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

BCLC Treatment Strategy for Hepatocellular Carcinoma

Overview of the BCLC Staging System

The Barcelona Clinic Liver Cancer (BCLC) staging system stratifies HCC patients into five prognostic categories (stages 0, A, B, C, and D) based on tumor burden, liver function (Child-Pugh score), portal hypertension, and performance status, with each stage having distinct treatment recommendations that prioritize curative therapies for early disease and palliative approaches for advanced stages. 1

The BCLC system integrates tumor extent, liver function, portal pressure, and clinical performance status to guide therapeutic decisions from curative interventions to palliative care 1. This staging approach has resulted in increased survival by preventing treatment failures from faulty staging and empirical decisions 2.

Stage-Specific Treatment Strategies

BCLC Stage 0 (Very Early Stage)

Characteristics:

• Single tumor <2 cm
• Child-Pugh A liver function
• Performance status 0 1

Treatment Approach:

• Hepatic resection, liver transplantation, or percutaneous local ablation are the recommended curative therapies, providing 5-year survival rates of 50-75% 2, 1
• Radiofrequency ablation (RFA) or percutaneous ethanol injection (PEI) serve as alternatives for patients unsuitable for resection 2
• RFA provides superior local control compared to PEI, particularly for tumors >2 cm 2

BCLC Stage A (Early Stage)

Characteristics:

• Single nodule ≤5 cm OR up to three nodules ≤3 cm (Milan criteria)
• Child-Pugh A-B
• Performance status 0 1

Treatment Algorithm:

1. Assess liver function and portal hypertension:

   • Measure hepatic venous pressure gradient (HVPG) and serum bilirubin 2
   • Patients with HVPG >10 mmHg combined with bilirubin >1 mg/dL have significantly increased risk of postoperative decompensation 2

2. For patients WITHOUT cirrhosis or significant portal hypertension:

   • Surgical resection is the preferred treatment as long as R0-resection can be achieved without causing liver failure 2
   • Ensure adequate future liver remnant (FLR): ≥20% for normal liver, ≥30% for chronic liver disease, ≥40% for cirrhotic liver 1

3. For patients WITH cirrhosis and preserved liver function:

   • Resection is effective and safe (postoperative mortality <5%) if dealing with a single lesion, good performance status, and NO clinically significant portal hypertension 2
   • Local ablation (RFA or PEI) is recommended for single nodules <2 cm or for patients who are not resection candidates 2
   • The number and diameter of lesions treated by RFA should not exceed five lesions and 5 cm, respectively 2

4. For patients meeting Milan criteria with decompensated cirrhosis:

   • Liver transplantation should be considered, offering 5-year disease-free and overall survival >70% 2, 1
   • Bridge therapy with TACE or RFA can be used for patients awaiting transplantation to prevent tumor progression 1

Critical Pitfall: Neo-adjuvant or adjuvant therapies are NOT recommended to improve outcomes after resection or local ablation 2. Antiviral therapy should be administered to patients with HBV or HCV-related HCC to reduce postoperative decompensation risk 1.

BCLC Stage B (Intermediate Stage)

Characteristics:

• Large/multinodular tumors
• Child-Pugh A-B
• Performance status 0 1

Treatment Approach:

Transarterial chemoembolization (TACE) is the standard of care for BCLC B, providing median survival of 16-22 months 2, 1. However, this stage encompasses substantial heterogeneity requiring individualized assessment 3.

Treatment Selection Algorithm:

1. For patients with preserved liver function and resectable disease:

   • Asian guidelines and NCCN suggest liver resection for resectable multinodular HCCs, even beyond Milan criteria 4
   • Growing evidence shows better outcomes after surgical resection compared with TACE in selected BCLC B patients 4, 5
   • Patients at BCLC B with good liver function can achieve 3-year survival of 62.7% with resection 5

2. For patients unsuitable for resection:

   • Repeated TACE treatments are advocated with clinical benefits (median survival 16-22 months) 2
   • TACE plus RFA provides better local tumor control than RFA alone 1, 3
   • Trans-arterial radioembolization (TARE) and stereotactic body radiation therapy (SBRT) can play important roles in this setting 4

3. For patients who do not respond to TACE:

   • Consider transition to systemic therapy with sorafenib or lenvatinib 2

Important Caveat: Up to one-third of BCLC B patients do not fit standard therapeutic criteria due to advanced age, significant comorbidities, or strategic tumor location 2. Better patient stratification systems are needed to select optimal TACE candidates 3.

BCLC Stage C (Advanced Stage)

Characteristics:

• Vascular invasion and/or extrahepatic spread
• Child-Pugh A-B
• Performance status 1-2 1

Treatment Approach:

First-Line Systemic Therapy:

1. Atezolizumab plus bevacizumab is the recommended first-line systemic therapy for patients with Child-Pugh A and ECOG performance status 0-1 6

   • This represents the current standard of care based on superior efficacy compared to sorafenib

2. Durvalumab plus tremelimumab is an alternative first-line combination therapy with similar indications 6

3. If combination immunotherapy cannot be applied, sorafenib or lenvatinib are alternative first-line options 6

   • Sorafenib demonstrated median OS of 10.7 months vs 7.9 months with placebo in the SHARP trial 1
   • Lenvatinib showed non-inferiority to sorafenib with median OS of 13.6 months vs 12.3 months 7

Second-Line Systemic Therapy:

• Regorafenib is indicated for patients with Child-Pugh A who previously received sorafenib, demonstrating median OS of 10.6 months vs 7.8 months with placebo 8

Locoregional Therapy Considerations:

1. For patients with portal vein invasion (PVI):

   • Assess extent of portal vein thrombosis: PV1 (segmentary), PV2 (secondary branch), PV3 (first-order branch), or PV4 (main trunk) 6
   • For PV1/PV2 with intrahepatic localized tumors and preserved liver function: TACE can be considered 6
   • TACE combined with external beam radiation therapy (EBRT) may be more effective than TACE alone for portal vein invasion 6, 3
   • Liver resection can ONLY be considered for PV1/2 extension within research settings, NOT as standard practice 6

2. EBRT can be performed for HCC with portal vein invasion and can be combined with systemic therapy 6

Critical Decision Point: Multidisciplinary tumor board discussion is essential for optimal management decisions in BCLC C patients 6. The presence of macroscopic vascular invasion or extrahepatic spread was present in 81% of patients in the RESORCE trial 8.

BCLC Stage D (End-Stage)

Characteristics:

• Any tumor burden
• Child-Pugh C
• Performance status 3-4 1

Treatment Approach:

Symptomatic treatment and best supportive care are recommended, with expected survival <3 months 2, 1. Liver transplantation may be considered in highly selected patients with tumor burden within Milan criteria despite Child-Pugh C status 1.

Key Limitations and Real-World Considerations

Important Reality Check: In daily practice, up to one-third of HCC patients do not fit recommendations drafted by international societies due to advanced age, significant comorbidities, or strategic tumor location 2. Treatment of HCC beyond guidelines is often advocated in these cases 2.

Evidence Quality Caveat: Most BCLC recommendations are based on uncontrolled studies and expert opinions rather than well-designed controlled trials 2. The use of therapeutic algorithms outside recommendations results in lower survival compared to guideline-driven approaches 2.

Geographic Variations: Asian guidelines often adopt more aggressive surgical approaches for intermediate-stage disease compared to Western guidelines 1, 4. Studies from Asian centers demonstrate that carefully selected BCLC B and even some BCLC C patients can achieve acceptable long-term survival with resection 5, 9.

Treatment Beyond BCLC Guidelines

While adherence to BCLC guidelines remains the mainstay for optimizing treatment outcomes 2, certain patient populations may benefit from treatments outside standard recommendations:

• BCLC A patients with moderate portal hypertension could still be eligible for hepatic resection if 50% survival at 5 years is perceived as cost-effective 2
• Selected BCLC B patients may benefit from surgical resection rather than TACE, particularly in centers with expertise in hepatic surgery 4, 5
• BCLC C patients with limited portal vein invasion (PV1/PV2) may be considered for combined locoregional and systemic approaches 6, 3

Multimodal Treatment: Treatment of HCC is multimodal in patients who do not reach radiological complete response with one type of treatment alone 2. However, multimodal treatments should be applied within carefully designed protocols rather than as routine practice 2.