The efficacy and prognostic markers of anti-PD-1 immunotherapy combined with anti-angiogenic therapy for advanced hepatocellular carcinoma
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摘要:
目的 探讨程序性死亡受体-1(programmed cell death-1, PD-1)抑制剂联合小分子抗血管生成药物在晚期肝细胞癌的有效性及安全性并探索其潜在的预后影响因素。 方法 收集2020年3月—2022年12月就诊于淮北市人民医院接受PD-1抑制剂和小分子抗血管生成药物治疗的晚期肝细胞癌患者的相关临床资料，观察其有效性及安全性。采用Kaplan-Meier生存分析和log-rank检验进行生存分析，并构建Cox比例风险模型探索其预后的独立影响因素。 结果 共纳入55例晚期肝细胞癌患者，客观缓解率为18.2%(10/55)，疾病控制率为74.5%(41/55)，中位无进展生存期(mPFS)为8.5个月，中位总生存期(mOS)为17.4个月。接受经肝动脉化疗栓塞术(TACE)治疗患者mPFS和mOS分别为10.2个月、18.4个月，显著高于未接受经肝动脉化疗栓塞术(TACE)治疗患者(6.2个月、14.1个月)差异均有统计学意义(P < 0.05)；中性粒细胞与淋巴细胞比值(NLR)高水平组与低水平组mOS分别为14.9个月、18.6个月，mPFS分别为6.5个月、10.1个月，差异均有统计学意义(P＜0.05)。治疗常见不良反应为疲劳、高血压等，中重度不良反应发生率为20.0%。 结论 PD-1抑制剂联合小分子抗血管生成药物可显著延长晚期HCC患者的生存期，尤以接受TACE治疗患者为著，且总体耐受性较好，治疗前NLR水平是患者PFS及OS的独立影响因素，其有助于筛选治疗获益优势人群。 -
关键词:
- 肝细胞癌 /
- 抗血管生成药物 /
- 程序性死亡受体-1抑制剂 /
- 中性粒细胞与淋巴细胞比值 /
- 经肝动脉化疗栓塞术 /
- 预后
Abstract:Objective To evaluate the efficacy and safety of anti-PD-1 immunotherapy combined with anti-angiogenic therapy in the treatment of advanced hepatocellular carcinoma and to explore the potential prognostic factors. Methods We collected the clinical data of patients with advanced hepatocellular carcinoma who were treated with PD-1 inhibitors combined with anti-angiogenic therapy from March 2020 to December 2022 in Huaibei People's Hospital and observed the clinical efficacy, adverse events. Kaplan-Meier was used to analyze the survival benefit. Univariate and multivariate Cox analysis were performed to evaluate the association between prognostic factors and survival outcomes. Results Among the 55 patients enrolled in this study, the objective response rate was 18.2% (10/55) and the disease control rate was 74.5% (41/55). Survival analysis showed that the median progression-free survival (mPFS) was 8.5 months and the median overall survival (mOS) was 17.4 months. Patients who received transcatheter arterial chemoembolization (TACE) had better PFS and OS than those who did not (P < 0.005). PFS and OS were longer in patients with lower NLR (mPFS: 10.1 months vs. 6.5 months; mOS: 18.6 months vs. 14.9 months, P < 0.05). The most common adverse events were fatigue, hypertension, etc. 11 patients experienced grade 3-4 adverse events. Conclusion In this real-world study, anti-PD-1 immunotherapy combined with anti-angiogenic therapy could significantly prolong the survival of advanced HCC patients, especially in patients receiving TACE treatment, and the adverse events were controllable. The pre-treatment serum NLR level is an independent prognostic factor to predict PFS and OS, which could help to screen the potential patients who can benefit from immunotherapy. -
图 2 是否接受TACE治疗HCC患者的PFS和OS曲线
Figure 2. K-M curves of PFS and OS in HCC patients treated with or without TACE
图 3 治疗前NLR不同表达水平HCC患者的PFS和OS曲线
Figure 3. K-M curves of PFS and OS in HCC patients with different levels of NLR
表 1 55例HCC患者基本临床病理特征
Table 1. Basic clinicopathological features of 55 HCC patients
项目 类别 例(%) 性别 男性 40(72.7) 女性 15(27.3) 年龄(岁) ≤60 34(61.8) ＞60 21(38.2) ECOG评分(分) 0 24(43.6) 1 31(56.4) 肝内最大肿瘤直径(cm) ≤5 25(45.5) ＞5 30(54.5) 肝内肿瘤数目(个) ≤3 27(49.1) ＞3 28(50.9) Child-Pugh分级 A级 49(89.1) B级 6(10.9) 肝血管侵犯 有 13(23.6) 无 42(76.4) 门静脉癌栓 有 21(38.2) 无 34(61.8) TACE 有 17(30.9) 无 38(69.1) 治疗前乳酸脱氢酶(U/L) ≤250 28(50.9) ＞250 27(49.1) 治疗前PLR ≤140 26(47.3) ＞140 29(52.7) 治疗前NLR ≤2.5 28(50.9) ＞2.5 27(49.1) 乙型病毒性肝炎 有 55(100.0) 无 0 
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表 2 自变量赋值情况
Table 2. Independent variable assignment methods
变量 赋值方法 性别 男性=0，女性=1 年龄(岁) ≤60=0，＞60=1 ECOG评分(分) 0=0，1=1 肝内肿瘤数目(个) ≤3=0，＞3=1 肝内最大肿瘤直径(cm) ≤5=0，＞5=1 Child-Pugh分级 A级=0，B级=1 治疗前甲胎蛋白水平(ng/mL) ≤400=0，＞400=1 肝血管侵犯 无侵犯=0，侵犯=1 门静脉癌栓 无=0，有=1 TACE 无=0，有=1 远处转移 无=0，有=1 治疗前乳酸脱氢酶(U/L) ≤250=0，＞250=1 治疗前PLR ≤140=0，＞140=1 治疗前NLR ≤2.5=0，＞2.5=1
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表 3 影响HCC患者PFS的单因素及多因素分析
Table 3. Multivariable Cox regression analysis for PFS
变量 单因素分析 多因素分析 HR值 95% CI P值 HR值 95% CI P值 性别 0.723 0.365~1.435 0.354 年龄 1.267 0.688~2.333 0.447 ECOG评分 1.850 0.993~3.445 0.053 肝内肿瘤数目 2.033 1.109~3.727 0.021 1.756 0.934~3.302 0.081 肝内最大肿瘤直径 1.190 0.654~2.163 0.569 Child-Pugh分级 0.756 0.407~1.403 0.375 治疗前甲胎蛋白水平 1.128 0.621~2.051 0.693 肝血管侵犯 1.381 0.744~2.564 0.306 门静脉癌栓 1.559 0.854~2.849 0.148 TACE 0.408 0.218~0.761 0.005 0.454 0.233~0.885 0.020 远处转移 1.271 0.700~2.309 0.430 治疗前乳酸脱氢酶 2.043 1.116~3.742 0.021 1.808 0.620~5.274 0.278 治疗前PLR 2.073 1.126~3.815 0.019 0.929 0.302~2.852 0.929 治疗前NLR 2.583 1.405~4.749 0.002 1.940 1.024~3.675 0.042 注：以性别(女性)、年龄(＞60岁)、ECOG评分(1分)、肝内肿瘤数目(＞3个)、肝内最大肿瘤直径(＞5 cm)、Child-Pugh分级(B级)、治疗前甲胎蛋白水平(＞400 ng/mL)、肝血管侵犯(有)、门静脉癌栓(有)、TACE(有)、远处转移(有)、治疗前乳酸脱氢酶(＞250 U/L)、治疗前PLR(＞140)、治疗前NLR(＞2.5)为参照。
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表 4 影响HCC患者OS的单因素及多因素分析
Table 4. Multivariable Cox regression analysis for OS
变量 单因素分析 多因素分析 HR值 95% CI P值 HR值 95%CI P值 性别 0.701 0.345~1.424 0.326 年龄 1.179 0.630~2.204 0.606 ECOG评分 1.652 0.890~3.067 0.112 肝内肿瘤数目 2.140 1.147~3.992 0.017 1.887 0.991~3.591 0.053 肝内最大肿瘤直径 1.035 0.567~1.889 0.911 Child-Pugh分级 0.762 0.409~1.421 0.393 治疗前甲胎蛋白水平 1.251 0.685~2.284 0.467 肝血管侵犯 1.124 0.610~2.071 0.708 门静脉癌栓 1.425 0.768~2.641 0.261 TACE 0.421 0.225~0.778 0.007 0.461 0.235~0.904 0.024 远处转移 1.024 0.560~1.872 0.939 治疗前乳酸脱氢酶 2.043 1.117~3.736 0.020 1.721 0.591~5.015 0.320 治疗前PLR 1.948 1.056~3.595 0.033 0.921 0.301~2.817 0.885 治疗前NLR 2.532 1.360~4.751 0.003 1.945 1.021~3.707 0.043 注：以性别(女性)、年龄(＞60年)、ECOG评分(1分)、肝内肿瘤数目(＞3个)、肝内最大肿瘤直径(＞5 cm)、Child-Pugh分级(B级)、治疗前甲胎蛋白水平(＞400 ng/mL)、肝血管侵犯(有)、门静脉癌栓(有)、TACE(有)、远处转移(有)、治疗前乳酸脱氢酶(＞250 U/L)、治疗前PLR(＞140)、治疗前NLR(＞2.5)为参照。
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表 5 HCC患者的药物相关不良反应情况[例(%)]
Table 5. Treatment-related adverse enents according to category and grade[cases (%)]
治疗相关不良反应 任何级别不良反应 中重度不良反应 高血压 12(21.8) 2(3.6) 手足综合征 6(10.9) 1(1.8) 反应性毛细血管增生症 5(9.1) 0 蛋白尿 9(16.4) 2(3.6) 腹泻 7(12.7) 1(1.8) 甲状腺功能减退 9(16.4) 0 免疫相关性肺炎 4(7.3) 2(3.6) 免疫相关性肠炎 2(3.6) 1(1.8) 免疫相关性心肌炎 0 1(1.8) 疲劳 11(20.0) 0 血小板减少 5(9.1) 1(1.8) 皮疹 5(9.1) 1(1.8) 垂体功能下降 1(1.8) 0
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