Postoperative Adjuvant Hepatic Arterial Infusion Chemotherapy With FOLFOX in Hepatocellular Carcinoma With Microvascular Invasion: A Multicenter, Phase III, Randomized Study

Abstract

Purpose: To report the efficacy and safety of postoperative adjuvant hepatic arterial infusion chemotherapy (HAIC) with 5-fluorouracil and oxaliplatin (FOLFOX) in hepatocellular carcinoma (HCC) patients with microvascular invasion (MVI).

Patients and methods: In this randomized, open-label, multicenter trial, histologically confirmed HCC patients with MVI were randomly assigned (1:1) to receive adjuvant FOLFOX-HAIC (treatment group) or routine follow-up (control group). The primary end point was disease-free survival (DFS) by intention-to-treat (ITT) analysis while secondary end points were overall survival, recurrence rate, and safety.

Results: Between June 2016 and August 2021, a total of 315 patients (ITT population) at five centers were randomly assigned to the treatment group (n = 157) or the control group (n = 158). In the ITT population, the median DFS was 20.3 months (95% CI, 10.4 to 30.3) in the treatment group versus 10.0 months (95% CI, 6.8 to 13.2) in the control group (hazard ratio, 0.59; 95% CI, 0.43 to 0.81; P = .001). The overall survival rates at 1 year, 2 years, and 3 years were 93.8% (95% CI, 89.8 to 98.1), 86.4% (95% CI, 80.0 to 93.2), and 80.4% (95% CI, 71.9 to 89.9) for the treatment group and 92.0% (95% CI, 87.6 to 96.7), 86.0% (95% CI, 79.9 to 92.6), and 74.9% (95% CI, 65.5 to 85.7) for the control group (hazard ratio, 0.64; 95% CI, 0.36 to 1.14; P = .130), respectively. The recurrence rates were 40.1% (63/157) in the treatment group and 55.7% (88/158) in the control group. Majority of the adverse events were grade 0-1 (83.8%), with no treatment-related death in both groups.

Conclusion: Postoperative adjuvant HAIC with FOLFOX significantly improved the DFS benefits with acceptable toxicities in HCC patients with MVI.

Trial registration: ClinicalTrials.gov NCT03192618.

FIG 1.

CONSORT diagram. AHGUCM, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China; FAHJNU, The First Affiliated Hospital of Jinan University, Guangzhou, China; FPHF, The First People's Hospital of Foshan, Foshan, China; HAIC, hepatic arterial infusion chemotherapy; ITT, intention-to-treat; PD-1, programmed cell death protein 1; PD-L1, programmed death ligand-1; PP, per-protocol; SYSUCC, Sun Yat-sen University Cancer Center, Guangzhou, China; ZJHSMU, Zhujiang Hospital of Southern Medical University, Guangzhou, China.

FIG 2.

Kaplan-Meier curves demonstrating (A) DFS in the ITT population, (B) OS in the ITT population, (C) DFS in the PP population, and (D) OS in the PP population. DFS, disease-free survival; HAIC, hepatic arterial infusion chemotherapy; ITT, intention-to-treat; OS, overall survival; PP, per-protocol.

FIG 3.

Forest plots by subgroup: (A) DFS in the ITT population, (B) OS in the ITT population, (C) DFS in the PP population, and (D) OS in the PP population. Unadjusted Cox model was used to estimate HRs with 95% CIs and to test for interactions among subgroups using two-sided P values. AFP, alpha-fetoprotein; DFS, disease-free survival; HBV-DNA, hepatitis B virus–DNA; HR, hazard ratio; ITT, intention-to-treat; OS, overall survival; PP, per-protocol.