Advertisement
Journal of Hepatology
EASL
Advanced searchSave search
Research Article| Volume 56, ISSUE 5, P1080-1088, May 2012

Download started.

Ok

Relationship between baseline hepatic status and outcome, and effect of sorafenib on liver function: SHARP trial subanalyses

  • Author Footnotes
    † On behalf of the SHARP Investigators Study Group (The names of the investigators in the SHARP Investigators Study Group are listed in the Appendix).
    Jean-Luc Raoul
    Correspondence
    Corresponding author. Address: Institut Paoli-Calmettes, 232 Boulevard Ste Marguerite, 13009 Marseille, France.
    Footnotes
    † On behalf of the SHARP Investigators Study Group (The names of the investigators in the SHARP Investigators Study Group are listed in the Appendix).
    Affiliations
    Institut Paoli-Calmettes, Marseille, France

    Institut National de la Santé et de la Recherche Médicale (INSERM) U991, Rennes, France
    Search for articles by this author
  • Author Footnotes
    † On behalf of the SHARP Investigators Study Group (The names of the investigators in the SHARP Investigators Study Group are listed in the Appendix).
    Jordi Bruix
    Footnotes
    † On behalf of the SHARP Investigators Study Group (The names of the investigators in the SHARP Investigators Study Group are listed in the Appendix).
    Affiliations
    Barcelona Clínic Liver Cancer (BCLC) Group, Liver Unit, CIBERehd, Institut d’Investigacions Biomèdiques, August Pi i Sunyer (IDIBAPS), Hospital Clínic Barcelona, Barcelona, Spain
    Search for articles by this author
  • Author Footnotes
    † On behalf of the SHARP Investigators Study Group (The names of the investigators in the SHARP Investigators Study Group are listed in the Appendix).
    Tim F. Greten
    Footnotes
    † On behalf of the SHARP Investigators Study Group (The names of the investigators in the SHARP Investigators Study Group are listed in the Appendix).
    Affiliations
    Medizinische Hochschule Hannover, Abteilung fur Gastroenterologie, Hepatologie und Endokrinologie, Hannover, Germany
    Search for articles by this author
  • Author Footnotes
    † On behalf of the SHARP Investigators Study Group (The names of the investigators in the SHARP Investigators Study Group are listed in the Appendix).
    Morris Sherman
    Footnotes
    † On behalf of the SHARP Investigators Study Group (The names of the investigators in the SHARP Investigators Study Group are listed in the Appendix).
    Affiliations
    Toronto General Hospital, Toronto, ON, Canada
    Search for articles by this author
  • Author Footnotes
    † On behalf of the SHARP Investigators Study Group (The names of the investigators in the SHARP Investigators Study Group are listed in the Appendix).
    Vincenzo Mazzaferro
    Footnotes
    † On behalf of the SHARP Investigators Study Group (The names of the investigators in the SHARP Investigators Study Group are listed in the Appendix).
    Affiliations
    National Cancer Institute, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Foundation, Milan, Italy
    Search for articles by this author
  • Author Footnotes
    † On behalf of the SHARP Investigators Study Group (The names of the investigators in the SHARP Investigators Study Group are listed in the Appendix).
    Philip Hilgard
    Footnotes
    † On behalf of the SHARP Investigators Study Group (The names of the investigators in the SHARP Investigators Study Group are listed in the Appendix).
    Affiliations
    University Hospital of Essen, Essen, Germany
    Search for articles by this author
  • Author Footnotes
    † On behalf of the SHARP Investigators Study Group (The names of the investigators in the SHARP Investigators Study Group are listed in the Appendix).
    Hans Scherubl
    Footnotes
    † On behalf of the SHARP Investigators Study Group (The names of the investigators in the SHARP Investigators Study Group are listed in the Appendix).
    Affiliations
    Medizinische Klinik “Charite”, Campus Benjamin Franklin, Berlin, Germany
    Search for articles by this author
  • Author Footnotes
    † On behalf of the SHARP Investigators Study Group (The names of the investigators in the SHARP Investigators Study Group are listed in the Appendix).
    Max E. Scheulen
    Footnotes
    † On behalf of the SHARP Investigators Study Group (The names of the investigators in the SHARP Investigators Study Group are listed in the Appendix).
    Affiliations
    Innere Klinik (Tumorforschung), West German Cancer Center, Universitätsklinikum Essen, Essen, Germany
    Search for articles by this author
  • Author Footnotes
    † On behalf of the SHARP Investigators Study Group (The names of the investigators in the SHARP Investigators Study Group are listed in the Appendix).
    Georgios Germanidis
    Footnotes
    † On behalf of the SHARP Investigators Study Group (The names of the investigators in the SHARP Investigators Study Group are listed in the Appendix).
    Affiliations
    AHEPA University Hospital, First Department of Medicine, Thessaloniki, Greece
    Search for articles by this author
  • Author Footnotes
    † On behalf of the SHARP Investigators Study Group (The names of the investigators in the SHARP Investigators Study Group are listed in the Appendix).
    Sophie Dominguez
    Footnotes
    † On behalf of the SHARP Investigators Study Group (The names of the investigators in the SHARP Investigators Study Group are listed in the Appendix).
    Affiliations
    Centre Oscar Lambret, Departement de Cancerologie Digestive et Urologique, Lille, France
    Search for articles by this author
  • Author Footnotes
    † On behalf of the SHARP Investigators Study Group (The names of the investigators in the SHARP Investigators Study Group are listed in the Appendix).
    Sergio Ricci
    Footnotes
    † On behalf of the SHARP Investigators Study Group (The names of the investigators in the SHARP Investigators Study Group are listed in the Appendix).
    Affiliations
    St. Chiara University Hospital, Milan, Italy
    Search for articles by this author
  • Author Footnotes
    † On behalf of the SHARP Investigators Study Group (The names of the investigators in the SHARP Investigators Study Group are listed in the Appendix).
    Andrea Nadel
    Footnotes
    † On behalf of the SHARP Investigators Study Group (The names of the investigators in the SHARP Investigators Study Group are listed in the Appendix).
    Affiliations
    Bayer HealthCare Pharmaceuticals, Montville, NJ, USA
    Search for articles by this author
  • Author Footnotes
    † On behalf of the SHARP Investigators Study Group (The names of the investigators in the SHARP Investigators Study Group are listed in the Appendix).
    Marius Moscovici
    Footnotes
    † On behalf of the SHARP Investigators Study Group (The names of the investigators in the SHARP Investigators Study Group are listed in the Appendix).
    Affiliations
    Bayer Schering Pharma, Milan, Italy
    Search for articles by this author
  • Author Footnotes
    † On behalf of the SHARP Investigators Study Group (The names of the investigators in the SHARP Investigators Study Group are listed in the Appendix).
    Dimitris Voliotis
    Footnotes
    † On behalf of the SHARP Investigators Study Group (The names of the investigators in the SHARP Investigators Study Group are listed in the Appendix).
    Affiliations
    Bayer Schering Pharma, Milan, Italy
    Search for articles by this author
  • Author Footnotes
    † On behalf of the SHARP Investigators Study Group (The names of the investigators in the SHARP Investigators Study Group are listed in the Appendix).
    Josep M. Llovet
    Footnotes
    † On behalf of the SHARP Investigators Study Group (The names of the investigators in the SHARP Investigators Study Group are listed in the Appendix).
    Affiliations
    Barcelona Clínic Liver Cancer (BCLC) Group, Liver Unit, CIBERehd, Institut d’Investigacions Biomèdiques, August Pi i Sunyer (IDIBAPS), Hospital Clínic Barcelona, Barcelona, Spain

    Mount Sinai Liver Cancer Program, Mount Sinai School of Medicine, New York, NY, USA

    Institució Catalana de Recerca I Estudis Avançats, Catalonia, Spain
    Search for articles by this author
  • Author Footnotes
    † On behalf of the SHARP Investigators Study Group (The names of the investigators in the SHARP Investigators Study Group are listed in the Appendix).
Published:January 16, 2012DOI:https://doi.org/10.1016/j.jhep.2011.12.009
Relationship between baseline hepatic status and outcome, and effect of sorafenib on liver function: SHARP trial subanalyses
Previous ArticleRETRACTED: Molecular forms of HMGB1 and keratin-18 as mechanistic biomarkers for mode of cell death and prognosis during clinical acetaminophen hepatotoxicity
Next ArticleCost-effectiveness of semi-annual surveillance for hepatocellular carcinoma in cirrhotic patients of the Italian Liver Cancer population

      Background & Aims

      Hepatic markers are utilized in many classification systems of patients with hepatocellular carcinoma and, by measuring organ damage and tumor stage, can influence treatment. Moreover, elevated serum concentrations of aminotransferases and alpha-fetoprotein are indicators of poor prognosis in patients with hepatocellular carcinoma. We examined the effects of sorafenib on hepatic markers by performing exploratory subset analyses of the Sorafenib HCC Assessment Randomized Protocol (SHARP) trial in patients categorized by baseline concentrations of alanine aminotransferase/aspartate aminotransferase, alpha-fetoprotein, and bilirubin; and by evaluating the effects of sorafenib on bilirubin concentrations during treatment.

      Methods

      Patients (n = 602) were grouped by baseline concentrations of alanine aminotransferase/aspartate aminotransferase (not significantly elevated, mildly elevated, or moderately elevated), alpha-fetoprotein (normal or elevated), and bilirubin (normal or elevated). Bilirubin was measured at baseline and on day 1 of each cycle.

      Results

      Patients with elevated baseline concentrations of alanine aminotransferase/aspartate aminotransferase, alpha-fetoprotein, or bilirubin had shorter overall survival (OS) than those with normal baseline concentrations, irrespective of treatment group. No notable differences in safety profiles were observed between patients with normal vs. elevated alanine aminotransferase/aspartate aminotransferase, alpha-fetoprotein, or bilirubin. Median changes from baseline in bilirubin concentration at the last cycle of treatment were +0.17 and +0.19 mg/dl in the sorafenib and placebo groups, respectively.

      Conclusions

      These subset analyses suggest that sorafenib is safe and effective for hepatocellular carcinoma, irrespective of baseline alanine aminotransferase/aspartate aminotransferase, alpha-fetoprotein, or bilirubin concentration and that hepatic function remains stable over the course of sorafenib therapy.

      Abbreviations:

      HCC (hepatocellular carcinoma), AFP (alpha-fetoprotein), OS (overall survival), ALT (alanine aminotransferase), AST (aspartic aminotransferase), SHARP (Sorafenib HCC Assessment Randomized Protocol), AP (Sorafenib Asia-Pacific Trial), TTP (time to disease progression), ECOG (Eastern Cooperative Oncology Group), ULN (upper limit of normal), DCR (disease control rate), RECIST (Response Evaluation Criteria in Solid Tumors), CR (complete response), PR (partial response), SD (stable disease), NCI–CTCAE (National Cancer Institute–Common Terminology Criteria for Adverse Events), HR (hazard ratio), CI (confidence interval), AE (adverse event), SAE (serious adverse event)

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Journal of Hepatology
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Register: Create an account
      Institutional Access: Sign in to ScienceDirect

      References

        • Carr B.I.
        • Pancoska P.
        • Branch R.A.
        Tumor and liver determinants of prognosis in unresectable hepatocellular carcinoma: a large case cohort study.
        Hepatol Int. 2009; 4: 396-405
        View in Article
        • Nomura F.
        • Ohnishi K.
        • Tanabe Y.
        Clinical features and prognosis of hepatocellular carcinoma with reference to serum alpha-fetoprotein levels: analysis of 606 patients.
        Cancer. 1989; 64: 1700-1707
        View in Article
        • Baek K.K.
        • Kim J.H.
        • Uhm J.E.
        • Park S.H.
        • Lee J.
        • Park J.O.
        • et al.
        Prognostic factors in patients with advanced hepatocellular carcinoma treated with sorafenib: a retrospective comparison with previously known prognostic models.
        Oncology. 2011; 80: 167-174
        View in Article
        • Changchien C.S.
        • Chen C.L.
        • Yen Y.H.
        • Wang J.H.
        • Hu T.H.
        • Lee C.M.
        • et al.
        Analysis of 6381 hepatocellular carcinoma patients in southern Taiwan: prognostic features, treatment outcome, and survival.
        J Gastroenterol. 2008; 43: 159-170
        View in Article
        • Pugh R.N.
        • Murray-Lyon I.M.
        • Dawson J.L.
        • Pietroni M.C.
        • Williams R.
        Transection of the oesophagus for bleeding oesophageal varices.
        Br J Surg. 1973; 60: 646-649
        View in Article
        • Okuda K.
        • Ohtsuki T.
        • Obata H.
        • Tomimatsu M.
        • Okazaki N.
        • Hasegawa H.
        • et al.
        Natural history of hepatocellular carcinoma and prognosis in relation to treatment: study of 850 patients.
        Cancer. 1985; 56: 918-928
        View in Article

      7. A new prognostic system for hepatocellular carcinoma: a retrospective study of 435 patients: the Cancer of the Liver Italian Program (CLIP) investigators. Hepatology 1998;28:751–755.

        View in Article

      8. Prospective validation of the CLIP score: a new prognostic system for patients with cirrhosis and hepatocellular carcinoma: the Cancer of the Liver Italian Program (CLIP) investigators. Hepatology 2000;31:840–845.

        View in Article
        • Leung T.W.
        • Tang A.M.
        • Zee B.
        • Lau W.Y.
        • Lai P.B.
        • Leung K.L.
        • et al.
        Construction of the Chinese University Prognostic Index for hepatocellular carcinoma and comparison with the TNM staging system, the Okuda staging system, and the Cancer of the Liver Italian Program staging system: a study based on 926 patients.
        Cancer. 2002; 94: 1760-1769
        View in Article
        • Kudo M.
        • Chung H.
        • Osaki Y.
        Prognostic staging system for hepatocellular carcinoma (CLIP score): its value and limitations, and a proposal for a new staging system, the Japan Integrated Staging Score (JIS score).
        J Gastroenterol. 2003; 38: 207-215
        View in Article
        • Kudo M.
        • Chung H.
        • Haji S.
        • Osaki Y.
        • Oka H.
        • Seki T.
        • et al.
        Validation of a new prognostic staging system for hepatocellular carcinoma: the JIS score compared with the CLIP score.
        Hepatology. 2004; 40: 1396-1405
        View in Article
        • Llovet J.M.
        • Bru C.
        • Bruix J.
        Prognosis of hepatocellular carcinoma: the BCLC staging classification.
        Semin Liver Dis. 1999; 19: 329-338
        View in Article

      13. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Hepatobiliary Cancers v. 2.2010, www.nccn.org [accessed 19.07.11].

        View in Article
        • Riley L.B.
        • Desai D.C.
        The molecular basis of cancer and the development of targeted therapy.
        Surg Clin North Am. 2009; 89: 1-15
        View in Article
        • Llovet J.M.
        • Bruix J.
        Molecular targeted therapies in hepatocellular carcinoma.
        Hepatology. 2008; 48: 1312-1327
        View in Article
        • Zhu A.X.
        Development of sorafenib and other molecularly targeted agents in hepatocellular carcinoma.
        Cancer. 2008; 112: 250-259
        View in Article
        • Wilhelm S.
        • Chien D.S.
        BAY 43-9006: preclinical data.
        Curr Pharm Des. 2002; 8: 2255-2257
        View in Article
        • Wilhelm S.M.
        • Carter C.
        • Tang L.
        • Wilkie D.
        • McNabola A.
        • Rong H.
        • et al.
        BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis.
        Cancer Res. 2004; 64: 7099-7109
        View in Article
        • Carlomagno F.
        • Anaganti S.
        • Guida T.
        • Salvatore G.
        • Troncone G.
        • Wilhelm S.M.
        • et al.
        BAY 43-9006 inhibition of oncogenic RET mutants.
        J Nat Cancer Inst. 2006; 98: 326-334
        View in Article
        • Llovet J.M.
        • Ricci S.
        • Mazzaferro V.
        • Hilgard P.
        • Gane E.
        • Blanc J.F.
        • et al.
        SHARP Investigators Study Group. Sorafenib in advanced hepatocellular carcinoma.
        N Engl J Med. 2008; 359: 378-390
        View in Article
        • Cheng A.L.
        • Kang Y.K.
        • Chen Z.
        • Tsao C.J.
        • Qin S.
        • Kim J.S.
        • et al.
        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.
        Lancet Oncol. 2009; 10: 25-34
        View in Article
        • Pinter M.
        • Sieghart W.
        • Graziadei I.
        • Vogel W.
        • Maieron A.
        • Konigsberg R.
        • et al.
        Sorafenib in unresectable hepatocellular carcinoma from mild to advanced stage liver cirrhosis.
        Oncologist. 2009; 14: 70-76
        View in Article
        • Marrero J.A.
        • Fontana R.J.
        • Barrat A.
        • Askari F.
        • Conjeevaram H.S.
        • Su G.L.
        • et al.
        Prognosis of hepatocellular carcinoma: comparison of 7 staging systems in an American cohort.
        Hepatology. 2005; 41: 707-716
        View in Article
        • Pratt D.S.
        • Kaplan M.M.
        Evaluation of abnormal liver-enzyme results in asymptomatic patients.
        N Engl J Med. 2000; 342: 1266-1271
        View in Article
        • Tarao K.
        • Rino Y.
        • Ohkawa S.
        • Tamai S.
        • Miyakawa K.
        • Takakura H.
        • et al.
        Close association between high serum alanine aminotransferase levels and multicentric hepatocarcinogenesis in patients with hepatitis C virus-associated cirrhosis.
        Cancer. 2002; 94: 1787-1795
        View in Article
        • Kim H.J.
        • Oh S.W.
        • Kim D.J.
        • Choi E.Y.
        Abundance of immunologically active alanine aminotransferase in sera of liver cirrhosis and hepatocellular carcinoma patients.
        Clin Chem. 2009; 55: 1022-1025
        View in Article
        • Johnson P.J.
        The role of serum alpha-fetoprotein estimation in the diagnosis and management of hepatocellular carcinoma.
        Clin Liver Dis. 2001; 5: 145-159
        View in Article
        • Chevret S.
        • Trinchet J.C.
        • Mathieu D.
        • Rached A.A.
        • Beaugrand M.
        • Chastang C.
        A new prognostic classification for predicting survival in patients with hepatocellular carcinoma. Groupe d’Etude et de Traitement du Carcinome Hepatocellulaire.
        J Hepatol. 1999; 31: 133-141
        View in Article
        • Yau T.
        • Yao T.J.
        • Chan P.
        • Ng K.
        • Fan S.T.
        • Poon R.T.P.
        A new prognostic score system in patients with advanced hepatocellular carcinoma not amenable to locoregional therapy: implication for patient selection in systemic therapy trials.
        Cancer. 2008; 113: 2742-2751
        View in Article
        • Yau T.
        • Yao T.J.
        • Chan P.
        • Wong H.
        • Pang R.
        • Fan S.T.
        • et al.
        The significance of early alpha-fetoprotein level changes in predicting clinical and survival benefits in advanced hepatocellular carcinoma patients receiving sorafenib.
        Oncologist. 2011; 16: 1270-1279
        View in Article
        • Limdi J.K.
        • Hyde G.M.
        Evaluation of abnormal liver function tests.
        Postgrad Med J. 2003; 79: 307-312
        View in Article
        • Liu Y.
        • Ramirez J.
        • Ratain M.J.
        Inhibition of paracetamol glucuronidation by tyrosine kinase inhibitors.
        Br J Clin Pharmacol. 2011; 71: 917-920
        View in Article
        • Burchell B.
        • Hume R.
        Molecular genetic basis of Gilbert’s syndrome.
        J Gastroenterol Hepatol. 1999; 14: 960-966
        View in Article
        • Meza-Junco J.
        • Chu Q.S.C.
        • Christensen O.
        • Rajagopalan P.
        • Das S.
        • Stefanyschyn R.
        • et al.
        UGT1A1 polymorphism and hyperbilirubinemia in a patient who received sorafenib.
        Cancer Chemother Pharmacol. 2009; 65: 1-4
        View in Article

      Article info

      Publication history

      Published online: January 16, 2012
      Accepted: December 12, 2011
      Received in revised form: December 6, 2011
      Received: October 3, 2011

      Footnotes

      ☆Presented in part in abstract form at: (1) American Gastroenterological Association (AGA) Institute/American Society of Clinical Oncology (ASCO)/American Society for Radiation Oncology (ASTRO)/Society of Surgical Oncology (SSO) 2010 Gastrointestinal Cancers Symposium; Orlando, Florida, USA, January 22–24, 2010; (2) 46th ASCO Annual Meeting; Chicago, Illinois, USA, June 4–8, 2010; (3) 4th Annual International Liver Cancer Association (ILCA) Conference; Montreal, Québec, Canada, September 10–12, 2010; (4) European Society for Medical Oncology (ESMO) Annual Meeting; Milan, Italy, October 8–12, 2010.

      Identification

      DOI: https://doi.org/10.1016/j.jhep.2011.12.009

      Copyright

      © 2012 European Association for the Study of the Liver. Published by Elsevier Inc. All rights reserved.

      ScienceDirect

      Access this article on ScienceDirect

      The content on this site is intended for healthcare professionals.


      We use cookies to help provide and enhance our service and tailor content. To update your cookie settings, please visit the Cookie Preference Center for this site.
      Copyright © 2023 Elsevier Inc. except certain content provided by third parties.


      RELX