Supplementary Material for: Proton Radiotherapy Alone versus Combined with Immunotherapies or Tyrosine Kinase Inhibitors for BCLC Stage B or C Hepatocellular Carcinoma

Purpose: This study aimed to compare the outcomes of proton radiotherapy alone versus its combination with immunotherapies (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 (LC) 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 <0.001), TTP (P <0.001), and DMFS (P = 0.004). Grade 3–4 upper gastrointestinal (UGI) bleeding was observed in two (1.5%) patients (proton monotherapy, n = 1; Proton-IO, n = 1). There were no significant differences among the groups in the incidence of grade ≥3 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 ≥3 toxicity compared with proton radiotherapy alone or in combination with TKIs.