What is the role of proton therapy in the treatment of hepatocellular carcinoma (HCC)?

Proton Beam Therapy in Hepatocellular Carcinoma

Proton beam therapy (PBT) is a highly effective treatment option for HCC across all disease stages, achieving 89% local control at 5 years in unresectable patients and demonstrating non-inferiority to radiofrequency ablation for small tumors ≤3 cm. 1

Primary Clinical Indications

Early-Stage HCC (BCLC 0-A)

• PBT achieves equivalent outcomes to radiofrequency ablation (RFA) for tumors ≤3 cm, with no difference in local control rate, progression-free survival, or overall survival. 2, 1
• Use PBT when tumors are inaccessible to ablation due to location near major vessels, bile ducts, or diaphragm. 1
• Consider PBT as bridging therapy before liver transplantation in patients with preserved liver function (Child-Pugh A or B7). 2
• PBT demonstrates 94.8% of patients achieving >80% local control at 2 years for early-stage disease. 1

Intermediate-Stage HCC (BCLC B)

• PBT shows superior outcomes compared to transarterial chemoembolization (TACE), with significantly fewer hospitalization days and trends toward improved 2-year local control and progression-free survival. 1
• Use PBT after TACE failure or when TACE is contraindicated. 2
• PBT can be combined with TACE for incomplete response, though this combination should ideally be performed in experienced centers. 2

Advanced-Stage HCC (BCLC C)

• PBT demonstrates effectiveness even for large tumors >10 cm, achieving 87% tumor control at 2 years. 1, 3
• For HCC with portal vein tumor thrombus (PVTT), PBT achieves 10.9-month overall survival with safe toxicity profiles. 1
• PBT combined with external beam radiation therapy can be considered for HCC with portal vein invasion when tumors are localized and liver function is preserved. 2

Dosing Protocols Based on Tumor Location

Three validated treatment protocols exist, selected based on proximity to critical structures: 4

• Protocol A: 66 GyE in 10 fractions for tumors distant from gastrointestinal organs
• Protocol B: 72.6 GyE in 22 fractions for intermediate-risk locations
• Protocol C: 77 GyE in 35 fractions for tumors near critical structures (bile ducts, stomach, bowel)

A hypofractionated regimen of 70 GyE in 10 fractions achieved 95.2% local progression-free survival at 3 years in a phase II trial. 5

Patient Selection Criteria

Mandatory Requirements

• Child-Pugh class A or B7 liver function (PBT is contraindicated in Child-Pugh C). 2, 1
• ECOG performance status 0-1. 2
• Tumor must be ≥2 cm from gastrointestinal organs when using hypofractionated regimens. 5
• Expected remnant liver volume receiving ≤30 Gy should be ≥40% of total liver volume. 2

Optimal Clinical Scenarios for PBT

PBT should be prioritized when: 1

• Tumors are located near critical structures (bile ducts, major vessels, diaphragm)
• Large tumor volumes (≥4 cm) require high-dose radiation
• Patients have limited hepatic reserve where conventional photon therapy would pose excessive hepatotoxicity risk
• HCC has portal vein tumor thrombus
• Recurrent disease after other local therapies

Comparative Efficacy Data

PBT vs. RFA for Small Tumors

A randomized phase III trial demonstrated non-inferiority of PBT compared to RFA for recurrent HCC ≤3 cm, representing Level A2 evidence. 1, 6

PBT vs. TACE for Intermediate Stage

PBT shows superior quality of life measures and local control compared to TACE, with significantly fewer hospitalization days (P<0.001). 1

Long-Term Outcomes

• 5-year local control rate: 89% in surgically unresectable patients 1
• 5-year overall survival: 23.5% in unresectable disease 1
• 3-year local progression-free survival: 95.2% with hypofractionated regimens 5
• Overall survival rates at 1,3, and 5 years: 87%, 61%, and 48% respectively 4

Guideline Recommendations

International Guidelines

• NCCN recommends PBT as an appropriate treatment option for HCC (Category 2B), emphasizing treatment at experienced centers. 1
• EASL acknowledges PBT alongside SBRT as effective external beam radiation therapy options. 1
• Korean practice guidelines recommend PBT as non-inferior to RFA for small HCC ≤3 cm with A2 level of evidence. 1
• Japanese guidelines expanded health insurance coverage for particle therapies using protons for large (≥4 cm) and difficult-to-resect HCCs since April 2022. 1

Asian Guidelines

The APASL guidelines state that EBRT and proton beam are reasonable options for HCC in which other local therapies have failed, though EBRT has not been shown to improve outcomes in general HCC populations. 2

Critical Advantages Over Photon Therapy

PBT provides superior dose sparing to non-tumor liver tissue due to the Bragg peak phenomenon, reducing progression to liver failure compared to conventional photon therapy. 1, 7

This dosimetric advantage is particularly valuable in: 1

• Patients with limited hepatic reserve
• Large tumor volumes requiring ablative doses
• Tumors near critical structures where photon exit dose would cause unacceptable toxicity

Safety Profile

• No Grade 3 or higher late treatment-related toxicity observed in large series 4, 3
• Grade ≥3 acute toxicity did not occur in phase II hypofractionated protocol 5
• Selection of treatment schedules based on tumor location reduces risk of late complications (gastrointestinal ulceration, bile duct stenosis) 4

Common Pitfalls to Avoid

• Do not use PBT in Child-Pugh C cirrhosis or decompensated liver disease—these patients should not receive liver radiation outside clinical trials. 1
• Ensure adequate distance (≥2 cm) from gastrointestinal organs when using hypofractionated regimens to prevent ulceration. 5
• Verify that ≥40% of total liver volume will receive ≤30 Gy to prevent radiation-induced liver disease. 2
• PBT should be delivered at centers with specialized expertise in treatment planning and delivery. 1

Treatment Algorithm

For tumors ≤3 cm: Use PBT when RFA is technically unfeasible due to location, or as equivalent alternative to RFA. 2, 1

For tumors 3-10 cm: Consider PBT as first-line option, particularly if near critical structures or after TACE failure. 2, 1

For tumors >10 cm: PBT is effective and safe, achieving 87% tumor control at 2 years. 1, 3

For HCC with PVTT: Use PBT alone or combined with TACE when tumors are localized and liver function is Child-Pugh A or B7. 2, 1