Advertisement

Gemcitabine plus oxaliplatin in advanced hepatocellular carcinoma: A large multicenter AGEO study

  • Author Footnotes
    † For AGEO: Association des Gastro-Entérologues Oncologues.
    Aziz Zaanan
    Footnotes
    † For AGEO: Association des Gastro-Entérologues Oncologues.
    Affiliations
    Service d’Hépato-Gastroentérologie et Oncologie digestive, Hôpital Européen Georges Pompidou, AP-HP, Paris, France

    Paris Sorbonne Cité, Université Paris Descartes, Paris, France

    Cancer Research Personalized Medicine (CARPEM), Hôpital Européen Georges Pompidou, AP-HP, Paris, France
    Search for articles by this author
  • Author Footnotes
    † For AGEO: Association des Gastro-Entérologues Oncologues.
    Nicolas Williet
    Footnotes
    † For AGEO: Association des Gastro-Entérologues Oncologues.
    Affiliations
    Service d’Hépato-Gastroentérologie et Oncologie digestive, Hôpital Européen Georges Pompidou, AP-HP, Paris, France
    Search for articles by this author
  • Author Footnotes
    † For AGEO: Association des Gastro-Entérologues Oncologues.
    Mohamed Hebbar
    Footnotes
    † For AGEO: Association des Gastro-Entérologues Oncologues.
    Affiliations
    Service d’Oncologie Médicale, CHRU, Lille, France
    Search for articles by this author
  • Author Footnotes
    † For AGEO: Association des Gastro-Entérologues Oncologues.
    Tienhan Sandrine Dabakuyo
    Footnotes
    † For AGEO: Association des Gastro-Entérologues Oncologues.
    Affiliations
    Unité de Biostatistiques et d’Epidémiologie, Centre Georges-François Leclerc, Dijon, France
    Search for articles by this author
  • Author Footnotes
    † For AGEO: Association des Gastro-Entérologues Oncologues.
    Laetitia Fartoux
    Footnotes
    † For AGEO: Association des Gastro-Entérologues Oncologues.
    Affiliations
    Service d’Hépato-Gastroentérologie, Hôpital Saint Antoine, AP-HP, Paris, France
    Search for articles by this author
  • Author Footnotes
    † For AGEO: Association des Gastro-Entérologues Oncologues.
    Touraj Mansourbakht
    Footnotes
    † For AGEO: Association des Gastro-Entérologues Oncologues.
    Affiliations
    Service d’Hépato-Gastroentérologie, Hôpital Pitié-Salpêtrière, AP-HP, Paris, France
    Search for articles by this author
  • Author Footnotes
    † For AGEO: Association des Gastro-Entérologues Oncologues.
    Olivier Dubreuil
    Footnotes
    † For AGEO: Association des Gastro-Entérologues Oncologues.
    Affiliations
    Service d’Hépato-Gastroentérologie et Oncologie digestive, Hôpital Européen Georges Pompidou, AP-HP, Paris, France

    Paris Sorbonne Cité, Université Paris Descartes, Paris, France
    Search for articles by this author
  • Author Footnotes
    † For AGEO: Association des Gastro-Entérologues Oncologues.
    Olivier Rosmorduc
    Footnotes
    † For AGEO: Association des Gastro-Entérologues Oncologues.
    Affiliations
    Service d’Hépato-Gastroentérologie, Hôpital Saint Antoine, AP-HP, Paris, France
    Search for articles by this author
  • Author Footnotes
    † For AGEO: Association des Gastro-Entérologues Oncologues.
    Stéphane Cattan
    Footnotes
    † For AGEO: Association des Gastro-Entérologues Oncologues.
    Affiliations
    Service d’Hépato-Gastroentérologie, CHRU, Lille, France
    Search for articles by this author
  • Author Footnotes
    † For AGEO: Association des Gastro-Entérologues Oncologues.
    Franck Bonnetain
    Footnotes
    † For AGEO: Association des Gastro-Entérologues Oncologues.
    Affiliations
    Unité de Biostatistiques et d’Epidémiologie, Centre Georges-François Leclerc, Dijon, France
    Search for articles by this author
  • Author Footnotes
    † For AGEO: Association des Gastro-Entérologues Oncologues.
    Valérie Boige
    Footnotes
    † For AGEO: Association des Gastro-Entérologues Oncologues.
    Affiliations
    Service d’Oncologie digestive, Institut de cancérologie Gustave Roussy, Villejuif, France
    Search for articles by this author
  • Author Footnotes
    † For AGEO: Association des Gastro-Entérologues Oncologues.
    Julien Taïeb
    Correspondence
    Corresponding author. Address: Department of Gastroenterology and Digestive Oncology, Georges Pompidou European Hospital, University of Paris Descartes, 20 rue Leblanc, 75015 Paris, France. Tel.: +33 1 56 09 35 51; fax: +33 1 56 09 35 29.
    Footnotes
    † For AGEO: Association des Gastro-Entérologues Oncologues.
    Affiliations
    Service d’Hépato-Gastroentérologie et Oncologie digestive, Hôpital Européen Georges Pompidou, AP-HP, Paris, France

    Paris Sorbonne Cité, Université Paris Descartes, Paris, France

    Cancer Research Personalized Medicine (CARPEM), Hôpital Européen Georges Pompidou, AP-HP, Paris, France
    Search for articles by this author
  • Author Footnotes
    † For AGEO: Association des Gastro-Entérologues Oncologues.
Published:September 17, 2012DOI:https://doi.org/10.1016/j.jhep.2012.09.006

      Background & Aims

      The current standard treatment for advanced hepatocellular carcinoma (HCC) is sorafenib. This drug is effective but generally does not induce tumor shrinkage and other treatment options are still needed.

      Methods

      This retrospective multicenter study included all consecutive patients with advanced HCC treated with gemcitabine and oxaliplatin (GEMOX) between 2001 and 2010. Survival curves were drawn with the Kaplan–Meier method and compared with the log-rank test. Univariate and multivariate analyses were used to evaluate prognostic factors.

      Results

      Two hundred four consecutive patients were treated with GEMOX (median age, 60 years; men, 86%; underlying cirrhosis, 76%). Grade 3–4 toxicity was observed in 44% of the patients (thrombocytopenia 24%, neutropenia 18%, diarrhea 14%, neurotoxicity 12%) leading to treatment discontinuation in 16% of the cases. The overall response and disease control rates were 22% (95% CI, 16–27) and 66% (95% CI, 59–72), respectively. No clinical or biological factors were associated with the treatment response, and 8.5% of the patients were subsequently eligible for curative-intent therapies after downstaging. Median PFS, TTP, and OS were 4.5 (95% CI, 4–6), 8 (95% CI, 6–11), and 11 months (95% CI, 9–14), respectively. In multivariate analysis, gender (p = 0.03), underlying cirrhosis (p = 0.01), CLIP score (p = 0.03), and response to GEMOX (p <0.0001) were independently associated with OS.

      Conclusions

      This large study confirms that GEMOX is effective with manageable toxicity in patients with advanced HCC. Tumor responses permitted potentially curative treatment that was not initially feasible in a significant proportion of patients.

      Abbreviations:

      HCC (hepatocellular carcinoma), OS (overall survival), AFP (α-fetoprotein), TACE (transarterial chemoembolization), TTP (time to progression), PFS (progression-free survival), PS (performance status), CLIP (Cancer of the Liver Italian Program), ORR (overall response rate)

      Keywords

      To read this article in full you will need to make a payment
      Subscribe to Journal of Hepatology
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Parkin D.M.
        • Bray F.
        • Ferlay J.
        • Pisani P.
        Global cancer statistics, 2002.
        CA Cancer J Clin. 2005; 55: 74-108
        • El-Serag H.B.
        • Rudolph K.L.
        Hepatocellular carcinoma: epidemiology and molecular carcinogenesis.
        Gastroenterology. 2007; 132: 2557-2576
        • Smedile A.
        • Bugianesi E.
        Steatosis and hepatocellular carcinoma risk.
        Eur Rev Med Pharmacol Sci. 2005; 9: 291-293
        • Taieb J.
        • Barbare J.C.
        • Rougier P.
        Medical treatments for hepatocellular carcinoma (HCC): what’s next?.
        Ann Oncol. 2006; 17: x308-x314
        • Rougier P.
        • Mitry E.
        • Barbare J.C.
        • Taieb J.
        Hepatocellular carcinoma (HCC): an update.
        Semin Oncol. 2007; 34: S12-S20
        • Hsu C.
        • Shen Y.C.
        • Cheng C.C.
        • Hu F.C.
        • Cheng A.L.
        Geographic difference in survival outcome for advanced hepatocellular carcinoma: implications on future clinical trial design.
        Contemp Clin Trials. 2010; 31: 55-61
        • Llovet J.M.
        • Ricci S.
        • Mazzaferro V.
        • Hilgard P.
        • Gane E.
        • Blanc J.F.
        • et al.
        Sorafenib in advanced hepatocellular carcinoma.
        N Engl J Med. 2008; 359: 378-390
        • 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
        • Burroughs A.
        • Hochhauser D.
        • Meyer T.
        Systemic treatment and liver transplantation for hepatocellular carcinoma: two ends of the therapeutic spectrum.
        Lancet Oncol. 2004; 5: 409-418
        • Taieb J.
        • Bonyhay L.
        • Golli L.
        • Ducreux M.
        • Boleslawski E.
        • Tigaud J.M.
        • et al.
        Gemcitabine plus oxaliplatin for patients with advanced hepatocellular carcinoma using two different schedules.
        Cancer. 2003; 98: 2664-2670
        • Asnacios A.
        • Fartoux L.
        • Romano O.
        • Tesmoingt C.
        • Louafi S.S.
        • Mansoubakht T.
        • et al.
        Gemcitabine plus oxaliplatin (GEMOX) combined with cetuximab in patients with progressive advanced stage hepatocellular carcinoma: results of a multicenter phase 2 study.
        Cancer. 2008; 112: 2733-2739
        • Louafi S.
        • Boige V.
        • Ducreux M.
        • Bonyhay L.
        • Mansourbakht T.
        • de Baere T.
        • et al.
        Gemcitabine plus oxaliplatin (GEMOX) in patients with advanced hepatocellular carcinoma (HCC): results of a phase II study.
        Cancer. 2007; 109: 1384-1390
        • Boige V.
        • Taieb J.
        • Hebbar M.
        • Malka D.
        • Debaere T.
        • Hannoun L.
        • et al.
        Irinotecan as first-line chemotherapy in patients with advanced hepatocellular carcinoma: a multicenter phase II study with dose adjustment according to baseline serum bilirubin level.
        Eur J Cancer. 2006; 42: 456-459
        • Zhu A.X.
        • Blaszkowsky L.S.
        • Ryan D.P.
        • Clark J.W.
        • Muzikansky A.
        • Horgan K.
        • et al.
        Phase II study of gemcitabine and oxaliplatin in combination with bevacizumab in patients with advanced hepatocellular carcinoma.
        J Clin Oncol. 2006; 24: 1898-1903
        • Bruix J.
        • Sherman M.
        • Llovet J.M.
        • Beaugrand M.
        • Lencioni R.
        • Burroughs A.K.
        • et al.
        Clinical management of hepatocellular carcinoma. Conclusions of the Barcelona-2000 EASL conference. European Association for the Study of the Liver.
        J Hepatol. 2001; 35: 421-430
        • Caussanel J.P.
        • Levi F.
        • Brienza S.
        • Misset J.L.
        • Itzhaki M.
        • Adam R.
        • et al.
        Phase I trial of 5-day continuous venous infusion of oxaliplatin at circadian rhythm-modulated rate compared with constant rate.
        J Natl Cancer Inst. 1990; 82: 1046-1050
        • Nowak A.K.
        • Chow P.K.
        • Findlay M.
        Systemic therapy for advanced hepatocellular carcinoma: a review.
        Eur J Cancer. 2004; 40: 1474-1484
        • Gish R.G.
        • Porta C.
        • Lazar L.
        • Ruff P.
        • Feld R.
        • Croitoru A.
        • et al.
        Phase III randomized controlled trial comparing the survival of patients with unresectable hepatocellular carcinoma treated with nolatrexed or doxorubicin.
        J Clin Oncol. 2007; 25: 3069-3075
        • Lai C.L.
        • Wu P.C.
        • Chan G.C.
        • Lok A.S.
        • Lin H.J.
        Doxorubicin versus no antitumor therapy in inoperable hepatocellular carcinoma. A prospective randomized trial.
        Cancer. 1988; 62: 479-483
        • Lombardi G.
        • Zustovich F.
        • Farinati F.
        • Cillo U.
        • Vitale A.
        • Zanus G.
        • et al.
        Pegylated liposomal doxorubicin and gemcitabine in patients with advanced hepatocellular carcinoma: results of a phase 2 study.
        Cancer. 2011; 117: 125-133
        • Qin S.
        • Bai Y.
        • Ye S.
        • Fan J.
        • Lim H.
        • Cho J.Y.
        • et al.
        Phase III study of oxaliplatin plus 5-fluorouracil/leucovorin (FOLFOX4) versus doxorubicin as palliative systemic chemotherapy in advanced HCC in Asian patients.
        J Clin Oncol. 2010; 28 ([suppl.; abstr 4008]): 15s
        • Leung T.W.
        • Patt Y.Z.
        • Lau W.Y.
        • Ho S.K.
        • Yu S.C.
        • Chan A.T.
        • et al.
        Complete pathological remission is possible with systemic combination chemotherapy for inoperable hepatocellular carcinoma.
        Clin Cancer Res. 1999; 5: 1676-1681
        • Yeo W.
        • Mok T.S.
        • Zee B.
        • Leung T.W.
        • Lai P.B.
        • Lau W.Y.
        • et al.
        A randomized phase III study of doxorubicin versus cisplatin/interferon alpha-2b/doxorubicin/fluorouracil (PIAF) combination chemotherapy for unresectable hepatocellular carcinoma.
        J Natl Cancer Inst. 2005; 97: 1532-1538
        • Hebbar M.
        • Ernst O.
        • Cattan S.
        • Dominguez S.
        • Oprea C.
        • Mathurin P.
        • et al.
        Phase II trial of docetaxel therapy in patients with advanced hepatocellular carcinoma.
        Oncology. 2006; 70: 154-158
        • Guan Z.
        • Wang Y.
        • Maoleekoonpairoj S.
        • Chen Z.
        • Kim W.S.
        • Ratanatharathorn V.
        • et al.
        Prospective randomised phase II study of gemcitabine at standard or fixed dose rate schedule in unresectable hepatocellular carcinoma.
        Br J Cancer. 2003; 89: 1865-1869
        • Alexandre J.
        • Tigaud J.M.
        • Gross-Goupil M.
        • Gornet J.M.
        • Romain D.
        • Azoulay D.
        • et al.
        Combination of topotecan and oxaliplatin in inoperable hepatocellular cancer patients.
        Am J Clin Oncol. 2002; 25: 198-203
        • Stuart K.
        • Tessitore J.
        • Rudy J.
        • Clendennin N.
        • Johnston A.
        A Phase II trial of nolatrexed dihydrochloride in patients with advanced hepatocellular carcinoma.
        Cancer. 1999; 86: 410-414
        • Collette S.
        • Bonnetain F.
        • Paoletti X.
        • Doffoel M.
        • Bouche O.
        • Raoul J.L.
        • et al.
        Prognosis of advanced hepatocellular carcinoma: comparison of three staging systems in two French clinical trials.
        Ann Oncol. 2008; 19: 1117-1126
        • Tournoux-Facon C.
        • Paoletti X.
        • Barbare J.C.
        • Bouche O.
        • Rougier P.
        • Dahan L.
        • et al.
        Development and validation of a new prognostic score of death for patients with hepatocellular carcinoma in palliative setting.
        J Hepatol. 2011; 54: 108-114
        • Qin L.X.
        • Tang Z.Y.
        The prognostic significance of clinical and pathological features in hepatocellular carcinoma.
        World J Gastroenterol. 2002; 8: 193-199
        • Vora S.R.
        • Zheng H.
        • Stadler Z.K.
        • Fuchs C.S.
        • Zhu A.X.
        Serum alpha-fetoprotein response as a surrogate for clinical outcome in patients receiving systemic therapy for advanced hepatocellular carcinoma.
        Oncologist. 2009; 14: 717-725
        • Chan S.L.
        • Mo F.K.
        • Johnson P.J.
        • Hui E.P.
        • Ma B.B.
        • Ho W.M.
        • et al.
        New utility of an old marker: serial alpha-fetoprotein measurement in predicting radiologic response and survival of patients with hepatocellular carcinoma undergoing systemic chemotherapy.
        J Clin Oncol. 2009; 27: 446-452
        • 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