What is the recommended management approach for a patient with hepatocellular carcinoma (HCC) classified as Barcelona Clinic Liver Cancer (BCLC) stage C?

Management of BCLC Stage C Hepatocellular Carcinoma

For BCLC stage C HCC with well-preserved liver function (Child-Pugh A) and ECOG performance status 0-1, systemic therapy with atezolizumab plus bevacizumab is the preferred first-line treatment, with lenvatinib or sorafenib as alternative options. 1

First-Line Systemic Therapy

Atezolizumab plus bevacizumab is the preferred first-line systemic therapy for advanced HCC with preserved liver function, demonstrating superiority to sorafenib in survival outcomes. 1 This represents the current standard of care based on the most recent high-quality evidence.

Alternative first-line options include:

• Lenvatinib (12 mg for body weight ≥60 kg or 8 mg for <60 kg once daily) showed non-inferiority to sorafenib with median OS of 13.6 months versus 12.3 months, and is approved for patients with ECOG PS 0-1 without main portal vein invasion. 2, 3
• Sorafenib (400 mg twice daily) remains a standard option, providing median survival of 10.7 months versus 7.9 months with placebo (HR 0.69), particularly for patients with well-preserved liver function (Child-Pugh A). 2

Second-Line Systemic Therapy Options

After progression on first-line therapy, the following options are available for patients with Child-Pugh A and ECOG PS 0-1:

• Regorafenib is standard for patients who tolerated sorafenib but progressed, with ESMO-MCBS score of 4. 2
• Cabozantinib can be considered after one or two prior systemic therapies, with ESMO-MCBS score of 3. 2
• Ramucirumab is an option for patients with baseline AFP ≥400 ng/mL. 2
• Nivolumab may be considered for patients intolerant to or progressing on approved tyrosine kinase inhibitors, though definitive recommendations await randomized trial results. 2

Locoregional Therapy Considerations for Selected BCLC C Patients

BCLC stage C encompasses substantial heterogeneity, and locoregional therapies may be appropriate for carefully selected patients:

For Patients with Macrovascular Invasion (MVI) Without Extrahepatic Spread:

• TACE plus radiotherapy can be considered as first-line treatment for patients with MVI, particularly those with excellent liver function and no extrahepatic disease. 2 Asian studies demonstrate median survival of 10.7 months with this approach, with better outcomes in selected subgroups. 4
• Selective internal radiotherapy (SIRT) with Y-90 may be competitive with sorafenib or TACE in patients with prior TACE failure, excellent liver function, macrovascular invasion, and absence of extrahepatic disease. 2
• Hepatic arterial infusion chemotherapy (HAIC) has shown benefit in some Asian studies for advanced non-metastatic HCC with MVI. 2

For Patients with Multinodular Disease Without MVI or Extrahepatic Spread:

• TACE is recommended for patients with excellent liver function and multinodular asymptomatic tumors without macroscopic vascular invasion or extrahepatic spread, even if technically classified as BCLC C. 2
• TACE with drug-eluting beads is preferred to minimize systemic side effects. 2

Critical Treatment Selection Criteria

Child-Pugh classification is the primary determinant of treatment eligibility:

• Child-Pugh A patients are candidates for systemic therapy or carefully selected locoregional approaches. 2, 1
• Child-Pugh B patients should be considered only for carefully selected systemic therapy or clinical trials. 1
• Child-Pugh C patients should receive best supportive care only, as they have poor prognosis with median survival under 6 months. 2, 1, 5

Performance status must be assessed:

• ECOG PS 0-1 is required for most systemic therapies. 2
• ECOG PS 2 patients have limited treatment options and worse outcomes. 6

Treatment Combinations and Sequences

TACE plus sorafenib cannot be recommended outside clinical trials based on current evidence. 2, 5

For patients progressing on or intolerant to first-line systemic therapy, best supportive care or enrollment in clinical trials is recommended if second-line options are not available or appropriate. 2

Response Assessment and Monitoring

Dynamic CT or MRI using modified RECIST criteria should be performed every 2 months to evaluate tumor response and guide therapy decisions. 2, 5

Clinical evaluation for liver decompensation must accompany imaging assessments, as deteriorating liver function may necessitate treatment discontinuation or transition to supportive care. 2, 5

Important Caveats

Systemic chemotherapy is not recommended for HCC management, as it shows low objective response rates (<10%) without proven survival benefit and is poorly tolerated due to underlying cirrhosis. 5 The exception is FOLFOX, which may be used in selected Asian patients when tyrosine kinase inhibitors are unavailable, though this has low-level evidence. 2

Adjuvant therapy with atezolizumab plus bevacizumab after resection improves recurrence-free survival, though longer-term follow-up is required. 2

Real-world practice often deviates from strict BCLC guidelines, particularly in Asian centers where multidisciplinary teams frequently employ locoregional therapies for selected BCLC C patients with favorable characteristics. 6, 7 This reflects the substantial heterogeneity within BCLC C and the need for individualized assessment of tumor burden, liver function, and performance status. 7, 8