Prospective Registry and Meta‐Analysis of Particle Therapy for Hepatocellular Carcinoma: Clinical Outcomes and Real‐World Impact

Background and Aims This study aimed to evaluate the clinical efficacy of particle therapy for hepatocellular carcinoma (HCC) by integrating a prospective registry and a systematic meta‐analysis. Our findings also reflect the real‐world impact of this evidence, which contributed to the national health insurance approval of particle therapy for HCC tumors ≥ 4 cm in Japan. Methods Patients who received particle therapy for HCC from May 2016 to June 2018 were registered. Ninety studies (25 particle therapy, 26 non‐SBRT, 36 SBRT, 3 studies reporting multiple modalities) were selected. Results A total of 836 cases (proton beam therapy 576, carbon therapy 260) were examined. The median overall survival (OS) was 53.7 months (95% CI 47.4‐NA). The 1‐, 2‐, 3‐ and 4‐year OS rates were 85.2% (95% CI 82.6%–87.4%), 71.4% (68.1%–74.4%), 60.5% (56.9%–63.9%), and 53.5% (49.1%–57.7%), respectively; and the 1‐, 2‐, 3‐ and 4‐year local recurrence rates were 3.5% (2.1%–4.9%), 8.8% (6.3%–10.8%), 12.0% (9.3%–14.8%), and 13.6% (10.5%–16.7%), respectively. In the meta‐analysis and registry data, the 1‐, 2‐, and 3‐year OS rates of particle therapy and SBRT for small HCC (< 4 cm) were 90.0%/87.7% ( p = 0.4788), 75.3%/73.6% ( p = 0.6724), and 62.8%/63.5% ( p = 0.9771), respectively; and the 1‐, 2‐, and 3‐year OS rates of particle therapy, SBRT and non‐SBRT for large HCC (≥ 4 cm) were 81.1%/62.0% ( p = 0.0032)/66.8% ( p = 0.0021), 65.4%/38.1% ( p = 0.0001)/38.4% ( p = 0.0001), and 50.4%/31.8% ( p = 0.0001)/25.9% ( p = 0.0001), respectively. Conclusions A prospective registry study and meta‐analysis indicated that particle therapy is a better treatment modality than SBRT for large HCC. Particle therapy and SBRT gave similar outcomes for small HCC. These findings contributed to the adoption of particle therapy for tumors ≥ 4 cm under Japan's national health insurance, highlighting its real‐world impact.