What are the chemotherapy options for advanced hepatocellular carcinoma (HCC)?

Chemotherapy Options for Advanced Hepatocellular Carcinoma (HCC)

For patients with advanced hepatocellular carcinoma, sorafenib has been the standard first-line systemic therapy, but newer options including lenvatinib, regorafenib, cabozantinib, and ramucirumab (for AFP ≥400 ng/mL) are now available, with atezolizumab plus bevacizumab currently being the preferred first-line regimen due to superior survival outcomes. 1, 2

First-Line Systemic Therapy Options

• Atezolizumab plus bevacizumab is the current preferred first-line treatment for advanced HCC with preserved liver function (Child-Pugh A), showing superiority to sorafenib alone in survival outcomes 2

• Lenvatinib (12 mg for patients ≥60 kg or 8 mg for patients <60 kg) is FDA-approved as first-line treatment for unresectable HCC, having shown non-inferiority to sorafenib 1, 3

• Sorafenib remains a standard option for patients with advanced HCC (BCLC stage C) and well-preserved liver function (Child-Pugh A), with demonstrated survival benefit of approximately 2.8 months 1

• First-line therapy selection should be based on:

  • Liver function (Child-Pugh score A preferred) 1
  • Presence of vascular invasion (lenvatinib not recommended with main portal vein invasion) 1
  • Tumor burden (lenvatinib not recommended when tumor occupies >50% of liver volume) 1

Second-Line Systemic Therapy Options

• Regorafenib is recommended for patients who have tolerated but progressed on sorafenib, with well-preserved liver function (Child-Pugh A) and good performance status (ECOG 0-1) 1

• Cabozantinib can be considered for patients who had progressive disease on one or two prior systemic therapies with well-preserved liver function and good performance status 1

• Ramucirumab is indicated as a single agent for HCC patients with alpha-fetoprotein (AFP) ≥400 ng/mL who have been previously treated with sorafenib 1, 4

• Immunotherapy options (nivolumab, pembrolizumab) can be considered in patients who are intolerant to, or have progressed under, approved tyrosine kinase inhibitors 1

Considerations for Systemic Therapy

• Traditional systemic chemotherapy containing anthracyclines, cisplatin, and 5-FU has shown limited efficacy with only about 10% response rate and no proven survival benefit 1

• Hepatic arterial infusion chemotherapy (HAIC) may be considered in select cases, particularly in Asian countries, as it provides direct drug delivery to tumor-feeding vessels while minimizing systemic toxicities 5, 6

• Treatment selection should consider:

  • Hepatic functional reserve (Child-Pugh score) 1
  • Performance status 1
  • Extent of disease and presence of extrahepatic spread 1
  • Prior treatments received 1, 2

Treatment Algorithm for Advanced HCC

1. First-line therapy:

   • Atezolizumab plus bevacizumab (if no contraindications) 2
   • Lenvatinib (if no main portal vein invasion) 1, 3
   • Sorafenib (if other options contraindicated) 1

2. Second-line therapy (after progression on first-line):

   • After sorafenib: Regorafenib (if sorafenib was tolerated) 1
   • After any first-line: Cabozantinib 1
   • If AFP ≥400 ng/mL: Ramucirumab 1, 4
   • Consider immunotherapy options 1

3. For patients with poor liver function (Child-Pugh B/C):

   • Best supportive care is recommended for Child-Pugh C patients 1
   • Clinical trials or carefully selected systemic therapy for Child-Pugh B 1

Important Caveats and Considerations

• Most clinical trials for systemic therapies in HCC have enrolled only patients with Child-Pugh A liver function, limiting evidence for those with more advanced cirrhosis 2

• Response assessment should be based on dynamic CT or MRI studies using modified RECIST criteria, which accounts for tumor necrosis rather than just size reduction 1

• Pharmacogenetic factors may influence treatment response and toxicity profiles, contributing to inter-individual heterogeneity in therapy outcomes 7

• Combination approaches including locoregional therapies (TACE, radioembolization) with systemic agents are being investigated but are not yet standard of care outside clinical trials 1, 8