{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T01:52:34Z","timestamp":1787017954903,"version":"build-2736575974"},"reference-count":65,"publisher":"S. Karger AG","license":[{"start":{"date-parts":[[2025,12,12]],"date-time":"2025-12-12T00:00:00Z","timestamp":1765497600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2025,12,12]],"date-time":"2025-12-12T00:00:00Z","timestamp":1765497600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Liver Cancer"],"abstract":"<jats:p>Purpose: This study aimed to compare the outcomes of proton radiotherapy alone versus its combination with immuno-oncology agents (Proton-IO) or tyrosine kinase inhibitors (Proton-TKI) in patients with intermediate- to advanced-stage hepatocellular carcinoma (HCC). Methods: We retrospectively reviewed the medical records of 137 patients with Barcelona Clinic Liver Cancer (BCLC) stage B or C HCC treated with proton radiotherapy at Linkou Chang Gung Memorial Hospital between 2020 and 2023. Patients were stratified into three groups: proton radiotherapy alone (n = 64), Proton-IO (n = 44), and Proton-TKI (n = 29). The most frequently used immuno-oncology agents were atezolizumab-bevacizumab (n = 33) and pembrolizumab (n = 5). Tyrosine kinase inhibitors (TKIs) included lenvatinib (n = 16) and sorafenib (n = 13). Results: With a median follow-up of 30 months, patients in the Proton-IO group were significantly associated with higher 2-year overall survival (OS) rates compared with those receiving Proton-TKI or proton radiotherapy alone (77.0% vs. 47.2% vs. 52.7%; p = 0.002). Proton-IO was also associated with significantly longer time to progression (TTP) and distant metastasis-free survival (DMFS) (2-year TTP: 50.5% vs. 28.1% vs. 24.2%, p = 0.003; 2-year DMFS: 83.4% vs. 61.1% vs. 67.2%, p = 0.027). No significant differences in 2-year local control rates were observed among the treatment groups (97.7% vs. 92.9% vs. 86.8%; p = 0.230). Multivariate analysis identified Proton-IO as an independent predictor of improved OS (p &lt; 0.001), TTP (p &lt; 0.001), and DMFS (p = 0.004). Grade 3\u20134 upper gastrointestinal (UGI) bleeding was observed in 2 (1.5%) patients (proton monotherapy, n = 1; Proton-IO, n = 1). There were no significant differences among the groups in the incidence of grade \u22653 UGI bleeding, liver toxicity, colitis, rib fractures, or hematologic adverse events. Conclusion: In BCLC stage B\/C HCC, proton radiotherapy combined with immunotherapy was significantly associated with higher OS, TTP, and DMFS without an increase in grade \u22653 toxicity compared with proton radiotherapy alone or Proton-TKIs.<\/jats:p>","DOI":"10.1159\/000550067","type":"journal-article","created":{"date-parts":[[2025,12,12]],"date-time":"2025-12-12T17:00:57Z","timestamp":1765558857000},"page":"1-16","source":"Crossref","is-referenced-by-count":1,"title":["Proton Radiotherapy Alone versus Combined with Immunotherapies or Tyrosine Kinase Inhibitors for Barcelona Clinic Liver Cancer Stage B or C Hepatocellular Carcinoma"],"prefix":"10.1159","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2038-4537","authenticated-orcid":false,"given":"Rodney Cheng-En","family":"Hsieh","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Willy 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