What are the treatment approaches for Hepatocellular Carcinoma (HCC)?

Treatment Approaches for Hepatocellular Carcinoma (HCC)

For early-stage HCC, surgical resection is the first-line treatment for patients with solitary tumors and well-preserved liver function (Child-Pugh A), achieving 5-year survival rates of 50-68%, while liver transplantation should be prioritized for patients meeting Milan criteria who have decompensated cirrhosis. 1, 2

Treatment Algorithm Based on Liver Function and Tumor Characteristics

Non-Cirrhotic Liver

For single peripheral or central lesions in non-cirrhotic liver, surgical excision by partial hepatectomy is standard treatment. 1 The 3-year survival reaches 54% after R0 resections in non-cirrhotic patients. 1

• Multifocal disease: No standard treatment exists; percutaneous techniques, chemo-embolization, or radioactive lipiodol are options. 1
• Metastatic disease: Chemotherapy, high-dose interferon, hormone therapy, or surgical excision if feasible can be considered, though no standard treatment exists. 1

Cirrhotic Liver - Treatment Stratified by Child-Pugh Class

Child-Pugh A (Well-Compensated Cirrhosis)

Unifocal HCC (<5 cm):

• Surgical resection is recommended as first-line when feasible, particularly for patients without clinically significant portal hypertension and adequate future liver remnant (≥20-40% of total liver volume). 1, 2
• Liver transplantation and percutaneous ablation techniques are alternative options. 1
• For tumors ≤3 cm, radiofrequency ablation (RFA) or microwave ablation (MWA) provides comparable outcomes to resection with lower morbidity, shorter hospital stay, and lower costs. 2, 3

Multifocal HCC (≤3 lesions, each <5 cm):

• Surgical resection is recommended for peripheral tumors. 1
• Liver transplantation is recommended for central tumors. 1
• Percutaneous techniques are recommended for microtumors (<5 cm). 1

Multifocal HCC (>3 lesions or >5 cm):

• Transarterial chemoembolization (TACE) is the standard of care for multifocal HCC with preserved liver function without vascular invasion or extrahepatic spread. 4
• Radioactive lipiodol injections are alternative options. 1

Child-Pugh B (Moderately Decompensated Cirrhosis)

Unifocal HCC (<5 cm):

• Liver transplantation should be evaluated within formal protocols. 1
• For small lesions, percutaneous techniques are recommended. 1
• Radioactive lipiodol or chemo-embolization can be considered. 1

Multifocal HCC (≤3 lesions, each <5 cm):

• Same approach as Child-Pugh A: surgical resection for peripheral tumors, transplantation for central tumors, percutaneous techniques for microtumors. 1

Multifocal HCC (>3 lesions or >5 cm):

• Chemo-embolization or radioactive lipiodol injections. 1

Child-Pugh C (Severely Decompensated Cirrhosis)

The objective is palliation, not cure. 1

• Liver transplantation can be considered for patients within Milan criteria (solitary tumor ≤5 cm or 2-3 nodules ≤3 cm). 1, 2
• Hormone therapy or best supportive care are options for those exceeding transplant criteria. 1

Liver Transplantation Criteria

Liver transplantation offers the best long-term survival for HCC in cirrhosis. 1, 2

• Milan criteria (standard): Single tumor ≤5 cm OR 2-3 tumors, none >3 cm, with no vascular invasion. 1, 2
• UCSF criteria (expanded): Single tumor ≤6.5 cm OR 2-3 tumors, none >4.5 cm, with total tumor diameter ≤8 cm, no vascular invasion. 1
• Living donor liver transplantation achieves 1-, 3-, and 5-year survival rates of 85%, 75%, and 70%, respectively. 1, 2

Advanced/Unresectable HCC - Systemic Therapy

First-Line Treatment

Atezolizumab plus bevacizumab is the preferred first-line treatment for advanced HCC with preserved liver function, showing superiority to sorafenib in survival outcomes. 5, 4

• Lenvatinib is FDA-approved as first-line treatment for unresectable HCC, with dosing of 12 mg for patients ≥60 kg or 8 mg for patients <60 kg. 5, 6
• Lenvatinib demonstrated non-inferiority to sorafenib and can be considered if no main portal vein invasion is present. 5
• Sorafenib remains a standard option, extending survival by approximately 2.8 months. 5, 4

Second-Line Treatment

• 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 1-2 prior systemic therapies with well-preserved liver function. 5
• Ramucirumab is indicated for patients with AFP ≥400 ng/mL who were previously treated with sorafenib. 5

Important Caveats and Pitfalls

Portal hypertension is a critical contraindication to resection even in Child-Pugh A patients, as it significantly increases perioperative mortality. 1, 2 Surrogate indices include varices, ascites, and portal hypertensive gastropathy. 1

Future liver remnant must be adequate (≥20-40% of total liver volume) to prevent postoperative liver failure. 1, 2 Portal vein embolization can be used preoperatively to induce hypertrophy of the remnant liver. 1

Vascular invasion indicates aggressive tumor biology and mandates systemic therapy rather than locoregional treatment. 4

Traditional systemic chemotherapy (anthracyclines, cisplatin, 5-FU) has limited efficacy with only 10% response rate and no proven survival benefit. 5

RFA is size-dependent: optimal outcomes comparable to or better than resection are limited to tumors ≤2 cm where adequate safety margins can be achieved. 3

Follow-Up Protocol

After curative resection, perform AFP determination and liver imaging (ultrasound, CT, or MRI) every 3-6 months for at least 2 years, as curative therapy can still be offered at relapse. 2, 4

Response assessment should use modified RECIST criteria on dynamic CT or MRI. 5, 2, 4