What are the options for systemic therapy and combination therapy in a patient with BCLC (Barcelona Clinic Liver Cancer) stage B hepatocellular carcinoma (HCC), multinodular disease, preserved liver function (Child-Pugh A-B), and good performance status (ECOG (Eastern Cooperative Oncology Group) PS (Performance Status) 0)?

Systemic Therapy and Combination Therapy for BCLC Stage B HCC

First-Line Systemic Therapy Recommendations

For BCLC stage B HCC patients with preserved liver function (Child-Pugh A-B), ECOG PS 0, and multinodular disease who are not candidates for or have failed locoregional therapy, atezolizumab plus bevacizumab represents the preferred first-line systemic treatment option, with lenvatinib or sorafenib as alternatives when immunotherapy combinations are contraindicated. 1

Primary Treatment Option: Atezolizumab + Bevacizumab

• Atezolizumab plus bevacizumab is now the first-choice standard of care for advanced HCC with preserved liver function based on superior efficacy in overall survival, progression-free survival, and quality of life compared to sorafenib. 2

• This combination can be used for treating patients with unresectable HCC who have not received prior systemic therapy and do not have a high risk of upper gastrointestinal bleeding. 1

• Critical contraindication: All patients must undergo endoscopic evaluation and treatment for esophageal varices before initiating bevacizumab, as gastrointestinal bleeding occurred in 7% of patients receiving atezolizumab+bevacizumab versus 4.5% with sorafenib. 1

Alternative First-Line Options: TKI Monotherapy

• When atezolizumab+bevacizumab is not suitable, either lenvatinib or sorafenib should be used over no systemic therapy (conditional recommendation, low certainty evidence). 1

• Lenvatinib demonstrated non-inferiority to sorafenib with median OS of 13.6 versus 12.3 months (HR 0.92,95% CI 0.79-1.06), but showed superior progression-free survival (7.3 vs 3.6 months, p<0.001) and objective response rate (41% vs 12%, p<0.001) per modified RECIST criteria. 3

• Lenvatinib dosing is weight-based: 12 mg daily for patients ≥60 kg or 8 mg daily for patients <60 kg. 3

• Critical limitation: Lenvatinib has not been studied in patients with main portal vein invasion and should not be used in this population. 1

• Sorafenib (400 mg twice daily) improved median OS compared to placebo (10.7 vs 7.9 months, HR 0.68) in patients with 95-98% Child-Pugh A, with 17-18% having BCLC stage B disease. 1

Combination Therapy: TACE Plus Systemic Therapy

A paradigm shift has occurred in BCLC stage B management, where targeted therapy combined with TACE can be considered in highly selected patients with unresectable BCLC stage B HCC, Child-Pugh A liver function, and ECOG PS 0-1. 1

• The combination of TACE with tyrosine kinase inhibitors is suggested for patients with unresectable BCLC stage B HCC who have preserved liver function and good performance status. 1

• This represents a departure from traditional BCLC guidelines that recommended TACE monotherapy for all stage B patients, reflecting recognition of the heterogeneity within this population. 4

Patient Selection Algorithm for Systemic Therapy

Step 1: Assess Candidacy for Immunotherapy Combination

• If no contraindications to bevacizumab (no high-risk varices after endoscopic screening, no recent bleeding) → Atezolizumab + bevacizumab 1
• If bevacizumab contraindicated → Proceed to Step 2

Step 2: Select TKI Monotherapy Based on Patient Factors

• If main portal vein invasion present → Sorafenib (lenvatinib not studied in this population) 1
• If patient prioritizes radiologic disease progression delay and can tolerate adverse events → Lenvatinib (superior PFS: 7.3 vs 3.6 months) 1, 3
• If patient prioritizes blood pressure control over skin reactions → Sorafenib 1
• If patient has body weight <60 kg → Consider lenvatinib 8 mg daily (weight-adjusted dosing available) 3

Step 3: Consider TACE Combination in Selected BCLC B Patients

• If Child-Pugh A, ECOG PS 0-1, unresectable but limited tumor burden → TACE + TKI combination 1
• If Child-Pugh B or ECOG PS ≥2 → Systemic therapy alone 1

Adverse Event Profiles to Guide Selection

Lenvatinib-Specific Toxicities

• More serious adverse events and higher discontinuation rates compared to sorafenib, though risk of bias exists due to lack of blinding. 1
• Hypertension, proteinuria, and hypothyroidism are more common with lenvatinib. 1
• Hand-foot skin reaction less common (3% grade 3-4) compared to sorafenib (11% grade 3-4). 1

Sorafenib-Specific Toxicities

• Hand-foot skin reaction (8-11% grade 3-4), diarrhea (6-8% grade 3-4), and skin reactions more prominent. 1
• Better blood pressure control compared to lenvatinib. 1

Atezolizumab + Bevacizumab Toxicities

• Hypertension (15% grade 3-4), proteinuria, and gastrointestinal bleeding (7%) are key concerns. 1
• Mandatory variceal screening and treatment before initiation. 1

Critical Pitfalls to Avoid

• Do not use traditional systemic chemotherapy (anthracyclines, cisplatin, 5-FU) - it shows only 10% response rate with no proven survival benefit and poor tolerance due to underlying cirrhosis. 5, 2

• Do not continue TACE indefinitely in BCLC stage B patients - repeated TACE reduces treatment effect and induces liver function impairment; switching to systemic therapy before liver function deterioration may improve prognosis. 4

• Do not use lenvatinib in patients with main portal vein invasion - this population was excluded from the REFLECT trial. 1

• Do not initiate bevacizumab without endoscopic variceal evaluation and treatment - this is mandatory to reduce bleeding risk. 1

Survival Expectations

• Atezolizumab + bevacizumab: Superior to sorafenib in OS (specific median not provided in evidence but statistically significant improvement). 2
• Lenvatinib: Median OS 13.6 months (non-inferior to sorafenib). 3
• Sorafenib: Median OS 10.7-12.3 months versus 7.9 months with placebo. 1, 3
• Survival benefit with sorafenib is 2.8 months - patients valuing adverse event avoidance over this modest survival gain may reasonably decline systemic therapy. 1