{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,18]],"date-time":"2025-12-18T19:52:57Z","timestamp":1766087577772,"version":"build-2065373602"},"reference-count":40,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2020,7,8]],"date-time":"2020-07-08T00:00:00Z","timestamp":1594166400000},"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>Proton beam therapy (PBT) is a curative treatment for hepatocellular carcinoma (HCC), because it can preserve liver function due to dose targeting via the Bragg peak. However, the degree of direct liver damage by PBT is unclear. In this study, we retrospectively analyzed liver\/biliary enzymes and total bilirubin (T-Bil) as markers of direct liver damage during and early after PBT in 300 patients. The levels of these enzymes and bilirubin were almost stable throughout the treatment period. In patients with normal pretreatment levels, aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), gamma-glutamyl transpeptidase (GGT), and T-Bil were abnormally elevated in only 2 (1.2%), 1 (0.4%), 0, 2 (1.2%), and 8 (3.5%) patients, respectively, and in 8 of these 13 patients (61.5%) the elevations were temporary. In patients with abnormal pretreatment levels, the levels tended to decrease during PBT. GGT and T-Bil were elevated by 1.62 and 1.57 times in patients who received 66 Gy (RBE) in 10 fractions and 74 Gy (RBE) in 37 fractions, respectively, but again these changes were temporary. These results suggest that direct damage to normal liver caused by PBT is minimal, even if a patient has abnormal pretreatment enzyme levels.<\/jats:p>","DOI":"10.3390\/cancers12071840","type":"journal-article","created":{"date-parts":[[2020,7,10]],"date-time":"2020-07-10T09:45:31Z","timestamp":1594374331000},"page":"1840","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Transitions of Liver and Biliary Enzymes during Proton Beam Therapy for Hepatocellular Carcinoma"],"prefix":"10.3390","volume":"12","author":[{"given":"Taisuke","family":"Sumiya","sequence":"first","affiliation":[{"name":"Department of Radiation Oncology, Proton Medical Research Center, University of Tsukuba Hospital, Tsukuba 305-8576, Japan"},{"name":"Department of Radiation Oncology, Tsukuba Medical Center Hospital, Tsukuba 305-8558, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7837-1301","authenticated-orcid":false,"given":"Masashi","family":"Mizumoto","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Proton Medical Research Center, University of Tsukuba Hospital, Tsukuba 305-8576, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yoshiko","family":"Oshiro","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Proton Medical Research Center, University of Tsukuba Hospital, Tsukuba 305-8576, Japan"},{"name":"Department of Radiation Oncology, Tsukuba Medical Center Hospital, Tsukuba 305-8558, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Keiichiro","family":"Baba","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Proton Medical Research Center, University of Tsukuba Hospital, Tsukuba 305-8576, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Motohiro","family":"Murakami","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Proton Medical Research Center, University of Tsukuba Hospital, Tsukuba 305-8576, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6298-9713","authenticated-orcid":false,"given":"Shosei","family":"Shimizu","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Proton Medical Research Center, University of Tsukuba Hospital, Tsukuba 305-8576, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Masatoshi","family":"Nakamura","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Proton Medical Research Center, University of Tsukuba Hospital, Tsukuba 305-8576, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuichi","family":"Hiroshima","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Proton Medical Research Center, University of Tsukuba Hospital, Tsukuba 305-8576, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Toshiki","family":"Ishida","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Proton Medical Research Center, University of Tsukuba Hospital, Tsukuba 305-8576, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takashi","family":"Iizumi","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Proton Medical Research Center, University of Tsukuba Hospital, Tsukuba 305-8576, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takashi","family":"Saito","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Proton Medical Research Center, University of Tsukuba Hospital, Tsukuba 305-8576, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Haruko","family":"Numajiri","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Proton Medical Research Center, University of Tsukuba Hospital, Tsukuba 305-8576, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0702-2304","authenticated-orcid":false,"given":"Kei","family":"Nakai","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Proton Medical Research Center, University of Tsukuba Hospital, Tsukuba 305-8576, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Toshiyuki","family":"Okumura","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Proton Medical Research Center, University of Tsukuba Hospital, Tsukuba 305-8576, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hideyuki","family":"Sakurai","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Proton Medical Research Center, University of Tsukuba Hospital, Tsukuba 305-8576, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2020,7,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Ghouri, Y.A., Mian, I., and Rowe, J.H. (2017). Review of hepatocellular carcinoma: Epidemiology, etiology, and carcinogenesis. J. Carcinog., 16.","DOI":"10.4103\/jcar.JCar_9_16"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"S2","DOI":"10.1097\/MCG.0b013e3182872f29","article-title":"Epidemiology of HCC: Consider the Population","volume":"47","author":"Mittal","year":"2013","journal-title":"J. Clin. Gastroenterol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2557","DOI":"10.1053\/j.gastro.2007.04.061","article-title":"Hepatocellular Carcinoma: Epidemiology and Molecular Carcinogenesis","volume":"132","author":"Rudolph","year":"2007","journal-title":"Gastroenterology"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1007\/s12072-017-9799-9","article-title":"Asia\u2013Pacific clinical practice guidelines on the management of hepatocellular carcinoma: A 2017 update","volume":"11","author":"Omata","year":"2017","journal-title":"Hepatol. Int."},{"key":"ref_5","unstructured":"(2018). European Association for the Study of the Liver EASL Clinical Practice Guidelines: Management of hepatocellular carcinoma. J. Hepatol., 69, 182\u2013236."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"723","DOI":"10.1002\/hep.29913","article-title":"Diagnosis, Staging, and Management of Hepatocellular Carcinoma: 2018 Practice Guidance by the American Association for the Study of Liver Diseases","volume":"68","author":"Marrero","year":"2018","journal-title":"Hepatology"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1111\/cas.13145","article-title":"Long-term outcomes of proton beam therapy in patients with previously untreated hepatocellular carcinoma","volume":"108","author":"Fukuda","year":"2017","journal-title":"Cancer Sci."},{"key":"ref_8","first-page":"31","article-title":"Three cases of hepatocellular carcinoma treated 4 times with proton beams","volume":"12","author":"Murakami","year":"2020","journal-title":"Mol. Clin. Oncol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"711","DOI":"10.1007\/s00432-019-03096-7","article-title":"Proton beam therapy for hepatocellular carcinoma associated with inferior vena cava tumor thrombus","volume":"146","author":"Sekino","year":"2020","journal-title":"J. Cancer Res. Clin. Oncol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"632","DOI":"10.1093\/jrr\/rry056","article-title":"A validated proton beam therapy patch-field protocol for effective treatment of large hepatocellular carcinoma","volume":"59","author":"Nakamura","year":"2018","journal-title":"J. Radiat. Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1007\/s11604-018-0757-9","article-title":"Normal liver tissue change after proton beam therapy","volume":"36","author":"Fukumitsu","year":"2018","journal-title":"Jpn. J. Radiol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"570","DOI":"10.14338\/IJPT-15-00035.2","article-title":"Proton Beam Therapy for Hepatocellular Carcinoma: A Review of the University of Tsukuba Experience","volume":"2","author":"Mizumoto","year":"2016","journal-title":"Int. J. Part. Ther."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1039","DOI":"10.1016\/j.ijrobp.2010.07.015","article-title":"Proton Beam Therapy for Hepatocellular Carcinoma: A Comparison of Three Treatment Protocols","volume":"81","author":"Mizumoto","year":"2011","journal-title":"Int. J. Radiat. Oncol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"782","DOI":"10.1007\/s00066-009-2020-x","article-title":"Proton-Beam Therapy for Hepatocellular Carcinoma Associated with Portal Vein Tumor Thrombosis","volume":"185","author":"Sugahara","year":"2009","journal-title":"Strahlenther. Onkol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"460","DOI":"10.1016\/j.ijrobp.2009.02.030","article-title":"Proton Beam Therapy for Large Hepatocellular Carcinoma","volume":"76","author":"Sugahara","year":"2010","journal-title":"Int. J. Radiat. Oncol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"831","DOI":"10.1016\/j.ijrobp.2008.10.073","article-title":"A Prospective Study of Hypofractionated Proton Beam Therapy for Patients With Hepatocellular Carcinoma","volume":"74","author":"Fukumitsu","year":"2009","journal-title":"Int. J. Radiat. Oncol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"462","DOI":"10.1016\/j.ijrobp.2007.09.056","article-title":"Proton Beam Therapy for Hepatocellular Carcinoma Adjacent to the Porta Hepatis","volume":"71","author":"Mizumoto","year":"2008","journal-title":"Int. J. Radiat. Oncol."},{"key":"ref_18","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."},{"key":"ref_19","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_20","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1016\/j.radonc.2014.08.015","article-title":"Association between pretreatment retention rate of indocyanine green 15min after administration and life prognosis in patients with HCC treated by proton beam therapy","volume":"113","author":"Mizumoto","year":"2014","journal-title":"Radiother. Oncol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"e529","DOI":"10.1016\/j.ijrobp.2011.05.056","article-title":"Evaluation of Liver Function After Proton Beam Therapy for Hepatocellular Carcinoma","volume":"82","author":"Mizumoto","year":"2012","journal-title":"Int. J. Radiat. Oncol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1016\/j.radonc.2017.03.004","article-title":"Analysis of repeated proton beam therapy for patients with hepatocellular carcinoma","volume":"123","author":"Oshiro","year":"2017","journal-title":"Radiother. Oncol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1038\/ajg.2016.517","article-title":"ACG Clinical Guideline: Evaluation of Abnormal Liver Chemistries","volume":"112","author":"Kwo","year":"2017","journal-title":"Am. J. Gastroenterol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2027","DOI":"10.1093\/clinchem\/46.12.2027","article-title":"Diagnosis and Monitoring of Hepatic Injury. I. Performance Characteristics of Laboratory Tests","volume":"46","author":"Dufour","year":"2000","journal-title":"Clin. Chem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2050","DOI":"10.1093\/clinchem\/46.12.2050","article-title":"Diagnosis and Monitoring of Hepatic Injury. II. Recommendations for Use of Laboratory Tests in Screening, Diagnosis, and Monitoring","volume":"46","author":"Dufour","year":"2000","journal-title":"Clin. Chem."},{"key":"ref_26","unstructured":"Walker, H.K., Hall, W.D., and Hurst, J.W. (1990). Alkaline Phosphatase and Gamma Glutamyltransferase. Clinical Methods: The History, Physical, and Laboratory Examinations, Butterworths."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1016\/S0168-8278(86)80014-9","article-title":"What can we learn from analysis of serum bilirubin?","volume":"2","author":"Fevery","year":"1986","journal-title":"J. Hepatol."},{"key":"ref_28","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_29","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1016\/j.meddos.2007.04.008","article-title":"Proton Radiotherapy for Liver Tumors: Dosimetric Advantages Over Photon Plans","volume":"33","author":"Wang","year":"2008","journal-title":"Med. Dosim."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1016\/j.prro.2015.01.004","article-title":"Clinical decision tool for optimal delivery of liver stereotactic body radiation therapy: Photons versus protons","volume":"5","author":"Gandhi","year":"2015","journal-title":"Pract. Radiat. Oncol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"e447","DOI":"10.1016\/j.ijrobp.2011.04.011","article-title":"Stereotactic Body Radiotherapy for Primary Hepatocellular Carcinoma","volume":"81","author":"Andolino","year":"2011","journal-title":"Int. J. Radiat. Oncol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"412","DOI":"10.1016\/j.radonc.2014.05.002","article-title":"Outcomes following definitive stereotactic body radiotherapy for patients with Child-Pugh B or C hepatocellular carcinoma","volume":"111","author":"Culleton","year":"2014","journal-title":"Radiother. Oncol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1237","DOI":"10.1016\/0360-3016(94)00418-K","article-title":"Hepatic toxicity resulting from cancer treatment","volume":"31","author":"Lawrence","year":"1995","journal-title":"Int. J. Radiat. Oncol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"3053","DOI":"10.1002\/cncr.25809","article-title":"The safety and efficacy of high-dose proton beam radiotherapy for hepatocellular carcinoma: A phase 2 prospective trial","volume":"117","author":"Bush","year":"2011","journal-title":"Cancers"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"4114","DOI":"10.3390\/cancers3044114","article-title":"Distribution of Functional Liver Volume in Hepatocellular Carcinoma Patients with Portal Vein Tumor Thrombus in the 1st Branch and Main Trunk Using Single Photon Emission Computed Tomography\u2014Application to Radiation Therapy","volume":"3","author":"Shirai","year":"2011","journal-title":"Cancers"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"853","DOI":"10.1016\/0360-3016(89)90078-3","article-title":"Irradiation synchronized with respiration gate","volume":"17","author":"Ohara","year":"1989","journal-title":"Int. J. Radiat. Oncol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"951","DOI":"10.1016\/j.ijrobp.2004.06.026","article-title":"Correlation between the respiratory waveform measured using a respiratory sensor and 3D tumor motion in gated radiotherapy","volume":"60","author":"Tsunashima","year":"2004","journal-title":"Int. J. Radiat. Oncol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"87","DOI":"10.2307\/2340521","article-title":"On the Interpretation of \u03c72 from Contingency Tables, and the Calculation of P","volume":"85","author":"Fisher","year":"1922","journal-title":"J. R. Stat. Soc."},{"key":"ref_39","first-page":"28","article-title":"The generalization of students\u2019 problem when several different population variances are involved","volume":"34","author":"Welch","year":"1947","journal-title":"Biometrika"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"452","DOI":"10.1038\/bmt.2012.244","article-title":"Investigation of the freely available easy-to-use software \u2018EZR\u2019 for medical statistics","volume":"48","author":"Kanda","year":"2013","journal-title":"Bone Marrow Transplant."}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/12\/7\/1840\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T09:48:59Z","timestamp":1760176139000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/12\/7\/1840"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,7,8]]},"references-count":40,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2020,7]]}},"alternative-id":["cancers12071840"],"URL":"https:\/\/doi.org\/10.3390\/cancers12071840","relation":{},"ISSN":["2072-6694"],"issn-type":[{"type":"electronic","value":"2072-6694"}],"subject":[],"published":{"date-parts":[[2020,7,8]]}}}