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不可切除肝细胞癌的经肝动脉化疗栓塞术联合靶向药物或程序性死亡受体1及其配体单抗治疗进展
DOI: 10.3969/j.issn.1001-5256.2023.07.033
利益冲突声明：本文不存在任何利益冲突。
作者贡献声明：彭秋菊、晏媛完成课题设计；彭秋菊完成文献筛选，文献数据整理与文章初稿写作；晏媛、戴涛负责指导文章写作；谢贵波、陈金军、程笑负责修改文章；陈金军提供基金支持。
Research advances in transcatheter arterial chemoembolization combined with targeted agents or anti-PD-1/PD-L1 monoclonal antibody in treatment of patients with unresectable hepatocellular carcinoma
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摘要: 经肝动脉化疗栓塞术(TACE)被国内外指南推荐用于不可切除肝细胞癌(uHCC)患者的治疗，是uHCC患者最常用的治疗方法之一。TACE治疗HCC常用的化疗药物包括表柔比星、顺铂、氟尿嘧啶等，不过哪种化疗药物更优效还不清楚。本文总结了近5年关于使用不同化疗药物的TACE方案治疗uHCC患者的研究。TACE联合索拉非尼显著改善中晚期HCC患者的生存，已被中国临床肿瘤学会指南推荐用于这类患者，TACE联合其他酪氨酸激酶抑制剂(TKI)的疗效也成为研究热点。研究提示TACE联合仑伐替尼较TACE联合索拉非尼治疗晚期HCC患者的中位无进展生存期显著更高、中位总生存期有提高的趋势。而由于靶受体或下游信号的变异，分子靶向药物耐药仍然是一个挑战性问题。TKI结合免疫检查点抑制剂的治疗对uHCC患者可能是一个有希望的策略。一些研究初步提示TACE联合TKI及程序性死亡受体1及程序性死亡受体及其配体(PD-1/PD-L1)单抗的三联治疗在改善uHCC患者生存方面有较佳的疗效。本文综述了近5年TACE联合靶向药物、TACE联合PD-1/PD-L1单抗治疗uHCC患者的疗效与安全性研究。Abstract: Transcatheter arterial chemoembolization (TACE) is recommended by domestic and international guidelines for the treatment of patients with unresectable hepatocellular carcinoma (uHCC), and it is one of the most common treatment methods for patients with uHCC. The chemotherapy drugs commonly used in TACE for HCC include epirubicin, cisplatin, and fluorouracil, while it is still unclear which chemotherapy drug has a better clinical effect. This article summarizes the studies of different TACE regimens using different chemotherapy drugs in the treatment of patients with uHCC in the recent five years. TACE combined with sorafenib can significantly improve the survival of patients with advanced HCC and has been recommended for the treatment of such patients by Chinese Society of Clinical Oncology guidelines, and the efficacy of TACE combined with other tyrosine kinase inhibitors (TKI) has become a research hotspot. Studies have shown that compared with TACE combined with sorafenib in the treatment of patients with advanced HCC, TACE combined with lenvatinib can achieve a significantly longer progression-free survival time and a tendency of increase in median overall survival time. However, due to the variation of target receptors or downstream signals, resistance to molecular-targeted agents is still a challenging problem. TKI combined with immune checkpoint inhibitors may be a promising strategy for the treatment of patients with uHCC. Some studies suggest that triple therapy using TACE combined with TKIs and anti-PD-1/PD-L1 monoclonal antibody has better efficacy in improving the survival of patients with uHCC. This article reviews the studies of the efficacy and safety of TACE combined with targeted agents and TACE combined with anti-PD-1/PD-L1 monoclonal antibody in the treatment of patients with uHCC in the recent five years.
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表 1 近5年关于含不同化疗药物的TACE方案治疗uHCC患者的研究汇总
Table 1. Summary of studies on the treatment of uHCC patients using TACE containing different chemotherapy drugs in recent five years
研究者 受试者 研究设计 例数 试验组 对照组 mOS mPFS ORR ≥3级AE发生率 Aramaki O, 2021年[8] uHCC患者 Ⅱ/Ⅲ期
RCT研究455 cTACE(顺铂) cTACE
(表柔比星)2.9年vs 2.7年 未提供 65.3% vs 60.6% 49.8% vs 48.3 % Ikeda M, 2018年[9] uHCC患者 Ⅲ期RCT研究 247 cTACE(米铂) cTACE
(表柔比星)3.0年vs 3.1年 未提供 未提供 AST升高：39.5% vs 57.7 %，ALT升高：31.5% vs 53.7% Fu J, 2021年[11] uHCC患者，且对多柔比星耐药 前瞻性、RCT研究 160 cTACE(博来霉素) cTACE(多柔比星) 8.1个月vs 4.0个月 5.8个月vs 2.9个月 27.5% vs 7.5% AST升高：
5.0% vs 3.75 %Wang Y, 2018年[12] 中晚期HCC患者，且经≥2次cTACE治疗进展后 前瞻性、RCT研究 160 cTACE(博来霉素+吡柔比星+FOLFOX) cTACE(吡柔比星+FOLFOX) 8.1个月vs 4.0个月 5.8个月vs 2.9个月 27.5% vs 7.5% 两组均未出现严重治疗相关AE 注：FOLFOX，奥沙利铂联合氟尿嘧啶。 
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表 2 近5年关于TACE联合不同的靶向药物治疗uHCC患者的前瞻性研究汇总
Table 2. Summary of prospective studies on TACE combined with different molecular targeted agents in the treatment of uHCC patients in recent five years
研究者 受试者 研究设计 总样本量(例) 试验组 对照组 mOS/2年OS率 mPFS ORR Kudo M, 2020年[17] uHCC患者(BCLC A/B/C期) 多中心、RCT研究 156 TACE+索拉非尼 TACE 77.2% vs 64.6% 25.2个月vs 13.5个月 71.3% vs 61.8 % Xu X, 2018年[19] 肝癌患者(BCLC B/C期) RCT研究 156 TACE+索拉非尼 组2：TACE；
组3：索拉非尼未提供 未提供 28.6% vs 24.5% vs 22.2 % Ding X, 2021年[21] HCC合并门静脉瘤栓患者 RCT研究 64 TACE+仑伐替尼 TACE+索拉非尼 14.5个月vs 10.8个月 4.7个月vs 3.1个月 53.1% vs 25.0 % Lu W, 2017年[22] uHCC患者(BCLC B/C期) RCT研究 44 TACE+阿帕替尼 TACE 未提供 12.5个月vs 6.0个月 50.0% vs 27.3 % Turpin A, 2021年[27] uHCC患者(BCLC A/B期) RCT研究 78 TACE+舒尼替尼 TACE+安慰剂 25.0个月vs 20.5个月 9.1个月vs 5.5个月 26.0% vs 47.3 % Xu Q, 2018年[28] uHCC患者(BCLC A/B/C期) RCT研究 104 TACE+舒尼替尼 TACE+索拉非尼 9.2个月vs 13.2个月 6.9个月vs 10.2个月 37.3% vs 58.5 % Chan SL, 2017年[29] uHCC患者(BCLC B/C期) 单臂临床研究 50 TACE+阿昔替尼 无 18.8个月 8.4个月 68.2%
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