What is the role of adjuvant therapy in patients with resected Hepatocellular Carcinoma (HCC)?

Adjuvant Therapy for Resected Hepatocellular Carcinoma

Adjuvant therapy is not recommended after curative resection or ablation of hepatocellular carcinoma, as no systemic or locoregional adjuvant treatment has demonstrated a significant survival advantage in high-quality randomized controlled trials. 1

Current Evidence Against Adjuvant Therapy

The most recent and authoritative guideline from the European Association for the Study of the Liver (EASL) in 2025 provides a strong recommendation against adjuvant treatment after resection or ablation (Level of Evidence 2, strong recommendation, strong consensus). 1 This recommendation is based on multiple failed randomized controlled trials:

Failed Systemic Therapy Trials

• Immune checkpoint inhibitors have uniformly failed to show survival benefit in three major trials: 1

  • Checkmate-9DX (nivolumab vs. placebo) - no significant survival advantage
  • KEYNOTE-937 (pembrolizumab vs. placebo) - no significant survival advantage
  • EMERALD-2 (durvalumab ± bevacizumab vs. placebo) - no significant survival advantage

• IMbrave050 trial (atezolizumab plus bevacizumab vs. active surveillance) showed an updated recurrence-free survival HR of 0.90 (95% CI 0.72–1.12), which was not statistically significant, and overall survival remained immature with an unfavorable trend (HR 1.26; 95% CI 0.85–1.87). 1

• Sorafenib in the STORM trial failed to improve recurrence-free survival or overall survival after resection or ablation. 1

• Other systemic agents including interferon, vitamin K, and peretinoid have all failed to demonstrate significant survival advantages in randomized trials. 1

Locoregional Adjuvant Therapy Limitations

While some Eastern studies suggest potential benefit from adjuvant locoregional treatments, these findings have critical limitations:

• Adjuvant TACE showed improved outcomes in meta-analyses (HR 0.67 for OS, HR 0.71 for disease-free survival), but most data come from Eastern countries, limiting generalizability to Western populations. 1

• Hepatic artery infusion chemotherapy and internal radiotherapy showed improved survival in network meta-analyses, but again, these studies predominantly enrolled Asian patients. 1

• Radioactive iodine-labeled metuximab met its primary endpoint in a Chinese RCT (5-year RFS 43.4% vs. 21.7%), but lacks validation in Western patients. 1

• The EASL explicitly states that trials recruiting significant proportions of Western patients are needed before these locoregional adjuvant treatments can be recommended for European populations. 1

Historical Context

Older guidelines from 2001 acknowledged that "the role of adjuvant treatment remains to be established" for resected HCC. 1 The 2018 AASLD guidelines similarly noted the lack of proven active agents, stating that most adjuvant agents studied did not have clinical evidence of improving survival in any stage of HCC. 1

Alternative Strategy: Pre-emptive Liver Transplantation

For patients with high-risk pathological features after resection (microvascular invasion, satellites, poor differentiation, beyond Milan criteria), the EASL 2025 guidelines suggest considering pre-emptive liver transplantation rather than adjuvant therapy:

• Resected patients with high-risk pathological findings may be considered for liver transplantation if a predicted transplant benefit can be shown and adequate observation time (>6 months) has elapsed. 1

• This approach is specifically for patients who would not be eligible for salvage transplantation in case of recurrence beyond Milan criteria. 1

• High-risk features include microvascular invasion, poor differentiation, AFP >400 ng/ml, lymphovascular invasion, and high tumor burden score. 1

Clinical Approach

Given the absence of effective adjuvant therapy:

• Surveillance is the standard of care after curative resection or ablation. 1

• Patients should undergo regular imaging surveillance to detect early recurrence when potentially curative treatments (repeat resection, ablation, or salvage transplantation) remain possible. 1

• For patients with high-risk pathological features, evaluation for pre-emptive liver transplantation should be considered rather than adjuvant systemic or locoregional therapy. 1

• Enrollment in clinical trials evaluating novel adjuvant approaches remains appropriate for eligible patients. 1

Important Caveats

• The 5-year recurrence rate after resection remains 50-70%, highlighting the unmet need for effective adjuvant strategies. 2, 3

• While antiviral therapy for hepatitis-related HCC may reduce recurrence rates, this addresses the underlying liver disease rather than serving as cancer-directed adjuvant therapy. 2

• Traditional chemotherapy shows limited efficacy (<10% response rate) and is poorly tolerated in cirrhotic patients, making it inappropriate in the adjuvant setting. 4