经动脉化疗栓塞术（TACE）联合酪氨酸激酶抑制剂和免疫检查点抑制剂治疗不可切除肝细胞癌的意义：系统治疗时代的系统评价。

BACKGROUND AND AIMS: Regardless of great progress in early detection of hepatocellular carcinoma (HCC), unresectable HCC (uHCC) still accounts for the majority of newly diagnosed HCC with poor prognosis. With the promising results of a double combination of transarterial chemo(embolization) and tyrosine kinase inhibitors (TKIs), and TKIs and immune checkpoint inhibitors (ICIs), a more aggressive strategy, a triple combination of transarterial chemo(embolization), TKIs, and ICIs has been tried in the recent years. Hence, we aimed to conduct a systematic review to verify the safety and efficacy of the triple therapy for uHCC. METHODS: PubMed, MedLine, Embase, the Cochrane Library, and Web of Knowledge were used to screen the eligible studies evaluating the clinical efficacy and safety of triple therapy for patients with uHCC up to April 25th 2022, as well as Chinese databases. The endpoints were the complete response (CR), objective response rate (ORR), disease control rate (DCR), conversion rate, progression-free survival (PFS) rate, overall survival (OS) rate, and the incidence of adverse events (AEs). RESULTS: A total of 15 studies were eligible with 741 patients receiving transarterial chemoembolization (TACE) or hepatic arterial infusion chemotherapy (HAIC) combined with TKIs and ICIs. The pooled rate and 95% confidence interval (CI) for CR, ORR, and DCR were 0.124 (0.069-0.190), 0.606 (0.528-0.682), and 0.885 (0.835-0.927). The pooled rates for PFS at 0.5 years and 1 year were 0.781 (0.688-0.862) and 0.387 (0.293-0.486), respectively. The pooled rates for OS at 1, 2, and 3 years were 0.690 (0.585-0.786), 0.212 (0.117-0.324), and 0.056 (0.028-0.091), respectively. In addition, the pooled rate and 95%CI for the conversion surgery was 0.359 (0.153-0.595). The subgroup analysis of control studies showed that triple therapy was superior to TACE+TKIs, TKIs+ICIs, and TKIs in CR, ORR, and DCR, conversion rate; PFS; and OS. No fatal AEs were reported, and the top three most common AEs were elevated ALT, elevated AST, and hypertension, as well as severe AEs (grading ≥3). CONCLUSION: With the current data, we concluded that the triple therapy of TACE/HAIC, TKIs, and ICIs would provide a clinical benefit for uHCC both in short- and long-term outcomes without increasing severe AEs, but the conclusion needs further validation. SYSTEMATIC REVIEW REGISTRATION: http://www.crd.york.ac.uk/PROSPERO/, Review registry: CRD42022321970.

背景与目的：尽管在肝细胞癌（HCC）的早期检测方面取得了重大进展，但不可切除的 HCC（uHCC）仍然占新诊断 HCC 的大多数，预后较差。随着经动脉化疗栓塞（TACE）联合酪氨酸激酶抑制剂（TKI）和 TKI 联合免疫检查点抑制剂（ICI）的双重联合治疗取得了可喜的结果，近年来，一种更具侵袭性的策略，即 TACE、TKI 和 ICI 的三联疗法，已在最近几年进行了尝试。因此，我们旨在进行系统评价，以验证三联疗法治疗 uHCC 的安全性和疗效。

方法：截至 2022 年 4 月 25 日，我们使用 PubMed、MedLine、Embase、Cochrane 图书馆和 Web of Knowledge 筛选了评估三联疗法治疗 uHCC 患者的临床疗效和安全性的合格研究，以及中文数据库。终点是完全缓解（CR）、客观缓解率（ORR）、疾病控制率（DCR）、转化率、无进展生存期（PFS）率、总生存期（OS）率和不良事件（AE）的发生率。

结果：共有 15 项研究符合条件，共纳入 741 例接受 TACE 或肝动脉灌注化疗（HAIC）联合 TKI 和 ICI 治疗的患者。CR、ORR 和 DCR 的汇总率和 95%置信区间（CI）分别为 0.124（0.069-0.190）、0.606（0.528-0.682）和 0.885（0.835-0.927）。0.5 年和 1 年的 PFS 汇总率分别为 0.781（0.688-0.862）和 0.387（0.293-0.486）。1、2 和 3 年的 OS 汇总率分别为 0.690（0.585-0.786）、0.212（0.117-0.324）和 0.056（0.028-0.091）。此外，转化手术的汇总率和 95%CI 为 0.359（0.153-0.595）。对照研究的亚组分析表明，三联疗法在 CR、ORR 和 DCR、转化率、PFS 和 OS 方面均优于 TACE+TKI、TKI+ICI 和 TKI。未报告致命 AE，前三种最常见的 AE 是 ALT 升高、AST 升高和高血压以及严重 AE（≥3 级）。

结论：根据目前的数据，我们得出结论，TACE/HAIC、TKI 和 ICI 的三联疗法在短期和长期结果中为 uHCC 提供了临床获益，而不会增加严重 AE，但这一结论需要进一步验证。

系统评价注册：http://www.crd.york.ac.uk/PROSPERO/，注册编号：CRD42022321970。