{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,11]],"date-time":"2026-03-11T17:52:39Z","timestamp":1773251559805,"version":"3.50.1"},"reference-count":29,"publisher":"Oxford University Press (OUP)","issue":"9","license":[{"start":{"date-parts":[[2021,11,29]],"date-time":"2021-11-29T00:00:00Z","timestamp":1638144000000},"content-version":"vor","delay-in-days":768,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,9,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Lessons Learned<\/jats:title>\n                  <jats:p>Recruitment of patients with advanced hepatocellular carcinoma and Child-Pugh B for sorafenib treatment and additional pharmacokinetic studies is challenging. Patients with Child-Pugh B liver cirrhosis have high rates of cirrhosis-related adverse events.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Few data are available on the pharmacokinetics (PK) of sorafenib in patients with advanced hepatocellular carcinoma (HCC) and Child-Pugh B liver cirrhosis. This study aimed to explore the sorafenib PK and its relationship with efficacy and toxicity in these patients.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>Patients with advanced HCC and Child-Pugh B7-8 liver function were prospectively recruited at a tertiary center. Adverse events (AEs), progression-free survival (PFS), and overall survival (OS) were recorded. Patients received a starting dose of 200 b.i.d. with toxicity-adjusted dose escalation to a target dose of 400 mg b.i.d. with PK sampling at fixed time points.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Between May 2014 and March 2017, 12 patients were screened, of whom 7 progressed to a terminal stage during the screening (n =\u20096) or shortly after recruitment (n =\u20091). The five included patients had median PFS of 3.8 months (range, 1.7\u201310.8) and OS of 7.4 months (range, 1.7\u201325.8). Three patients had severe AEs and one patient had a partial response with an OS of 25.8 months. In 2017, the trial was aborted for lack of accrual.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>Because of low accrual, no conclusion can be drawn on the sorafenib PK in patients with advanced HCC and Child-Pugh B liver cirrhosis. The poor survival and frequent cirrhosis-related AEs suggest limited benefit for most of these patients.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1634\/theoncologist.2019-0718","type":"journal-article","created":{"date-parts":[[2019,10,23]],"date-time":"2019-10-23T18:45:17Z","timestamp":1571856317000},"page":"e1274-e1279","source":"Crossref","is-referenced-by-count":12,"title":["Sorafenib for Patients with Hepatocellular Carcinoma and Child-Pugh B Liver Cirrhosis: Lessons Learned from a Terminated Study"],"prefix":"10.1093","volume":"25","author":[{"given":"Tim A.","family":"Labeur","sequence":"first","affiliation":[{"name":"Department of Medical Oncology, Amsterdam University Medical Centers, University of Amsterdam, Meibergdreef 9, Amsterdam, The Netherlands"},{"name":"Cancer Center Amsterdam, Amsterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Roos","family":"Achterbergh","sequence":"additional","affiliation":[{"name":"Hospital Pharmacy, Amsterdam University Medical Centers, University of Amsterdam, Meibergdreef 9, Amsterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bart","family":"Takkenberg","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Amsterdam University Medical Centers, University of Amsterdam, Meibergdreef 9, Amsterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Otto","family":"Van Delden","sequence":"additional","affiliation":[{"name":"Department of Radiology and Nuclear Medicine, Amsterdam University Medical Centers, University of Amsterdam, Meibergdreef 9, Amsterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ron","family":"Math\u00f4t","sequence":"additional","affiliation":[{"name":"Hospital Pharmacy, Amsterdam University Medical Centers, University of Amsterdam, Meibergdreef 9, Amsterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Heinz-Josef","family":"Kl\u00fcmpen","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Amsterdam University Medical Centers, University of Amsterdam, Meibergdreef 9, Amsterdam, The Netherlands"},{"name":"Cancer Center Amsterdam, Amsterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2019,10,23]]},"reference":[{"key":"2021122510543327200_onco13123-bib-0001","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1016\/j.jhep.2018.03.019","article-title":"EASL clinical practice guidelines: Management of hepatocellular carcinoma","volume":"69","year":"2018","journal-title":"J Hepatol"},{"key":"2021122510543327200_onco13123-bib-0002","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1002\/hep.29086","article-title":"AASLD guidelines for the treatment of hepatocellular carcinoma","volume":"67","author":"Heimbach","year":"2018","journal-title":"Hepatology"},{"key":"2021122510543327200_onco13123-bib-0003","doi-asserted-by":"crossref","first-page":"iv238","DOI":"10.1093\/annonc\/mdy308","article-title":"Hepatocellular carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up","volume":"29","author":"Vogel","year":"2018","journal-title":"Ann Oncol"},{"key":"2021122510543327200_onco13123-bib-0004","first-page":"40","article-title":"Safety and efficacy of sorafenib in patients with hepatocellular carcinoma (HCC) and Child-Pugh A versus B cirrhosis","volume":"4","author":"Abou-Alfa","year":"2011","journal-title":"Gastrointest Cancer Res"},{"key":"2021122510543327200_onco13123-bib-0005","doi-asserted-by":"crossref","first-page":"793","DOI":"10.3892\/mco.2015.536","article-title":"Safety and efficacy of sorafenib in patients with Child-Pugh B advanced hepatocellular carcinoma","volume":"3","author":"DA Fonseca","year":"2015","journal-title":"Mol Clin Oncol"},{"key":"2021122510543327200_onco13123-bib-0006","doi-asserted-by":"crossref","first-page":"1821","DOI":"10.1111\/liv.13170","article-title":"A multicentre comparison between child pugh and albumin-bilirubin scores in patients treated with sorafenib for hepatocellular carcinoma","volume":"36","author":"Edeline","year":"2016","journal-title":"Liver Int"},{"key":"2021122510543327200_onco13123-bib-0007","doi-asserted-by":"crossref","first-page":"1193","DOI":"10.1111\/j.1365-2036.2011.04860.x","article-title":"Safety and efficacy of sorafenib in hepatocellular carcinoma: The impact of the Child-Pugh score","volume":"34","author":"Hollebecque","year":"2011","journal-title":"Aliment Pharmacol Ther"},{"key":"2021122510543327200_onco13123-bib-0008","doi-asserted-by":"crossref","first-page":"2055","DOI":"10.1002\/hep.24644","article-title":"Field-practice study of sorafenib therapy for hepatocellular carcinoma: A prospective multicenter study in italy","volume":"54","author":"Iavarone","year":"2011","journal-title":"Hepatology"},{"key":"2021122510543327200_onco13123-bib-0009","doi-asserted-by":"crossref","first-page":"1467","DOI":"10.1080\/0284186X.2018.1479070","article-title":"Are we SHARP enough? The importance of adequate patient selection in sorafenib treatment for hepatocellular carcinoma","volume":"57","author":"Labeur","year":"2018","journal-title":"Acta Oncologica"},{"key":"2021122510543327200_onco13123-bib-0010","doi-asserted-by":"crossref","first-page":"1140","DOI":"10.1016\/j.jhep.2016.07.020","article-title":"Observational registry of sorafenib use in clinical practice across Child-Pugh subgroups: The GIDEON study","volume":"65","author":"Marrero","year":"2016","journal-title":"J Hepatol"},{"key":"2021122510543327200_onco13123-bib-0011","doi-asserted-by":"crossref","first-page":"729","DOI":"10.1007\/s10637-015-0237-3","article-title":"Sorafenib treatment in Child-Pugh A and B patients with advanced hepatocellular carcinoma: Safety, efficacy and prognostic factors","volume":"33","author":"Ogasawara","year":"2015","journal-title":"Invest New Drugs"},{"key":"2021122510543327200_onco13123-bib-0012","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1634\/theoncologist.2008-0191","article-title":"Sorafenib in unresectable hepatocellular carcinoma from mild to advanced stage liver cirrhosis","volume":"14","author":"Pinter","year":"2009","journal-title":"The Oncologist"},{"key":"2021122510543327200_onco13123-bib-0013","doi-asserted-by":"crossref","first-page":"406","DOI":"10.1093\/annonc\/mds343","article-title":"Sorafenib in patients with Child-Pugh class A and B advanced hepatocellular carcinoma: A prospective feasibility analysis","volume":"24","author":"Pressiani","year":"2013","journal-title":"Ann Oncol"},{"key":"2021122510543327200_onco13123-bib-0014","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1097\/MCG.0b013e31818ddfc6","article-title":"Safety and efficacy of sorafenib in patients with advanced hepatocellular carcinoma in consideration of concomitant stage of liver cirrhosis","volume":"43","author":"Worns","year":"2009","journal-title":"J Clin Gastroenterol"},{"key":"2021122510543327200_onco13123-bib-0015","first-page":"2011","year":"2011"},{"key":"2021122510543327200_onco13123-bib-0016","doi-asserted-by":"crossref","first-page":"4293","DOI":"10.1200\/JCO.2005.01.3441","article-title":"Phase II study of sorafenib in patients with advanced hepatocellular carcinoma","volume":"24","author":"Abou-Alfa","year":"2006","journal-title":"J Clin Oncol"},{"key":"2021122510543327200_onco13123-bib-0017","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1111\/j.1365-2125.2011.03963.x","article-title":"Population pharmacokinetic analysis of sorafenib in patients with solid tumours","volume":"72","author":"Jain","year":"2011","journal-title":"Br J Clin Pharmacol"},{"key":"2021122510543327200_onco13123-bib-0018","first-page":"29","article-title":"Effect of hepatic impairment on sorafenib pharmacokinetics: Results of a multicenter, open-label, single-dose, phase I trial","volume":"2011","author":"Lettieri","year":"2580","journal-title":"J Clin Oncol"},{"key":"2021122510543327200_onco13123-bib-0019","doi-asserted-by":"crossref","first-page":"1800","DOI":"10.1200\/JCO.2008.20.0931","article-title":"Phase I and pharmacokinetic study of sorafenib in patients with hepatic or renal dysfunction: CALGB 60301","volume":"27","author":"Miller","year":"2009","journal-title":"J Clin Oncol"},{"key":"2021122510543327200_onco13123-bib-0020","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1016\/j.ctrv.2010.08.006","article-title":"Moving towards dose individualization of tyrosine kinase inhibitors","volume":"37","author":"Kl\u00fcmpen","year":"2011","journal-title":"Cancer Treat Rev"},{"key":"2021122510543327200_onco13123-bib-0021","author":"Ricke","year":"2019"},{"key":"2021122510543327200_onco13123-bib-0022","author":"BTG International Inc","year":"2019"},{"key":"2021122510543327200_onco13123-bib-0023","author":"Daniele","year":"2019"},{"key":"2021122510543327200_onco13123-bib-0024","doi-asserted-by":"crossref","first-page":"1274","DOI":"10.1002\/hep.23485","article-title":"A meta-analysis of survival rates of untreated patients in randomized clinical trials of hepatocellular carcinoma","volume":"51","author":"Cabibbo","year":"2010","journal-title":"Hepatology"},{"key":"2021122510543327200_onco13123-bib-0025","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 randomised, double-blind, placebo-controlled trial","volume":"10","author":"Cheng","year":"2009","journal-title":"Lancet Oncol"},{"key":"2021122510543327200_onco13123-bib-0026","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":"2021122510543327200_onco13123-bib-0027","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1038\/s41416-019-0488-4","article-title":"Using prognostic and predictive clinical features to make personalised survival prediction in advanced hepatocellular carcinoma patients undergoing sorafenib treatment","volume":"121","author":"Berhane","year":"2019","journal-title":"Br J Cancer"},{"key":"2021122510543327200_onco13123-bib-0028","doi-asserted-by":"crossref","first-page":"999","DOI":"10.1016\/j.jhep.2017.06.026","article-title":"Prognostic factors and predictors of sorafenib benefit in patients with hepatocellular carcinoma: Analysis of two phase III studies","volume":"67","author":"Bruix","year":"2017","journal-title":"J Hepatol"},{"key":"2021122510543327200_onco13123-bib-0029","article-title":"Improved survival prediction and comparison of prognostic models for patients with hepatocellular carcinoma treated with sorafenib","author":"Labeur","year":"2019","journal-title":"Liver Int"}],"container-title":["The Oncologist"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1634\/theoncologist.2019-0718","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1634\/theoncologist.2019-0718","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/academic.oup.com\/oncolo\/article-pdf\/25\/9\/e1274\/41920193\/oncolo_25_9_e1274.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/oncolo\/article-pdf\/25\/9\/e1274\/41920193\/oncolo_25_9_e1274.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,12,25]],"date-time":"2021-12-25T10:55:18Z","timestamp":1640429718000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/oncolo\/article\/25\/9\/e1274\/6443749"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,10,23]]},"references-count":29,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2019,10,23]]},"published-print":{"date-parts":[[2020,9,1]]}},"URL":"https:\/\/doi.org\/10.1634\/theoncologist.2019-0718","relation":{},"ISSN":["1083-7159","1549-490X"],"issn-type":[{"value":"1083-7159","type":"print"},{"value":"1549-490X","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2020,9,1]]},"published":{"date-parts":[[2019,10,23]]}}}