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Multicenter Study
. 2026 Jan;46(1):e70465.
doi: 10.1111/liv.70465.

Proton Beam Therapy Boosts Outcomes of Atezolizumab/Bevacizumab in Advanced Hepatocellular Carcinoma: A Propensity Score Analysis

Yuan-Hung Kuo  1   2 , Wei Teng  2   3 , Po-Ting Lin  2   3 , Yen-Hao Chen  2   4 , Chung-Wei Su  2   3 , Eric Yi-Liang Shen  2   5 , Bing-Shen Huang  2   5 , Tsung-Han Wu  2   6 , Jen-Yu Cheng  2   7 , Yi-Chung Hsieh  2   3 , Wei-Ting Chen  2   3 , Chao-Hung Hung  1   2 , Shi-Ming Lin  2   3 , Chen-Chun Lin  2   8 , Jing-Houng Wang  1   2 , Chun-Yen Lin  2   3
Affiliations
Multicenter Study

Proton Beam Therapy Boosts Outcomes of Atezolizumab/Bevacizumab in Advanced Hepatocellular Carcinoma: A Propensity Score Analysis

Yuan-Hung Kuo et al. Liver Int. 2026 Jan.

Abstract

Introduction: Hepatocellular carcinoma (HCC) is a major cause of cancer-related mortality, particularly in patients with advanced stage. Atezolizumab plus bevacizumab (Ate/Bev) is the standard first-line therapy; however, its efficacy may be further enhanced using combination strategies.

Methods: This study evaluated the clinical impact of proton beam therapy (PBT) with Ate/Bev in patients with unresectable HCC (uHCC). We retrospectively evaluated 362 patients with uHCC treated with Ate/Bev between November 2020 and June 2023 at two centers in Taiwan. The patients were divided into the Ate/Bev-PBT and Ate/Bev groups based on whether they received first-line Ate/Bev combined with PBT or Ate/Bev alone. Propensity score matching was performed at a 1:2 ratio to reduce selection bias.

Results: There were 39 and 71 patients in the Ate/Bev-PBT and Ate/Bev groups, respectively. Treatment-related adverse events were comparable between the two groups and were manageable, primarily involving mild-to-moderate liver inflammation. Compared with the Ate/Bev group, the Ate/Bev-PBT group demonstrated significantly better objective response rates (56.8% vs 17.3%, p < 0.001), disease control rates (75.7% vs 44.2%, p < 0.001), progression-free survival (7.3 vs 2.3 months, p < 0.001), and overall survival (16.7 vs 7.1 months, p = 0.02). In the multivariate analysis, Ate/Bev-PBT was strongly associated with reduced mortality (hazard ratio [HR], 0.406; 95% confidence interval [CI]: 0.236-0.700, p = 0.001) after adjusting for preserved liver function, prognostic nutritional index and receiving sequential therapy.

Conclusion: The addition of PBT to Ate/Bev was associated with improved treatment response and survival in patients with uHCC without compromising safety of the treatment. This combined approach may represent a promising therapeutic strategy that warrants prospective validation.

Keywords: Atezolizumab and bevacizumab; propensity score matching; proton beam therapy; unresectable hepatocellular carcinoma.

Plain language summary

The combination of atezolizumab plus bevacizumab (Ate/Bev) with proton beam therapy (PBT) significantly improved outcomes compared to Ate/Bev alone, including higher ORR (56.8% vs 17.3%) and DCR (75.7% vs 44.2%), longer PFS (7.3 vs 2.3 months), and OS (16.7 vs 7.1 months). Ate/Bev plus PBT was an independent predictor of reduced mortality (HR 0.406), with consistent benefits across subgroups, such as patients with viral aetiology, macrovascular invasion, or high tumour burden. The safety profile was manageable, with mainly mild‐to‐moderate liver enzyme elevations and no significant increase in severe adverse events, supporting the clinical feasibility of Ate/Bev‐PBT in advanced HCC.

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