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Gemcitabine and oxaliplatin as second-line treatment in patients with hepatocellular carcinoma pre-treated with sorafenib

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Abstract

Some patients with advanced hepatocellular carcinoma (HCC) progressing under sorafenib remain eligible for further systemic therapy. Little is known on the feasibility of systemic treatment beyond sorafenib in this setting. Consecutive HCC patients pre-treated with sorafenib received gemcitabine 1,000 mg/m² and oxaliplatin 100 mg/m² every 14 days. Exclusion criteria included Child C cirrhosis, PS ≥ 3, creatinine clearance <20 ml/min, albumin <25 g/L and bilirubin > 54 μmol/L. Pre-treatment body composition was evaluated by CT scan to detect muscle wasting (sarcopenia). The primary evaluation criterion was safety. Secondary evaluation criteria were response rate, and progression-free (PFS) and overall survival (OS). Eighteen patients (median age: 64 years, range 25–77) received a total of 90 cycles (median per patient: 4, range 1–16). Eight patients (44.4 %) had a PS of 2, 5 (27.8 %) had Child-Pugh B cirrhosis and 13 (72.2 %) had a CLIP score >3. The most frequent toxicities were thrombocytopenia (grade 2–4: n = 7, 38.9 %) and peripheral neuropathy (grade 2–3: n = 7, 38.9 %). The overall response rate was 18.8 % (95 % CI: 0–37.9), and another 18.8 % of patients had stable disease. The median PFS and OS were 3.2 (95 % CI: 2.3–3.9) and 4.7 (95 % CI: 3.8–8.1) months, respectively. Overall survival was significantly longer in patients without sarcopenia [10.0 months (95 % CI: 7.0–13.8) vs. 3.0 months (95 % CI: 2.5–3.9), p < 0.001] and in patients with an ECOG PS < 2 [8.1 months (95 % CI: 7.0–13.8) vs. 3.8 months (95 % CI: 2.5–3.9), p = 0.017]. In our experience, gemcitabine–oxaliplatin was feasible and had detectable clinical activity in HCC patients pre-treated with sorafenib. Further studies are needed to confirm these findings.

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References

  1. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61(2):69–90. doi:10.3322/caac.20107.

    Article  PubMed  Google Scholar 

  2. Llovet JM, Burroughs A, Bruix J. Hepatocellular carcinoma. Lancet. 2003;362(9399):1907–17. doi:10.1016/S0140-6736(03)14964-1.

    Article  PubMed  Google Scholar 

  3. Wilhelm S, Carter C, Lynch M, Lowinger T, Dumas J, Smith RA, et al. Discovery and development of sorafenib: a multikinase inhibitor for treating cancer. Nat Rev Drug Discov. 2006;5(10):835–44. doi:10.1038/nrd2130.

    Article  PubMed  CAS  Google Scholar 

  4. Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359(4):378–90. doi:10.1056/NEJMoa0708857.

    Article  PubMed  CAS  Google Scholar 

  5. Jelic S, Sotiropoulos GC. Hepatocellular carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2010;21(Suppl 5):v59–64. doi:10.1093/annonc/mdq166.

    Article  PubMed  Google Scholar 

  6. Alexandre J, Tigaud JM, Gross-Goupil M, Gornet JM, Romain D, Azoulay D, et al. Combination of topotecan and oxaliplatin in inoperable hepatocellular cancer patients. Am J Clin Oncol. 2002;25(2):198–203.

    Article  PubMed  Google Scholar 

  7. Coriat R, Mir O, Cessot A, Brezault C, Ropert S, Durand JP, et al. Feasibility of oxaliplatin, 5-fluorouracil and leucovorin (FOLFOX-4) in cirrhotic or liver transplant patients: experience in a cohort of advanced hepatocellular carcinoma patients. Invest New Drugs. 2010;. doi:10.1007/s10637-010-9525-0.

    Google Scholar 

  8. 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(7):1384–90. doi:10.1002/cncr.22532.

    Article  PubMed  CAS  Google Scholar 

  9. Taieb J, Bonyhay L, Golli L, Ducreux M, Boleslawski E, Tigaud JM, et al. Gemcitabine plus oxaliplatin for patients with advanced hepatocellular carcinoma using two different schedules. Cancer. 2003;98(12):2664–70. doi:10.1002/cncr.11869.

    Article  PubMed  CAS  Google Scholar 

  10. Faivre S, Le Chevalier T, Monnerat C, Lokiec F, Novello S, Taieb J, et al. Phase I-II and pharmacokinetic study of gemcitabine combined with oxaliplatin in patients with advanced non-small-cell lung cancer and ovarian carcinoma. Ann Oncol. 2002;13(9):1479–89.

    Article  PubMed  CAS  Google Scholar 

  11. Faivre S, Raymond E, Woynarowski JM, Cvitkovic E. Supraadditive effect of 2′,2′-difluorodeoxycytidine (gemcitabine) in combination with oxaliplatin in human cancer cell lines. Cancer Chemother Pharmacol. 1999;44(2):117–23.

    Article  PubMed  CAS  Google Scholar 

  12. Mir O, Alexandre J, Ropert S, Amsellem-Ouazana D, Flam T, Beuzeboc P, et al. Combination of gemcitabine and oxaliplatin in urothelial cancer patients with severe renal or cardiac comorbidities. Anticancer Drugs. 2005;16(9):1017–21.

    Article  PubMed  CAS  Google Scholar 

  13. Raymond E, Chaney SG, Taamma A, Cvitkovic E. Oxaliplatin: a review of preclinical and clinical studies. Ann Oncol. 1998;9(10):1053–71.

    Article  PubMed  CAS  Google Scholar 

  14. Synold TW, Takimoto CH, Doroshow JH, Gandara D, Mani S, Remick SC, et al. 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. 2007;13(12):3660–6. doi:10.1158/1078-0432.CCR-06-2385.

    Article  PubMed  CAS  Google Scholar 

  15. Takimoto CH, Graham MA, Lockwood G, Ng CM, Goetz A, Greenslade D, et al. Oxaliplatin pharmacokinetics and pharmacodynamics in adult cancer patients with impaired renal function. Clin Cancer Res. 2007;13(16):4832–9. doi:10.1158/1078-0432.CCR-07-0475.

    Article  PubMed  CAS  Google Scholar 

  16. Fearon K, Strasser F, Anker SD, Bosaeus I, Bruera E, Fainsinger RL, et al. Definition and classification of cancer cachexia: an international consensus. Lancet Oncol. 2011;12(5):489–95. doi:10.1016/S1470-2045(10)70218-7.

    Article  PubMed  Google Scholar 

  17. Prado CM, Lieffers JR, McCargar LJ, Reiman T, Sawyer MB, Martin L, et al. Prevalence and clinical implications of sarcopenic obesity in patients with solid tumours of the respiratory and gastrointestinal tracts: a population-based study. Lancet Oncol. 2008;9(7):629–35. doi:10.1016/S1470-2045(08)70153-0.

    Article  PubMed  Google Scholar 

  18. Durand JP, Madelaine I, Scotte F. Guidelines for prophylaxis and treatment of chemotherapy-induced nausea and vomiting. Bull Cancer. 2009;96(10):951–60. doi:10.1684/bdc.2009.0924.

    PubMed  CAS  Google Scholar 

  19. Durand JP, Deplanque G, Montheil V, Gornet JM, Scotte F, Mir O, et al. Efficacy of venlafaxine for the prevention and relief of oxaliplatin-induced acute neurotoxicity: results of EFFOX, a randomized, double-blind, placebo-controlled phase III trial. Ann Oncol. 2011;23(1):200–5. doi:10.1093/annonc/mdr045.

    Article  PubMed  Google Scholar 

  20. Mitsiopoulos N, Baumgartner RN, Heymsfield SB, Lyons W, Gallagher D, Ross R. Cadaver validation of skeletal muscle measurement by magnetic resonance imaging and computerized tomography. J Appl Physiol. 1998;85(1):115–22.

    PubMed  CAS  Google Scholar 

  21. Mourtzakis M, Prado CM, Lieffers JR, Reiman T, McCargar LJ, Baracos VE. A practical and precise approach to quantification of body composition in cancer patients using computed tomography images acquired during routine care. Appl Physiol Nutr Metab. 2008;33(5):997–1006. doi:10.1139/H08-075.

    Article  PubMed  Google Scholar 

  22. Prado CM, Baracos VE, McCargar LJ, Reiman T, Mourtzakis M, Tonkin K, et al. Sarcopenia as a determinant of chemotherapy toxicity and time to tumor progression in metastatic breast cancer patients receiving capecitabine treatment. Clin Cancer Res. 2009;15(8):2920–6. doi:10.1158/1078-0432.CCR-08-2242.

    Article  PubMed  CAS  Google Scholar 

  23. Caussanel JP, Levi F, Brienza S, Misset JL, 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(12):1046–50.

    Article  PubMed  CAS  Google Scholar 

  24. Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst. 2000;92(3):205–16.

    Article  PubMed  CAS  Google Scholar 

  25. Cosqueric G, Sebag A, Ducolombier C, Thomas C, Piette F, Weill-Engerer S. Sarcopenia is predictive of nosocomial infection in care of the elderly. Br J Nutr. 2006;96(5):895–901.

    Article  PubMed  CAS  Google Scholar 

  26. Prado CM, Lima IS, Baracos VE, Bies RR, McCargar LJ, Reiman T, et al. An exploratory study of body composition as a determinant of epirubicin pharmacokinetics and toxicity. Cancer Chemother Pharmacol. 2010;67(1):93–101. doi:10.1007/s00280-010-1288-y.

    Article  PubMed  Google Scholar 

  27. Antoun S, Baracos VE, Birdsell L, Escudier B, Sawyer MB. Low body mass index and sarcopenia associated with dose-limiting toxicity of sorafenib in patients with renal cell carcinoma. Ann Oncol. 2010;21(8):1594–8. doi:10.1093/annonc/mdp605.

    Article  PubMed  CAS  Google Scholar 

  28. Meza-Junco J, Montano-Loza A, Prado CMM, Lieffers JR, Baracos VE, Bain V, Spratlin JL, Sawyer MB. Sarcopenia in patients (pts) with hepatocelluar carcinoma (HCC). J Clin Oncol. 2011;29(suppl):e14570.

    Google Scholar 

  29. Antoun S, Birdsell L, Sawyer MB, Venner P, Escudier B, Baracos VE. Association of skeletal muscle wasting with treatment with sorafenib in patients with advanced renal cell carcinoma: results from a placebo-controlled study. J Clin Oncol. 2010;28(6):1054–60. doi:10.1200/JCO.2009.24.9730.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

The authors wish to thank the nurses, residents and clinical research staff of the Cochin Teaching Hospital.

Conflicts of interest

Prof. Goldwasser has acted as paid consultant for Bayer Healthcare and Pfizer. Dr. Ropert has acted as paid consultant for Bayer Healthcare and Sanofi-Aventis. Dr. Mir and Dr. Coriat have acted as paid consultants for Roche. The other authors have no conflict of interest to declare.

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Authors and Affiliations

  1. Department of Medical Oncology, Centre for Research on Angiogenesis Inhibitors (CERIA), Cochin Teaching Hospital, AP-HP, Université Paris Descartes, Sorbonne Paris Cité, 27, rue du faubourg Saint Jacques, 75014, Paris, France

    Olivier Mir, Pascaline Boudou-Rouquette, Stanislas Ropert, Jean-Philippe Durand, Anatole Cessot & François Goldwasser

  2. Department of Gastro-Enterology, Cochin Teaching Hospital, AP-HP, Université Paris Descartes, Sorbonne Paris Cité, Paris, France

    Romain Coriat & Stanislas Chaussade

  3. Department of Hepatology and INSERM U1016, Cochin Teaching Hospital, AP-HP, Université Paris Descartes, Sorbonne Paris Cité, Paris, France

    Vincent Mallet, Philippe Sogni & Stanislas Pol

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  1. Olivier Mir
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Correspondence to Olivier Mir.

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The authors Olivier Mir and Romain Coriat contributed equally to this work.

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Mir, O., Coriat, R., Boudou-Rouquette, P. et al. Gemcitabine and oxaliplatin as second-line treatment in patients with hepatocellular carcinoma pre-treated with sorafenib. Med Oncol 29, 2793–2799 (2012). https://doi.org/10.1007/s12032-012-0208-x

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