Background and Objective
Hepatocellular carcinoma (HCC) is among the most common malignancies globally, with a high recurrence rate after resection, especially in patients with risk factors like large tumor size, vascular invasion, or multiple nodules. Although immune checkpoint inhibitors (ICIs) are standard in advanced HCC, their role as adjuvant therapy post-surgery—and more importantly, the optimal duration of such therapy—remains unclear. This prospective multicenter study led by Dr. Jianhong Zhong aimed to evaluate whether adjuvant ICIs improve recurrence-free survival (RFS) and overall survival (OS), and whether duration of therapy influences outcomes.
Study Population and Design
Between January 1, 2019, and December 31, 2023, a total of 3,304 HCC patients underwent hepatic resection across three centers in China. After exclusions for non-curative surgery, missing high-risk features, or severe postoperative complications, 1,313 patients were included. Of these, 239 received adjuvant ICIs (with or without molecular targeted therapy), and 1,032 received active surveillance. After 1:2 propensity score matching (PSM), 239 adjuvant patients and 478 active surveillance patients were analyzed. The most common ICI agents included tislelizumab (99 patients), sintilimab (59), camrelizumab (42), and toripalimab (20).
Clinical Outcomes
With a median follow-up of 30.2 months, recurrence occurred in 47.3% of the adjuvant group and 67.4% of the active surveillance group. Median RFS was significantly longer in the adjuvant cohort (22.6 months, 95% CI: 18.3–26.9) than in the surveillance cohort (19.1 months, 95% CI: 16.4–21.4), corresponding to a hazard ratio (HR) of 0.79 (95% CI: 0.66–0.95, p = 0.019). After PSM, the benefit remained significant (HR 0.75, 95% CI: 0.61–0.92, p = 0.014). At 3 years, RFS was 40.6% in the adjuvant group vs. 28.4% in the surveillance group.
In terms of overall survival, the adjuvant therapy cohort showed a mortality rate of 19.2% compared to 29.6% in the surveillance cohort. Although median OS was not reached, 3-year OS was 72.4% in the adjuvant group versus 65.7% in the control group. This difference translated into a statistically significant survival benefit both before (HR 0.72, 95% CI: 0.54–0.94, p = 0.010) and after PSM (HR 0.71, 95% CI: 0.52–0.96, p = 0.040).
Subgroup Analysis
Subgroups that appeared to derive the most benefit from adjuvant therapy included patients aged ≥65 years, those with high alpha-fetoprotein (≥400 ng/mL), cirrhosis, single large tumors (>5 cm), macro/microvascular invasion, Edmondson-Steiner grade III–IV, and those with hepatitis B virus (HBV) DNA ≥20 IU/mL. Conversely, patients with fatty liver disease did not significantly benefit from adjuvant ICI therapy, echoing previous observations that NAFLD-related HCC may respond differently to immunotherapy.
Duration of Adjuvant ICI Therapy
The impact of treatment duration was explored among 200 patients who had received adjuvant ICIs and were recurrence-free for the first 2–6 months post-resection. Of these, 95 received ≤6 months of therapy, and 105 received >6 months. Patients treated longer tended to have better RFS (HR 0.66, 95% CI: 0.42–1.04, p = 0.071) and OS (HR 0.59, 95% CI: 0.30–1.17, p = 0.128), although these differences did not reach statistical significance. After 1:1 PSM, the trends remained favorable (RFS HR 0.68, p = 0.198; OS HR 0.47, p = 0.078), suggesting a potential benefit from extending therapy beyond 6 months.
Safety Profile
Adverse events (AEs) occurred in 73.6% of patients receiving adjuvant therapy. Grade 1–2 AEs were reported in 51.9%, while grade 3–4 events were noted in 21.8%. No grade 5 toxicity occurred. Liver-related AEs were the most common, including hyperbilirubinemia (30.1%) and elevated liver enzymes (AST 26.8%, ALT 25.9%). Grade 3–4 toxicities were more frequent in those receiving therapy >6 months but were not markedly severe. Skin reactions, neutropenia, and fatigue were among the leading causes of moderate to severe AEs.
Conclusion
This prospective study, under the leadership of Dr. Jianhong Zhong, provides valuable real-world evidence supporting the use of adjuvant ICIs following curative hepatic resection in HCC patients at high risk of recurrence. While therapy for longer than 6 months was associated with a trend toward better outcomes, the increase in adverse events warrants caution. These findings underline the need for individualized treatment planning and call for future randomized trials to define the optimal duration of adjuvant immunotherapy in this patient population.
