What are the NCCN guideline recommendations for treating hepatocellular carcinoma based on disease stage and liver function?

NCCN Guidelines for Hepatocellular Carcinoma Treatment

Treatment Selection Framework

The NCCN guideline uses a resectability-based algorithm rather than a single staging system, requiring multidisciplinary evaluation of tumor characteristics, liver reserve, and comorbidities to determine whether disease is resectable, unresectable, or metastatic. 1

Initial Assessment Parameters

Before treatment selection, evaluate:

• Liver function: Child-Pugh classification (A, B, or C) 1
• Portal hypertension: Presence and severity via hepatic venous pressure gradient or platelet count 2
• Tumor characteristics: Number, size, location, vascular invasion, extrahepatic spread 1
• Performance status: ECOG score 1
• Future liver remnant: Minimum 40% for cirrhotic liver 3

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Treatment Algorithm by Resectability Status

Resectable Disease

Surgical resection is first-line treatment when:

• Single tumor of any size 4, 2
• Child-Pugh class A liver function 4, 2
• No clinically significant portal hypertension 1
• Adequate future liver remnant (≥40% for cirrhotic liver) 3
• No macroscopic vascular invasion or extrahepatic spread 3

Expected perioperative mortality: 2-3% 2

For small tumors (<2-3 cm):

• Radiofrequency ablation (RFA) is an alternative when surgery is not feasible due to tumor location, portal hypertension, or comorbidities 1, 4
• RFA should not exceed 5 lesions or 5 cm diameter 1

Unresectable Disease Meeting Transplant Criteria

Liver transplantation is first-line when:

• Tumor meets Milan criteria (single ≤5 cm OR up to 3 tumors each ≤3 cm) 1, 4, 2
• No vascular invasion or extrahepatic spread 4
• Child-Pugh class C liver function 1
• Age typically ≤65 years 1

3-year survival after transplant: up to 88% 4, 2

Downstaging is permitted: Patients initially exceeding Milan criteria who achieve successful downstaging with locoregional therapy can be reconsidered for transplantation 1

Bridging therapy during wait time >6 months: Consider resection, RFA, or TACE to prevent tumor progression 1

Unresectable Disease Not Meeting Transplant Criteria

Transarterial chemoembolization (TACE) is standard when:

• Child-Pugh class A or B7 without ascites 4
• Performance status ECOG <2 4
• Multinodular asymptomatic tumors 1
• No macroscopic vascular invasion 1
• No extrahepatic spread 1
• Limited tumor burden (solitary <7 cm or <4 tumors) 4

TACE with doxorubicin-eluting beads is preferred to minimize systemic chemotherapy side effects 1

Advanced/Metastatic Disease

Atezolizumab plus bevacizumab is now first-line systemic therapy for advanced HCC with preserved liver function, based on superior efficacy over sorafenib 4, 2

Sorafenib remains an alternative first-line option:

• For BCLC stage C (advanced HCC with vascular invasion or extrahepatic spread) 1
• For intermediate stage (BCLC B) progressing after TACE 1
• Median survival benefit: 2.8 months vs placebo 1, 2

Second-line options after progression/intolerance:

• Best supportive care 1
• Clinical trial enrollment 1

Terminal Stage Disease

Child-Pugh class C with poor performance status: Best supportive care only 1, 2

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Critical Contraindications

Traditional systemic chemotherapy (anthracyclines, cisplatin, 5-FU) is NOT recommended:

• Only 10% response rate 1, 4, 2
• No proven survival benefit 1, 4, 2
• Poor tolerance due to underlying cirrhosis 4

Other ineffective therapies to avoid:

• Tamoxifen 1
• Anti-androgen agents 1
• Somatostatin analogues 1
• Immunotherapy (non-checkpoint inhibitor types) 1

Neo-adjuvant or adjuvant therapies are not recommended to improve outcomes after resection or ablation 1, 2

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Surveillance and Follow-Up

After curative treatment (resection/ablation):

• Dynamic CT or MRI every 3 months for first 2 years 1, 4, 2
• Then every 6 months thereafter 1
• Serum AFP may be helpful but should not be sole determinant 1
• Recurrence rates: 50-60% at 5 years 4, 3

During palliative treatment (TACE/systemic therapy):

• Clinical evaluation for liver decompensation 1
• Dynamic CT or MRI every 2 months to guide therapy decisions 1
• Use modified RECIST criteria for response assessment 1, 2

On transplant waiting list:

• Ongoing imaging surveillance to detect tumor progression 2

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Special Considerations

Radioembolization (Y-90 spheres): May be competitive with sorafenib or TACE in select patients with prior TACE failure, excellent liver function, macrovascular invasion, and absence of extrahepatic disease 1

External beam radiotherapy: Limited to palliative pain control for bone metastases 1

Combination TACE plus sorafenib: Cannot be recommended outside clinical trials 1