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

Abstract

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.

Keywords: HCC; hepatocellular carcinoma; meta‐analysis; particle therapy; prospective; systematic review.

FIGURE 1

(a) Overall survival stratified by the extent of portal vein tumor thrombus (PVTT): Vp0–2 (no PVTT to second‐order branch involvement) versus Vp3–4 (first‐order branch/main trunk involvement). Numbers at risk are shown below. (b) Overall survival rates divided by tumor size (< 4 cm vs. 4 cm or more).

FIGURE 2

Forest plot for each modality of 1‐year overall survival rate (All selected manuscript). (a) 1‐year overall survival rate in all selected studies (particle therapy). (b) 1‐year overall survival rate of all selected manuscripts (SBRT). (c) 1‐year overall survival rate of all selected manuscripts (3DCRT).

FIGURE 3

Forest plot for each modality of 1‐year overall survival rate (PVTT/IVCTT). (a) 1‐year overall survival rate for studies with PVTT/IVCTT (particle therapy). (b) 1‐year overall survival rate focused on PVTT/IVCTT (SBRT). (c) 1‐year overall survival rate focused on PVTT/IVCTT (3DCRT).

FIGURE 4

Forest plot for each modality of 1‐year overall survival rate (without PVTT/IVCTT). (a) 1‐year overall survival rate excluding studies with only PVTT/IVCTT (particle therapy). (b) 1‐year overall survival rate excluding only PVTT/IVCTT (SBRT). (c) 1‐year overall survival rate excluding only PVTT/IVCTT (3DCRT).

FIGURE 5

Forest plot for each modality of 1‐year overall survival rate (Small HCC). (a) 1‐year overall survival rate for small tumors (particle therapy). (b) 1‐year overall survival rate focused on small tumor (SBRT).

FIGURE 6

Forest plot for each modality of 1‐year overall survival rate (Large HCC). (a) 1‐year overall survival rate for large tumors (particle therapy). (b) 1‐year overall survival rate focused on large tumor (SBRT). (c) 1‐year overall survival rate focused on large tumor (3DCRT).