What are the treatment options for hepatocellular carcinoma?

Treatment of Hepatocellular Carcinoma

Treatment of HCC must be guided by the Barcelona Clinic Liver Cancer (BCLC) staging system, which stratifies patients into five prognostic categories (0, A, B, C, D) based on tumor burden, liver function (Child-Pugh class), and performance status—this staging directly determines whether curative therapies (resection, transplantation, ablation), palliative locoregional therapy (TACE), systemic therapy, or supportive care should be offered. 1, 2

Treatment Algorithm by BCLC Stage

BCLC 0 and A (Very Early and Early Stage)

For patients with single tumors ≤5 cm or up to 3 nodules ≤3 cm (Milan criteria), Child-Pugh A-B, and performance status 0, curative therapies are the priority with 5-year survival rates of 50-75%. 3, 2

Surgical Resection

• Resection is first-line for patients with solitary tumors, well-preserved liver function (Child-Pugh A), no clinically significant portal hypertension, and adequate future liver remnant (≥40% for cirrhotic liver, ≥30% for chronic liver disease, ≥20% for normal liver). 1, 3, 2
• Achieves 5-year survival of 50-68% with perioperative mortality of 2-3% in cirrhotic patients, though recurrence rates remain high at 50-70%. 3
• Child-Pugh C patients should not undergo resection due to prohibitive risk of liver failure. 3

Liver Transplantation

• Transplantation is first-line for patients meeting Milan criteria (single tumor ≤5 cm or ≤3 nodules ≤3 cm, no vascular invasion) who have impaired liver function or clinically significant portal hypertension. 1, 3
• Offers the best long-term survival with 3-year survival up to 88% and addresses both the cancer and underlying cirrhosis. 1
• Living donor liver transplantation achieves 1-, 3-, and 5-year survival rates of 85%, 75%, and 70%, respectively. 3

Local Ablation

• Radiofrequency ablation (RFA) or microwave ablation (MWA) is recommended for tumors ≤3 cm, particularly single nodules <2 cm, or when resection is not feasible. 3, 2
• RFA provides superior local control compared to percutaneous ethanol injection (PEI), especially for tumors >2 cm. 1, 3

BCLC B (Intermediate Stage)

For patients with multinodular tumors, Child-Pugh A-B, and performance status 0, transarterial chemoembolization (TACE) is the standard of care with median survival of 16-22 months. 1, 2

• TACE involves intra-arterial injection of cytotoxic drugs (doxorubicin and/or cisplatin and/or mitomycin) followed by lipiodol and gelfoam for vessel occlusion. 1
• However, TACE may be inappropriate for patients with extensive tumor bulk, multi-nodular spread, or impaired liver function—in these cases, consider systemic therapy or clinical trials. 4
• Combination approaches such as TACE plus RFA may improve local tumor control in selected cases. 2

BCLC C (Advanced Stage)

For patients with vascular invasion and/or extrahepatic spread, Child-Pugh A-B, and performance status 1-2, systemic therapy is indicated. 2, 5

First-Line Systemic Therapy

• Atezolizumab (1200 mg IV every 3 weeks) plus bevacizumab (15 mg/kg IV every 3 weeks) is the preferred first-line treatment for unresectable or metastatic HCC with preserved liver function, showing superiority to sorafenib alone. 5, 6
• Lenvatinib is FDA-approved as first-line treatment (12 mg daily for patients ≥60 kg or 8 mg daily for patients <60 kg), demonstrating non-inferiority to sorafenib. 5, 7
• Sorafenib remains a standard option with demonstrated survival benefit of approximately 2.8 months (10.7 vs 7.9 months). 1, 5

Second-Line Systemic Therapy

• Regorafenib is recommended for patients who tolerated but progressed on sorafenib, with well-preserved liver function and good performance status. 5
• Cabozantinib can be considered for patients with progressive disease on one or two prior systemic therapies. 5
• Ramucirumab is indicated for patients with AFP ≥400 ng/mL previously treated with sorafenib. 5

BCLC D (End-Stage)

For patients with Child-Pugh C, performance status 3-4, or any tumor burden with severe hepatic decompensation, best supportive care is recommended. 1, 2

• Highly selected Child-Pugh C patients with tumors within Milan criteria may be considered for liver transplantation in specialized centers. 1, 2

Critical Decision Points and Pitfalls

Multidisciplinary Planning

Every HCC patient must be discussed by a multidisciplinary team before treatment initiation, as the treatment plan depends on cirrhosis presence, tumor extent, hepatic functional reserve, and performance status. 1

Common Pitfalls to Avoid

• Up to one-third of early-stage patients do not fit standard recommendations due to advanced age, significant comorbidities, or strategic tumor location—these patients may require palliative TACE despite early-stage disease. 1, 2
• Traditional systemic chemotherapy (anthracyclines, cisplatin, 5-FU) has only 10% response rate with no survival benefit and should not be used outside clinical trials. 1, 5
• Response assessment must use dynamic CT or MRI with modified RECIST criteria, as standard size-based RECIST is inadequate due to noncompliant cirrhotic liver and altered tumor vascularity with biologic agents. 1, 5

Bridge Therapy and Antiviral Treatment

• TACE or RFA can be used as bridge therapy for patients awaiting liver transplantation to prevent tumor progression. 2
• Antiviral therapy is essential for HBV or HCV-related HCC to reduce postoperative decompensation risk and prevent late recurrence from second primary tumors. 2

Follow-Up Protocol

Patients undergoing curative resection should be followed every 3-6 months with AFP determination and liver imaging for at least 2 years, as curative therapy can still be offered at relapse. 1, 3