What are the benefits of proton therapy for Hepatocellular Carcinoma (HCC) cases?

Benefits of Proton Therapy for Hepatocellular Carcinoma

Proton beam therapy (PBT) offers significant benefits for HCC patients, including superior local tumor control, improved overall survival compared to photon therapy, reduced liver toxicity, and non-inferior outcomes to radiofrequency ablation for small tumors, making it a valuable treatment option across multiple HCC stages.

Superior Local Control and Survival Outcomes

PBT demonstrates excellent local control rates with 94.8% of patients achieving >80% local control at 2 years and 87% tumor control at 2 years for large tumors. 1, 2 The 5-year local control rate reaches 89% in surgically unresectable patients, with 5-year overall survival of 23.5%. 1

When compared directly to conventional radiotherapy, charged particle therapy (predominantly PBT) shows significantly superior outcomes: 1

• Overall survival: relative risk 25.9 (95% CI, 1.64–408.5; P=.02)
• Progression-free survival: relative risk 1.86 (95% CI, 1.08–3.22; P=.013)
• Locoregional control: relative risk 4.30 (95% CI, 2.09–8.84; P<.001) through 5 years

Reduced Hepatotoxicity and Improved Survival vs. Photon Therapy

The most clinically significant advantage of PBT is the dramatic reduction in post-treatment liver decompensation, which directly translates to improved survival. 3 In a comparative study, proton therapy was associated with:

• Improved overall survival (adjusted HR 0.47; P=.008; 95% CI, 0.27-0.82)
• Median survival of 31 months vs. 14 months for photon therapy
• 24-month survival of 59.1% vs. 28.6% for photon therapy
• Decreased risk of non-classic radiation-induced liver disease (odds ratio 0.26; P=.03; 95% CI, 0.08-0.86) 3

This survival benefit appears driven by the superior dose-sparing properties of protons (Bragg peak effect), which allows high-dose delivery to tumors while minimizing exposure to surrounding normal liver tissue. 4, 5

Non-Inferiority to Standard Ablation for Small Tumors

For recurrent or residual HCC ≤3 cm, PBT demonstrates non-inferior local control compared to radiofrequency ablation (RFA), the current standard of care. 1 A phase III randomized controlled trial showed:

• No difference in local control rate between PBT and RFA
• Equivalent progression-free survival
• Equivalent overall survival
• Comparable toxicity profiles 1

This establishes PBT as a curative therapeutic option for small HCC, particularly valuable when RFA is technically challenging due to tumor location near major vessels or bile ducts. 1

Advantages Compared to TACE

PBT shows favorable outcomes compared to transarterial chemoembolization (TACE) in intermediate-stage HCC. 1 A prospective randomized trial demonstrated:

• Trend toward improved 2-year local control (P=.06)
• Better progression-free survival (P=.06)
• Significantly fewer hospitalization days after treatment (P<.001) 1

A more recent phase III trial confirmed these findings, with PBT showing superior outcomes to TACE in terms of local control and quality of life measures. 1

Efficacy Across All Tumor Sizes and Stages

PBT demonstrates effectiveness even for large tumors (>10 cm) and advanced disease with portal vein tumor thrombus (PVTT), scenarios where other local therapies often fail. 1, 2 For large HCC:

• 87% tumor control rate at 2 years
• 64% one-year overall survival
• 36% two-year overall survival
• No Grade 3 or higher late toxicity 2

For HCC with PVTT, PBT achieves better overall survival (10.9 months) compared to sorafenib (4.8 months; P=.025) or surgery (12.3 vs. 10.3 months; P=.029). 1

Safety Profile and Patient Selection

PBT can be safely delivered to patients with Child-Pugh class A liver function, with careful dose modifications possible for Child-Pugh class B patients. 1 The treatment demonstrates:

• Low toxicity rates, primarily gastrointestinal
• Minimal late treatment-related toxicity
• Preservation of liver function when appropriate dose constraints are followed 1, 6, 2

Critical dose constraints include: 6

• Normal liver V0Gy <30% volume
• V30Gy <18-25% volume

Current Guideline Recommendations

Multiple international guidelines now recognize PBT as an appropriate treatment option for HCC. The NCCN guidelines state that PBT may be considered in select settings, emphasizing treatment at experienced centers. 1 The Korean practice guidelines recommend PBT as non-inferior to RFA for small HCC (≤3 cm) with an A2 level of evidence. 1

The 2025 EASL guidelines acknowledge PBT alongside SBRT as effective external beam radiation therapy options, noting their use in case series, propensity-matched studies, and randomized controlled trials. 1

Clinical Scenarios Where PBT Offers Particular Advantage

PBT should be prioritized in the following situations: 1, 4, 3

• Tumors near critical structures (major vessels, bile ducts, gastrointestinal tract)
• Large tumor volumes requiring high-dose radiation
• Patients with limited hepatic reserve (Child-Pugh B7)
• Recurrent HCC after prior liver-directed therapy
• HCC with portal vein tumor thrombus
• Bridging therapy to liver transplantation
• Patients at high risk for liver decompensation

Important Caveats

Treatment should be performed at experienced centers with expertise in proton therapy for HCC. 1 While PBT shows no significant difference compared to SBRT in head-to-head comparisons for some outcomes, the reduced integral dose to normal liver tissue may provide long-term benefits in terms of preserved liver function. 1

The main limitation remains cost and availability, as proton therapy facilities are less widely accessible than photon-based radiation therapy centers. 4, 5