What is the role of radiotherapy in hepatocellular carcinoma (HCC)?

Role of Radiotherapy in Hepatocellular Carcinoma

Radiotherapy is now a versatile and effective treatment option across all BCLC stages of HCC, particularly valuable for tumors inaccessible to ablation, unsuitable for TACE, or with portal vein invasion, with modern techniques like SBRT and proton therapy achieving excellent local control comparable to ablation for small tumors. 1

Primary Indications by Disease Stage

BCLC Stage A (Early-Stage)

• Use radiotherapy when HCC is inaccessible to ablation or unresectable 1
• Consider as bridge therapy before liver transplantation 1
• SBRT can serve as an alternative to other liver-directed therapies, with comparable drop-out rates and survival to TACE and RFA when used as bridge to transplant 1
• For solitary nodules <3 cm, no significant survival difference exists between external radiation and ablative techniques, though ablation shows a trend toward better outcomes 1
• Proton beam radiotherapy demonstrates comparable local tumor control and overall survival to radiofrequency ablation in HCCs ≤3 cm 1

BCLC Stage B (Intermediate-Stage)

• Consider EBRT when HCC is inaccessible or unsuitable for TACE 1
• Use for TACE-refractory disease 1
• Apply when localized tumor presents with symptoms or threatens liver reserve 1
• TACE combined with radiotherapy shows better survival and response rates than TACE alone, though at the cost of more gastro-duodenal ulcers and transient liver enzyme elevations 1

BCLC Stage C (Advanced-Stage)

• Radiotherapy is particularly valuable for patients with portal vein tumor thrombus (PVTT) 1
• Use for HCC unsuitable or refractory to TACE 1
• Apply for localized tumors with symptoms or threatening liver reserve 1
• Consider for patients not candidates for systemic therapy but requiring local tumor control 1

BCLC Stage D (End-Stage)

• Use EBRT for symptomatic metastasis as palliation 1
• Consider for oligometastases 1
• External beam radiotherapy controls pain in patients with bone metastases 1

Modern Radiotherapy Techniques

Stereotactic Body Radiotherapy (SBRT)

• SBRT delivers ablative radiation doses in five or fewer highly focused treatments with rapid dose fall-off to surrounding tissues 1
• Particularly effective for tumors in locations difficult to access with percutaneous ablation 2
• Can be safely combined with TACE for large tumors (>5 cm) 1
• Requires careful patient selection based on liver function, with indocyanin green retention testing recommended for high-risk patients 1

Proton Therapy

• Proton RT provides superior dose sparing to non-tumor tissues compared to photon therapy 1
• Interim analysis of randomized trial comparing TACE to proton beam radiation showed trend toward improved local control and progression-free survival with radiotherapy 1
• Increasingly used in Asian countries with favorable outcomes 1

Three-Dimensional Conformal Radiotherapy

• Allows high-dose radiation directed to HCC while sparing surrounding non-tumoral liver parenchyma 1
• Technological innovations have overcome historical limitations of low liver tolerance 3, 4

Combination Strategies

With TACE

• Meta-analysis of 25 trials (2,577 patients) demonstrated better survival and response rates with combined TACE plus radiotherapy versus TACE alone 1
• However, all randomized studies were rated as low to very low quality 1
• Combination increases risk of gastro-duodenal ulcers and transient hepatotoxicity 1

With Systemic Therapy

• Combination approaches are under investigation but lack high-quality evidence 1
• Intrahepatic therapies may stimulate cytokine production that could drive tumor progression, making concurrent targeted systemic therapy evaluation essential 1

Critical Patient Selection Factors

Liver Function Requirements

• Patients must have adequate liver reserve to tolerate radiation 1
• Child-Pugh A or favorable B classification preferred 1
• Avoid in decompensated cirrhosis (Child-Pugh C) 1

Tumor Characteristics

• Most effective for localized disease without extensive bilobar involvement 1
• Contraindicated in massive tumors or main portal vein thrombus with poor liver function 1
• Size considerations: ablative techniques preferred for nodules >3 cm when feasible 1

Important Caveats and Limitations

Evidence Quality

• Despite signs of efficacy and safety, there remains a compelling need for large prospective randomized phase III trials evaluating radiotherapy's role 1
• Most current evidence comes from single-institution cohort studies rather than high-quality randomized trials 1
• Asian guidelines more aggressively endorse radiotherapy based on regional experience, while Western guidelines remain more cautious 1

Risk of Radiation-Induced Liver Disease (RILD)

• Historical limitation that has been largely overcome with modern techniques 4
• Requires careful treatment planning with dose-volume constraints for normal liver 3
• Image-guided radiotherapy (IGRT) reduces inter- and intra-fractional errors from daily changes 2

Reimbursement and Access

• In Taiwan, EBRT is commonly used and reimbursed by national health insurance 1
• Access to proton therapy and SBRT varies significantly by region and healthcare system 1

Practical Algorithm for Radiotherapy Selection

For early-stage HCC (BCLC A): Use radiotherapy when ablation is technically unfeasible due to tumor location (subcapsular, near vessels/bile ducts) or when patient refuses surgery 1

For intermediate-stage HCC (BCLC B): Consider radiotherapy after TACE failure or when TACE is contraindicated due to vascular anatomy 1

For advanced-stage HCC (BCLC C): Prioritize radiotherapy for PVTT or symptomatic localized disease threatening liver function, particularly when systemic therapy alone provides insufficient local control 1

For oligometastatic disease: Use SBRT for symptomatic lesions or when local control may improve quality of life 1