背景：进展期肝细胞癌(HCC)合并巨大肝肿块和大血管侵犯多见于初诊，而肝外转移较少(77.5%比 37.9%)。然而，在 IMbrave150、夏普和亚太夏普的临床试验中，肝外转移的比例分别达到了 63%、53%和 68.7%，而大血管侵犯只占 38%、36%和 36%。与之前和正在进行的探索 Firstline 治疗晚期肝癌的最佳系统用药的 3 期临床试验不同，这项研究主要针对肝内肿瘤负担增加的人群。

Background: Advanced hepatocellular carcinoma (HCC) with mega liver masses and macrovascular invasion were commonly observed at the first diagnosis, while with less extrahepatic metastases (77.5% vs. 37.9%). However, in clinical trials IMbrave150, SHARP, and Asia-Pacific SHARP, the percentage of extrahepatic metastases reached 63%, 53%, and 68.7%, respectively, while macrovascular invasion only accounted for 38%, 36%, and 36%. Unlike the previous and ongoing phase 3 clinical trials exploring the optimal systemic medication in the first-line treatment of advanced HCC, this study mainly focused on a population with a heavy intrahepatic tumor burden.

方法：在这项开放的 3 期试验中，患者按 1：1 的比例随机分配，接受 FOLFOX 方案的肝动脉灌注化疗(HAIC-FO)或索拉非尼治疗。HAIC-FO 组的患者接受肿瘤和正常组织的活检，以寻找预测治疗反应的潜在基因组生物标志物。

Methods: In this open-label, phase 3 trial, patients were randomly assigned in a 1:1 ratio to undergo hepatic arterial infusion chemotherapy (HAIC) of FOLFOX regimens (HAIC-FO) or sorafenib treatment. Patients in the HAIC-FO group were recommended to receive tumor and normal tissue biopsy to search for the potential genomic biomarkers in predicting the response to treatment.

结果:2017 年 5 月至 2020 年 5 月期间，共招募了 551 名患者。260 名符合条件的患者被随机分配接受 HAIC-FO(n=130)或索拉非尼(n=132)治疗，并纳入意向治疗人群。大血管侵犯伴或不伴肝外转移占 82.8%(84.6%和 81.1%；P=0.446)。肿瘤平均直径 HAIC-FO 组为 11.7 cm(IQR8.314.0)，索拉非尼组为 10.8 cm(8.7~13.6)(P=0.439)。肿瘤体积>50%的患者肝脏受累比例分别为 41.5%和 39.4%(P=0.724)。截止到数据截止时(2020 年 10 月 31 日，190 例死亡[HAIC-FO 组 79 例，索拉非尼组 111 例])，接受 HAIC-FO 治疗的患者的中位总生存期为 13.9 个月(95%可信区间为 10.6-17.2)，而接受索拉非尼治疗的患者的中位总生存期为 8.2 月 (7.5-9.0)(HR 0.408[95%可信区间 0.301-0.552]，P<0.001)。HAIC-FO 组有 16 例(12.3%)患者肿瘤减小，其中 15 例(93.8%)接受根治性手术或消融，最终获得 20.8(16.4)个月(95%CI 9.1~32.5[7.5~25.3])的中位总生存期(无进展生存期)，1 年生存率 93.8%(68.8%)。HAIC-FO 组正在进行基于全基因组测序的预测生物标志物分析。

Results: Between May 2017 and May 2020, 551 patients were recruited. Two hundred sixty eligible patients were randomly assigned to receive HAIC-FO (n = 130) or sorafenib (n = 132) and were included in the intention-to-treatment population. Macrovascular invasion with or without extrahepatic metastasis was present in 82.8% of patients (84.6% and 81.1%; P = 0.446). The median tumor diameter was 11.7 cm (IQR 8.3-14.0) of the HAIC-FO group and 10.8 cm (8.7-13.6) of the sorafenib group (P = 0.439). The percentage of patients with > 50% tumor volume involvement of the liver was 41.5% and 39.4%, respectively (P = 0.724). At the time of data cutoff (Oct 31, 2020, at 190 deaths [79 of HAIC-FO and 111 of sorafenib]), patients receiving HAIC-FO had a median overall survival of 13.9 months (95%CI 10.6-17.2), compared with 8.2 months (7.5-9.0) for those receiving sorafenib (HR 0.408 [95%CI 0.301-0.552], P < 0.001). Tumor downstaging occurred in 16 (12.3% of 130) patients of the HAIC-FO group, including 15 (93.8%) receiving curative surgery or ablation and finally achieving a median overall survival (progression-free survival) of 20.8 (16.4) months (95%CI 9.1-32.5 [7.5-25.3]) with a 1-year rate of 93.8% (68.8%). Analyses of predictive biomarkers based on the whole genome sequencing were ongoing in the HAIC-FO group.

结论：这项随机 3 期研究证明，HAIC-FO 在原发性诊断的晚期肝癌一线治疗中的疗效和生存结果优于索拉非尼，提示对于肝内肿瘤负荷较重的患者，HAIC-FO 单一治疗可能是比索拉非尼更好的治疗策略。

Conclusions: This randomized phase 3 study proved that HAIC-FO had superior efficacy and survival outcome than sorafenib in the first-line treatment of primary diagnostic, advanced HCC, indicating that patients with heavy intrahepatic tumor burden, HAIC-FO monotherapy might be a better strategy than sorafenib.