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载药栓塞微球经肝动脉化疗栓塞术联合阿帕替尼治疗不可切除肝癌后二线追加卡瑞利珠单抗的安全性和有效性分析
DOI: 10.3969/j.issn.1001-5256.2023.04.014
伦理学声明：本研究方案于2020年11月24日经郑州大学第一附属医院伦理委员会审批，批号：SS-2020-017。
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。
作者贡献声明：张延藏、王满周、段旭华对研究的思路有关键贡献；王满周负责课题设计，资料分析，撰写论文；张延藏负责撰写、修改论文；李浩、王文辉、许文泽负责数据收集和整理分析；韩新巍、段旭华、任建庄负责拟定写作思路，指导撰写文章并最后定稿。
Safety and efficacy of camrelizumab added to second-line therapy after drug-eluting bead transarterial chemoembolization combined with apatinib for unresectable hepatocellular carcinoma
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摘要:
目的 分析在载药栓塞微球经肝动脉化疗栓塞术(DTACE)联合阿帕替尼治疗不可切除肝癌后，二线追加卡瑞利珠单抗的安全性和有效性。 方法 回顾性分析2019年12月—2020年12月于郑州大学第一附属医院就诊的89例二线追加卡瑞利珠单抗的肝癌患者资料。主要观察终点是使用卡瑞利珠单抗后总生存期(OS)和无进展生存期(PFS)，次要终点包括客观缓解率(ORR)、疾病控制率(DCR)和治疗相关不良事件(TRAE)。采用Kaplan-Meier法估算生存曲线，基线特征亚组分层分析采用Log-rank检验进行比较，分析影响患者预后的相关因素。 结果 本研究共筛选并随访了89例患者。随访至2021年12月，中位随访时间为16个月，中位OS为17.0(95%CI：15.3~18.7)个月，中位PFS为7.0(95%CI：6.2~7.8)个月。不同ECOG-PS、肝功能Child-Pugh分级、门静脉侵犯、进展模式、DTACE次数、口服阿帕替尼时长和应用卡瑞利珠单抗时长的患者OS及PFS之间差异具有统计学意义(P值均＜0.05)。应用卡瑞利珠单抗后3个月与6个月ORR分别为39.3%和22.4%，DCR分别为80.9%和54.1%。Log-rank检验单因素分析结果表明：DTACE次数为3~4、1~2比0次的患者显著改善中位OS [22.0 (95%CI：21.1~22.9)个月vs 17.0 (95%CI：15.8~18.2)个月vs 10.0 (95%CI：7.0~13.0)个月, χ2=31.423，P＜0.001]与PFS [10.0 (95%CI：7.0~13.0)个月vs 7.0(95%CI：6.2~7.8)个月vs 3.0 (95%CI：1.9~4.1)个月, χ2=20.741，P＜0.001]; 阿帕替尼应用时长＞4个月比≤4个月的患者显著改善中位OS [21.0 (95%CI：19.1~22.9) 个月vs 14.0(95%CI：10.4~17.6)个月, χ2=19.399，P＜0.001]与PFS [9.0 (95%CI：7.3~10.7)个月vs 5.0 (95%CI：4.0~6.0)个月, χ2=27.733，P＜0.001]; 卡瑞利珠单抗应用时长＞5个月比≤5个月的患者显著改善中位OS [22.0(95%CI：20.2~23.8)个月vs 13.0(95%CI：9.3~16.7)个月, χ2=22.336，P＜0.001]与PFS [9.0 (95%CI：7.0~11.0)个月vs 5.0 (95%CI：4.1~5.9)个月, χ2=26.141，P＜0.001]。DTACE术后不良事件为栓塞后综合征，给予对症处理后缓解。靶向药物和免疫治疗相关不良反应经对症支持治疗后均缓解，无4级及以上不良反应，无患者因TRAE而停用靶免治疗。 结论 DTACE联合阿帕替尼治疗不可切除肝癌进展后追加卡瑞利珠单抗疗效确切，TRAE总体安全可控。 Abstract:Objective To investigate the safety and efficacy of camrelizumab added to second-line therapy after drug- eluting bead transarterial chemoembolization (DTACE) combined with apatinib for unresectable hepatocellular carcinoma (HCC). Methods A retrospective analysis was performed for 89 HCC patients with camrelizumab added to second-line therapy who attended The First Affiliated Hospital of Zhengzhou University from December 2019 to December 2020. The primary endpoints were overall survival (OS) and progression-free survival (PFS) after the application of camrelizumab, and the secondary endpoints were objective remission rate (ORR), disease control rate (DCR), and treatment-related adverse events (TRAEs). The Kaplan-Meier method was used to plot survival curves, the Log-rank test was used for stratified analysis of subgroups based on baseline characteristics, and the influencing factors for prognosis were analyzed. Results A total of 89 patients were screened and followed up in this study. The patients were followed up to December 2021, with a median follow-up time of 16 months, a median OS time of 17.0 (95% confidence interval [CI]: 15.3-18.7) months, and a median PFS time of 7.0 (95% CI: 6.2-7.8) months. There were significant differences in OS and PFS between the patients with different ECOG-PS scores, liver function Child-Pugh classes, portal vein invasion, patterns of progression, times of DTACE treatment, durations of oral administration of apatinib, and durations of application of camrelizumab (all P < 0.05). At 3 and 6 months after the application of camrelizumab, ORR was 39.3% and 22.4%, respectively, and DCR was 80.9% and 54.1%, respectively. The univariate analysis using the Log-rank test showed that compared with the patients receiving 0 time of DTACE treatment, the patients receiving 3-4 or 1-2 times of DTACE treatment had significant improvements in median OS [22.0 (95% CI: 21.1-22.9) months and 17.0 (95% CI: 15.8-18.2) months vs 10.0 (95% CI: 7.0-13.0) months, χ2=31.423, P < 0.001] and PFS [10.0 (95% CI: 7.0-13.0) months and 7.0 (95% CI: 6.2-7.8) months vs 3.0 (95% CI: 1.9-4.1) months, χ2=20.741, P < 0.001]; compared with the patients using apatinib for ≤4 months, the patients using apatinib for > 4 months had significant improvements in median OS [21.0 (95% CI: 19.1-22.9) months vs 14.0 (95% CI: 10.4-17.6) months, χ2=19.399, P < 0.001] and PFS [9.0 (95% CI: 7.3-10.7) months vs 5.0 (95% CI: 4.0-6.0) months, χ2=27.733, P < 0.001]; compared with the patients using camrelizumab for ≤5 months, the patients using camrelizumab for > 5 months had significant improvements in median OS [22.0 (95% CI: 20.2-23.8) months vs 13.0 (95% CI: 9.3-16.7) months, χ2=22.336, P < 0.001] and PFS [9.0 (95% CI: 7.0-11.0) months vs 5.0 (95% CI: 4.1-5.9) months, χ2=26.141, P < 0.001]. Post-embolization syndrome was the adverse event after DTACE and resolved after symptomatic treatment. Adverse reactions related to targeted drugs and immunotherapy all resolved after symptomatic supportive treatment, with no grade ≥4 adverse reactions, and no patients withdrew from target-free therapy due to TRAEs. Conclusion As for DTACE combined with apatinib in the treatment of unresectable HCC, camrelizumab added after progression has a marked therapeutic efficacy with safe and controllable TRAEs. -
Key words:
- Liver Neoplasms /
- Chemoembolization, Therapeutic /
- Apatinib /
- Camrelizumab
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图 1 患者应用卡瑞利珠单抗后OS曲线
Figure 1. Overall survival of patients after Camrelizumab application
图 2 患者应用卡瑞利珠单抗后PFS曲线
Figure 2. Progression-free survival of patients after Camrelizumab application
表 1 患者临床基线特征
Table 1. Baseline characteristics of patients
临床特征 数据 性别[例(%)] 男 75(84.3) 女 14(15.7) ECOG-PS[例(%)] 0 35(39.3) 1 35(39.3) 2 19(21.3) Child-Pugh肝功能分级[例(%)] A级 51(57.3) B级 38(42.7) 甲胎蛋白[例(%)] ≤400 ng/mL 41(46.1) ＞400 ng/mL 48(53.9) 门静脉侵犯[例(%)] Vp1~2 71(79.8) Vp3 12(13.5) Vp4 6(6.7) 病因学[例(%)] 乙/丙型肝炎 68(76.4) 其他 21(23.6) 合并肝硬化[例(%)] 否 28(31.5) 是 61(68.5) 进展模式[例(%)] 靶区病灶 57(64.0) 非靶区病灶 23(25.8) 新发病灶 9(10.1) DTACE次数[例(%)] 0 19(21.3) 1~2 49(55.1) 3~4 21(23.6) 阿帕替尼应用时长[例(%)] ≤4个月 48(53.9) ＞4个月 41(46.1) 卡瑞利珠单抗应用时长[例(%)] ≤5个月 51(57.3) ＞5个月 38(42.7) 注: Vp, 日本肝细胞癌研究会门静脉癌栓分型。 
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表 2 影响患者OS的临床基线特征变量的单因素分析
Table 2. Univariate analysis of clinical baseline characteristic variables affecting OS
临床特征 中位OS (95%CI)
(月)χ2值 P值 性别 0.699 0.403 男 17.0 (15.4~18.6) 女 16.0 (5.9~26.1) ECOG-PS 10.961 0.004 0 20.0 (15.9~24.1) 1 17.0 (13.2~20.8) 2 10.0 (8.4~11.6) Child-Pugh分级 7.991 0.005 A级 20.0 (17.2~22.8) B级 13.0 (8.5~17.5) 甲胎蛋白 1.161 0.688 ≤400 ng/mL 16.0 (13.1~18.9) ＞400 ng/mL 17.0 (15.4~18.6) 门静脉侵犯 30.288 ＜0.001 Vp1~2 19.0 (17.0~21.0) Vp3 14.0 (8.7~19.3) Vp4 7.0 (3.4~10.6) 病因学 0.540 0.462 乙/丙型肝炎 17.0 (14.7~19.3) 其他 17.0 (15.7~18.3) 合并肝硬化 0.064 0.800 否 18.0 (13.4~22.6) 是 17.0 (14.8~19.2) 进展模式 7.689 0.021 靶区病灶 15.0 (12.5~17.5) 非靶区病灶 21.0 (18.1~23.9) 新发病灶 21.0 (19.6~22.4) DTACE次数 31.423 ＜0.001 0 10.0 (7.0~13.0) 1~2 17.0 (15.8~18.2) 3~4 22.0 (21.1~22.9) 阿帕替尼应用时长 19.399 ＜0.001 ≤4个月 14.0 (10.4~17.6) ＞4个月 21.0 (19.1~22.9) 卡瑞利珠单抗应用时长 22.336 ＜0.001 ≤5个月 13.0 (9.3~16.7) ＞5个月 22.0 (20.2~23.8)
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表 3 影响患者PFS的临床基线特征变量的单因素分析
Table 3. Univariate analysis of clinical baseline characteristic variables affecting PFS
临床特征 中位PFS (95%CI)
(月)χ2值 P值 性别 0.016 0.898 男 6.0(5.0~7.0) 女 7.0(5.8~8.2) ECOG-PS 6.330 0.042 0 7.0(6.0~8.0) 1 7.0(5.7~8.3) 2 5.0(2.4~7.6) Child-Pugh分级 3.973 0.046 A级 7.0(5.3~8.7) B级 6.0(4.9~7.1) 甲胎蛋白 0.213 0.644 ≤400 ng/mL 6.0(4.6~7.4) ＞400 ng/mL 7.0(6.0~8.0) 门静脉侵犯 10.446 0.005 Vp1~2 7.0(5.8~8.2) Vp3 5.0(1.6~8.4) Vp4 4.0(0.4~7.6) 病因学 0.067 0.796 乙/丙型肝炎 7.0(6.1~7.9) 其他 6.0(3.8~8.2) 合并肝硬化 3.093 0.079 否 7.0(3.6~10.4) 是 7.0(6.1~7.9) 进展模式 6.586 0.037 靶区病灶 6.0(5.1~6.9) 非靶区病灶 9.0(6.7~11.3) 新发病灶 8.0(6.6~9.4) DTACE次数 20.741 ＜0.001 0 3.0(1.9~4.1) 1~2 7.0(6.2~7.8) 3~4 10.0(7.0~13.0) 阿帕替尼应用时长 27.733 ＜0.001 ≤4个月 5.0(4.0~6.0) ＞4个月 9.0(7.3~10.7) 卡瑞利珠单抗应用时长 26.141 ＜0.001 ≤5个月 5.0(4.1~5.9) ＞5个月 9.0(7.0~11.0)
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表 4 首次输注卡瑞利珠单抗后3个月和6个月的治疗应答
Table 4. Treatment response at 3 and 6 months after first infusion of Camrelizumab
肿瘤应答评估 3个月
(n=89)6个月
(n=85)总体反应[例(%)] CR 12(13.5) 6(7.1) PR 23(25.8) 13(15.3) SD 37(41.6) 27(31.8) PD 17(19.1) 39(45.9) ORR(CR+PR)[例(%)] 35(39.3) 19(22.4) DCR(CR+PR+SD)[例(%)] 72(80.9) 46(54.1) 注: CR, 完全缓解; PR, 部分缓解; SD, 疾病稳定; PD, 疾病进展。
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表 5 TRAE发生情况
Table 5. Treatment-related adverse events
TRAE 1~5级 3级 DTACE相关[例(%)] 发热 36(40.4) 0 疼痛 19(21.3) 3(3.4) 胃肠道反应 26(29.2) 0 肝脓肿 2(2.2) 2(2.2) 阿帕替尼/卡瑞利珠单抗相关[例(%)] 乏力 23(25.8) 0 手足综合征 17(19.1) 0 高血压 16(18.0) 0 肝性脑病 15(16.9) 4(4.5) 发热 11(12.4) 0 疼痛 10(11.2) 0 蛋白尿 5(5.6) 0 皮疹 3(3.4) 0 甲状腺功能异常 3(3.4) 0 反应性皮肤毛细血管增生症 14(15.7) 0 骨髓抑制 1(1.1) 0 免疫相关肺炎 1(1.1) 1(1.1) 上消化道出血 7(7.9) 3(3.4) 注: 根据CTCAE 4.03评估AE。
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