Does proton therapy have benefits for patients with Hepatocellular Carcinoma (HCC)?

Proton Beam Therapy for Hepatocellular Carcinoma

Yes, proton beam therapy (PBT) provides significant benefits for HCC patients, with demonstrated superior local control rates (89% at 5 years), non-inferior outcomes to radiofrequency ablation for small tumors, and reduced hepatotoxicity compared to conventional radiation—making it an appropriate treatment option particularly for unresectable disease, tumors near critical structures, and patients with limited hepatic reserve. 1, 2

Guideline-Based Recommendations

Current Status in Major Guidelines

The 2025 EASL guidelines and 2017 NCCN guidelines both recognize PBT as an acceptable treatment modality for HCC, though NCCN emphasizes treatment at experienced centers. 1 The NCCN classifies hypofractionation with protons as an acceptable option for intrahepatic tumors, with PBT being "appropriate in specific situations" (Category 2B recommendation). 1

Japanese guidelines have expanded coverage, with particle therapies using protons now covered by health insurance since April 2022 for large (≥4 cm) and difficult-to-resect HCCs. 1

Clinical Efficacy Evidence

Local Control and Survival Outcomes

PBT achieves exceptional local control rates: 94.8% of patients demonstrate >80% local control at 2 years, with 5-year local control reaching 89% in surgically unresectable patients. 2 The 5-year overall survival for all-comers is 23.5%, but this improves dramatically to 53.5% in patients with solitary tumors and least impaired hepatic function. 3

For large tumors (>10 cm), PBT maintains an 87% tumor control rate at 2 years, demonstrating effectiveness even in challenging scenarios. 2

Comparison to Standard Ablation Techniques

A randomized phase III trial demonstrated non-inferiority of PBT compared to radiofrequency ablation (RFA) for recurrent HCC, with equivalent local control rates, progression-free survival, and overall survival for small tumors (≤3 cm). 1, 2 This represents Level A2 evidence in Korean practice guidelines. 2

The key advantage: PBT offers a non-invasive alternative to RFA with comparable efficacy, particularly valuable when tumors are in locations difficult to access percutaneously or near critical structures. 2

Comparison to Transarterial Chemoembolization (TACE)

PBT demonstrates superior outcomes to TACE in intermediate-stage HCC, with significantly fewer hospitalization days after treatment (P<0.001) and trends toward improved 2-year local control (P=0.06) and progression-free survival (P=0.06). 1, 2 This quality-of-life advantage is clinically meaningful for patient selection. 1, 2

Specific Clinical Scenarios Where PBT Excels

Tumors Near Critical Structures

PBT should be prioritized when tumors are adjacent to critical structures due to the Bragg peak phenomenon, which provides near-zero exit dose and superior normal tissue sparing. 2, 4 This physical property allows safe dose escalation while protecting surrounding organs. 4

Advanced Disease with Portal Vein Tumor Thrombus

For HCC with portal vein tumor thrombus (PVTT), PBT achieves 10.9-month overall survival with effective in-field disease control and safe toxicity profiles. 2 This represents a viable option for advanced disease where other local therapies are contraindicated. 2

Patients with Limited Hepatic Reserve

PBT's superior normal liver sparing makes it particularly valuable for patients with compromised liver function (Child-Pugh A or B), where conventional radiation would pose excessive hepatotoxicity risk. 1, 2, 4 The improved dosimetric profile reduces progression to liver failure compared to photon therapy. 4

Important caveat: Safety in Child-Pugh C cirrhosis remains unestablished, and these patients should not receive liver radiation outside clinical trials. 1

Large or Multifocal Tumors

PBT enables treatment of larger tumor volumes and multifocal disease that would exceed normal liver tolerance with conventional photon therapy. 2, 4 The reduced integral dose to normal liver allows safe dose escalation even in challenging anatomic scenarios. 4

Safety Profile

PBT demonstrates minimal acute reactions and few late sequelae, with treatment being well-tolerated and repeatable. 3 The therapy is safe regardless of tumor size, location, vascular invasion status, or presence of intercurrent diseases. 3

For Child-Pugh B patients, treatment is safe but requires dose modifications and strict adherence to dose constraints. 1

Practical Implementation Considerations

Patient Selection Algorithm

1. First-line consideration: Unresectable HCC, medically inoperable patients, or those declining surgery 1
2. Tumor characteristics favoring PBT:
   • Proximity to critical structures 2
   • Large tumors (≥4 cm) 1
   • Portal vein tumor thrombus 2
   • Recurrent disease after other therapies 1
3. Hepatic function requirement: Child-Pugh A or B only 1
4. Alternative to ablation/embolization: When these therapies have failed, are contraindicated, or anatomically unfavorable 1, 2

Treatment at Experienced Centers

Both EASL and NCCN guidelines emphasize that PBT should be delivered at centers with experience in this modality. 1 This recommendation reflects the technical complexity and need for specialized expertise in treatment planning and delivery. 1

Emerging Evidence and Future Directions

Ongoing randomized controlled trials are comparing PBT versus photon therapy to definitively establish superiority in survival and toxicity outcomes, specifically regarding progression to liver failure. 4 Additional trials are investigating PBT versus RFA and PBT versus TACE. 1

The concept of combined proton-photon treatments is being explored to optimize limited proton resources, potentially allowing dose escalation in proton fractions while distributing access across more patients. 5