QuestionÌý Does combined transarterial chemoembolization and sorafenib (SOR-TACE) improve survival in patients with recurrent intermediate-stage hepatocellular carcinoma after R0 hepatectomy with positive microvascular invasion compared with transarterial chemoembolization (TACE) alone?

FindingsÌý In this randomized clinical trial of 162 patients, those treated with SOR-TACE had a significantly longer median overall survival than TACE alone (22.2 months vs 15.1 months) and median progression-free survival (16.2 months vs 11.8 months). The SOR-TACE safety profile was acceptable compared with TACE alone.

MeaningÌý SOR-TACE for patients with recurrent intermediate-stage hepatocellular carcinoma with microvascular invasion improved survival compared with TACE alone.

ImportanceÌý Transarterial chemoembolization (TACE) is commonly used to treat patients with recurrent intermediate-stage hepatocellular carcinoma (HCC) and positive microvascular invasion (MVI); however, TACE alone has demonstrated unsatisfactory survival benefits. A previous retrospective study suggested that TACE plus sorafenib (SOR-TACE) may be a better therapeutic option compared with TACE alone.

ObjectiveÌý To investigate the clinical outcomes of SOR-TACE vs TACE alone for patients with recurrent intermediate-stage HCC after R0 hepatectomy with positive MVI.

Design, Setting, and ParticipantsÌý In this phase 3, open-label, multicenter randomized clinical trial, patients with recurrent intermediate-stage HCC and positive MVI were randomly assigned in a 1:1 ratio via a computerized minimization technique to either SOR-TACE treatment or TACE alone. This trial was conducted at 5 hospitals in China, and enrolled patients from October 2019 to December 2021, with a follow-up period of 24 months. Data were analyzed from June 2023 to September 2023.

InterventionsÌý Randomization to on-demand TACE (conventional TACE: doxorubicin, 50 mg, mixed with lipiodol and gelatin sponge particles [diameter: 150-350 μm]; drug-eluting bead TACE: doxorubicin, 75 mg, mixed with drug-eluting particles [diameter: 100-300 μm or 300-500 μm]) (TACE group) or sorafenib, 400 mg, twice daily plus on-demand TACE (SOR-TACE group) (conventional TACE: doxorubicin, 50 mg, mixed with lipiodol and gelatin sponge particles [diameter, 150-350 μm]; drug-eluting bead TACE: doxorubicin, 75 mg, mixed with drug-eluting particles [diameter: 100-300 μm or 300-500 μm]).

Main Outcomes and MeasuresÌý The primary end point was overall survival by intention-to-treat analysis. Safety was assessed in patients who received at least 1 dose of study treatment.

ResultsÌý A total of 162 patients (median [range] age, 55 [28-75] years; 151 males [93.2%]), were randomly assigned to be treated with either SOR-TACE (n = 81) or TACE alone (n = 81). The median overall survival was significantly longer in the SOR-TACE group than in the TACE group (22.2 months vs 15.1 months; hazard ratio [HR], 0.55; P < .001). SOR-TACE also prolonged progression-free survival (16.2 months vs 11.8 months; HR, 0.54; P < .001), and improved the objective response rate when compared with TACE alone based on the modified Response Evaluation Criteria in Solid Tumors criteria (80.2% vs 58.0%; P = .002). Any grade adverse events were more common in the SOR-TACE group, but all adverse events responded well to treatment. No unexpected adverse events or treatment-related deaths occurred in this study.

Conclusions and RelevanceÌý The results of this randomized clinical trial demonstrated that SOR-TACE achieved better clinical outcomes than TACE alone. These findings suggest that combined treatment should be used for patients with recurrent intermediate-stage HCC after R0 hepatectomy with positive MVI.

Trial RegistrationÌý ClinicalTrials.gov Identifier: