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冷冻消融协同仑伐替尼和程序性死亡受体1单抗治疗不可切除肝细胞癌的效果及安全性分析

刘腾 常秀娟 何权威 徐然 杨永平

引用本文:
Citation:

冷冻消融协同仑伐替尼和程序性死亡受体1单抗治疗不可切除肝细胞癌的效果及安全性分析

DOI: 10.12449/JCH240317
基金项目: 

国家“十三五”科技重大专项 (2018ZX10725506)

北京市自然科学基金 (7212101)

伦理学声明:本研究方案于2021年12月1日经由解放军总医院第五医学中心伦理委员会审批,批号:KY-2021-12-33-1,所纳入患者均签署知情同意书。
利益冲突声明:本文不存在任何利益冲突。
作者贡献声明:刘腾负责研究数据的获取分析、解释过程以及论文起草;何权威参与部分影像学评估;徐然参与部分随访;常秀娟负责修改文章内容;杨永平设计研究思路。
详细信息
    通信作者:

    杨永平, yongpingyang@ hotmail.com (ORCID: 0000-0002-8307-1095)

Efficacy and safety of cryoablation combined with lenvatinib and anti-PD-1 monoclonal antibody in treatment of unresectable hepatocellular carcinoma

Research funding: 

National Science and Technology Major Project during the 13th Five-Year Plan Period (2018ZX10725506);

Beijing Natural Science Foundation (7212101)

More Information
  • 摘要:   目的  分析程序性死亡受体1(PD-1)单抗是否提高冷冻消融联合仑伐替尼治疗不可切除性肝细胞癌(uHCC)患者的疗效和安全性。  方法  回顾性收集2018年1月—2022年12月在解放军总医院第五医学中心治疗的uHCC患者232例,其中128例接受冷冻消融联合仑伐替尼(二联)治疗,104例接受冷冻消融联合仑伐替尼和PD-1单抗(三联)治疗,用倾向性评分匹配方法(PSM)以1∶1进行匹配,经匹配后两组各86例。评估匹配后的2组患者客观缓解率(ORR)和疾病控制率(DCR)、总生存期(OS)、无进展生存期(PFS)和不良事件发生情况。定量资料若符合正态分布2组间比较采用成组t检验;非正态分布2组间比较采用Mann-Whitney U检验。定性资料采用χ2检验进行2组间比较。绘制生存曲线,运用Kaplan-Meier法计算2组患者的生存率,并利用Log-rank检验比较2组差异。通过Cox回归模型计算风险比(HR)和95%置信区间(95%CI),实现预后影响因素的单因素及多因素分析。  结果  中位随访时间为28个月,三联组死亡33例(38.0%),二联组死亡40例(46.0%)。三联治疗组的ORR和DCR较二联组明显增高(ORR:35.6% vs14.5%,P=0.008;DCR:86.1% vs64.1%,P=0.003)。三联组的OS和PFS较二联组均显著提高(P值分别为0.045、0.026)。单因素和多因素Cox风险比例模型分析显示治疗方案(HR=0.60,P=0.038)、AFP水平(HR=2.37,P=0.001)是影响OS的独立危险因素;治疗方案(HR=0.65,P=0.025)、糖尿病(HR=1.94,P=0.005)、之前是否接受过局部治疗(HR=0.63,P=0.014)、远处转移(HR=0.58,P=0.009)是影响PFS的独立危险因素。两组患者不良反应发生率相当,无明显差异(P值均>0.05)。  结论  对于uHCC患者,冷冻消融联合仑伐替尼和PD-1单抗三联治疗较冷冻消融联合仑伐替尼二联治疗显著提高了疗效,改善患者生存情况,而且不增加不良反应事件,为优化不可切除性肝癌的治疗方案提供了临床依据。

     

  • 图  1  患者入组流程图

    Figure  1.  Flow chart of patient enrollment

    图  2  两组患者PSM前后的OS和PFS比较

    Figure  2.  Comparison of OS and PFS before and after PSM between the two groups of patients

    图  3  PSM前后两组行1次或>1次冷冻消融患者的OS比较

    Figure  3.  OS comparison of the number of 1 or more cryoablation before and after PSM between the two groups

    图  4  PSM前后Child-Pugh A或B期患者的OS比较

    Figure  4.  Comparison of OS before and after PSM in patients with Child-Pugh A or B

    图  5  PSM前后BCLC B或C期患者的OS比较

    Figure  5.  Comparison of OS before and after PSM in BCLC B or C patients

    图  6  PSM前后两组有或无远处转移患者的OS比较

    Figure  6.  Comparison of OS before and after PSM patients with or without distant metastasis

    表  1  冷冻消融+仑伐替尼+抗PD-1组(三联)和冷冻消融+仑伐替尼组(二联)PSM前后的临床特征

    Table  1.   Clinical features before and after PSM in Cryo+Lenvatinib+anti-PD-1 group and Cryo+Lenvatinib group

    项目 PSM前 PSM后
    合计(n=232) 三联 (n=104) 二联 (n=128) 统计值 P 三联(n=86) 二联 (n=86) 统计值 P
    性别[例(%)] χ2=0.000 0.987 χ2=0.657 0.418
    20(8.6) 9(8.7) 11(8.6) 9(10.5) 6(7.0)
    212(91.4) 95(91.3) 117(91.4) 77(89.5) 80(93.0)
    年龄[例(%)] χ2=0.100 0.752 χ2=0.102 0.749
    <60岁 152(65.5) 67(64.4) 85(66.4) 55(64.0) 57(66.3)
    ≥60岁 80(34.5) 37(35.6) 43(33.6) 31(36.0) 29(33.7)
    BMI[例(%)] χ2=0.525 0.469 χ2=0.024 0.878
    <24 kg/m2 102(44.0) 43(41.3) 59(46.1) 37(43.0) 38(44.2)
    ≥24 kg/m2 130(56.0) 61(58.7) 69(53.9) 49(57.0) 48(55.8)
    门静脉高压[例(%)] χ2=0.009 0.926 χ2=0.000 >0.05
    188(81.0) 84(80.8) 104(81.2) 70(81.4) 70(81.4)
    44(19.0) 20(19.2) 24(18.8) 16(18.6) 16(18.6)
    病因[例(%)] χ2=3.561 0.169 χ2=0.657 0.720
    HBV 206(88.8) 96(92.3) 110(85.9) 80(93.0) 77(89.5)
    HCV 13(5.6) 2(1.9) 9(7.0) 2(2.3) 3(3.5)
    其他 19(8.2) 6(5.8) 9(7.0) 4(4.7) 6(7.0)
    抗病毒[例(%)] χ2=2.740 0.098 χ2=1.758 0.185
    190(81.9) 90(86.5) 100(78.1) 72(83.7) 65(75.6)
    42(18.1) 14(13.5) 28(21.9) 14(16.3) 21(24.4)
    AFP[例(%)] χ2=9.316 0.002 χ2=0.595 0.440
    <400 ng/mL 126(54.3) 68(65.4) 58(45.3) 52(60.5) 47(54.7)
    ≥400 ng/mL 106(45.7) 36(34.6) 70(54.7) 34(39.5) 39(45.3)
    PLT(×109/L) 125.0 (90.0~187.0) 118.0(80.0~146.0) 142.0 (96.2~203.8) U=5 183 0.002 119.5 (88.8~155.8) 133.0 (92.8~203.3) U=3 180 0.115
    ALT(U/L) 35.0 (22.0~57.0) 37.0 (24.0~74.5) 33.0 (19.5~53.1) U=5 826 0.121 36.0 (23.5~55.3) 33.5 (21.8~59.0) U=3 530 0.607
    AST(U/L) 41.0 (28.0~77.9) 38.0 (27.3~78.8) 44.0 (28.3~77.5) U=6 583 0.747 37.0 (27.0~61.2) 37.0 (27.0~76.3) U=3 655 0.896
    下载: 导出CSV

    表  2  PSM后影响患者OS和PFS的Cox单因素及多因素回归分析

    Table  2.   Cox single and multi-factor regression analysis of influencing OS and PFS after PSM

    项目 OS PFS
    单因素分析 多因素分析 单因素分析 多因素分析
    HR(95%CI P HR(95%CI P HR(95%CI P HR(95%CI P
    治疗方案(三联 vs 二联) 0.63(0.39~0.99) 0.047 0.60(0.37~0.97) 0.038 0.66(0.46~0.96) 0.028 0.65(0.44~0.95) 0.025
    性别(男 vs 女) 0.73(0.31~1.68) 0.453 1.09(0.60~1.98) 0.782
    年龄(≥60岁 vs <60岁) 0.88(0.54~1.43) 0.615 1.03(0.70~1.51) 0.886
    BMI(≥24 kg/m2 vs <24 kg/m2 1.49(0.93~2.39) 0.100 1.37(0.94~2.00) 0.099
    Child-Pugh分级(B vs A) 0.95(0.58~1.57) 0.842 0.96(0.65~1.42) 0.847
    BCLC分级(C vs B) 1.82(1.05~3.14) 0.032 0.86(0.33~2.23) 0.758 0.79(0.54~1.17) 0.234
    糖尿病(有 vs 无) 0.70(0.37~1.30) 0.256 1.69(1.08~2.64) 0.022 1.94(1.22~3.09) 0.005
    门静脉高压(有 vs 无) 2.08(1.03~4.20) 0.042 1.73(0.83~3.58) 0.142 0.89(0.57~1.41) 0.625
    肝硬化(有 vs 无) 20.72(0.01~5 207.00) 0.448 0.81(0.20~3.27) 0.763
    HBV(有 vs 无) 0.89(0.38~2.05) 0.776 0.88(0.45~1.75) 0.722
    抗病毒(有 vs 无) 0.93(0.52~1.63) 0.789 0.94(0.59~1.48) 0.779
    肿瘤数目(>1 vs 1) 0.96(0.54~1.73) 0.901 1.00(0.61~1.62) 0.988
    肿瘤大小(≥7.07 cm vs <7.07 cm) 1.68(1.05~2.68) 0.030 1.18(0.70~1.98) 0.537 0.76(0.52~1.12) 0.161
    AFP(≥400 ng/mL vs <400 ng/mL) 2.46(1.55~3.92) <0.001 2.37(1.44~3.88) 0.001 1.06(0.73~1.53) 0.772
    之前局部治疗(有 vs 无) 0.55(0.34~0.87) 0.012 0.67(0.41~1.11) 0.123 0.63(0.44~0.91) 0.013 0.63(0.43~0.89) 0.014
    之前系统治疗(有 vs 无) 0.64(0.26~1.58) 0.331 0.74(0.39~1.42) 0.372
    后续局部治疗(有 vs 无) 0.41(0.10~1.70) 0.22 1.80(0.87~3.72) 0.110
    后续系统治疗(有 vs 无) 0.39(0.16~0.97) 0.042 0.62(0.24~1.61) 0.325 1.17(0.72~1.89) 0.532
    冷冻消融次数(>1 vs 1) 0.79(0.47~1.33) 0.382 1.56(0.99~2.45) 0.054
    远处转移(有 vs 无) 1.16(0.72~1.86) 0.539 0.53(0.35~0.80) 0.002 0.58(0.38~0.87) 0.009
    血管侵犯(有 vs 无) 1.86(1.11~3.12) 0.019 1.79(0.73~4.41) 0.204 0.89(0.61~1.30) 0.553
    下载: 导出CSV

    表  3  PSM前影响患者OS和PFS的Cox单及多因素回归分析

    Table  3.   Cox single and multi-factor regression analysis of influencing OS and PFS before PSM

    项目 OS PFS
    单因素分析 多因素分析 单因素分析 多因素分析
    HR(95%CI P HR(95%CI P HR(95%CI P HR(95%CI P
    治疗方案(三联 vs 二联) 0.57(0.38~0.85) 0.005 0.63(0.41~0.98) 0.039 0.82(0.60~1.13) 0.228 0.77(0.54~1.10) 0.149
    性别(男 vs 女) 0.86(0.42~1.78) 0.693 1.19(0.70~2.02) 0.526
    年龄(≥60岁 vs <60岁) 0.83(0.55~1.26) 0.379 0.90(0.64~1.25) 0.520
    BMI(≥24 kg/m2 vs <24 kg/m2 1.31(0.88~1.96) 0.179 1.24(0.90~1.70) 0.190
    Child-Pugh分级(B vs A) 1.22(0.81~1.84) 0.335 0.99 (0.71~1.38) 0.946
    BCLC分级(C vs B) 1.69(1.07~2.65) 0.024 0.92(0.41~2.07) 0.846 0.79 (0.57~1.10) 0.171 0.61 (0.32~1.16) 0.132
    糖尿病(有 vs 无) 0.72(0.43~1.22) 0.227 1.44(0.98~2.12) 0.062
    门静脉高压(有 vs 无) 1.72(0.99~3.00) 0.053 0.89(0.60~1.31) 0.549
    肝硬化(有 vs 无) 1.12(0.41~3.06) 0.819 1.04(0.46~2.35) 0.929
    HBV(有 vs 无) 1.08(0.56~2.07) 0.826 0.97(0.58~1.60) 0.894
    抗病毒(有 vs 无) 0.77(0.48~1.24) 0.285 0.86 (0.57~1.29) 0.464
    肿瘤数目(>1 vs 1) 0.85(0.53~1.35) 0.487 1.09(0.73~1.62) 0.682
    肿瘤大小(≥7.07 cm vs <7.07 cm) 1.83(1.24~2.71) 0.002 1.09(0.71~1.68) 0.689 0.76 (0.55~1.05) 0.100 0.71(0.49~1.02) 0.064
    AFP(≥400 ng/mL vs<400 ng/mL) 2.11(1.42~3.12) <0.001 1.75(1.16~2.64) 0.008 0.94(0.69~1.29) 0.709 1.00(0.72~1.40) 0.989
    之前局部治疗(有 vs 无) 0.45(0.30~0.68) <0.001 0.58(0.38~0.90) 0.014 0.84(0.61~1.15) 0.274 0.78 (0.56~1.09) 0.152
    之前系统治疗(有 vs 无) 0.67(0.32~1.37) 0.270 0.91(0.55~1.50) 0.701
    后续局部治疗(有 vs 无) 0.26(0.06~1.08) 0.064 1.63(0.88~3.01) 0.120
    后续系统治疗(有 vs 无) 0.41(0.20~0.84) 0.015 0.66(0.30~1.42) 0.284 1.16(0.77~1.74) 0.489 1.18 (0.74~1.86) 0.491
    冷冻消融次数(>1 vs 1) 0.62(0.41~0.95) 0.028 0.60(0.39~0.93) 0.023 1.43(0.97~2.10) 0.070 1.35 (0.91~2.00) 0.135
    远处转移(有 vs 无) 0.91(0.60~1.38) 0.661 1.12(0.81~1.56) 0.498
    血管侵犯(有 vs 无) 1.79(1.15~2.76) 0.009 1.73(0.78~3.82) 0.178 0.90(0.65~1.25) 0.523 1.42(0.74~2.71) 0.292
    下载: 导出CSV

    表  4  肿瘤反应

    Table  4.   Tumor response

    肿瘤疗效评价 PSM前 PSM后
    三联 二联 P 三联 二联 P
    CR[例(%)] 9(8.7) 5(3.9) 0.131 7(8.1) 4(4.7) 0.350
    PR[例(%)] 27(26.0) 13(10.2) 0.002 22(25.6) 10(11.6) 0.019
    SD[例(%)] 50(48.1) 66(51.6) 0.597 43(50.0) 41(47.7) 0.760
    PD[例(%)] 18(17.3) 44(34.4) 0.003 14(18.3) 31(36.0) 0.003
    ORR[例(%)] 36(34.6) 14(14.1) 0.000 29(35.6) 14(14.5) 0.008
    DCR[例(%)] 86(82.7) 84(65.6) 0.003 72(86.1) 55(64.1) 0.003
    下载: 导出CSV

    表  5  PSM后不良反应

    Table  5.   Adverse reactions after PSM

    不良反应 1~5级 3~5级
    三联(n=86) 二联(n=86) P 三联(n=86) 二联(n=86) P
    高血压[例(%)] 22(25.6) 26(30.2) 0.497 5(5.8) 4(4.7) 0.899
    手足综合征[例(%)] 19(22.1) 12(14.0) 0.165 3(3.5) 3(3.5) 0.676
    乏力[例(%)] 18(20.9) 15(17.4) 0.561 2(2.3) 3(3.5) 0.375
    肺炎[例(%)] 2(2.3) 0(0.0) 0.155 1(1.1) 0(0.0) 0.375
    发热[例(%)] 7(8.1) 2(2.3) 0.087 1(1.1) 0(0.0) 0.375
    腹胀[例(%)] 3(3.5) 3(3.5) >0.05 0(0.0) 0(0.0)
    腹痛[例(%)] 7(8.1) 3(3.5) 0.192 1(1.1) 0(0.0) 0.375
    腹泻[例(%)] 23(26.7) 21(24.4) 0.727 2(2.3) 2(2.3) 0.748
    厌食[例(%)] 15(17.4) 18(20.9) 0.561 3(3.5) 2(2.3) 0.882
    体质量下降[例(%)] 3(3.5) 1(1.2) 0.312 0(0.0) 0(0.0)
    恶心呕吐[例(%)] 6(7.0) 7(8.1) 0.773 0(0.0) 0(0.0)
    消化道出血[例(%)] 2(2.3) 0(0.0) 0.115 2(2.3) 0(0.0) 0.198
    肾病综合征[例(%)] 2(2.3) 1(1.1) 0.560 1(1.1) 0(0.0) 0.375
    脱皮[例(%)] 5(5.8) 3(3.5) 0.469 0(0.0) 1(1.1) 0.237
    皮疹[例(%)] 10(11.6) 8(9.3) 0.618 1(1.1) 0(0.0) 0.375
    肝区疼痛[例(%)] 7(8.1) 9(10.5) 0.600 0(0.0) 2(2.3) 0.086
    肝性脑病[例(%)] 2(2.3) 1(1.2) 0.560 2(2.3) 1(1.1) 0.719
    声音嘶哑[例(%)] 5(5.8) 2(2.3) 0.247 0(0.0) 0(0.0)
    甲状腺功能减退[例(%)] 11(12.8) 8(9.3) 0.466 0(0.0) 1(1.1) 0.237
    肝衰竭[例(%)] 0(0.0) 1(1.2) 0.316 0(0.0) 1(1.1) 0.237
    蛋白尿[例(%)] 18(20.9) 13(15.1) 0.321 3(3.5) 4(4.7) 0.350
    水肿[例(%)] 6(7.0) 6(7.0) >0.05 2(2.3) 3(3.5) 0.375
    皮肤瘙痒[例(%)] 9(10.5) 7(8.1) 0.793 1(1.1) 1(1.1) 0.830
    口腔溃疡[例(%)] 5(5.8) 2(2.3) 0.247 1(1.1) 1(1.1) 0.830
    脱发[例(%)] 2(2.3) 0(0.0) 0.155 1(1.1) 0(0.0) 0.375
    肌肉疼痛[例(%)] 2(2.3) 2(2.3) >0.05 0(0.0) 0(0.0)
    AST 升高[例(%)] 31(36.0) 21(24.4) 0.097 0(0.0) 0(0.0)
    ALT升高[例(%)] 29(33.7) 20(23.3) 0.128 5(5.8) 1(1.1) 0.125
    高胆红素血症[例(%)] 25(29.1) 29(33.7) 0.511 2(2.3) 5(5.8) 0.061
    低蛋白血症[例(%)] 35(40.7) 31(36.0) 0.531 5(5.8) 6(7.0) 0.256
    腹水[例(%)] 1(1.2) 0(0.0) 0.316 1(0.0) 0(0.0) 0.375
    白细胞减少症[例(%)] 21(24.4) 21(24.4) >0.05 5(5.8) 4(4.7) 0.899
    PLT下降[例(%)] 4(4.7) 2(2.3) 0.406 1(1.1) 1(1.1) 0.830
    下载: 导出CSV
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  • 收稿日期:  2023-10-24
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