Neoadjuvant hepatic arterial infusion chemotherapy with FOLFOX could improve outcomes of resectable BCLC stage A/B hepatocellular carcinoma patients beyond Milan criteria: A multi-center, phase 3, randomized, controlled clinical trial.
Authors: Wei Wei , Li Shaohua , Zhao Rongce , Cheng Yuan , Li Qiang , Lu Lianghe , Mei Jie , Shang Changzhen , Luo Rui , Pan Mingxin , Xiang Bangde , Jiang Yuchuan , Lei Qiucheng , Cao Mingrong , Li Ji-Bin , Zheng Lie , Chen Huanwei , Zhong Jian-Hong , Zhong Chong , Guo Rongping 
Published: June 2023

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Background: The efficacy of operation, as the only radical option for resectable BCLC stage A/B hepatocellular carcinoma (HCC) patients beyond Milan criteria, is still unsatisfactory. This study aimed to investigate to efficacy and safety of preoperative neoadjuvant hepatic arterial infusion chemotherapy (HAIC) with FOLFOX regimen for these patients. Methods: In this multi-center, prospective, phase 3, randomized, open-labeled, controlled clinical trial, resectable BCLC stage A/B HCC patients beyond Milan criteria were randomly assigned (1:1) before hepatectomy to receive either neoadjuvant HAIC (treatment group) or operation directly without any neoadjuvant treatment (control group). The primary endpoint was overall survival (OS), the secondary endpoints are progression-free survival (PFS) and safety. Results: Between March 2016 and August 2022, a total of 487 patients were screened from seven Chinese hospitals, and 392 patients were randomly assigned to receive neoadjuvant FOLFOX-HAIC before hepatectomy (treatment group, n = 195), or operation directly without any neoadjuvant treatment (control group, n = 197) and were included in the ITT population. Among them, 14 patients from the treatment group and 13 patients from the control group were excluded from the PP population. In the ITT population, the OS rates at 1-, 2-, and 3-year were 97.7%, 86.3%, and 77.1%, respectively, for the treatment group and were 90.0%, 80.9%, and 70.6%, respectively, for the control group. The median PFS of the treatment and control groups was 17.4 months (95% CI, 9.0-25.8) and 9.8 months (8.2-11.4), respectively, in the ITT population. The OS and PFS were significantly better in treatment group than in control group (p = 0.032 and < 0.001, respectively) in ITT population. In the PP population, the OS rates at 1-, 2-, and 3-year were 98.7%, 91.1%, and 79.7%, respectively, for the treatment group and were 89.2%, 79.3%, and 67.7%, respectively, for the control group. The median PFS of the treatment and control groups was 22.7 months (95% CI, 10.9-34.5) and 10.2 months (8.4-12.1), respectively, in the PP population. The OS and PFS were significantly better in treatment group than in control group (p = 0.001 and < 0.001, respectively) in PP population. In treatment group of ITT population, the complete regression (CR) rate, object response rate (ORR), disease control rate (DCR) was 11.3%, 61.5%, and 97.4%, respectively. Safety analysis showed HAIC was quite safe, 191 (97.9%) patients had mild HAIC related adverse events (HRAEs) (grade 0-2). The operation related adverse events (ORAEs) were similar between two groups (p = 0.265). Conclusions: Neoadjuvant HAIC with FOLFOX regimen before hepatectomy may bring survival benefits for resectable BCLC stage A/B HCC patients beyond Milan criteria. Clinical trial information: NCT03851913 .