What is the frontline treatment approach for a patient with multifocal hepatocellular carcinoma (HCC) arising from hepatic steatosis?

Frontline Treatment of Multifocal Hepatocellular Carcinoma from Hepatic Steatosis

Primary Recommendation

For multifocal HCC arising from hepatic steatosis, liver transplantation is the recommended first-line treatment if the patient meets accepted criteria (typically Milan criteria: single tumor <5 cm or ≤3 nodules ≤3 cm each) and has adequate liver function. 1 If transplantation is not feasible, transarterial chemoembolization (TACE) is the standard first-line therapy for intermediate-stage multifocal disease without vascular invasion or extrahepatic spread. 1, 2

Treatment Algorithm Based on Clinical Staging

Step 1: Assess Transplant Eligibility

• Liver transplantation is the preferred option for multifocal HCC within Milan criteria (≤3 nodules ≤3 cm or single tumor <5 cm), particularly when underlying liver dysfunction from steatosis precludes resection. 1
• Transplant is specifically recommended for decompensated cirrhosis with HCC within criteria, offering both tumor treatment and correction of liver dysfunction. 1
• While awaiting transplant, neoadjuvant locoregional therapy (TACE or ablation) should be administered to prevent waitlist dropout from disease progression. 1

Step 2: If Transplant Not Feasible - Locoregional Therapy

TACE is the standard of care for intermediate-stage (BCLC B) multifocal HCC without vascular invasion or extrahepatic disease. 1, 2

• Conventional lipiodol-based TACE is the established standard, though drug-eluting bead TACE (DEB-TACE) can minimize systemic chemotherapy side effects. 1
• TACE is most effective in asymptomatic patients with Child-Pugh A liver function and multinodular tumors confined to the liver. 1
• Response should be assessed after 2-3 sessions using modified RECIST (mRECIST) criteria with dynamic CT or MRI. 1, 3
• TACE improves 2-year survival by 20-60% compared to untreated patients. 1, 2

Selective internal radiotherapy (SIRT/TARE) is an alternative to TACE for intermediate or advanced stage HCC without extrahepatic disease, achieving similar survival with better quality of life in some studies. 1

Step 3: Advanced Disease - Systemic Therapy

If multifocal HCC is unresectable with preserved liver function (Child-Pugh A, ECOG 0-1), atezolizumab plus bevacizumab is the preferred first-line systemic therapy. 1, 2

• This combination demonstrates superior overall survival compared to sorafenib (67.2% vs 54.6% at 12 months). 1
• Critical caveat: Patients must undergo endoscopic evaluation and treatment of esophageal varices before starting bevacizumab due to bleeding risk. 1
• The regimen is contraindicated in patients with autoimmune disease history, solid organ transplantation, or untreated high-risk varices. 1

Alternative first-line options if atezolizumab/bevacizumab is contraindicated:

• Lenvatinib is approved for first-line treatment showing non-inferiority to sorafenib (13.6 vs 12.3 months median survival). 1, 4

  • Dosing: 12 mg daily for patients ≥60 kg; 8 mg daily for patients <60 kg. 4
  • Important limitation: Not studied in main portal vein invasion. 1

• Sorafenib remains an option with proven survival benefit (2-3 months over placebo), particularly when immunotherapy is unsuitable. 1

Step 4: Combination Approaches for Selected Cases

Surgical resection may be considered for multifocal disease in highly selected patients not suitable for transplant, though this is not first-line therapy. 1

• Resection requires Child-Pugh A liver function, absence of clinically significant portal hypertension (HVPG ≤10 mmHg), and adequate future liver remnant volume. 1
• Adjuvant therapy with atezolizumab plus bevacizumab after resection improves recurrence-free survival. 1

Combination locoregional therapies (TACE plus microwave ablation) show improved survival for larger multifocal tumors (>5 cm) compared to single modality treatment. 1

Critical Contraindications and Pitfalls

Absolute contraindications to specific therapies:

• Vascular invasion and extrahepatic metastases contraindicate liver transplantation. 1
• Child-Pugh C cirrhosis contraindicates all treatments except best supportive care. 2
• ECOG performance status ≥2 limits systemic therapy options. 1

Common pitfalls to avoid:

• Do not combine TACE with sorafenib either sequentially or concomitantly—this is not recommended and shows no benefit. 1
• Do not use systemic chemotherapy (including FOLFOX) as standard treatment; it has failed to improve survival in randomized trials. 1
• Do not proceed with bevacizumab-containing regimens without endoscopic variceal screening and treatment. 1
• Ablation alone is not appropriate as first-line curative therapy for multifocal disease; it serves only an adjunctive role. 1

Hepatic Steatosis-Specific Considerations

While the treatment algorithm follows standard HCC guidelines regardless of etiology, patients with steatosis-related HCC warrant particular attention to:

• Liver function assessment may be complicated by steatohepatitis-related inflammation. 5, 6
• These patients often lack traditional cirrhosis markers, requiring pathological confirmation before systemic therapy. 1
• The rising incidence of metabolic dysfunction-associated steatotic liver disease (MASLD) as an HCC risk factor emphasizes the importance of early detection programs. 5