{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T11:51:15Z","timestamp":1791287475048,"version":"4.1.0"},"reference-count":43,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2012,11,8]],"date-time":"2012-11-08T00:00:00Z","timestamp":1352332800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Aliment Pharmacol Ther"],"published-print":{"date-parts":[[2013,1]]},"abstract":"<jats:title>Summary<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Deregulation of mammalian target of rapamycin (<jats:styled-content style=\"fixed-case\">mTOR<\/jats:styled-content>) signalling is common in human hepatocellular carcinoma (<jats:styled-content style=\"fixed-case\">HCC<\/jats:styled-content>).<\/jats:p><\/jats:sec><jats:sec><jats:title>Aim<\/jats:title><jats:p>To determine the maximum tolerated dose (<jats:styled-content style=\"fixed-case\">MTD<\/jats:styled-content>) of the oral <jats:styled-content style=\"fixed-case\">mTOR<\/jats:styled-content> inhibitor everolimus in advanced <jats:styled-content style=\"fixed-case\">HCC<\/jats:styled-content> patients.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Patients with locally advanced or metastatic <jats:styled-content style=\"fixed-case\">HCC<\/jats:styled-content> (Child\u2010Pugh class A or B) were enrolled in an open\u2010label phase 1 study and randomly assigned to daily (2.5\u201310\u00a0mg) or weekly (20\u201370\u00a0mg) everolimus in a standard 3\u00a0+\u00a03 dose\u2010escalation design. <jats:styled-content style=\"fixed-case\">MTD<\/jats:styled-content> was based on the rate of dose\u2010limiting toxicities (<jats:styled-content style=\"fixed-case\">DLT<\/jats:styled-content>s). Secondary endpoints included safety, pharmacokinetics and tumour response. In a <jats:italic>post hoc<\/jats:italic> analysis, serum hepatitis B virus (<jats:styled-content style=\"fixed-case\">HBV<\/jats:styled-content>) <jats:styled-content style=\"fixed-case\">DNA<\/jats:styled-content> levels were quantified.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Thirty\u2010nine patients were enrolled. <jats:styled-content style=\"fixed-case\">DLT<\/jats:styled-content>s occurred in five of 21 patients in the daily and two of 19 patients in the weekly cohort. Daily and weekly <jats:styled-content style=\"fixed-case\">MTD<\/jats:styled-content>s were 7.5\u00a0mg and 70\u00a0mg respectively. Grade 3\/4 adverse events with a \u226510% incidence were thrombocytopenia, hypophosphataemia and alanine transaminase (<jats:styled-content style=\"fixed-case\">ALT<\/jats:styled-content>) elevation. In four hepatitis B surface antigen (HBsAg)\u2010seropositive patients, grade 3\/4 <jats:styled-content style=\"fixed-case\">ALT<\/jats:styled-content> elevations were accompanied by significant (&gt;1 log) increases in serum <jats:styled-content style=\"fixed-case\">HBV<\/jats:styled-content> levels. The incidence of hepatitis flare (defined as <jats:styled-content style=\"fixed-case\">ALT<\/jats:styled-content> increase &gt;100\u00a0IU\/mL from baseline) in HBsAg\u2010seropositive patients with and without detectable serum <jats:styled-content style=\"fixed-case\">HBV DNA<\/jats:styled-content> before treatment was 46.2% and 7.1% respectively (<jats:italic>P\u00a0<\/jats:italic>&lt;<jats:italic>\u00a0<\/jats:italic>0.01, Fisher exact test). Disease control rates in the daily and weekly cohorts were 71.4% and 44.4% respectively.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>The recommended everolimus dosing schedule for future hepatocellular carcinoma studies is 7.5\u00a0mg daily. Prophylactic anti\u2010viral therapy should be mandatory for <jats:styled-content style=\"fixed-case\">HB<\/jats:styled-content>sAg\u2010seropositive patients (<jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"ClinicalTrials.gov\">ClinicalTrials.gov<\/jats:ext-link> NCT00390195).<\/jats:p><\/jats:sec>","DOI":"10.1111\/apt.12132","type":"journal-article","created":{"date-parts":[[2012,11,8]],"date-time":"2012-11-08T07:46:22Z","timestamp":1352360782000},"page":"62-73","source":"Crossref","is-referenced-by-count":59,"title":["Randomised clinical trial: comparison of two everolimus dosing schedules in patients with advanced hepatocellular carcinoma"],"prefix":"10.1111","volume":"37","author":[{"given":"H.\u2010S.","family":"Shiah","sequence":"first","affiliation":[{"name":"National Institute of Cancer Research National Health Research Institutes Tainan Taiwan"},{"name":"Department of Internal Medicine National Cheng Kung University Hospital College of Medicine National Cheng Kung University Tainan Taiwan"},{"name":"Department of Internal Medicine Division of Hematology and Oncology Taipei Medical University Hospital Taipei Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C.\u2010Y.","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine National Cheng Kung University Hospital College of Medicine National Cheng Kung University Tainan Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C.\u2010Y.","family":"Dai","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine and Cancer Center Kaohsiung Medical University Hospital Kaohsiung Medical University Kaohsiung Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C.\u2010F.","family":"Hsiao","sequence":"additional","affiliation":[{"name":"Institute of Population Health Sciences National Health Research Institutes Zhunan Miaoli County Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Y.\u2010J.","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Surgery National Cheng Kung University Hospital College of Medicine National Cheng Kung University Tainan Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"W.\u2010C.","family":"Su","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine National Cheng Kung University Hospital College of Medicine National Cheng Kung University Tainan Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J.\u2010Y.","family":"Chang","sequence":"additional","affiliation":[{"name":"National Institute of Cancer Research National Health Research Institutes Tainan Taiwan"},{"name":"Department of Internal Medicine National Cheng Kung University Hospital College of Medicine National Cheng Kung University Tainan Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J.","family":"Whang\u2010Peng","sequence":"additional","affiliation":[{"name":"National Institute of Cancer Research National Health Research Institutes Tainan Taiwan"},{"name":"Cancer Center Wan Fang Hospital Taipei Medical University Taipei Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"P.\u2010W.","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Surgery National Cheng Kung University Hospital College of Medicine National Cheng Kung University Tainan Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J.\u2010D.","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Pharmacology College of Medicine National Cheng Kung University Tainan Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"L.\u2010T.","family":"Chen","sequence":"additional","affiliation":[{"name":"National Institute of Cancer Research National Health Research Institutes Tainan Taiwan"},{"name":"Department of Internal Medicine National Cheng Kung University Hospital College of Medicine National Cheng Kung University Tainan Taiwan"},{"name":"Department of Internal Medicine and Cancer Center Kaohsiung Medical University Hospital Kaohsiung Medical University Kaohsiung Taiwan"},{"name":"Department of Pharmacology College of Medicine National Cheng Kung University Tainan Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2012,11,8]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.25516"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2007.04.061"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(11)61347-0"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2036.2006.02932.x"},{"key":"e_1_2_7_6_1","unstructured":"National Comprehensive Cancer Network Inc.NCCN Clinical Practice Guidelines in Oncology: Hepatobiliary Cancers. 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