What are the considerations for converting to systemic therapy with tyrosine kinase inhibitors (TKIs) such as sorafenib (sorafenib) or lenvatinib (lenvatinib) in a patient with hepatocellular carcinoma (HCC) who has undergone initial treatment with transarterial chemoembolization (TACE)?

Conversion Therapy in Hepatocellular Carcinoma

Definition and Core Concept

Conversion therapy in HCC refers to treatment strategies designed to downstage initially unresectable tumors to enable curative surgical resection or ablation. 1 This approach transforms patients from unresectable to resectable status through systemic therapy, locoregional therapy, or combination approaches, with the ultimate goal of achieving radical tumor removal.

When to Consider Conversion Therapy

Defining TACE-Refractoriness (Triggers for Conversion)

The 2022 Korean guidelines provide the most specific criteria for when to switch from TACE to systemic therapy 2:

• No objective response (CR or PR) after two or more sessions of on-demand TACE within 6 months 2
• Development of vascular invasion 2
• Development of extrahepatic metastasis 2

Additional prognostic indicators that suggest poor TACE response and need for conversion 2:

• MoRAL score ≥89.5 with increase of ≥5% after initial TACE (median OS <10 months) 2
• Consecutive insufficient tumor response (≥2 sessions) in ≥50% of lesions 2
• Two or more consecutive progressions in tumor number 2
• Continuous elevation of tumor markers 2

Treatment Options for Conversion Therapy

First-Line Systemic Therapy After TACE Failure

For patients with preserved liver function (Child-Pugh A) who develop TACE-refractoriness, atezolizumab plus bevacizumab is the preferred first-line systemic therapy. 2 This combination has superior efficacy compared to sorafenib, with median OS of 19.2 months versus 13.4 months 2.

Critical prerequisite: Patients must undergo upper GI endoscopy within 6 months with adequate treatment of esophageal varices before starting bevacizumab due to bleeding risk (7% vs 4.5% with sorafenib) 2.

Alternative first-line options when atezolizumab/bevacizumab is contraindicated 2:

• Lenvatinib: Non-inferior OS to sorafenib, with better progression-free survival and response rates 2
  • Contraindication: Main portal vein invasion, >50% liver tumor burden 2
  • Dose: 12 mg daily for ≥60 kg; 8 mg daily for <60 kg 3
• Sorafenib: Median OS 10.7 months in advanced HCC 2
  • Dose: 400 mg twice daily 4

Combination Approaches (TACE + Systemic Therapy)

Current guidelines recommend AGAINST routine combination of TACE with systemic agents outside clinical trials. 2 The evidence shows:

• TACE plus sorafenib: Failed to show OS benefit in multiple trials (SPACE, ORIENTAL) 2
• TACE plus immune checkpoint inhibitors: Insufficient evidence despite promising early signals 2

However, emerging research data suggests potential benefit in specific contexts:

Recent research (not yet incorporated into guidelines) shows promising results for triple therapy:

• TACE + TKI + ICI conversion rate: 42% versus TACE monotherapy 10% 1
• TACE + lenvatinib + PD-1 inhibitor: Median OS 26.7 months versus 14.4 months with TACE + sorafenib 5
• TACE + lenvatinib (TACTICS-L trial): Median PFS 28.0 months, CR rate 67.7% 6
• TACE + lenvatinib (LAUNCH trial): Median OS 17.8 months versus 11.5 months with lenvatinib alone in advanced HCC 7

Important caveat: These combination approaches should be considered investigational until incorporated into formal guidelines, though they represent the most promising conversion strategies based on current research 1, 6, 5, 7.

Second-Line Options After Progression

For Child-Pugh A patients who progress on first-line therapy, multiple second-line options exist 2:

After atezolizumab/bevacizumab progression 2:

• Sorafenib or lenvatinib (reasonable based on mechanism of action, though no prospective data) 2

After sorafenib progression 2:

• Regorafenib: Median OS benefit 2.8 months (only for patients who tolerated sorafenib) 2
• Cabozantinib: Median OS benefit 2.2 months 2
• Pembrolizumab: Median OS benefit 3.3 months 2
• Ramucirumab: Only for AFP >400 ng/mL, median OS benefit 1.2 months 2

All second-line agents require Child-Pugh A and ECOG PS 0-1. 8 No second-line agents are approved for Child-Pugh B patients. 8

Outcomes After Successful Conversion

For patients achieving successful surgical resection after conversion therapy 1:

• 1-year OS: 90% 1
• 2-year OS: 58% 1
• 5-year OS: 42% 1

Major postoperative complications 1:

• Biliary leakage: 7% 1
• Liver failure: 3% 1

Critical Clinical Pitfalls

1. Do NOT use adjuvant sorafenib after TACE - Multiple guidelines recommend against this 2

2. Do NOT combine TACE with sorafenib routinely - No OS benefit demonstrated in major trials 2

3. Do NOT use systemic therapy in Child-Pugh C patients - Only best supportive care is appropriate 9

4. Do NOT use bevacizumab without variceal screening - Mandatory endoscopy and treatment before initiation 2

5. Do NOT use lenvatinib with main portal vein invasion - Not studied in this population 2

6. Do NOT use regorafenib in patients intolerant to sorafenib - Only for those who tolerated but progressed 2

7. Monitor liver function closely - Watch for hepatic decompensation (worsening ascites, encephalopathy, rising bilirubin) 8

Practical Treatment Algorithm

Step 1: Assess TACE response after 2 sessions over 6 months 2

Step 2: If TACE-refractory (no CR/PR, vascular invasion, or extrahepatic spread) 2:

• Confirm Child-Pugh A and ECOG PS 0-1 2
• Perform upper GI endoscopy and treat varices 2
• Start atezolizumab + bevacizumab 2

Step 3: If atezolizumab/bevacizumab contraindicated 2:

• Use lenvatinib (if no main portal vein invasion) 2
• OR use sorafenib 2

Step 4: If progression on first-line therapy and still Child-Pugh A 2:

• After atezolizumab/bevacizumab: Consider lenvatinib or sorafenib 2
• After sorafenib: Use regorafenib (if tolerated), cabozantinib, or pembrolizumab 2

Step 5: Reassess for surgical resection every 2-3 months with imaging 9