经肝动脉化疗栓塞联合系统治疗对不可切肝细胞癌的疗效分析

李文利 杜阳峰 袁国盛 臧梦雅 朱培琳 李榕 陈泳如 苏开妍 李祺 胡晓云 庞桦进 陈锦章

李文利, 杜阳峰, 袁国盛, 臧梦雅, 朱培琳, 李榕, 陈泳如, 苏开妍, 李祺, 胡晓云, 庞桦进, 陈锦章. 经肝动脉化疗栓塞联合系统治疗对不可切肝细胞癌的疗效分析[J]. 中国肿瘤临床, 2023, 50(22): 1135-1141. doi: 10.12354/j.issn.1000-8179.2023.20231001
引用本文: 李文利, 杜阳峰, 袁国盛, 臧梦雅, 朱培琳, 李榕, 陈泳如, 苏开妍, 李祺, 胡晓云, 庞桦进, 陈锦章. 经肝动脉化疗栓塞联合系统治疗对不可切肝细胞癌的疗效分析[J]. 中国肿瘤临床, 2023, 50(22): 1135-1141. doi: 10.12354/j.issn.1000-8179.2023.20231001
Wenli Li, Yangfeng Du, Guosheng Yuan, Mengya Zang, Peilin Zhu, Rong Li, Yongru Chen, Kaiyan Su, Qi Li, Xiaoyun Hu, Huajin Pang, Jinzhang Chen. Analysis of the therapeutic efficacy of transcatheter arterial chemoembolization combined with systemic treatment in unresectable hepatocellular carcinoma[J]. CHINESE JOURNAL OF CLINICAL ONCOLOGY, 2023, 50(22): 1135-1141. doi: 10.12354/j.issn.1000-8179.2023.20231001
Citation: Wenli Li, Yangfeng Du, Guosheng Yuan, Mengya Zang, Peilin Zhu, Rong Li, Yongru Chen, Kaiyan Su, Qi Li, Xiaoyun Hu, Huajin Pang, Jinzhang Chen. Analysis of the therapeutic efficacy of transcatheter arterial chemoembolization combined with systemic treatment in unresectable hepatocellular carcinoma[J]. CHINESE JOURNAL OF CLINICAL ONCOLOGY, 2023, 50(22): 1135-1141. doi: 10.12354/j.issn.1000-8179.2023.20231001

经肝动脉化疗栓塞联合系统治疗对不可切肝细胞癌的疗效分析

doi: 10.12354/j.issn.1000-8179.2023.20231001
基金项目: 本文课题受国家自然科学基金(编号:82102879)、广东省自然科学基金(编号:2022A1515010526、2021A1515012518)、中国博士后科研基金(编号:2021M691468)和广东省医学科研基金(编号:A2021343)资助
详细信息
    作者简介:

    李文利:专业方向为肝胆恶性肿瘤的综合治疗

    通讯作者:

    陈锦章 chenjinzhang@smu.edu.cn

Analysis of the therapeutic efficacy of transcatheter arterial chemoembolization combined with systemic treatment in unresectable hepatocellular carcinoma

Funds: This work was supported by the National Natural Science Foundation of China (No. 82102879), Natural Science Foundation of Guangdong Province(No. 2022A1515010526, No. 2021A1515012518), the Postdoctoral Research Foundation of China (No. 2021M691468) and Guangdong Medical Research Fund (No.A2021343)
More Information
  • 摘要:   目的  探索经肝动脉化疗栓塞(transcatheter arterial chemoembolization, TACE)为基础的不同方案治疗不可切除肝细胞癌(unresectable hepatocellular carcinoma,uHCC)患者的疗效和安全性,以及TACE联合酪氨酸激酶抑制剂(tyrosine kinase inhibitors,TKIs)和免疫检査点抑制剂(immune checkpoint inhibitors,ICIs)的最佳时机。  方法  回顾性分析2016年4月至2021年12月期间在南方医科大学南方医院接受基于TACE治疗的555例uHCC患者资料。根据不同治疗方案分为:TACE组(n=317)、TACE+TKIs组(n=66)、TACE+ICIs组(n=33)、TACE+TKIs+ICIs组(n=139)。在亚组分析中,根据不同的联合时间将TACE+TKIs+ICIs组分为 “TACE前”和“TACE后”组。采用单因素、多因素Cox回归分析影响OS的预后因素。  结果  TACE+TKIs+ICIs组获得最长的OS(21.9个月,95% CI: 17.2~26.6,P=0.030)和PFS(8.3个月,95% CI: 7.3~9.3,P=0.004)。在亚组分析中,“TACE后”组比“TACE前”组获得更长的OS(26.8个月vs.19.2个月,P=0.011)。 TACE组、TACE+TKIs组、TACE+ICIs组、TACE+TKIs+ICIs组的ORR分别为32.8%、41.1%、42.4%、52.5%(P=0.001),DCR分别为59.6%、71.2%、69.7%、82.7%(P<0.001)。不良反应事件与既往研究相似。Cox回归分析提示肿瘤数量、肝外转移及治疗方案是患者OS的独立预后因素(均P<0.05)。  结论  TKIs或ICIs可以提高TACE治疗uHCC患者的OS和PFS,TKIs+ICIs联合TACE生存获益更佳。首次TACE术后3个月内联合“TKIs+ICIs”治疗方案的总生存期获益更显著。

     

  • 图  1  无进展生存期及总生存期分析

    A:无进展生存期;B:总生存期

    图  2  “TACE前”和“TACE后”组OS分析

    表  1  基线特征 例(%)或$\bar x \pm s $或M(范围)

    参数 TACE(n=317) TACE+TKIs(n=66) TACE+ICIs(n=33) TACE+TKIs+ICIs(n=139) P
    年龄(岁) 58±12 59±12 59±11 58±11 0.765
    性别 0.434
     男 290(91.5) 61(92.4) 29(87.9) 121(87.1)
     女 27(8.5) 5(7.6) 4(12.1) 18(12.9)
    BCLC分期 0.404
     B 215(67.8) 48(72.7) 19(57.6) 99(71.2)
     C 102(32.2) 18(27.3) 14(42.4) 40(28.8)
    ECOG评分 0.492
     0 259(81.7) 58(87.9) 29(87.9) 118(84.9)
     1 58(18.3) 8(12.1) 4(12.1) 21(15.1)
    肿瘤数量(个) 0.486
     <3 68(21.5) 20(30.3) 8(24.2) 32(23.0)
     ≥3 249(78.5) 46(69.7) 25(48.5) 107(77.0)
    肿瘤最大直径(cm) 0.396
     <7 109(34.4) 16(24.2) 9(27.3) 45(32.4)
     ≥7 208(65.6) 50(75.8) 24(72.7) 94(67.6)
    门脉癌栓 0.934
     无 241(76.0) 51(77.3) 24(72.7) 108(77.7)
     有 76(24.0) 15(22.7) 9(27.3) 31(22.3)
    远处转移 0.014
     无 249(48.5) 57(86.4) 20(60.6) 116(83.5)
     有 68(21.5) 9(13.6) 13(39.4) 23(16.5)
    甲胎蛋白(ng/mL) 0.917
     <400 242(76.3) 51(77.3) 24(72.7) 103(74.1)
     ≥400 75(23.7) 15(22.7) 9(27.3) 36(25.9)
    腹水 0.022
     无 252(79.5) 54(81.8) 19(57.6) 112(80.6)
     有 65(20.5) 12(18.2) 14(42.4) 27(19.4)
    Child-Pugh分级 0.856
     A 270(85.2) 54(81.8) 29(87.9) 119(85.6)
     B 47(14.8) 12(18.2) 4(12.1) 20(14.4)
    HBV DNA(IU/mL) 0(0~1 950) 0(0~1 760) 0(0~6 710) 0(0~6 605) 0.638
    丙肝抗体 0.629
     阴性 305(95.2) 65(98.5) 31(93.9) 135(97.1)
     阳性 12(3.8) 1(1.5) 2(6.1) 4(2.9)  
    下载: 导出CSV

    表  2  mRECIST疗效评估 例 (%)

    肿瘤应答 TACE(n=317) TACE+TKIs(n=66) TACE+ICIs(n=33) TACE+TKIs+ICIs(n=139)
    完全缓解(CR) 6(1.9) 3(4.5) 1(3.0) 9(6.5)
    部分缓解(PR) 98(30.9) 24(36.4) 13(39.4) 64(46.0)
    稳定(SD) 85(26.8) 20(30.3) 9(27.3) 42(30.2)
    进展(PD) 128(40.4) 19(28.8) 10(30.3) 24(17.3)
    客观缓解率(ORR) 104(32.8) 27(41.1) 14(42.4) 73(52.5)
    疾病控制率(DCR) 189(59.6) 47(71.2) 23(69.7) 115(82.7)
    下载: 导出CSV

    表  3  不良反应事件 例(%)

    不良反应 TACE(n=317) TACE+TKIs(n=66) TACE+ICIs(n=33) TACE+TKIs+ICIs(n=139) P
    任意级别AEs 248(78.2) 48(72.7) 25(75.8) 112(80.6) 0.083
    ≥3级的AEs 38(12.0) 12(18.2) 7(21.2) 38(27.3) 0.001
    ALT升高 134(42.3) 34(51.5) 18(54.5) 79(56.8) 0.024
    消化道出血 16(5.0) 6(9.1) 2(6.1) 13(9.4) 0.309
    AST升高 143(45.1) 39(59.1) 21(63.6) 86(61.9) 0.002
    腹泻 92(29.0) 23(34.8) 11(33.3) 51(36.7) 0.396
    疲乏 114(36.0) 28(42.4) 13(39.4) 87(62.6) <0.001
    发热 163(51.4) 35(53.0) 17(51.5) 77(16.5) 0.889
    口腔炎 62(19.6) 11(16.7) 6(18.2) 23(16.5) 0.865
    手足综合征 41(12.9) 38(57.6) 7(21.2) 72(51.8) <0.001
    血尿 34(10.7) 8(12.1) 2(6.1) 19(13.7) 0.61
    高胆红素血症 22(6.9) 13(19.7) 5(15.2) 42(30.2) <0.001
    高血压 17(5.4) 22(33.3) 9(27.3) 53(38.1) <0.001
    甲状腺功能亢进症 8(2.5) 2(3.0) 4(12.1) 5(3.6) 0.039
    甲状腺功能亢减低 4(1.3) 1(1.5) 6(18.2) 6(4.3) <0.001
    恶心 117(36.9) 27(40.9) 11(33.3) 67(48.2) 0.122
    腹痛 218(68.8) 36(54.5) 16(48.5) 71(51.1) 0.001
    蛋白尿 14(4.4) 39(59.1) 8(24.2) 83(59.7) <0.001
    皮疹 76(24.0) 24(36.4) 9(27.3) 53(38.1) 0.01
    血小板减少 158(49.8) 37(56.1) 14(42.4) 82(59.0) 0.177
    体重减轻 37(11.7) 18(27.3) 9(27.3) 71(51.1) <0.001
    ALT:丙氨酸转氨酶,AST:天冬氨酸转氨酶
    下载: 导出CSV

    表  4  总生存期单因素和多因素Cox回归分析

    项目 单因素分析 多因素分析
    HR 95% CI P HR 95% CI P
    年龄 1.002 0.993~1.011 0.696
    性别(男/女) 1.03 0.721~1.471 0.871
    BCLC分期(B期/C期) 1.617 1.292~2.025 <0.001 0.988 0.619~1.576 0.959
    ECOG评分(1/0分) 1.033 0.770~1.385 0.831
    肿瘤数量 (<3/≥3个) 0.743 0.580~0.953 0.019 0.702 0.545~0.903 0.006
    肿瘤最大径(<7/≥7 cm) 1.131 0.897~1.425 0.299
    门脉癌栓(无/有) 1.636 1.286~2.080 <0.001 1.485 0.949~2.326 0.084
    肝外转移(无/有) 1.661 1.294~2.132 <0.001 1.579 1.162~2.145 0.003
    血清甲胎蛋白(<400/≥400 ng/mL) 1.207 0.942~1.546 0.137
    Child-Pugh分级(A/B) 1.104 0.824~1.480 0.506
    治疗方案 0.032 0.039
    TACE/TACE+TKIs 0.842 0.602~1.179 0.317 0.861 0.614~1.206 0.238
    TACE/TACE+ICIs 0.793 0.469~1.341 0.387 0.733 0.432~1.243 0.211
    TACE/TACE+TKIs+ICIs 0.668 0.509~0.877 0.004 0.68 0.518~0.893 0.007
    下载: 导出CSV
  • [1] 国家卫生健康委办公厅.原发性肝癌诊疗指南(2022年版)[J].临床肝胆病杂志,2022,38(2):288-303. doi: 10.3969/j.issn.1001-5256.2022.02.009
    [2] Hyuna S, Jacques F, Siegel Rebecca L, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J]. CA Cancer J Clin, 2021, 71(3):209-249. doi: 10.3322/caac.21660
    [3] Finn RS, Qin SK, Ikeda M, et al. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma[J]. N Engl J Med, 2020, 382(20):1894-1905. doi: 10.1056/NEJMoa1915745
    [4] Ren, Z,Xu J, Bai Y,et al. Sintilimab plus a bevacizumab biosimilar (IBI305) versus sorafenib in unresectable hepatocellular carcinoma (ORIENT-32): a randomised, open-label, phase 2-3 study[J]. Lancet Oncol,, 2021, 22(7):977-990. doi: 10.1016/S1470-2045(21)00252-7
    [5] Qin, S,Chan SL, Gu S, et al. Camrelizumab plus rivoceranib versus sorafenib as first-line therapy for unresectable hepatocellular carcinoma (CARES-310): a randomised, open-label, international phase 3 study[J]. Lancet,, 2023, 402(10408):1133-1146. doi: 10.1016/S0140-6736(23)00961-3
    [6] Forner A, Reig M, Bruix J. Hepatocellular carcinoma[J]. Lancet, 2018, 391(10127):1301-1314. doi: 10.1016/S0140-6736(18)30010-2
    [7] Llovet, JM, De Baere T, Kulik L et al. Locoregional therapies in the era of molecular and immune treatments for hepatocellular carcinoma[J]. Nat Rev Gastroenterol Hepatol, 2021, 18(5):293-313.
    [8] Liu, K, Min XL, Peng J, et al. The changes of HIF-1α and VEGF expression after TACE in patients with hepatocellular carcinoma[J]. JClinMedRes, 2016, 8(4):297-302.
    [9] Kudo M. A new treatment option for intermediate-stage hepatocellular carcinoma with high tumor burden: initial lenvatinib therapy with subsequent selective TACE[J]. Liver Cancer, 2019, 8(5):299-311. doi: 10.1159/000502905
    [10] Kudo M, Ueshima K, Ikeda M,et al. Final results of TACTICS: a randomized, prospective trial comparing transarterial chemoembolization plus sorafenib to transarterial chemoembolization alone in patients with unresectable hepatocellular carcinoma[J]. Liver Cancer, 2022, 11(4):354-367. doi: 10.1159/000522547
    [11] Kudo M, Han KH, Ye SL, et al. A Changing paradigm for the treatment of intermediate-stage hepatocellular carcinoma: Asia-pacific primary liver cancer expert consensus statements[J]. Liver Cancer, 2020, 9(3):245-260. doi: 10.1159/000507370
    [12] Palmer DH, Malagari K, Kulik LM. Role of locoregional therapies in the wake of systemic therapy[J]. J Hepatol, 2020, 72(2):277-287. doi: 10.1016/j.jhep.2019.09.023
    [13] Guardascione M, Toffoli G. Immune checkpoint inhibitors as monotherapy or within a combinatorial strategy in advanced hepatocellular carcinoma[J]. Int J Mol Sci, 2020, 21(17):6302. doi: 10.3390/ijms21176302
    [14] Ke Q, Xin FL, Fang HP, et al. The significance of transarterial chemo(embolization) combined with tyrosine kinase inhibitors and immune checkpoint inhibitors for unresectable hepatocellular carcinoma in the era of systemic therapy: a systematic review[J]. Front Immunol, 2022, 13:913464.
    [15] Montasser A, Beaufrère A, Cauchy F, et al. Transarterialchemoembolisation enhances programmed death-1 and programmed death-ligand 1 expression in hepatocellular carcinoma[J]. Histopathology, 2021, 79(1):36-46. doi: 10.1111/his.14317
    [16] Teng Y, Ding X, Li W, et al. A Retrospective study on therapeutic efficacy of transarterial chemoembolization combined with immune checkpoint inhibitors plus lenvatinib in patients with unresectable hepatocellular carcinoma[J]. Technol Cancer Res Treat, 2022, 21: 15330338221075174.
    [17] Yang F, Xu GL, Huang JT, et al. Transarterial chemoembolization combined with immune checkpoint inhibitors and tyrosine kinase inhibitors for unresectable hepatocellular carcinoma: efficacy and systemic immune response[J]. Front Immunol, 2022, 13:847601. doi: 10.3389/fimmu.2022.847601
    [18] Liu JF, Li Z, Zhang WG, et al. Comprehensive treatment of trans-arterial chemoembolization plus lenvatinib followed by camrelizumab for advanced hepatocellular carcinoma patients[J]. Front Pharmacol, 2021, 12:709060. doi: 10.3389/fphar.2021.709060
    [19] Jin ZC, Zhong BY, Chen JJ, et al. Real-world efficacy and safety of TACE plus camrelizumab and apatinib in patients with HCC (CHANCE2211): a propensity score matching study[J]. Eur Radiol, 2023, 33(12):8669-8681. doi: 10.1007/s00330-023-09754-2
    [20] Zhu HD, Li HL, Huang MS ,et al. Transarterial chemoembolization with PD-(L)1 inhibitors plus molecular targeted therapies for hepatocellular carcinoma (CHANCE001)[J]. Signal Transduct Target Ther, 2023, 8(1):58. doi: 10.1038/s41392-022-01235-0
    [21] Hiroishi K, Eguchi J, Baba T, et al. Strong CD8(+) T-cell responses against tumor-associated antigens prolong the recurrence-free interval after tumor treatment in patients with hepatocellular carcinoma[J]. J Gastroenterol, 2010, 45(4):451-458. doi: 10.1007/s00535-009-0155-2
    [22] Kalathil SG, Hutson A, Barbi J, et al. Augmentation of IFN-γ+ CD8+ T cell responses correlates with survival of HCC patients on sorafenib therapy[J]. JCI Insight, 2019, 4(15):e130116. doi: 10.1172/jci.insight.130116
    [23] 中国医师协会介入医师分会临床诊疗指南专委会,滕皋军,赵明,等.中国肝细胞癌经动脉化疗栓塞(TACE)治疗临床实践指南(2021年版)[J].中华医学杂志,2021,101(24):1848-1862.
    [24] Raoul JL, Forner A, Bolondi L, et al. Updated use of TACE for hepatocellular carcinoma treatment: how and when to use it based on clinical evidence[J]. Cancer Treat Rev, 2019, 72:28-36. doi: 10.1016/j.ctrv.2018.11.002
    [25] 李榕,李文利,胡晓云,等.RALOX-HAIC联合免疫检查点抑制剂及靶向药物治疗中晚期肝癌的疗效分析[J].中国肿瘤临床,2023,50(11):555-560. doi: 10.12354/j.issn.1000-8179.2023.20230089
  • 加载中
图(2) / 表(4)
计量
  • 文章访问数:  97
  • HTML全文浏览量:  18
  • PDF下载量:  40
  • 被引次数: 0
出版历程
  • 收稿日期:  2023-10-13
  • 录用日期:  2023-12-07
  • 修回日期:  2023-11-29

目录

    /

    返回文章
    返回