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Phase I pilot study of oxaliplatin, infusional 5-FU, and cetuximab in recurrent or metastatic head and neck cancer

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Abstract

Platinum-based therapy is active in advanced head and neck squamous cell carcinoma (HNSCC). Patients with inoperable recurrent or metastatic HNSCC have a poor prognosis; many have difficulty tolerating cisplatin-based regimens. Oxaliplatin has antitumor activity without many of the toxicities of cisplatin. We conducted a phase I pilot study to investigate the dose limitation of oxaliplatin with 5-fluorouracil (5-FU) and cetuximab in patients with untreated recurrent or metastatic HNSCC. The planned dose escalation schedule included: dose level 1: oxaliplatin 100 mg/m2 day 1, 5-FU CIV 750 mg/m2/day over 96 h beginning day 1, and cetuximab 400 mg/m2 day 1 (then 250 mg/m2 weekly) every 21 days. Dose level 2: oxaliplatin 130 mg/m2 day 1, 5-FU CIV 1,000 mg/m2/day over 96 h beginning day 1, and the same dose and schedule of cetuximab. Seven patients were accrued at dose level 1 and three at dose level 2. Dose level 1 toxicity included grade 1–2 stomatitis, fatigue, acneiform rash, and anemia, and grade 1 nausea and transaminitis. Dose level 2 toxicity was unacceptable: 2 of 3 patients experienced grade 4 toxicities (stomatitis, diarrhea, and acute renal failure) requiring hospitalization with one treatment-related death. Accrual was therefore closed with dose level 1 considered the maximum tolerated dose. Observed responses were short-lived. The regimen of oxaliplatin 100 mg/m2 day 1, infusional 5-FU 750 mg/m2/day over 96 h beginning day 1, and cetuximab 400 mg/m2 day 1 (then 250 mg/m2 weekly), every 21 days, has manageable toxicity; these doses are recommended for phase II evaluation in the treatment for unresectable or metastatic HNSCC.

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References

  1. Adelstein DJ, Tan EH, Lavertu P. Treatment of head and neck cancer: the role of chemotherapy. Crit Rev Oncol Hematol. 1996;24:97–116.

    Article  PubMed  CAS  Google Scholar 

  2. Jacobs C, Lyman G, Velez-Garcia E, et al. A phase III randomized study comparing cisplatin and fluorouracil as single agents and in combination for advanced squamous cell carcinoma of the head and neck. J Clin Oncol. 1992;10:257–63.

    PubMed  CAS  Google Scholar 

  3. Forastiere AA, Metch B, Schuller DE, et al. Randomized comparison of cisplatin plus fluorouracil and carboplatin plus fluorouracil versus methotrexate in advanced squamous-cell carcinoma of the head and neck: a Southwest Oncology Group study. J Clin Oncol. 1992;10:1245–51.

    PubMed  CAS  Google Scholar 

  4. Clavel M, Vermorken JB, Cognetti F, et al. Randomized comparison of cisplatin, methotrexate, bleomycin and vincristine (CABO) versus cisplatin and 5-fluorouracil (CF) versus cisplatin (C) in recurrent or metastatic squamous cell carcinoma of the head and neck. A phase III study of the EORTC Head and Neck Cancer Cooperative Group. Ann Oncol. 1994;5:521–6.

    PubMed  CAS  Google Scholar 

  5. Vermorken JB, Mesia R, Rivera F, et al. Platinum-based chemotherapy plus cetuximab in head and neck cancer. N Engl J Med. 2008;359:1116–27.

    Article  PubMed  CAS  Google Scholar 

  6. Rubin Grandis J, Melhem MF, Gooding WE, et al. Levels of TGF-alpha and EGFR protein in head and neck squamous cell carcinoma and patient survival. J Natl Cancer Inst. 1998;90:824–32.

    Article  PubMed  CAS  Google Scholar 

  7. Chung CH, Ely K, McGavran L, et al. Increased epidermal growth factor receptor gene copy number is associated with poor prognosis in head and neck squamous cell carcinomas. J Clin Oncol. 2006;24:4170–6.

    Article  PubMed  CAS  Google Scholar 

  8. Temam S, Kawaguchi H, El-Naggar AK, et al. Epidermal growth factor receptor copy number alterations correlate with poor clinical outcome in patients with head and neck squamous cancer. J Clin Oncol. 2007;25:2164–70.

    Article  PubMed  CAS  Google Scholar 

  9. Goldstein NI, Prewett M, Zuklys K, et al. Biological efficacy of a chimeric antibody to the epidermal growth factor receptor in a human tumor xenograft model. Clin Cancer Res. 1995;1:1311–8.

    PubMed  CAS  Google Scholar 

  10. Li S, Schmitz KR, Jeffrey PD, et al. Structural basis for inhibition of the epidermal growth factor receptor by cetuximab. Cancer Cell. 2005;7:301–11.

    Article  PubMed  CAS  Google Scholar 

  11. Sato JD, Kawamoto T, Le AD, et al. Biological effects in vitro of monoclonal antibodies to human epidermal growth factor receptors. Mol Biol Med. 1983;1:511–29.

    PubMed  CAS  Google Scholar 

  12. Patel D, Guo X, Ng S, et al. IgG isotype, glycosylation, and EGFR expression determine the induction of antibody-dependent cellular cytotoxicity in vitro by cetuximab. Hum Antibod. 2010;19:89–99.

    CAS  Google Scholar 

  13. Kimura H, Sakai K, Arao T, et al. Antibody-dependent cellular cytotoxicity of cetuximab against tumor cells with wild-type or mutant epidermal growth factor receptor. Cancer Sci. 2007;98:1275–80.

    Article  PubMed  CAS  Google Scholar 

  14. Zhang W, Gordon M, Schultheis AM, et al. FCGR2A and FCGR3A polymorphisms associated with clinical outcome of epidermal growth factor receptor expressing metastatic colorectal cancer patients treated with single-agent cetuximab. J Clin Oncol. 2007;25:3712–8.

    Article  PubMed  CAS  Google Scholar 

  15. Vermorken JB, Trigo J, Hitt R, et al. Open-label, uncontrolled, multicenter phase II study to evaluate the efficacy and toxicity of cetuximab as a single agent in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck who failed to respond to platinum-based therapy. J Clin Oncol. 2007;25:2171–7.

    Article  PubMed  CAS  Google Scholar 

  16. Baselga J, Trigo JM, Bourhis J, et al. Phase II multicenter study of the antiepidermal growth factor receptor monoclonal antibody cetuximab in combination with platinum-based chemotherapy in patients with platinum-refractory metastatic and/or recurrent squamous cell carcinoma of the head and neck. J Clin Oncol. 2005;23:5569–77.

    Google Scholar 

  17. Herbst RS, Arquette M, Shin DM, et al. Phase II multicenter study of the epidermal growth factor receptor antibody cetuximab and cisplatin for recurrent and refractory squamous cell carcinoma of the head and neck. J Clin Oncol. 2005;23:5578–87.

    Article  PubMed  CAS  Google Scholar 

  18. Fan Z, Baselga J, Masui H, Mendelsohn J. Antitumor effect of anti-epidermal growth factor receptor monoclonal antibodies plus cis-diamminedichloroplatinum on well established A431 cell xenografts. Cancer Res. 1993;53:4637–42.

    PubMed  CAS  Google Scholar 

  19. Reed E, Kohn KW. Platinum analogues. In: Chabner BA, Collins JM, editors. Cancer chemotherapy. Philadelphia: J.B. Lippincott Co.; 1990. p. 465–90.

    Google Scholar 

  20. Al-Sarraf M. Head and neck cancer: chemotherapy concepts. Semin Oncol. 1988;15:70–85.

    PubMed  CAS  Google Scholar 

  21. Legallicier B, Leclere C, Monteil C, Elkaz V, Morin JP, Fillastre JP. The cellular toxicity of two antitumoural agents derived from platinum, cisplatinum versus oxaliplatin, on cultures of tubular proximal cells. Drugs Exp Clin Res. 1996;22:41–50.

    PubMed  CAS  Google Scholar 

  22. Rixe O, Ortuzar W, Alvarez M, et al. Oxaliplatin, tetraplatin, cisplatin, and carboplatin: spectrum of activity in drug-resistant cell lines and in the cell lines of the National Cancer Institute’s Anticancer Drug Screen panel. Biochem Pharmacol. 1996;52:1855–65.

    Article  PubMed  CAS  Google Scholar 

  23. Fukuda M, Ohe Y, Kanzawa F, Oka M, Hara K, Saijo N. Evaluation of novel platinum complexes, inhibitors of topoisomerase I and II in non-small cell lung cancer (NSCLC) sublines resistant to cisplatin. Anticancer Res. 1995;15:393–8.

    PubMed  CAS  Google Scholar 

  24. Dunn TA, Schmoll HJ, Grunwald V, Bokemeyer C, Casper J. Comparative cytotoxicity of oxaliplatin and cisplatin in non-seminomatous germ cell cancer cell lines. Invest New Drugs. 1997;15:109–14.

    Article  PubMed  CAS  Google Scholar 

  25. Extra JM, Marty M, Brienza S, Misset JL. Pharmacokinetics and safety profile of oxaliplatin. Semin Oncol. 1998;25:13–22.

    PubMed  CAS  Google Scholar 

  26. Woynarowski JM, Chapman WG, Napier C, Herzig MC, Juniewicz P. Sequence- and region-specificity of oxaliplatin adducts in naked and cellular DNA. Mol Pharmacol. 1998;54:770–7.

    PubMed  CAS  Google Scholar 

  27. Degardin M, Cappelaere P, Krakowski I, Fargeot P, Cupissol D, Brienza S. Phase II trial of oxaliplatin (L-OHP) in advanced, recurrent and/or metastatic squamous cell carcinoma of the head and neck. Eur J Cancer B Oral Oncol. 1996;32B:278–9.

    Article  PubMed  CAS  Google Scholar 

  28. Debled M, Gervais R, Laguerre B et al. (2003) Phase II study of oxaliplatin (OXA) in combination with 5-fluorouracil (5FU) in first line treatment of locally advanced (LA) or metastatic squamous cell carcinoma (SCC) of the head and neck. Proc Am Soc Clin Oncol 22:509 (abstr 2049).

    Google Scholar 

  29. Tabernero J, Van Cutsem E, Díaz-Rubio E, et al. Phase II trial of cetuximab in combination with fluorouracil, leucovorin, and oxaliplatin in the first-line treatment of metastatic colorectal cancer. J Clin Oncol. 2007;25:5225–32.

    Article  PubMed  CAS  Google Scholar 

  30. Bokemeyer C, Bondarenko I, Makhson A, et al. Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer. J Clin Oncol. 2009;27:663–71.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This study was supported by Sanofi-Aventis, Paris, France.

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Authors and Affiliations

  1. Edward Hines, Jr. VA Hospital, Hines, IL, 60411, USA

    Joseph I. Clark & Jay S. Dalal

  2. Loyola University Stritch School of Medicine, Cardinal Bernardin Cancer Center, 2160 S. First Avenue, Maywood, IL, 60153, USA

    Joseph I. Clark, Joshua B. Greene, Ann Lau Clark & Jay S. Dalal

  3. The Ohio State University, Columbus, OH, USA

    Craig C. Hofmeister

Authors
  1. Joseph I. Clark
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  2. Joshua B. Greene
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  3. Ann Lau Clark
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  4. Jay S. Dalal
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Correspondence to Joseph I. Clark.

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Clark, J.I., Greene, J.B., Lau Clark, A. et al. Phase I pilot study of oxaliplatin, infusional 5-FU, and cetuximab in recurrent or metastatic head and neck cancer. Med Oncol 30, 358 (2013). https://doi.org/10.1007/s12032-012-0358-x

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  • DOI: https://doi.org/10.1007/s12032-012-0358-x

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