How should hepatocellular carcinoma be treated based on tumor stage, liver functional reserve, and performance status?

Treatment of Hepatocellular Carcinoma

Treatment of hepatocellular carcinoma must be guided by the Barcelona Clinic Liver Cancer (BCLC) staging system, which integrates tumor burden, liver function (Child-Pugh score), and performance status to determine the optimal therapeutic approach ranging from curative resection or transplantation in early stages to systemic therapy with atezolizumab plus bevacizumab in advanced disease. 1, 2

Staging Assessment Required Before Treatment Selection

Before initiating any treatment, you must assess three critical domains:

• Tumor extent: Number and size of nodules, vascular invasion, extrahepatic spread using contrast-enhanced MRI or CT 1
• Liver function: Child-Pugh classification (bilirubin, albumin, ascites, prothrombin time, encephalopathy) 1
• Portal hypertension indicators: Esophageal varices and/or platelet count <100,000/μl suggest clinically significant portal hypertension 1
• Performance status: ECOG 0-4 scale determines treatment tolerance 1
• Chest CT and bone scan: Required in advanced disease to detect metastases 1

Treatment Algorithm by BCLC Stage

Very Early Stage (BCLC 0) and Early Stage (BCLC A)

For single tumors <2 cm:

• Radiofrequency ablation (RFA) is the first-line curative treatment, offering similar outcomes to resection with lower morbidity 3, 4
• Percutaneous ethanol injection is an alternative when RFA is not feasible 1

For single tumors 2-3 cm:

• RFA is preferred when surgery is not feasible due to tumor location, portal hypertension, or comorbidities 3, 4
• Surgical resection is recommended if Child-Pugh A, no portal hypertension, and adequate liver remnant (≥40% for cirrhotic liver) 1, 4

For single tumors 3-5 cm or up to 3 nodules ≤3 cm:

• Surgical resection is first-line in patients with Child-Pugh A, no clinically significant portal hypertension, and good performance status 1, 4
• Liver transplantation should be considered for patients meeting Milan criteria who are unsuitable for resection, offering 3-year survival up to 88% 3, 4
• Local ablation (RFA/microwave) is an alternative when resection is contraindicated 1, 4

Critical contraindication: Resection is unsafe with clinically important portal hypertension (hepatic-venous pressure gradient >10 mmHg) due to postoperative liver failure risk 1

Intermediate Stage (BCLC B)

Transarterial chemoembolization (TACE) is the standard of care for multinodular HCC in patients with:

• Child-Pugh A or B7 without ascites 4
• Performance status ECOG <2 4
• No vascular invasion or extrahepatic spread 1, 2
• Limited tumor burden (solitary nodule <7 cm or fewer than 4 tumors) 4

TACE is absolutely contraindicated in Child-Pugh C patients due to high risk of precipitating acute liver failure 2

Advanced Stage (BCLC C)

For patients with vascular invasion and/or extrahepatic spread:

First-line systemic therapy:

• Atezolizumab 1200 mg IV plus bevacizumab 15 mg/kg IV every 3 weeks is now the first-choice standard of care, demonstrating superior overall survival (median not reached vs 13.2 months with sorafenib, HR 0.58, p=0.0006) 4, 5
• This combination is only appropriate for Child-Pugh A patients with ECOG 0-1 5
• Critical exclusions: Variceal bleeding within 6 months, untreated/incompletely treated varices, moderate-severe ascites, hepatic encephalopathy, or autoimmune disease 5

Alternative first-line options when atezolizumab/bevacizumab is contraindicated:

• Lenvatinib: 12 mg daily for patients ≥60 kg or 8 mg daily for patients <60 kg, only for Child-Pugh A 3
• Sorafenib: 400 mg orally twice daily, validated for Child-Pugh A-B, showing 2.8-month survival benefit over placebo 3, 2

Both sorafenib and lenvatinib pivotal trials specifically excluded Child-Pugh B or C patients, and systemic therapy is poorly tolerated in decompensated cirrhosis due to unpredictable pharmacokinetics 2

Terminal Stage (BCLC D)

Best supportive care is recommended for patients with:

• Child-Pugh C cirrhosis (CTP score ≥10) 2
• ECOG performance status 3-4 1
• Expected survival <4 months without treatment 1, 2

Exception: If tumor burden is within Milan criteria despite Child-Pugh C status, liver transplantation should still be considered rather than classifying as terminal stage 1, 2

Focus on symptom management including pain control, ascites management, variceal bleeding prevention, and nutritional support 2

Critical Pitfalls to Avoid

Never use traditional systemic chemotherapy (anthracyclines, cisplatin, 5-FU) for HCC—it shows only 10% response rate with no proven survival benefit and poor tolerance due to underlying cirrhosis 3, 4

Do not perform TACE in Child-Pugh C patients—this precipitates acute liver failure through post-embolization syndrome 2

Do not use systemic therapy in Child-Pugh B or C patients—sorafenib and lenvatinib are only approved for Child-Pugh A, and trials excluded decompensated patients 2

Assess for varices before bevacizumab—patients with untreated varices or bleeding within 6 months are excluded from atezolizumab/bevacizumab therapy 5

Special Considerations

Antiviral therapy is essential for HBV or HCV-related HCC to reduce postoperative decompensation risk and prevent late recurrence 2

Neoadjuvant locoregional therapy should be considered for transplant-listed patients to reduce waiting list dropout from disease progression 2

Surveillance post-treatment with dynamic CT or MRI every 3-6 months for at least 2 years is mandatory, as recurrence rates reach 50-60% at 5 years 4

Expected Survival by Stage

• BCLC 0 and A: Median survival >36 months without therapy; 5-year survival 50-75% with curative treatment 1, 2
• BCLC B: Median survival 16 months without therapy 1
• BCLC C: Median survival 4-8 months without therapy; improved with systemic therapy 1
• BCLC D: Median survival <4 months; <3 months with Child-Pugh C 1, 2