Overview of Hepatocellular Carcinoma Treatment

Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and typically develops in the setting of chronic liver disease or cirrhosis. The treatment landscape has evolved dramatically with multiple FDA-approved systemic therapies now available. Early-stage disease is managed with curative-intent approaches including resection, liver transplantation, or ablation. For advanced HCC, atezolizumab plus bevacizumab has become the preferred first-line regimen based on superior survival compared to sorafenib. Multiple tyrosine kinase inhibitors (TKIs) are available for first-line and subsequent lines of therapy.

Treatment Approach by Stage

Very Early/Early Stage (BCLC 0-A)

  • Resection for preserved liver function, solitary tumor, no portal hypertension
  • Liver transplantation for Milan criteria (single ≀5 cm or 2-3 tumors ≀3 cm)
  • Ablation (RFA, MWA) for non-surgical candidates with preserved liver function

Intermediate Stage (BCLC B)

  • Transarterial chemoembolization (TACE) or radioembolization (TARE)
  • Consider systemic therapy if TACE-refractory
  • Combination locoregional + systemic therapy emerging

Advanced Stage (BCLC C) - First-line

  • Atezolizumab + bevacizumab (preferred for Child-Pugh A without contraindications)
  • Durvalumab + tremelimumab (alternative immunotherapy combination)
  • Sorafenib or lenvatinib (TKI monotherapy alternatives)

Advanced Stage - Subsequent Lines

  • After TKI: Regorafenib, cabozantinib, ramucirumab (if AFP β‰₯400)
  • After immunotherapy: TKI options (sorafenib, lenvatinib, cabozantinib)
  • Pembrolizumab for MSI-H/dMMR (rare in HCC)

Epidemiology & Impact

Hepatocellular carcinoma accounts for approximately 80% of primary liver cancers, with approximately 43,590 new cases and 30,520 deaths expected in 2025. NASH/MASLD is now the fastest-growing risk factor, replacing HCV. Other risks include HBV, alcoholic cirrhosis, and aflatoxin. Approximately 80% develops in cirrhosis. Five-year survival is approximately 23%, limited by treating both cancer and underlying liver disease.

Molecular Biology & Biomarkers

HCC has two major molecular classes: proliferation (HBV-associated, TP53 mutations, aggressive) and non-proliferation (alcohol/HCV-associated, CTNNB1 mutations, better prognosis). VEGF pathway activation drives efficacy of anti-angiogenics. No single targetable oncogene dominates most HCCs, making biomarker-directed therapy challenging. AFP remains an important diagnostic and prognostic marker.

Evolving Treatment Landscape

Atezolizumab-bevacizumab (IMbrave150) is the first-line standard for unresectable HCC. Tremelimumab-durvalumab (HIMALAYA STRIDE) is an alternative. TKIs remain important across lines. Curative options for early-stage include resection, transplant (Milan criteria), and ablation. TACE is standard for intermediate-stage.

Approved HCC Therapies

Tecentriq + Avastin
atezolizumab + bevacizumab
FDA Approved 2020 First-line
Approved Indications (US/FDA)
Treatment of patients with unresectable or metastatic hepatocellular carcinoma who have not received prior systemic therapy.
Dosing Schedule
Atezolizumab 1200 mg IV + bevacizumab 15 mg/kg IV on the same day every 3 weeks until disease progression or unacceptable toxicity. Requires endoscopy to rule out esophageal varices before starting bevacizumab.
Clinical Evidence
IMbrave150 trial: Atezolizumab + bevacizumab significantly improved median OS (19.2 vs 13.4 months, HR 0.66) and PFS (6.9 vs 4.3 months) vs sorafenib in treatment-naive advanced HCC. ORR was 30% vs 11%. Quality of life favored combination. This established atezo-bev as new standard first-line therapy. Main toxicities include hypertension, bleeding, proteinuria, and immune-related adverse events. Contraindicated with severe bleeding history or uncontrolled varices.
Manufacturers
Genentech
Approval Year
2020
Pivotal Trial
NCT03434379 β†—
Key Publication
Finn et al. NEJM 2020 β†—
Nexavar
sorafenib
FDA Approved 2007 First-line/Later
Approved Indications (US/FDA)
Treatment of unresectable hepatocellular carcinoma.
Dosing Schedule
400 mg orally twice daily on empty stomach (1 hour before or 2 hours after meals). Continue until disease progression or unacceptable toxicity. Dose reductions to 400 mg once daily or 400 mg every other day for toxicity management.
Clinical Evidence
SHARP trial: Sorafenib improved median OS from 7.9 to 10.7 months (HR 0.69) vs placebo in advanced HCC with preserved liver function. This was first systemic therapy to show survival benefit in HCC and established sorafenib as standard of care for over a decade. Sorafenib is a multi-kinase inhibitor targeting VEGFR, PDGFR, RAF kinases. Main adverse events include hand-foot skin reaction, diarrhea, hypertension, and fatigue. Still used as alternative first-line or after immunotherapy failure.
Manufacturer
Bayer
Approval Year
2007
Pivotal Trial
NCT00105443 β†—
Key Publication
Llovet et al. NEJM 2008 β†—
Lenvima
lenvatinib
FDA Approved 2018 First-line
Approved Indications (US/FDA)
First-line treatment of patients with unresectable hepatocellular carcinoma.
Dosing Schedule
12 mg (β‰₯60 kg body weight) or 8 mg (<60 kg) orally once daily until disease progression or unacceptable toxicity. Dose reductions to 8 mg or 4 mg daily for toxicity management.
Clinical Evidence
REFLECT trial: Lenvatinib demonstrated non-inferiority to sorafenib in first-line advanced HCC (median OS 13.6 vs 12.3 months). PFS and ORR significantly favored lenvatinib (7.3 vs 3.6 months; 19% vs 7%). Lenvatinib is a multi-kinase inhibitor targeting VEGFR1-3, FGFR1-4, PDGFR-Ξ±, RET, KIT. Main adverse events include hypertension, fatigue, decreased appetite, diarrhea, and hand-foot syndrome. Alternative to atezo-bev when immunotherapy contraindicated.
Manufacturer
Eisai
Approval Year
2018
Pivotal Trial
NCT01761266 β†—
Key Publication
Kudo et al. Lancet 2018 β†—
Cabometyx
cabozantinib
FDA Approved 2019 Second-line
Approved Indications (US/FDA)
Treatment of patients with hepatocellular carcinoma who have been previously treated with sorafenib.
Dosing Schedule
60 mg orally once daily on empty stomach (do not eat for at least 2 hours before and 1 hour after). Continue until disease progression or unacceptable toxicity. Dose reductions to 40 mg, then 20 mg for toxicity.
Clinical Evidence
CELESTIAL trial: Cabozantinib improved median OS (10.2 vs 8.0 months, HR 0.76) and PFS (5.2 vs 1.9 months) vs placebo in previously treated HCC. Cabozantinib inhibits VEGFR2, MET, AXL, and other RTKs. It's the most broad-spectrum TKI in HCC with activity after prior sorafenib or immunotherapy. Main adverse events include hand-foot syndrome, hypertension, diarrhea, decreased appetite, and fatigue. Requires careful dose management.
Manufacturer
Exelixis
Approval Year
2019
Pivotal Trial
NCT01908426 β†—
Key Publication
Abou-Alfa et al. NEJM 2018 β†—