lower overall survival rates at 1 year (OR: 0.41, 95%CI: 0.24-0.66), 2 years (OR: 0.54, 95%CI: 0.33-0.88), 3 years (OR: 0.66, 95%CI: 0.44-0.99), 4 years (OR: 0.42, 95%CI: 0.28-0.60), 5 years (OR: 0.59, 95%CI: 0.38-0.90), 6 years (OR: 0.51, 95%CI: 0.28-0.82), and 7 years (OR: 0.49, 95%CI: 0.27-0.84) after transplantation. Compared with liver transplant recipients receiving sirolimus-based immunosuppressive regimen, recipients receiving CNI had lower recurrence-free survival rates at 1 year (OR: 0.43, 95%CI: 0.23-0.77), 2 years (OR: 0.57, 95%CI: 0.34-0.95), 3 years (OR: 0.56, 95%CI: 0.34-0.92) and 4 years (OR: 0.47, 95%CI: 0.21-0.92) after transplantation.

Conclusions

Compared with the CNI-based immunosuppressive regimen, the prognosis of liver transplant recipients with hepatocellular carcinoma using the mammalian target of rapamycin inhibitor-based immunosuppressive regimen after transplantation is better.

Key words: Hepatocellular carcinoma, Liver transplantation, Immunosuppressive regimen, Sirolimus, Everolimus, Calcineurin inhibitor
图1 文献筛选流程及结果
表1 纳入27项研究基本特征情况
纳入研究 年份 国家/地区 研究类型 组别A(例) 组别B(例)
Chinnakotla[22] 2009 美国 回顾性队列研究 SRL(121) CNI(106)
Cholongitas[23] 2014 希腊 回顾性队列研究 EVR(21) CNI(22)
Cillo[24] 2019 意大利 RCT EVR(44) CNI(23)
Ekpanyapong[25] 2020 美国 回顾性队列研究 SRL(108) CNI(603)
Ferreiro[26] 2014 西班牙 回顾性队列研究 EVR(21) CNI(31)
Geissler[27] 2016 欧洲、加拿大和澳大利亚 RCT SRL(252) CNI(256)
Junge[28] 2015 法国 RCT EVR(136) CNI(67)
Kang[29] 2021 韩国 回顾性队列研究 EVR(114) CNI(189)
Lee[30] 2021 瑞士 RCT EVR(387) CNI(385)
Ling[31] 2020 中国 回顾性队列研究 SRL(76) CNI(128)
Liu[32] 2023 中国 回顾性队列研究 SRL(125) CNI(68)
Manzia[33] 2018 意大利 回顾性队列研究 EVR(24) CNI(25)
Rodríguez-Perálvarez[34] 2018 西班牙 前瞻性队列研究 EVR(64) CNI(128)
Sapisochin[35] 2022 加拿大和中国台湾省 RCT EVR(56) CNI(61)
Schnitzbauer[36] 2010 欧洲、加拿大和澳大利亚 RCT SRL(255) CNI(255)
Shen[37] 2016 中国 回顾性队列研究 SRL(26) CNI(30)
Teperman[38] 2013 加拿大和美国 RCT SRL(44) CNI(43)
Thorat[39] 2017 中国台湾省 回顾性队列研究 EVR(37) CNI(29)
Toso[40] 2010 美国 回顾性队列研究 SRL(109) CNI(2 382)
Vivarelli[41] 2010 意大利 回顾性队列研究 SRL(31) CNI(31)
Xu[42] 2016 中国 回顾性队列研究 SRL(62) CNI(80)
Yanik[43] 2016 美国 回顾性队列研究 SRL(234) CNI(3 702)
赵晓飞[44] 2014 中国 回顾性队列研究 SRL(94) CNI(71)
Zhou[45] 2008 中国 回顾性队列研究 SRL(27) CNI(46)
Zimmerman[46] 2008 美国 回顾性队列研究 SRL(45) CNI(52)
Bhangui[47] 2016 印度 回顾性队列研究 SRL(21) CNI(21)
Lee[48] 2017 韩国 RCT SRL(20) CNI(22)
表2 对纳入的27例研究的基本特征进行网状荟萃分析
组别比较 移植前年龄[MD值(95%CI)] 移植前甲胎蛋白[MD值(95%CI)] 移植前MELD评分[MD值(95%CI)] 移植前是否接受TACE[OR值(95%CI)] 是否符合米兰标准[OR值(95%CI)] 移植前是否发生血管侵犯[OR值(95%CI)]
CNI组与EVR组 －0.30(－1.51～0.86) －1 668.32(－7 004.80～3 178.36) －0.40(－3.60～2.80) 0.63(0.16～2.51) 1.15(0.69～1.97) 0.45(0.30～0.71)*
EVR组与SRL组 0.67(－0.72～2.40) 1 717.73(－7 848.81～11 761.85) 0.34(－3.61～4.48) 1.24(0.28～4.91) 1.03(0.53～1.88) 2.20(1.24～3.77)*
SRL组与CNI组 0.41(－0.59～1.49) 83.20(－8 663.68～8 555.19) －0.04(－2.41～2.47) 0.77(0.54～1.12) 1.18(0.82, 1.72) 1.00(0.69～1.43)
图2 纳入的27篇文献偏倚风险评价图
图3 肝移植术后接受不同免疫抑制方案受者总体生存率网状荟萃分析的Brooks-Gelman-Rubin诊断图注：EVR.依维莫司；SRL.西罗莫司；d．CNI.EVR. CNI与EVR比较的链条内收敛性；d．CNI.SRL. CNI与SRL比较的链条内收敛性；sd.d. CNI与EVR比较以及CNI与SRL比较链条间收敛性；shrink factor.缩减因子；last iteration in chain.最后一次链式迭代；median.中位数
表3 肝移植术后接受不同免疫抑制方案受者总体生存率网状荟萃分析[OR(95%CI)]
组别比较 总体生存率
1年[22，26，27，29，30，31，32，34，37，39，42，43，44，45，46，48] 2年[22，26，27，34，37，39，40，41，42，44，45，48] 3年[22，26，27，29，30，31，32，34，37，39，40，42，43，44，47，48] 4年[22，26，27，29，31，32，37，39，44] 5年[22，26，27，37，40，42，43，44，46] 6年[22，26，27，29，32，37，44] 7年[22，26，27，32，37，44]
CNI组与EVR组 0.42(0.15～1.13) 0.44(0.21～0.86)* 0.49(0.25～0.94)* 0.21(0.10～0.43)* 0.20(0.07～0.58)* 0.18(0.07～0.50)* 0.28(0.06～1.31)
CNI组与SRL组 0.41(0.24～0.66)* 0.54(0.33～0.88)* 0.66(0.44～0.99)* 0.42(0.28～0.60)* 0.59(0.38～0.90)* 0.51(0.28～0.82)* 0.49(0.27～0.84)*
EVR组与SRL组 0.97(0.31～2.85) 1.23(0.53～2.98) 1.35(0.63～2.97) 2.01(0.86～4.71) 3.00(0.92～9.37) 2.85(0.85～8.00) 1.75(0.33～9.21)
表4 肝移植术后接受不同免疫抑制方案受者总体生存率网状荟萃分析的收敛性检测
总体生存率 PSRF的点估计/95%置信上限 多变量PSRF
d.CNI.EVR d.CNI.SRL sd.d
1年 1.00/1.00 1.00/1.00 1.00/1.00 1.00
2年 1.00/1.00 1.00/1.00 1.00/1.00 1.00
3年 1.00/1.00 1.00/1.00 1.00/1.00 1.00
4年 1.00/1.00 1.00/1.00 1.00/1.00 1.00
5年 1.00/1.00 1.00/1.00 1.00/1.00 1.00
6年 1.00/1.00 1.00/1.00 1.00/1.00 1.00
7年 1.00/1.00 1.00/1.00 1.00/1.00 1.00
图4 肝移植术后接受不同免疫抑制方案受者无复发生存率网状荟萃分析的Brooks-Gelman-Rubin诊断图注：EVR.依维莫司；SRL.西罗莫司；d．CNI.EVR. CNI与EVR比较的链条内收敛性；d．CNI.SRL. CNI与SRL比较的链条内收敛性；sd.d. CNI与EVR比较以及CNI与SRL比较链条间收敛性；shrink factor.缩减因子；last iteration in chain.最后一次链式迭代；median.中位数
表5 肝移植术后接受不同免疫抑制方案受者无复发生存率网状荟萃分析[OR(95%CI)]
组别比较 无复发生存率
1年[27，30，31，32，34，37，41，42，44，45，46，48] 2年[27，30，31，32，34，35，37，41，42，44，45，46，48] 3年[27，30，31，32，34，35，37，41，42，44，46，47，48] 4年[27，32，35，37，41，46] 5年[27，31，32，35，36，37，42，44，46]
CNI组与EVR组 0.36(0.06～1.47) 0.60(0.16～1.96) 0.53(0.14～1.85) 0.24(0.02～2.42) 0.24(0.02～2.82)
CNI组与SRL组 0.43(0.23～0.77)* 0.57(0.34～0.95)* 0.56(0.34～0.92)* 0.47(0.21～0.92)* 0.60(0.29～1.17)
EVR组与SRL组 1.19(0.25～8.22) 0.96(0.26～3.79) 1.06(0.28～4.51) 1.94(0.16～26.03) 2.50(0.19～40.92)
表6 肝移植术后接受不同免疫抑制方案受者无复发生存率网状荟萃分析的收敛性检测
无复发生存率 PSRF的点估计/95%置信上限 多变量PSRF
d.CNI.EVR d.CNI.SRL sd.d
1年 1.00/1.00 1.00/1.00 1.00/1.00 1.00
2年 1.00/1.00 1.00/1.00 1.00/1.00 1.00
3年 1.00/1.00 1.00/1.00 1.00/1.00 1.00
4年 1.00/1.00 1.00/1.00 1.00/1.00 1.00
5年 1.00/1.00 1.00/1.00 1.00/1.00 1.00
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