What are the treatment options for hepatocellular carcinoma (HCC) based on the Barcelona Clinic Liver Cancer (BCLC) staging system?

Treatment Options for Hepatocellular Carcinoma Based on BCLC Staging

The Barcelona Clinic Liver Cancer (BCLC) staging system should guide all treatment decisions for HCC, with curative therapies (resection, transplantation, ablation) for BCLC 0-A, transarterial chemoembolization for BCLC B, systemic therapy for BCLC C, and best supportive care for BCLC D. 1, 2

BCLC Stage 0 (Very Early Stage)

Definition: Single tumor <2 cm, Child-Pugh A, performance status 0 1, 2

Treatment approach:

• Surgical resection is the first-line treatment for patients with solitary tumors, no portal hypertension, and normal bilirubin 1, 3
• Radiofrequency ablation (RFA) serves as an alternative when resection is not feasible due to tumor location or patient comorbidities 1, 2
• TACE can be considered for patients unsuitable for RFA or resection 4
• Expected 5-year survival: 50-75% 1, 2

BCLC Stage A (Early Stage)

Definition: Single tumor ≤5 cm OR up to 3 nodules ≤3 cm (Milan criteria), Child-Pugh A-B, performance status 0 1, 2

Treatment stratification:

• Surgical resection for patients with solitary tumors, no portal hypertension (hepatic venous pressure gradient ≤10 mmHg), normal bilirubin, and adequate future liver remnant 1, 3
  • Minimum future liver remnant requirements: ≥20% for normal liver, ≥30% for chronic liver disease, ≥40% for cirrhotic liver 2, 5
  • Portal vein embolization should be performed when future liver remnant is inadequate 2, 5
• Liver transplantation is the optimal treatment for patients with decompensated cirrhosis (Child-Pugh B-C) meeting Milan criteria 1, 2
  • Provides the lowest recurrence rate (10% vs 70% for resection/ablation) 1
  • Bridge therapy with TACE or RFA should be used while awaiting transplantation to prevent tumor progression 2, 6
• Percutaneous ablation (RFA or microwave) for patients with preserved liver function but unsuitable for resection due to portal hypertension, comorbidities, or tumor location 1, 2
• TACE plus RFA provides better local tumor control than RFA alone in selected cases 2, 4
• Expected 5-year survival: 50-75% 1, 2

Critical pitfall: Up to one-third of early-stage patients are unfit for radical therapy due to advanced age, significant comorbidities, or strategic tumor location and require palliative approaches 1, 2

BCLC Stage B (Intermediate Stage)

Definition: Multinodular tumors, Child-Pugh A-B, performance status 0, no vascular invasion or extrahepatic spread 1, 2

Treatment approach:

• Transarterial chemoembolization (TACE) is the standard of care 1, 2
  • Provides median survival improvement from 16 to 22 months 1, 2
  • Repeated treatments are typically required 1
• Surgical resection can be considered in highly selected BCLC B patients with well-compensated cirrhosis (Child-Pugh A) and limited tumor burden if 50% 5-year survival is achievable 1
• Transarterial radioembolization (TARE) with 90Y is an alternative locoregional therapy option 7
• Combination therapies (TACE plus RFA or TACE plus radiotherapy) may improve local tumor control and survival in selected cases 2, 4

Important consideration: BCLC B encompasses substantial heterogeneity in tumor burden and liver function, requiring individualized treatment selection within this stage 4, 7

BCLC Stage C (Advanced Stage)

Definition: Portal vein invasion and/or extrahepatic spread, Child-Pugh A-B, performance status 1-2 1, 2

Treatment approach:

• Sorafenib 400 mg twice daily is the first-line systemic therapy 1, 8
  • Demonstrated survival benefit: median overall survival 10.7 months vs 7.9 months with placebo in the SHARP trial 8
  • Only indicated for Child-Pugh A patients with adequate performance status 8
• Atezolizumab plus bevacizumab is now preferred first-line systemic therapy based on recent evidence 1
• Regorafenib 160 mg daily (21 days on/7 days off) is indicated for second-line therapy after sorafenib progression 9
  • Demonstrated survival benefit: median overall survival 10.6 months vs 7.8 months with placebo in RESORCE trial 9
  • Only for patients with Child-Pugh A who tolerated sorafenib ≥400 mg daily for median 7.8 months 9
• Locoregional therapies (TACE, TAE, TARE) can be performed in patients with segmental or subsegmental portal vein thrombosis and Child-Pugh A liver function 7
  • Surgery and TACE/TAE/TARE have no contraindications with subsegmental or segmental portal vein thrombosis 7
  • Only TARE should be utilized with lobar branch involvement 7
  • Main portal trunk thrombosis is a contraindication to locoregional therapy 7
• TACE plus radiotherapy yields better survival in patients with portal venous thrombosis compared to TACE alone 4
• Sorafenib plus TACE demonstrates effect in delaying tumor progression 4

Critical distinction: Performance status 1 alone should not automatically classify patients as BCLC C if they have no vascular invasion or extrahepatic spread, as this would preclude potentially effective locoregional treatments 7

Subclassification consideration: BCLC C includes heterogeneous populations with vastly different prognoses based on extent of portal vein thrombosis (subsegmental vs segmental vs lobar vs main trunk), presence of extrahepatic disease, and performance status 10, 7

BCLC Stage D (Terminal Stage)

Definition: Child-Pugh C cirrhosis OR performance status 3-4, any tumor burden 1, 2

Treatment approach:

• Best supportive care and symptomatic treatment only 1, 2, 6
• Exception: Liver transplantation should be considered for highly selected patients with Child-Pugh C but tumor burden within Milan criteria 1, 2
  • These patients should not be automatically denied transplantation based solely on poor liver synthetic function from underlying cirrhosis 1
• Expected median survival: <4 months without treatment 1

Essential Monitoring and Follow-up

• Clinical evaluation and dynamic CT or MRI every 3 months for the first 2 years, then every 6 months thereafter 5
• Response assessment should use modified RECIST criteria for HCC 5, 9
• Antiviral therapy is mandatory for HBV or HCV-related HCC to reduce postoperative decompensation risk and prevent late recurrence from second primary tumors 2, 6
• Tumor recurrence occurs in 50-60% of patients at 5 years after resection, compared to 10% after transplantation 1, 5

Key Algorithmic Decision Points

For BCLC 0-A patients:

1. Assess portal hypertension (HVPG >10 mmHg or varices/splenomegaly with platelets <100,000/μL) 1
2. If no portal hypertension + normal bilirubin + solitary tumor → Resection 1, 3
3. If portal hypertension OR decompensated cirrhosis + within Milan criteria → Transplantation 1, 2
4. If unsuitable for above → Ablation 1, 2

For BCLC C patients:

1. Assess Child-Pugh status (only Child-Pugh A eligible for active treatment) 9, 8
2. Assess extent of portal vein thrombosis 7
3. If subsegmental/segmental PVT + Child-Pugh A → Consider TACE/TARE 7
4. If lobar PVT + Child-Pugh A → Consider TARE only 7
5. If main trunk PVT OR extrahepatic disease + Child-Pugh A → Systemic therapy (atezolizumab/bevacizumab or sorafenib) 1, 8

Common pitfall: Neo-adjuvant or adjuvant therapies have not proven to improve outcomes after resection, so they should not be routinely recommended 5