What is the recommended treatment approach for a patient diagnosed with Hepatocellular Carcinoma (HCC)?

Treatment Approach for Hepatocellular Carcinoma

Treatment of HCC must be guided by the Barcelona Clinic Liver Cancer (BCLC) staging system, which stratifies patients into curative versus palliative treatment pathways based on tumor burden, liver function, and performance status. 1

Staging Framework

The BCLC staging system is the essential first step that determines all subsequent treatment decisions 1:

• BCLC Stage 0 and A (Early): Candidates for curative therapies with 5-year survival of 50-75% 2
• BCLC Stage B (Intermediate): Candidates for locoregional palliative therapy 1
• BCLC Stage C (Advanced): Candidates for systemic therapy 1
• BCLC Stage D (End-stage): Best supportive care only 1

Staging must include assessment of tumor extent via dynamic CT or MRI, liver function via Child-Pugh classification, portal hypertension status, and performance status 1, 3. For transplant candidates, add chest CT and bone scintigraphy 3.

Early Stage Disease (BCLC 0 and A): Curative Intent

Surgical Resection

Resection is the definitive first-line treatment for patients without cirrhosis or with compensated cirrhosis (Child-Pugh A, no portal hypertension, adequate future liver remnant ≥20-40%). 4, 2

• For non-cirrhotic patients: Resection is recommended as long as R0-resection can be achieved without causing postoperative liver failure 1
• For cirrhotic patients: Resection is safe (postoperative mortality <5%) only when dealing with a single lesion, good performance status, and no clinically significant portal hypertension 1
• Critical pitfall: Portal hypertension is an absolute contraindication to resection in cirrhotic patients, as it dramatically increases perioperative mortality 1

Radiofrequency Ablation (RFA)

RFA is the preferred ablative technique and serves as an alternative to resection for single nodules <2 cm or for early-stage patients who are not surgical candidates. 1

• RFA provides superior local control compared to percutaneous ethanol injection (PEI), especially for tumors >2 cm 1
• The number of lesions should not exceed five, and maximum diameter should not exceed 5 cm 1
• For solitary tumors <2 cm, RFA is considered first-line curative treatment 4

Liver Transplantation

Transplantation should be considered for patients with solitary lesions <5 cm or three nodules <3 cm who are not suitable for resection, offering 3-year survival up to 88%. 1, 4

• Patients must meet Milan criteria (single lesion <5 cm or up to 3 nodules <3 cm) 3, 2
• 5-year survival exceeds 75% in appropriate candidates 3
• If waiting time exceeds 6 months, bridge with resection, RFA, or TACE to prevent tumor progression 1

Adjuvant Therapy

Neo-adjuvant or adjuvant therapies are NOT recommended following resection or ablation, as they do not improve outcomes. 1

Intermediate Stage Disease (BCLC B): Locoregional Therapy

Transarterial Chemoembolization (TACE)

TACE is the standard of care for intermediate-stage HCC in patients with preserved liver function, multinodular asymptomatic tumors, and no macroscopic vascular invasion or extrahepatic spread. 1, 4

• TACE with doxorubicin-eluting beads is recommended to minimize systemic chemotherapy side effects 1
• TACE is appropriate for patients with excellent liver function and limited tumor burden without vascular invasion 2
• Critical contraindication: Vascular invasion indicates aggressive biology requiring systemic therapy instead of TACE 2
• Combination of TACE with sorafenib cannot be recommended outside clinical trials 1

Radioembolization

Y-90 radioembolization may be competitive with TACE or sorafenib in specific subsets: prior TACE failure, excellent liver function, macrovascular invasion without extrahepatic disease 1

Advanced Stage Disease (BCLC C): Systemic Therapy

First-Line Systemic Therapy

For advanced HCC with preserved liver function, atezolizumab plus bevacizumab is the preferred first-line immune checkpoint inhibitor-based regimen. 3, 2

Lenvatinib is recommended as first-line treatment for unresectable HCC, with dosing of 12 mg daily for patients ≥60 kg or 8 mg daily for patients <60 kg. 4, 5

• Sorafenib remains a validated alternative first-line option, showing survival benefit of approximately 2.8 months over placebo 4, 2
• Lenvatinib is FDA-approved for first-line treatment of unresectable HCC 5
• Take lenvatinib once daily with or without food at the same time each day; if a dose is missed and cannot be taken within 12 hours, skip that dose 5

Second-Line Systemic Therapy

For patients who progress on or are intolerant to first-line therapy, best supportive care is preferred or enrollment in clinical trials 1

Therapies to AVOID

Traditional systemic chemotherapy, tamoxifen, immunotherapy (non-checkpoint inhibitor), anti-androgens, and somatostatin analogues are NOT recommended for HCC management, showing only 10% response rates with no proven survival benefit and poor tolerance. 1, 4

End-Stage Disease (BCLC D): Supportive Care

For patients with heavily impaired liver function (Child-Pugh C) or poor performance status due to tumor involvement, only symptomatic treatment is indicated. 1

• External beam radiotherapy can control pain from bone metastases 1

Response Assessment and Follow-Up

Imaging Surveillance

Response assessment must be based on dynamic CT or MRI using modified RECIST (mRECIST) criteria, which measure viable tumor (arterial enhancement with washout) rather than total tumor size. 1, 3, 2

• Standard RECIST criteria are inadequate for HCC as they were designed for cytotoxic agents 1
• Viable tumor is defined as contrast uptake in arterial phase with washout in portal venous or delayed phases 1

Post-Curative Treatment Surveillance

After curative resection or ablation, perform AFP and dynamic liver imaging every 3 months for the first 2 years, then every 6 months thereafter. 1, 3, 2

• Early detection of recurrence allows for repeat curative therapy 3, 2
• Any deterioration in liver function in cirrhotic patients should raise suspicion for HCC recurrence 3

Advanced Disease Surveillance

Patients on TACE or systemic therapy should be evaluated clinically for liver decompensation and by dynamic CT or MRI every 2 months to guide treatment decisions 1

Critical Diagnostic Considerations

A hypervascular liver mass >2 cm on imaging combined with AFP >400 ng/mL in a cirrhotic patient is diagnostic without requiring biopsy. 2

• For nodules >2 cm, a single dynamic imaging study showing typical HCC features (arterial hypervascularity with washout) is diagnostic 3
• For nodules 1-2 cm, two dynamic imaging techniques showing typical appearance are required 3
• For nodules <1 cm, follow with ultrasound at 3-6 month intervals without advanced imaging or biopsy 3
• Critical pitfall: AFP is elevated in only 50-75% of HCC cases, and 35-40% have normal AFP even with large tumors, so AFP should never be used alone for diagnosis 3

Key Prognostic Factors

Liver function (Child-Pugh class) is the primary determinant of treatment eligibility and survival, superseding tumor characteristics in many cases. 4, 2

• Vascular invasion indicates aggressive biology, significantly worsens prognosis, and mandates systemic therapy over locoregional treatment 2
• Performance status is essential for systemic therapy candidacy 2
• Hepatic reserve must be assessed before any treatment, as liver function drives both morbidity and mortality 4