For a patient with intermediate or advanced hepatocellular carcinoma (HCC), which treatment should be started first, Transarterial Chemoembolization (TACE) or Lenvatinib (Lenvatinib)?

Treatment Sequencing for Intermediate or Advanced HCC: TACE vs Lenvatinib

For intermediate-stage HCC (BCLC-B) beyond up-to-seven criteria with preserved liver function (Child-Pugh A), lenvatinib should be started first as monotherapy, while for patients within up-to-seven criteria, TACE remains the initial treatment of choice. 1, 2

Treatment Selection Algorithm

Start with Lenvatinib First When:

• Intermediate-stage HCC beyond up-to-seven criteria with large or multinodular tumors and Child-Pugh A liver function 1
• Advanced-stage HCC (BCLC-C) with preserved liver function (Child-Pugh A) and ECOG performance status 0-1 3
• Patient has no main portal vein invasion, clear bile duct invasion, or >50% liver volume tumor occupancy 3, 2
• Patient requires systemic disease control rather than local tumor control 3

The European Association for the Study of the Liver (EASL) and Asia-Pacific Primary Liver Cancer Expert Association specifically recommend lenvatinib as initial treatment for intermediate-stage HCC beyond up-to-seven criteria 1. This represents a paradigm shift from traditional TACE-first approaches for all intermediate-stage disease.

Start with TACE First When:

• Intermediate-stage HCC within up-to-seven criteria with preserved liver function 1
• Patient has localized disease amenable to selective catheterization 1
• No contraindications to TACE exist (decompensated cirrhosis, complete portal vein occlusion, obstructive jaundice) 1

Combination Therapy Considerations

TACE plus lenvatinib combination therapy demonstrated superior outcomes compared to lenvatinib monotherapy in advanced HCC, with median overall survival of 17.8 months versus 11.5 months (HR 0.45, P<0.001) in the phase III LAUNCH trial 4. However, this approach requires careful patient selection:

• Ideal candidates: BCLC-B beyond up-to-seven criteria, Child-Pugh A, no main portal vein invasion 1
• Protocol: Initiate lenvatinib first (within 3 days), followed by TACE one day after lenvatinib initiation 4
• Critical caveat: British Society of Gastroenterology guidelines state TACE should not be combined with multikinase inhibitors outside clinical trials, though this conflicts with Asian practice patterns where combination therapy has been adopted 1

The combination approach showed significantly improved progression-free survival (10.6 vs 6.4 months, HR 0.43, P<0.001) and objective response rate (54.1% vs 25.0%, P<0.001) compared to lenvatinib alone 4.

Lenvatinib Dosing and Efficacy

Weight-based dosing is mandatory: 12 mg daily for patients ≥60 kg; 8 mg daily for patients <60 kg 2, 5

Lenvatinib demonstrated non-inferiority to sorafenib in overall survival (13.6 vs 12.3 months, HR 0.92) but showed superior secondary endpoints 3, 2:

• Progression-free survival: 7.4 vs 3.7 months 2
• Objective response rate: 24.1% vs 9.2% (P<0.001) 3, 2
• Time to progression: 8.9 vs 3.7 months 2

Critical Contraindications to Lenvatinib

Absolute contraindications include 1, 2:

• Decompensated cirrhosis (Child-Pugh B or C)
• Main portal vein invasion (lenvatinib not studied in this population)

• 50% liver volume tumor occupancy

• ECOG performance status ≥2
• Advanced kidney dysfunction

Adverse Event Management

Hypertension (42% of patients) and diarrhea (39%) are the most common adverse events requiring proactive monitoring 3, 2, 6. In clinical trials, 82.4% of patients required treatment interruptions and 67.8% required dose reductions 6.

Key management principles 7:

• Grade 1-2 adverse events generally do not require dose interruption
• Grade 2-3 persistent/intolerable adverse events require interruption until improvement to grade 0-1, then resume at same or lower dose
• Maintain lenvatinib at the highest tolerable dose to preserve efficacy
• Monitor blood pressure regularly and manage hypertension aggressively 6

Common Pitfalls to Avoid

• Do not perform extensive TACE with massive chemo-embolic materials for more than half the liver, as this significantly increases post-procedural liver failure risk 1
• Do not continue TACE indefinitely without response assessment; switch to systemic therapy after 2-3 failed sessions to preserve liver function 1
• Do not use lenvatinib in Child-Pugh B or C patients due to lack of safety data 1, 2
• Do not use lenvatinib in patients with main portal vein invasion, as it was excluded from the pivotal REFLECT trial 3

Second-Line Treatment After Lenvatinib

Following lenvatinib progression, second-line options include 3:

• Cabozantinib for patients with preserved liver function and ECOG PS 0-1
• Regorafenib (if patient previously tolerated sorafenib)
• Ramucirumab (for patients with AFP ≥400 ng/mL)
• Atezolizumab plus bevacizumab (if not used first-line)

Important note: Second-line therapies following lenvatinib have not been extensively studied, and treatment selection should be based on preserved liver function and performance status 3.