{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T05:02:27Z","timestamp":1789707747816,"version":"4.0.1"},"reference-count":34,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T00:00:00Z","timestamp":1789516800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background\/Objectives: The prognostic relevance of chronological age versus comorbidity burden in patients with hepatocellular carcinoma (HCC) undergoing proton beam therapy (PBT) is unclear. This study evaluated whether comorbidity burden provides prognostic information beyond age. Methods: We retrospectively analyzed 269 patients with HCC treated with PBT between December 2009 and March 2015. Patients were classified as elderly (\u226575 years, n = 105) or non-elderly (&lt;75 years, n = 164). Overall survival (OS), local control (LC), progression-free survival (PFS), and treatment-related adverse events were assessed. Comorbidity burden was evaluated using the Charlson Comorbidity Index (CCI). Multivariable Cox regression analyses were performed for OS and PFS. Results: The 3-year OS rates were 65.9% in the elderly group and 56.9% in the non-elderly group (p = 0.20), while the corresponding LC rates were 86.7% and 90.5% (p = 0.24) and PFS rates were 30.3% and 29.9% (p = 0.81), respectively. In multivariable analyses, age \u2265 75 years was not significantly associated with OS (HR, 1.25; 95% CI, 0.89\u20131.74; p = 0.198) or PFS (HR, 1.15; 95% CI, 0.86\u20131.54; p = 0.331). In contrast, CCI \u2265 3, compared with CCI 0, was independently associated with poorer OS (HR, 3.31; 95% CI, 1.54\u20137.15; p = 0.002), while its association with PFS did not reach statistical significance (HR, 1.87; 95% CI, 0.98\u20133.58; p = 0.057). No significant age \u00d7 CCI interaction was observed for OS or PFS. Conclusions: Chronological age was not independently associated with OS or PFS in patients with HCC treated with PBT, whereas a high comorbidity burden was independently associated with poorer OS. These findings suggest that comorbidity burden should be considered in addition to chronological age when estimating prognosis after PBT.<\/jats:p>","DOI":"10.3390\/cancers18183005","type":"journal-article","created":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T16:07:29Z","timestamp":1789574849000},"page":"3005","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Association of Chronological Age and Comorbidity Burden with Outcomes After Proton Beam Therapy for Hepatocellular Carcinoma"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-2293-2112","authenticated-orcid":false,"given":"Haruka","family":"Shirataki","sequence":"first","affiliation":[{"name":"Department of Radiation Oncology, University of Tsukuba, Tsukuba 305-8575, Ibaraki, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7837-1301","authenticated-orcid":false,"given":"Masashi","family":"Mizumoto","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, University of Tsukuba, Tsukuba 305-8575, Ibaraki, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6632-4356","authenticated-orcid":false,"given":"Takashi","family":"Iizumi","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, University of Tsukuba, Tsukuba 305-8575, Ibaraki, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-4663-5580","authenticated-orcid":false,"given":"Takashi","family":"Saito","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, University of Tsukuba, Tsukuba 305-8575, Ibaraki, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7181-4904","authenticated-orcid":false,"given":"Haruko","family":"Numajiri","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, University of Tsukuba, Tsukuba 305-8575, Ibaraki, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masahiko","family":"Harada","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, University of Tsukuba, Tsukuba 305-8575, Ibaraki, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-7670-6629","authenticated-orcid":false,"given":"Takuya","family":"Sawada","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, University of Tsukuba, Tsukuba 305-8575, Ibaraki, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3840-6527","authenticated-orcid":false,"given":"Masaaki","family":"Goto","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, University of Tsukuba, Tsukuba 305-8575, Ibaraki, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taisuke","family":"Sumiya","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, University of Tsukuba, Tsukuba 305-8575, Ibaraki, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takeshi","family":"Fujisawa","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, University of Tsukuba, Tsukuba 305-8575, Ibaraki, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keiichiro","family":"Baba","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, University of Tsukuba, Tsukuba 305-8575, Ibaraki, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-3329-5999","authenticated-orcid":false,"given":"Masatoshi","family":"Nakamura","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, University of Tsukuba, Tsukuba 305-8575, Ibaraki, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0702-2304","authenticated-orcid":false,"given":"Kei","family":"Nakai","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, University of Tsukuba, Tsukuba 305-8575, Ibaraki, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hideyuki","family":"Sakurai","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, University of Tsukuba, Tsukuba 305-8575, Ibaraki, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"370","DOI":"10.35772\/ghm.2025.01089","article-title":"Evaluation of the geographic distribution of patients with hepatocellular carcinoma and treatments in Japan using data from the Japanese national database","volume":"7","author":"Kokudo","year":"2025","journal-title":"Glob. Health Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1159\/000514174","article-title":"Management of hepatocellular carcinoma in Japan: JSH Consensus Statements and Recommendations 2021 Update","volume":"10","author":"Kudo","year":"2021","journal-title":"Liver Cancer"},{"key":"ref_3","unstructured":"European Association for the Study of the Liver (2025). EASL Clinical Practice Guidelines on the management of hepatocellular carcinoma. J. Hepatol., 82, 315\u2013374."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1016\/j.annonc.2025.02.006","article-title":"Hepatocellular carcinoma: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up","volume":"36","author":"Vogel","year":"2025","journal-title":"Ann. Oncol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"100281","DOI":"10.1016\/j.esmogo.2025.100281","article-title":"Stereotactic body radiotherapy in early-stage hepatocellular carcinoma: A systematic review and meta-analysis","volume":"11","author":"Verwijs","year":"2026","journal-title":"ESMO Gastrointest. Oncol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"110614","DOI":"10.1016\/j.radonc.2024.110614","article-title":"Comparison of stereotactic body radiotherapy and transcatheter arterial chemoembolization for hepatocellular carcinoma: Systematic review and meta-analysis","volume":"202","author":"Komiyama","year":"2025","journal-title":"Radiother. Oncol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"286","DOI":"10.17998\/jlc.2024.06.26","article-title":"Recent update of proton beam therapy for hepatocellular carcinoma: A systematic review and meta-analysis","volume":"24","author":"Bae","year":"2024","journal-title":"J. Liver Cancer"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1169","DOI":"10.2147\/JHC.S292516","article-title":"Carbon Ion Radiotherapy in the Man-agement of Hepatocellular Carcinoma","volume":"8","author":"Abousaida","year":"2021","journal-title":"J. Hepatocell. Carcinoma"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"725","DOI":"10.1016\/j.ijrobp.2023.09.047","article-title":"Proton beam therapy for hepatocellular carcinoma: Multicenter prospective registry study in Japan","volume":"118","author":"Mizumoto","year":"2024","journal-title":"Int. J. Radiat. Oncol. Biol. Phys."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"e71639","DOI":"10.1002\/cam4.71639","article-title":"Prospective registry and meta-analysis of particle therapy for hepatocellular carcinoma: Clinical outcomes and real-world impact","volume":"15","author":"Mizumoto","year":"2026","journal-title":"Cancer Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1007\/s10147-017-1190-2","article-title":"A systematic review of publications on charged particle therapy for hepatocellular carcinoma","volume":"23","author":"Igaki","year":"2018","journal-title":"Int. J. Clin. Oncol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"3554","DOI":"10.1002\/cncr.34965","article-title":"Proton beam radiotherapy versus transarterial chemoembolization for hepatocellular carcinoma: Results of a randomized clinical trial","volume":"129","author":"Bush","year":"2023","journal-title":"Cancer"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"460","DOI":"10.1200\/JCO.2015.64.2710","article-title":"Multi-institutional phase II study of High-dose hypofractionated proton beam therapy in patients with localized, unresectable hepatocellular carcinoma and intrahepatic cholangiocarcinoma","volume":"34","author":"Hong","year":"2016","journal-title":"J. Clin. Oncol."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Sanchini, V., Sala, R., and Gastmans, C. (2022). The concept of vulnerability in aged care: A systematic review of argument-based ethics literature. BMC Med. Ethics, 23.","DOI":"10.1186\/s12910-022-00819-3"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"e516010","DOI":"10.1200\/EDBK-26-516010","article-title":"Beyond Chronologic Age: Frailty, Geriatric As-sessment, and Personalized Care for Older Adults With Genitourinary Cancer","volume":"46","author":"Lee","year":"2026","journal-title":"Am. Soc. Clin. Oncol. Educ. Book."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1016\/j.tipsro.2020.09.001","article-title":"Personalised treatment for older adults with cancer: The role of frailty assessment","volume":"16","author":"Leech","year":"2020","journal-title":"Tech Innov. Patient Support Radiat. Oncol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1016\/0021-9681(87)90171-8","article-title":"A new method of classifying prognostic comorbidity in longitudinal studies: Development and validation","volume":"40","author":"Charlson","year":"1987","journal-title":"J. Chronic Dis."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Alimenti, E., Iavarone, M., Fracas, E., Canova, L., Bruccoleri, M., Antonelli, B., Ierardi, A.M., Biondetti, P., Sangiovanni, A., and Quintini, C. (2026). Modified Charlson Comorbidity Index to Im-prove Management of Patients with Hepatocellular Carcinoma: A Step Towards Mul-tiparametric Approach. Cancers, 18.","DOI":"10.3390\/cancers18071151"},{"key":"ref_19","unstructured":"National Cancer Institute (2009). Common Terminology Criteria for Adverse Events (CTCAE), Version 4.0."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Ushimaru, Y., Nagano, S., Nishikawa, K., Kawabata, R., Takeoka, T., Kitagawa, A., Ohara, N., Tomihara, H., Maeda, S., and Imazato, M. (2024). A comprehensive study on non-cancer-related mortality risk factors in elderly gastric cancer patients post-curative surgery. BMC Gastroenterol., 24.","DOI":"10.1186\/s12876-024-03170-6"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1016\/j.semradonc.2012.05.002","article-title":"Impact of age and comorbidity on treat-ment and outcomes in elderly cancer patients","volume":"22","author":"Chen","year":"2012","journal-title":"Semin. Radiat. Oncol."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Peng, X., Liu, Z., Luo, C., Sun, R., Zhang, Y., Li, B., Zou, Y., Zhu, J., and Yuan, R. (2025). PSMD12 promotes hepatocellular carcinoma progression by stabilizing CDK1. Front. Immunol., 16.","DOI":"10.3389\/fimmu.2025.1581398"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1002\/cncr.22039","article-title":"Proton beam therapy for hepatocellular carcinoma with limited treatment options","volume":"107","author":"Hata","year":"2006","journal-title":"Cancer"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"713","DOI":"10.1007\/s00066-006-1564-2","article-title":"Proton beam therapy for hepatocellular carcinoma patients with severe cirrhosis","volume":"182","author":"Hata","year":"2006","journal-title":"Strahlenther. Onkol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"805","DOI":"10.1016\/j.ijrobp.2007.04.016","article-title":"Proton beam therapy for aged patients with hepatocellular carcinoma","volume":"69","author":"Hata","year":"2007","journal-title":"Int. J. Radiat. Oncol. Biol. Phys."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"572","DOI":"10.1080\/00365521.2025.2487539","article-title":"Non-liver comorbidity in patients with hepatocellular carcinoma and curative treatments\u2014A Swedish national registry study","volume":"60","author":"Helmersson","year":"2025","journal-title":"Scand. J. Gastroenterol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"e70721","DOI":"10.1111\/liv.70721","article-title":"Summative Comorbidities Are Independently Associated With Mortality in Patients With Hepatocellular Carcinoma","volume":"46","author":"Meischl","year":"2026","journal-title":"Liver Int."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Lin, X., Zhang, S., Ong, M., Fang, J., Mu, A., Wang, K., Xu, L., Bi, X., Liu, X., and Chen, Y. (2026). Age-adjusted Charlson comorbidity index guides risk stratification for hepatocellular carcinoma patients treated with TACE combined with immune checkpoint inhibitors and targeted therapy: A multicenter retrospective cohort study. Liver Cancer.","DOI":"10.1159\/000550356"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1493","DOI":"10.24976\/Discov.Med.202537199.130","article-title":"Identification of Immune Eva-sion-Associated Genes in the Tumor Microenvironment of Hepatocellular Carcinoma and Development of a Prognostic Risk Model","volume":"37","author":"Bi","year":"2025","journal-title":"Discov. Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"156094","DOI":"10.1016\/j.phymed.2024.156094","article-title":"A multi-omic analysis reveals that Gamabufotalin exerts anti-hepatocellular carcinoma effects by regulating amino acid metabolism through targeting STAMBPL1","volume":"135","author":"Zheng","year":"2024","journal-title":"Phytomedicine"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Ding, W., Wu, J., Dou, J., Liu, F., Han, Z., Yu, J., and Liang, P. (2026). Biologically Explicable Multimodal Model Predicting Local Tumor Progression and Tumor Invasiveness of Hepatocellular Carcinoma. Hepatology, ahead of print.","DOI":"10.1097\/HEP.0000000000001678"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"676","DOI":"10.1093\/aje\/kwq433","article-title":"Updating and validating the Charlson comorbidity index and score for risk adjustment in hospital discharge abstracts using data from 6 countries","volume":"173","author":"Quan","year":"2011","journal-title":"Am. J. Epidemiol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1016\/S0895-4356(02)00585-1","article-title":"How to measure comorbidity. a critical review of available methods","volume":"56","author":"Beckerman","year":"2003","journal-title":"J. Clin. Epidemiol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2441","DOI":"10.1001\/jama.291.20.2441","article-title":"Prognostic importance of comorbidity in a hospital-based cancer registry","volume":"291","author":"Piccirillo","year":"2004","journal-title":"JAMA"}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/18\/18\/3005\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T04:13:28Z","timestamp":1789704808000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/18\/18\/3005"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,16]]},"references-count":34,"journal-issue":{"issue":"18","published-online":{"date-parts":[[2026,9]]}},"alternative-id":["cancers18183005"],"URL":"https:\/\/doi.org\/10.3390\/cancers18183005","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,16]]}}}