{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,15]],"date-time":"2026-06-15T13:49:23Z","timestamp":1781531363098,"version":"3.54.5"},"reference-count":41,"publisher":"Elsevier BV","issue":"11","license":[{"start":{"date-parts":[[2021,11,1]],"date-time":"2021-11-01T00:00:00Z","timestamp":1635724800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/tdm\/userlicense\/1.0\/"},{"start":{"date-parts":[[2021,11,1]],"date-time":"2021-11-01T00:00:00Z","timestamp":1635724800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/legal\/tdmrep-license"},{"start":{"date-parts":[[2021,8,9]],"date-time":"2021-08-09T00:00:00Z","timestamp":1628467200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100007449","name":"Takeda Science Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007449","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["clinicalkey.com","clinicalkey.com.au","clinicalkey.es","clinicalkey.fr","clinicalkey.jp","elsevier.com","sciencedirect.com"],"crossmark-restriction":true},"short-container-title":["Translational Oncology"],"published-print":{"date-parts":[[2021,11]]},"DOI":"10.1016\/j.tranon.2021.101201","type":"journal-article","created":{"date-parts":[[2021,8,11]],"date-time":"2021-08-11T01:20:31Z","timestamp":1628644831000},"page":"101201","update-policy":"https:\/\/doi.org\/10.1016\/elsevier_cm_policy","source":"Crossref","is-referenced-by-count":6,"title":["Efficacy and tolerability of Sorafenib plus metronomic chemotherapy S-1 for advanced hepatocellular carcinoma in preclinical and clinical assessments"],"prefix":"10.1016","volume":"14","author":[{"given":"Hiroyuki","family":"Suzuki","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hideki","family":"Iwamoto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masahito","family":"Nakano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toru","family":"Nakamura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Atsutaka","family":"Masuda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takahiko","family":"Sakaue","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toshimitsu","family":"Tanaka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dan","family":"Nakano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryoko","family":"Kuromatsu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takashi","family":"Niizeki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shusuke","family":"Okamura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shigeo","family":"Shimose","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomotake","family":"Shirono","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Noda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naoki","family":"Kamachi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hirohisa","family":"Yano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Atsushi","family":"Kawaguchi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hironori","family":"Koga","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takuji","family":"Torimura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"78","reference":[{"key":"10.1016\/j.tranon.2021.101201_bib0001","first-page":"209","article-title":"Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"71","author":"Sung","year":"2021","journal-title":"CA Cancer J. Clin."},{"key":"10.1016\/j.tranon.2021.101201_bib0002","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":"El-Serag","year":"2007","journal-title":"Gastroenterology"},{"key":"10.1016\/j.tranon.2021.101201_bib0003","first-page":"6","volume":"7","author":"Llovet","year":"2021","journal-title":"Hepatocellular carcinoma. Nat. Rev."},{"key":"10.1016\/j.tranon.2021.101201_bib0004","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1016\/j.suronc.2016.03.002","article-title":"Hepatocellular carcinoma: From diagnosis to treatment","volume":"25","author":"Grandhi","year":"2016","journal-title":"Surg. Oncol."},{"key":"10.1016\/j.tranon.2021.101201_bib0005","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1016\/j.jhep.2018.03.019","article-title":"European Association for the Study of the Liver. Electronic address eee, European Association for the Study of the L. EASL clinical practice guidelines: management of hepatocellular carcinoma","volume":"69","year":"2018","journal-title":"J. Hepatol."},{"key":"10.1016\/j.tranon.2021.101201_bib0006","doi-asserted-by":"crossref","first-page":"637","DOI":"10.2217\/imt-2021-0026","article-title":"Atezolizumab in advanced hepatocellular carcinoma: good things come to those who wait","volume":"13","author":"Rizzo","year":"2021","journal-title":"Immunotherapy"},{"key":"10.1016\/j.tranon.2021.101201_bib0007","doi-asserted-by":"crossref","first-page":"378","DOI":"10.1056\/NEJMoa0708857","article-title":"Sorafenib in advanced hepatocellular carcinoma","volume":"359","author":"Llovet","year":"2008","journal-title":"N. Engl. J. Med."},{"key":"10.1016\/j.tranon.2021.101201_bib0008","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/S1470-2045(08)70285-7","article-title":"Efficacy and safety of Sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomized, double-blind, placebo-controlled trial","volume":"10","author":"Cheng","year":"2009","journal-title":"Lancet Oncol."},{"key":"10.1016\/j.tranon.2021.101201_bib0009","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1200\/JCO.2013.53.7746","article-title":"SEARCH: a phase III, randomized, double-blind, placebo-controlled trial of Sorafenib plus Erlotinib in patients with advanced hepatocellular carcinoma","volume":"33","author":"Zhu","year":"2015","journal-title":"J. Clin. Oncol."},{"key":"10.1016\/j.tranon.2021.101201_bib0010","doi-asserted-by":"crossref","DOI":"10.1001\/jamaoncol.2019.2792","article-title":"Assessment of treatment with Sorafenib Plus Doxorubicin vs Sorafenib alone in patients with advanced hepatocellular carcinoma: phase 3 CALGB 80802 randomized clinical trial","author":"Abou-Alfa","year":"2019","journal-title":"JAMA Oncol"},{"key":"10.1016\/j.tranon.2021.101201_bib0011","doi-asserted-by":"crossref","first-page":"424","DOI":"10.1016\/S2468-1253(18)30078-5","article-title":"Sorafenib plus low-dose Cisplatin and fluorouracil hepatic arterial infusion chemotherapy versus Sorafenib alone in patients with advanced hepatocellular carcinoma (SILIUS): a randomized, open label, phase 3 trial","volume":"3","author":"Kudo","year":"2018","journal-title":"Lancet Gastroenterol. Hepatol."},{"key":"10.1016\/j.tranon.2021.101201_bib0012","doi-asserted-by":"crossref","first-page":"755","DOI":"10.3892\/etm.2012.484","article-title":"Combination therapy using oral S-1 and targeted agents against human tumor Xenografts in nude mice","volume":"3","author":"Nukatsuka","year":"2012","journal-title":"Exp. Ther. Med"},{"key":"10.1016\/j.tranon.2021.101201_bib0013","doi-asserted-by":"crossref","first-page":"548","DOI":"10.1097\/00001813-199607000-00010","article-title":"Development of a novel form of an oral 5-fluorouracil derivative (S-1) directed to the potentiation of the tumor selective cytotoxicity of 5-fluorouracil by two biochemical modulators","volume":"7","author":"Shirasaka","year":"1996","journal-title":"Anticancer Drugs"},{"key":"10.1016\/j.tranon.2021.101201_bib0014","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1016\/S2468-1253(17)30072-9","article-title":"S-1 versus placebo in patients with Sorafenib-refractory advanced hepatocellular carcinoma (S-CUBE): a randomized, double-blind, multi-centre, phase 3 trial","volume":"2","author":"Kudo","year":"2017","journal-title":"Lancet Gastroenterol. Hepatol."},{"key":"10.1016\/j.tranon.2021.101201_bib0015","doi-asserted-by":"crossref","first-page":"1045","DOI":"10.1172\/JCI9872","article-title":"Less is more, regularly: metronomic dosing of cytotoxic drugs can target tumor angiogenesis in mice","volume":"105","author":"Hanahan","year":"2000","journal-title":"J. Clin. Invest."},{"key":"10.1016\/j.tranon.2021.101201_bib0016","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1038\/nrc1369","article-title":"The anti-angiogenic basis of metronomic chemotherapy","volume":"4","author":"Kerbel","year":"2004","journal-title":"Nat. Rev. Cancer"},{"key":"10.1016\/j.tranon.2021.101201_bib0017","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1038\/nrclinonc.2015.89","article-title":"Gastrointestinal cancer: rationale for metronomic chemotherapy in phase III trials","volume":"12","author":"Kerbel","year":"2015","journal-title":"Nat. Rev. Clin Oncol"},{"key":"10.1016\/j.tranon.2021.101201_bib0018","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1593\/neo.101186","article-title":"Metronomic S-1 chemotherapy and Vandetanib: an efficacious and nontoxic treatment for hepatocellular carcinoma","volume":"13","author":"Iwamoto","year":"2011","journal-title":"Neoplasia"},{"key":"10.1016\/j.tranon.2021.101201_bib0019","first-page":"4342","article-title":"Maximum tolerable dose and low-dose metronomic chemotherapy have opposite effects on the mobilization and viability of circulating endothelial progenitor cells","volume":"63","author":"Bertolini","year":"2003","journal-title":"Cancer Res."},{"key":"10.1016\/j.tranon.2021.101201_bib0020","doi-asserted-by":"crossref","first-page":"320","DOI":"10.1002\/hep.1840180216","article-title":"Establishment of two distinct human hepatocellular carcinoma cell lines from a single nodule showing clonal dedifferentiation of cancer cells","volume":"18","author":"Yano","year":"1993","journal-title":"Hepatology"},{"key":"10.1016\/j.tranon.2021.101201_bib0021","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1007\/s00280-006-0393-4","article-title":"Sorafenib (BAY 43-9006) inhibits tumor growth and vascularization and induces tumor apoptosis and hypoxia in RCC xenograft models","volume":"59","author":"Chang","year":"2007","journal-title":"Cancer Chemother. Pharmacol."},{"key":"10.1016\/j.tranon.2021.101201_bib0022","first-page":"693","article-title":"Preclinical antitumor efficacy of S-1: a new oral formulation of 5-fluorouracil on human tumor xenografts","volume":"13","author":"Fukushima","year":"1998","journal-title":"Int J Oncol"},{"key":"10.1016\/j.tranon.2021.101201_bib0023","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1007\/s00795-013-0016-1","article-title":"A murine model for non-alcoholic Steatohepatitis showing evidence of association between diabetes and hepatocellular carcinoma","volume":"46","author":"Fujii","year":"2013","journal-title":"Med. Mol. Morphol."},{"key":"10.1016\/j.tranon.2021.101201_bib0024","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1055\/s-0030-1247132","article-title":"Modified RECIST (mRECIST) assessment for hepatocellular carcinoma","volume":"30","author":"Lencioni","year":"2010","journal-title":"Semin. Liver Dis."},{"key":"10.1016\/j.tranon.2021.101201_bib0025","doi-asserted-by":"crossref","first-page":"2606","DOI":"10.1111\/j.1349-7006.2010.01730.x","article-title":"Phase I\/II study of the pharmacokinetics, safety and efficacy of S-1 in patients with advanced hepatocellular carcinoma","volume":"101","author":"Furuse","year":"2010","journal-title":"Cancer Sci."},{"key":"10.1016\/j.tranon.2021.101201_bib0026","doi-asserted-by":"crossref","first-page":"e11416","DOI":"10.15252\/emmm.201911416","article-title":"Metronomic chemotherapy offsets HIFalpha induction upon maximum-tolerated dose in metastatic cancers","volume":"12","author":"Schito","year":"2020","journal-title":"EMBO Mol. Med."},{"key":"10.1016\/j.tranon.2021.101201_bib0027","doi-asserted-by":"crossref","DOI":"10.1155\/2019\/5483791","article-title":"Metronomic chemotherapy: a systematic review of the literature and clinical experience","volume":"2019","author":"Simsek","year":"2019","journal-title":"J. Oncol."},{"key":"10.1016\/j.tranon.2021.101201_bib0028","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1593\/tlo.13481","article-title":"Metronomic chemotherapy: possible clinical application in advanced hepatocellular carcinoma","volume":"6","author":"Torimura","year":"2013","journal-title":"Transl. Oncol."},{"key":"10.1016\/j.tranon.2021.101201_bib0029","doi-asserted-by":"crossref","first-page":"1557","DOI":"10.1007\/s00280-011-1660-6","article-title":"Sorafenib augments cytotoxic effect of S-1 in vitro and in vivo through TS suppression","volume":"68","author":"Takeuchi","year":"2011","journal-title":"Cancer Chemother. Pharmacol."},{"key":"10.1016\/j.tranon.2021.101201_bib0030","doi-asserted-by":"crossref","first-page":"1255","DOI":"10.1007\/s00280-013-2120-2","article-title":"Sorafenib enhances the chemotherapeutic efficacy of S-1 against hepatocellular carcinoma through down regulation of transcription factor E2F-1","volume":"71","author":"Zhai","year":"2013","journal-title":"Cancer Chemother. Pharmacol."},{"key":"10.1016\/j.tranon.2021.101201_bib0031","doi-asserted-by":"crossref","first-page":"928","DOI":"10.1593\/neo.10804","article-title":"Development of a resistance-like phenotype to Sorafenib by human hepatocellular carcinoma cells is reversible and can be delayed by metronomic UFT chemotherapy","volume":"12","author":"Tang","year":"2010","journal-title":"Neoplasia"},{"key":"10.1016\/j.tranon.2021.101201_bib0032","doi-asserted-by":"crossref","first-page":"1663","DOI":"10.3390\/cancers12061663","article-title":"Molecular bases of drug resistance in hepatocellular carcinoma","volume":"12","author":"Marin","year":"2020","journal-title":"Cancers"},{"key":"10.1016\/j.tranon.2021.101201_bib0033","doi-asserted-by":"crossref","first-page":"1029","DOI":"10.1007\/s00280-009-1108-4","article-title":"Beneficial effect of metronomic chemotherapy on tumor suppression and survival in a rat model of hepatocellular carcinoma with liver cirrhosis","volume":"65","author":"Park","year":"2010","journal-title":"Cancer Chemother. Pharmacol."},{"key":"10.1016\/j.tranon.2021.101201_bib0034","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1016\/j.biopha.2017.01.107","article-title":"Sorafenib: a potential therapeutic drug for hepatic fibrosis and its outcomes","volume":"88","author":"Ma","year":"2017","journal-title":"Biomed. Pharmacother."},{"key":"10.1016\/j.tranon.2021.101201_bib0035","doi-asserted-by":"crossref","first-page":"689","DOI":"10.1016\/j.cgh.2009.02.021","article-title":"Incidence, prevalence, and clinical significance of abnormal hematologic indices in compensated cirrhosis","volume":"7","author":"Qamar","year":"2009","journal-title":"Clin. Gastroenterol. Hepatol."},{"key":"10.1016\/j.tranon.2021.101201_bib0036","doi-asserted-by":"crossref","first-page":"1894","DOI":"10.1056\/NEJMoa1915745","article-title":"Atezolizumab plus Bevacizumab in Unresectable Hepatocellular Carcinoma","volume":"382","author":"Finn","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"10.1016\/j.tranon.2021.101201_bib0037","doi-asserted-by":"crossref","DOI":"10.3390\/cancers13020238","article-title":"The new immuno-oncology-based therapies and their perspectives in hepatocellular carcinoma","volume":"13","author":"Merle","year":"2021","journal-title":"Cancers (Basel)"},{"key":"10.1016\/j.tranon.2021.101201_bib0038","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1038\/s41586-021-03362-0","article-title":"NASH limits anti-tumour surveillance in immunotherapy-treated HCC","volume":"592","author":"Pfister","year":"2021","journal-title":"Nat"},{"key":"10.1016\/j.tranon.2021.101201_bib0039","doi-asserted-by":"crossref","first-page":"42499","DOI":"10.1038\/srep42499","article-title":"Metronomic capecitabine versus best supportive care as second-line treatment in hepatocellular carcinoma: a retrospective study","volume":"7","author":"Casadei Gardini","year":"2017","journal-title":"Sci Rep"},{"key":"10.1016\/j.tranon.2021.101201_bib0040","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1007\/s12032-017-1040-0","article-title":"Communicative reprogramming non-curative hepatocellular carcinoma with low-dose metronomic chemotherapy, COX-2 inhibitor and PPAR-gamma agonist: a phase II trial","volume":"34","author":"Walter","year":"2017","journal-title":"Med Oncol"},{"key":"10.1016\/j.tranon.2021.101201_bib0041","doi-asserted-by":"crossref","first-page":"128","DOI":"10.3350\/cmh.2016.0071","article-title":"A comparative study of Sorafenib and metronomic chemotherapy for Barcelona Clinic Liver Cancer-stage C hepatocellular carcinoma with poor liver function","volume":"23","author":"Yang","year":"2017","journal-title":"Clin Mol Hepatol"}],"container-title":["Translational Oncology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S1936523321001935?httpAccept=text\/xml","content-type":"text\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S1936523321001935?httpAccept=text\/plain","content-type":"text\/plain","content-version":"vor","intended-application":"text-mining"}],"deposited":{"date-parts":[[2025,10,30]],"date-time":"2025-10-30T17:19:55Z","timestamp":1761844795000},"score":1,"resource":{"primary":{"URL":"https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S1936523321001935"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,11]]},"references-count":41,"journal-issue":{"issue":"11","published-print":{"date-parts":[[2021,11]]}},"alternative-id":["S1936523321001935"],"URL":"https:\/\/doi.org\/10.1016\/j.tranon.2021.101201","relation":{},"ISSN":["1936-5233"],"issn-type":[{"value":"1936-5233","type":"print"}],"subject":[],"published":{"date-parts":[[2021,11]]},"assertion":[{"value":"Elsevier","name":"publisher","label":"This article is maintained by"},{"value":"Efficacy and tolerability of Sorafenib plus metronomic chemotherapy S-1 for advanced hepatocellular carcinoma in preclinical and clinical assessments","name":"articletitle","label":"Article Title"},{"value":"Translational Oncology","name":"journaltitle","label":"Journal Title"},{"value":"https:\/\/doi.org\/10.1016\/j.tranon.2021.101201","name":"articlelink","label":"CrossRef DOI link to publisher maintained version"},{"value":"article","name":"content_type","label":"Content Type"},{"value":"\u00a9 2021 Published by Elsevier Inc.","name":"copyright","label":"Copyright"}],"article-number":"101201"}}