International Journal of Clinical Oncology

, Volume 20, Issue 5, pp 952–959 | Cite as

First-line gemcitabine and oxaliplatin (GEMOX) plus sorafenib, followed by sorafenib as maintenance therapy, for patients with advanced hepatocellular carcinoma: a preliminary study

  • Ying Liu
  • Han Yue
  • Shuning Xu
  • Feng Wang
  • Ning Ma
  • Ke Li
  • Lei Qiao
  • Jufeng WangEmail author
Original Article



Because of the poor prognosis of unresectable or metastatic hepatocellular carcinoma there is a need for effective systemic therapy. The purpose of this study was to assess the efficacy and safety of gemcitabine and oxaliplatin (GEMOX) combined with sorafenib, as first-line therapy, followed by sorafenib as maintenance therapy for patients with advanced hepatocellular carcinoma (HCC).


In this open-label, multicenter, single-group, prospective study, eligible patients with advanced HCC received oral sorafenib 400 mg twice daily, gemcitabine 1,000 mg/m2 intravenously (i.v.) on day 1 and oxaliplatin 85 mg/m2 i.v. on day 2 every 14 days for up to six cycles. Patients without disease progression were then treated further with sorafenib as maintenance therapy until disease progression.


All forty-nine patients completed six cycles of combined GEMOX and sorafenib therapy. The objective response was 26.5 %. The median time to progression was 10.3 months (95 % CI: 8.7–11.9 months) and median overall survival was 15.7 months (95 % CI: 13.0–18.4 months). During the combination therapy, the most common grade 3/4 hematologic toxicity was neutropenia (22.4 %, 11/49 patients) and thrombocytopenia (14.3 %, 7/49 patients); grade 3/4 non-hematologic toxicity was fatigue (22.4 %, 11/49 patients) and appetite loss (18.4 %, 9/49 patients). During the maintenance therapy, grade 3/4 adverse events were nonhematologic toxicity, for example fatigue (16.0 %, 4/25 patients) and appetite loss (16.0 %, 4/25 patients).


GEMOX combined with sorafenib as first-line therapy followed by sorafenib as maintenance therapy was effective with manageable toxicity for patients with advanced hepatocellular carcinoma. However, the results should be further validated in controlled phase II trials.


Gemcitabine Oxaliplatin Sorafenib Hepatocellular carcinoma Chemotherapy 



The authors thank all of the patients who agreed to participate in this study. We want to express our gratitude to Dr Peng Liu for his support and suggestions relating to the initial draft of this manuscript. We are grateful for Professor Kaijuan Wang’s help with statistical analysis. We also thank Dr Jie Mao for her assistance in writing and editing this manuscript. Sanofi supported the medical writing and editing service for this manuscript.

Conflict of interest

The authors declare that they have no conflict of interest.


  1. 1.
    Parkin DM, Bray F, Ferlay J (2005) Global cancer statistics 2002. Cancer J Clin 55:74–108CrossRefGoogle Scholar
  2. 2.
    Hung H (2005) Treatment modalities for hepatocellular carcinoma. Curr Cancer Drug Targets 5:131–138CrossRefPubMedGoogle Scholar
  3. 3.
    Hsu C, Shen YC, Cheng CC (2010) Geographic difference in survival outcome for advanced hepatocellular carcinoma: implications on future clinical trial design. Contemp Clin Trials 31:55–61CrossRefPubMedGoogle Scholar
  4. 4.
    Chlebowski RT, Brzechwa-Adjukiewicz A, Cowden A (1984) Doxorubicin (75 mg/m2) for hepatocellular carcinoma: clinical and pharmacokinetic results. Cancer Treat Rep 68:487–491PubMedGoogle Scholar
  5. 5.
    Falkson G, Ryan LM, Johnson LA (1987) A random phase II study of mitoxantrone and cisplatin in patients with hepatocellular carcinoma. An ECOG study. Cancer 60:2141–2145CrossRefPubMedGoogle Scholar
  6. 6.
    Hebbar M, Ernst O, Cattan S (2006) Phase II trial of docetaxel therapy in patients with advanced hepatocellular carcinoma. Oncology 70:154–158CrossRefPubMedGoogle Scholar
  7. 7.
    Boige V, Taieb J, Hebbar M (2006) 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 42:456–459CrossRefPubMedGoogle Scholar
  8. 8.
    Guan Z, Wang Y, Maoleekoonpairoj S (2003) Prospective randomized phase II study of gemcitabine at standard or fixed dose rate schedule in unresectable hepatocellular carcinoma. Br J Cancer 89:1865–1869PubMedCentralCrossRefPubMedGoogle Scholar
  9. 9.
    Llovet JM, Ruff P, Tassopoulos N (2001) A phase II trial of oral eniluracil/5-fluorouracil in patients with inoperable hepatocellular carcinoma. Eur J Cancer 37:1352–1358CrossRefPubMedGoogle Scholar
  10. 10.
    Wilhelm SM, Carter C, Tang L (2004) 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 64:7099–7109CrossRefPubMedGoogle Scholar
  11. 11.
    Iyer R, Fetterly G, Lugade A (2010) Sorafenib: a clinical and pharmacologic review. Expert Opin Pharmacother 11:1943–1955CrossRefPubMedGoogle Scholar
  12. 12.
    Chang YS, Adnane J, Trail PA (2007) Sorafenib (BAY 43-9006) inhibits tumor growth and vascularization and induces tumor apoptosis and hypoxia in RCC xenograft models. Cancer Chemother Pharmacol 59:561–574CrossRefPubMedGoogle Scholar
  13. 13.
    Llovet JM, Ricci S, Mazzaferro V, SHARP Investigators Study Group (2008) Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 359:378–390CrossRefPubMedGoogle Scholar
  14. 14.
    Abou-Alfa GK, Johnson P, Knox JJ (2010) Doxorubicin plus sorafenib vs doxorubicin alone in patients with advanced hepatocellular carcinoma: a randomized trial. JAMA 304:2154–2160CrossRefPubMedGoogle Scholar
  15. 15.
    Srimuninnimit V, Sriuranpong V, Suwanvecho S (2014) Efficacy and safety of sorafenib in combination with gemcitabine in patients with advanced hepatocellular carcinoma: a multicenter, open-label, single-arm phase II study. Asia Pac J Clin Oncol 10:255–260CrossRefPubMedGoogle Scholar
  16. 16.
    Zaanan A, Williet N, Hebbar M (2013) Gemcitabine plus oxaliplatin in advanced hepatocellular carcinoma: a large multicenter AGEO study. J Hepatol 58:81–88CrossRefPubMedGoogle Scholar
  17. 17.
    Llovet JM, Brú C, Bruix J (1999) Prognosis of hepatocellular carcinoma: the BCLC staging classification. Semin Liver Dis 19(3):329–338CrossRefPubMedGoogle Scholar
  18. 18.
    Therasse P, Arbuck SG, Eisenhauer EA (2000) New guidelines to evaluate the response to treatment in solid tumors: European Organization for Research and Treatment of Cancer, National Cancer Institute of the US, National Cancer Institute of Canada. J Natl Cancer Inst 92:205–216CrossRefPubMedGoogle Scholar
  19. 19.
    The Criteria Committee of the New York Heart Association (1994) Nomenclature and criteria for diagnosis of diseases of the heart and great vessels, 9th edn. Little Brown, Boston, pp 253–256Google Scholar
  20. 20.
    Grothey A (2005) Clinical management of oxaliplatin-associated neurotoxicity. Clin Colorectal Cancer 5(1):S38–S46CrossRefPubMedGoogle Scholar
  21. 21.
    Lee SJ, Lee J, Park SH (2012) Phase 1 trial of S-1 in combination with sorafenib for patients with advanced hepatocellular carcinoma. Invest New Drugs 30:1540–1547CrossRefPubMedGoogle Scholar
  22. 22.
    Ooka Y, Chiba T, Ogasawara S et al (2014) a phase I/II study of S-1 with sorafenib in patients with advanced hepatocellular carcinoma. Invest New Drugs 32(4):723–728CrossRefPubMedGoogle Scholar
  23. 23.
    Hsu CH, Kang YK, Yang TS et al (2013) Bevacizumab with erlotinib as first-line therapy in Asian patients with advanced hepatocellular carcinoma: a multicenter phase II study. Oncology 85(1):44–52CrossRefPubMedGoogle Scholar
  24. 24.
    Kaseb AO, Garrett-Mayer E, Morris JS et al (2012) Efficacy of bevacizumab plus erlotinib for advanced hepatocellular carcinoma and predictors of outcome: final results of a phase II trial. Oncology 82(2):67–74CrossRefPubMedGoogle Scholar
  25. 25.
    Ikeda M, Shiina S, Nakachi K et al (2014) Phase I study on the safety, pharmacokinetic profile, and efficacy of the combination of TSU-68, an oral antiangiogenic agent, and S-1 in patients with advanced hepatocellular carcinoma. Invest New Drugs (Epub ahead of print)Google Scholar
  26. 26.
    Synold TW, Takimoto CH, Doroshow JH, National Cancer Institute Organ Dysfunction Working Group et al (2007) Dose-escalating and pharmacologic study of oxaliplatin in adult cancer patients with impaired hepatic function: a National Cancer Institute Organ Dysfunction Working Group study. Clin Cancer Res 13(12):3660–3666CrossRefPubMedGoogle Scholar
  27. 27.
    Ji YX, Zhang ZF, Lan KT et al (2014) Sorafenib in liver function impaired advanced hepatocellular carcinoma. Chin Med Sci J 29(1):7–14CrossRefPubMedGoogle Scholar
  28. 28.
    Venook AP, Egorin MJ, Rosner GL et al (2000) Phase I and pharmacokinetic trial of gemcitabine in patients with hepatic or renal dysfunction: cancer and leukemia group B 9565. J Clin Oncol 18(14):2780–2787PubMedGoogle Scholar

Copyright information

© Japan Society of Clinical Oncology 2015

Authors and Affiliations

  • Ying Liu
    • 1
  • Han Yue
    • 2
  • Shuning Xu
    • 1
  • Feng Wang
    • 3
  • Ning Ma
    • 4
  • Ke Li
    • 1
  • Lei Qiao
    • 1
  • Jufeng Wang
    • 1
    Email author
  1. 1.Department of Oncology, Henan Cancer HospitalZhengzhou University Affiliated Cancer HospitalZhengzhouChina
  2. 2.Department of OncologyThe First People’s Hospital of Zhengzhou CityZhengzhouChina
  3. 3.Department of OncologyThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouChina
  4. 4.Department of OncologyHenan Provincial People HospitalZhengzhouChina

Personalised recommendations