What treatment options are available for hepatocellular carcinoma (HCC) in the absence of immunotherapy?

Treatment Options for Hepatocellular Carcinoma Without Immunotherapy

For patients with advanced HCC who cannot access immunotherapy, lenvatinib and sorafenib are FDA-approved first-line systemic therapies, while locoregional treatments (TACE, ablation) and surgical options remain the backbone of management depending on tumor stage and liver function. 1, 2

First-Line Systemic Therapy Options

Lenvatinib (Preferred Targeted Therapy)

• Lenvatinib is FDA-approved as first-line treatment for unresectable HCC, with dosing based on body weight: 12 mg daily for patients ≥60 kg or 8 mg daily for patients <60 kg 2
• Lenvatinib demonstrated non-inferiority to sorafenib in pivotal trials and is particularly effective when there is no main portal vein invasion 1
• This agent can be used as monotherapy without requiring combination with immunotherapy 2

Sorafenib (Standard Alternative)

• Sorafenib remains a validated first-line option for advanced HCC with preserved liver function (Child-Pugh A or favorable B), showing a survival benefit of approximately 2.8 months over placebo 3, 1, 4
• Sorafenib is appropriate for patients with well-preserved hepatic reserve and good performance status 1
• Traditional systemic chemotherapy (anthracyclines, cisplatin, 5-FU) should NOT be used, as it shows only 10% response rates with no survival benefit and poor tolerance due to underlying cirrhosis 3, 1, 5

Second-Line Systemic Therapy Options

Regorafenib

• Regorafenib is FDA-approved for patients who tolerated but progressed on sorafenib, with well-preserved liver function (Child-Pugh A) and good performance status 1, 6
• This represents the standard second-line option after sorafenib failure 1

Cabozantinib

• Cabozantinib can be considered for patients with progressive disease on one or two prior systemic therapies, maintaining well-preserved liver function and good performance status 1

Ramucirumab

• Ramucirumab is indicated specifically for HCC patients with AFP ≥400 ng/mL who previously received sorafenib 1
• This is a biomarker-selected therapy requiring AFP measurement before initiation 1

Locoregional Treatment Options

Transarterial Chemoembolization (TACE)

• TACE is the standard of care for intermediate-stage HCC (BCLC B) in patients with preserved liver function (Child-Pugh A or B7 without ascites), performance status ECOG <2, and limited tumor burden 3, 5, 4
• TACE is recommended for 1-3 tumors >3 cm or four or more tumors without vascular invasion or extrahepatic spread 3
• TACE should NOT be used in patients with main portal vein thrombosis or decompensated cirrhosis 5

Hepatic Arterial Infusion Chemotherapy (HAIC)

• HAIC can be considered as second-line treatment after TACE failure or for patients with four or more tumors 3
• This represents an alternative locoregional approach when TACE is ineffective 3

Radiofrequency Ablation (RFA)

• RFA is first-line curative treatment for solitary tumors <2 cm and an alternative to resection for single nodules 2-3 cm when surgery is not feasible 3, 5
• RFA is recommended for 1-3 tumors with diameter <3 cm in patients with adequate hepatic reserve 3
• Percutaneous ethanol injection and microwave ablation are alternative ablative techniques for small tumors 3

Surgical Treatment Options

Hepatic Resection

• Surgical 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%) 5, 4
• Resection is recommended as first choice for solitary tumors regardless of size, or for 1-3 tumors >3 cm 3
• Perioperative mortality can reach 30-50% in Child-Pugh B or C patients, making careful patient selection critical 3

Liver Transplantation

• Liver transplantation should be considered for patients meeting Milan criteria (single tumor ≤5 cm or up to 3 tumors each ≤3 cm, no vascular invasion) who are not suitable for resection, offering 3-year survival up to 88% 5
• Transplantation is optimal for small HCC in moderate to severe cirrhosis (Child-Pugh B or C), as it eliminates both tumor and underlying cirrhotic liver 3
• Limited donor organ availability restricts this option to a minority of patients 3

Treatment Algorithm Based on Liver Function and Tumor Characteristics

Child-Pugh A or B Patients

Without extrahepatic metastases or vascular invasion:

• 1-3 tumors <3 cm: Hepatic resection or RFA (resection preferred for solitary tumors) 3
• 1-3 tumors >3 cm: Hepatic resection first choice, TACE second choice 3
• ≥4 tumors: TACE first choice, followed by HAIC or systemic therapy (lenvatinib/sorafenib) 3

With vascular invasion or extrahepatic spread:

• Systemic therapy with lenvatinib or sorafenib as first-line 1, 4
• Consider HAIC for portal vein thrombosis in selected cases 3

Child-Pugh C Patients

• Best supportive care is recommended for Child-Pugh C patients, as active treatment carries prohibitive risks 3, 1
• Clinical trials may be considered in highly selected cases 1

Critical Contraindications and Pitfalls

Avoid Traditional Chemotherapy

• Do NOT use traditional systemic chemotherapy (anthracyclines, cisplatin, 5-FU) for HCC management - it shows only 10% response rate with no proven survival benefit and poor tolerance 3, 1, 5

Assess Hepatic Reserve Before Any Treatment

• Child-Pugh classification must guide all treatment decisions, as liver function determines both treatment eligibility and survival 3, 4
• Surgery in patients with decompensated cirrhosis carries 30-50% mortality risk 3

Monitor for Vascular Invasion

• Vascular invasion indicates aggressive tumor biology requiring systemic therapy rather than locoregional treatment 4
• Main portal vein thrombosis is a contraindication to TACE 5

Response Assessment and Follow-Up

• Response assessment should use modified RECIST criteria on dynamic CT or MRI, as standard RECIST underestimates response in HCC due to altered vascularity without size change 3, 1, 4
• After curative resection, perform AFP measurement and liver imaging every 3-6 months for at least 2 years, as recurrence rates reach 50-60% at 5 years and curative therapy can still be offered at relapse 3, 5, 4