Skip to main content
SpringerLink
Log in

Phase I trial of combined irinotecan and oxaliplatin given every three weeks to patients with metastatic colorectal cancer

  • Published:
Investigational New Drugs Aims and scope Submit manuscript

Abstract

Background: Both irinotecan and oxaliplatin are active agents in the treatment of patients with metastatic colorectal cancer (MCC). There is a strong preclinical rationale for combining these two agents. We sought to determine the dose-limiting toxicity (DLT) and the maximum tolerated dose (MTD) of combined irinotecan and oxaliplatin given every three weeks. Methods: Cohorts of patients with MCC previously treated with 5-fluorouracil received escalating doses of irinotecan (150, 175, and 200 mg/m2) and a fixed dose of oxaliplatin (130 mg/m2), both given intravenously every 3 weeks. DLT was evaluated within the first course of treatment. Objective responses were evaluated every two courses and were confirmed at least four weeks later. Results: Fourteen patients were treated and evaluated for toxicity. The DLT was neutropenia, with or without fever, and delayed recovery of neutrophil counts was frequent (13 courses in six patients). Other toxic effects (peripheral neuropathy, nausea, vomiting, diarrhea, and fatigue) were mild to moderate. Among 13 patients evaluable for activity, four achieved partial responses and nine had stable disease. Conclusion: The combination of irinotecan and oxaliplatin is safe and apparently active in the treatment of MCC patients. The recommended dose for phase II studies is 175 mg/m2 irinotecan plus 130 mg/m2 oxaliplatin, given every 3 weeks. Neutropenia and delayed recovery of neutrophil counts are the predominant early toxicities with this schedule.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Jemal A, Murray T, Samuels A, Ghafoor A, Ward E, Thun MJ: Cancer statistics. CA Cancer J Clin 53: 5–26, 2003

    PubMed  Google Scholar 

  2. Ardalan B, Luis R, Jaime M, Franceschi D: Biomodulation of fluorouracil in colorectal cancer. Cancer Invest 16: 237–251, 1998

    CAS  PubMed  Google Scholar 

  3. Meta-analysis Group in Cancer: Efficacy of intravenous continuous infusion of fluorouracil compared with bolus administration in advanced colorectal cancer. J Clin Oncol 16: 301–308, 1998

    Google Scholar 

  4. Poon MA, O’Connell MJ, Moertel CG, Wieand HS, Cullinan SA, Everson LK, Krook JE, Mailliard JA, Laurie JA, Tschetter LK: Biochemical modulation of fluorouracil: Evidence of significant improvement of survival and quality of life in patients with advanced colorectal carcinoma. J Clin Oncol 7: 1407–1418, 1989

    CAS  PubMed  Google Scholar 

  5. Poon MA, O’Connell MJ, Wieand HS, Krook JE, Gerstner JB, Tschetter LK, Levitt R, Kardinal CG, Mailliard JA: Biochemical modulation of fluorouracil with leucovorin: Confirmatory evidence of improved therapeutic efficacy in advanced colorectal cancer. J Clin Oncol 9: 1967–1972, 1991

    Google Scholar 

  6. Advanced Colorectal Cancer Meta-Analysis Project: Modulation of fluorouracil by leucovorin in patients with advanced colorectal cancer: evidence in terms of response rate. J Clin Oncol 10: 896–903, 1992

    Google Scholar 

  7. Pitot HC, Wender DB, O’Connell MJ, Schroeder G, Goldberg RM, Rubin J, Mailliard JA, Knost JA, Ghosh C, Kirschling RJ, Levitt R, Windschitl HE: Phase II trial of irinotecan in patients with metastatic colorectal carcinoma. J Clin Oncol 15: 2910–2919, 1997

    CAS  PubMed  Google Scholar 

  8. Machover D, Diaz-Rubio E, de Gramont A, Schilf A, Gastiaburu JJ, Brienza S, Itzhaki M, Metzger G, N’Daw D, Vignoud J, Abad A, Francois E, Gamelin E, Marty M, Sastre J, Seitz JF, Ychou M: Two consecutive phase II studies of oxaliplatin (L-OHP) for treatment of patients with advanced colorectal carcinoma who were resistant to previous treatment with fluoropyrimidines. Ann Oncol 7: 95–98, 1996

    CAS  Google Scholar 

  9. Rothenberg ML, Eckardt JR, Kuhn JG, Burris HA 3rd, Nelson J, Hilsenbeck SG, Rodriguez GI, Thurman AM, Smith LS, Eckhardt SG, Weiss GR, Elfring GL, Rinaldi DA, Schaaf LJ, Von Hoff DD: Phase II trial of irinotecan in patients with progressive or rapidly recurrent colorectal cancer. J Clin Oncol 14: 1128–1135, 1996

    CAS  PubMed  Google Scholar 

  10. Diaz-Rubio E, Sastre J, Zaniboni A, Labianca R, Cortes-Funes H, de Braud F, Boni C, Benavides M, Dallavalle G, Homerin M: Oxaliplatin as single agent in previously untreated colorectal carcinoma patients: A phase II multicentric study. Ann Oncol 9: 105–108, 1998

    CAS  PubMed  Google Scholar 

  11. Becouarn Y, Ychou M, Ducreux M, Borel C, Bertheault-Cvitkovic F, Seitz JF, Nasca S, Nguyen TD, Paillot B, Raoul JL, Duffour J, Fandi A, Dupont-Andre G, Rougier P: Phase II trial of oxaliplatin as first-line chemotherapy in metastatic colorectal cancer patients. Digestive Group of French Federation of Cancer Centers. J Clin Oncol 16: 2739–2744, 1998

    CAS  PubMed  Google Scholar 

  12. Saltz LB, Cox JV, Blanke C, Rosen LS, Fehrenbacher L, Moore MJ, Maroun JA, Ackland SP, Locker PK, Pirotta N, Elfring GL, Miller LL: Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. Irinotecan Study Group. N Engl J Med 343: 905–914, 2000

    Article  CAS  PubMed  Google Scholar 

  13. Douillard JY, Cunningham D, Roth AD, Navarro M, James RD, Karasek P, Jandik P, Iveson T, Carmichael J, Alakl M, Gruia G, Awad L, Rougier P: Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: A multicentre randomised trial. Lancet 355: 1041–1047, 2000

    Article  CAS  PubMed  Google Scholar 

  14. de Gramont A, Figer A, Seymour M, Homerin M, Hmissi A, Cassidy J, Boni C, Cortes-Funes H, Cervantes A, Freyer G, Papamichael D, Le Bail N, Louvet C, Hendler D, de Braud F, Wilson C, Morvan F, Bonetti A: Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol 18: 2938–2947, 2000

    PubMed  Google Scholar 

  15. Hsiang YH, Liu LF: Identification of mammalian DNA topoisomerase I as an intracellular target of the anticancer drug camptothecin. Cancer Res 48: 1722–1726, 1988

    CAS  PubMed  Google Scholar 

  16. Raymond E, Chaney SG, Taamma A, Cvitkovic E: Oxaliplatin: A review of preclinical and clinical studies. Ann Oncol 9: 1053–1071, 1998

    CAS  PubMed  Google Scholar 

  17. Zeghari-Squalli N, Raymond E, Cvitkovic E, Goldwasser F: Cellular pharmacology of the combination of the DNA topoisomerase I inhibitor SN-38 and the diaminocyclohexane platinum derivative oxaliplatin. Clin Cancer Res 5: 1189–1196, 1999

    CAS  PubMed  Google Scholar 

  18. Wasserman E, Cuvier C, Lokiec F, Goldwasser F, Kalla S, Mery-Mignard D, Ouldkaci M, Besmaine A, Dupont-Andre G, Mahjoubi M, Marty M, Misset JL, Cvitkovic E: Combination of oxaliplatin plus irinotecan in patients with gastrointestinal tumors: Results of two independent phase I studies with pharmacokinetics. J Clin Oncol 17: 1751–1759, 1999

    CAS  PubMed  Google Scholar 

  19. Kemeny N, Tong W, Gonen M, Stockman J, DiLauro C, Teitcher J, White P, Price C, Saltz L, Sharma S, Graham MA: Phase I study of weekly oxaliplatin plus irinotecan in previously treated patients with metastatic colorectal cancer. Ann Oncol 13: 1490–1496, 2002

    CAS  PubMed  Google Scholar 

  20. Wasserman E, Myara A, Lokiec F, Goldwasser F, Trivin F, Mahjoubi M, Misset JL, Cvitkovic E: Severe CPT-11 toxicity in patients with Gilbert’s syndrome: Two case reports. Ann Oncol 8: 1049–1051, 1997

    CAS  PubMed  Google Scholar 

  21. Goldwasser F, Gross-Goupil M, Tigaud JM, Di Palma M, Marceau-Suissa J, Wasserman E, Yovine A, Misset JL, Cvitkovic E: Dose escalation of CPT-11 in combination with oxaliplatin using an every two weeks schedule: A phase I study in advanced gastrointestinal cancer patients. Ann Oncol 11: 1463–1470, 2000

    CAS  PubMed  Google Scholar 

  22. Goldberg RM, Morton RF, Sargent DJ, Fuchs C, Ramanathan RK, Williamson SK, Findlay BP: N9741: oxaliplatin (Oxal) or CPT-11 + 5-fluorouracil (5FU)/leucovorin (LV) or oxal + CPT-11 in advanced colorectal cancer (CRC). Updated efficacy and quality of life (QOL) data from an intergroup study. (Abstract) Proc Am Soc Clin Oncol 22: 252, 2003

    Google Scholar 

  23. Scheithauer W, Kornek GV, Raderer M, Valencak J, Weinlander G, Hejna M, Haider K, Kwasny W, Depisch D: Combined irinotecan and oxaliplatin plus granulocyte colony-stimulating factor in patients with advanced fluoropyrimidine/leucovorin-pretreated colorectal cancer. J Clin Oncol 17: 902–906, 1999

    CAS  PubMed  Google Scholar 

  24. Johnston PG, Lenz HJ, Leichman CG, Danenberg KD, Allegra CJ, Danenberg PV, Leichman L: Thymidylate synthase gene and protein expression correlate and are associated with response to 5-fluorouracil in human colorectal and gastric tumors. Cancer Res 55: 1407–1412, 1995

    CAS  PubMed  Google Scholar 

  25. Leichman CG, Lenz HJ, Leichman L, Danenberg K, Baranda J, Groshen S, Boswell W, Metzger R, Tan M, Danenberg PV: Quantitation of intratumoral thymidylate synthase expression predicts for disseminated colorectal cancer response and resistance to protracted-infusion fluorouracil and weekly leucovorin. J Clin Oncol 15: 3223–3229, 1997

    CAS  PubMed  Google Scholar 

  26. Salonga D, Danenberg KD, Johnson M, Metzger R, Groshen S, Tsao-Wei DD, Lenz HJ, Leichman CG, Leichman L, Diasio RB, Danenberg PV: Colorectal tumors responding to 5-fluorouracil have low gene expression levels of dihydropyrimidine dehydrogenase, thymidylate synthase, and thymidine phosphorylase. Clin Cancer Res 6: 1322–1327, 2000

    CAS  PubMed  Google Scholar 

  27. Bismuth H, Adam R: Reduction of nonresectable liver metastasis from colorectal cancer after oxaliplatin chemotherapy. Semin Oncol 25(2 suppl 5): 40–46, 1998

    CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Gastrointestinal Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX

    Paulo M. Hoff, Robert Wolff, Yvonne Lassere, Karla R. Bogaard & James L. Abbruzzese

  2. Albert Einstein Hospital, São Paulo, Brazil

    Everardo D. Saad

  3. U.S. Food and Drug Administration, Rockville, MD, USA

    Richard Pazdur

Authors
  1. Paulo M. Hoff
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Everardo D. Saad
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Richard Pazdur
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Robert Wolff
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yvonne Lassere
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Karla R. Bogaard
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. James L. Abbruzzese
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hoff, P.M., Saad, E.D., Pazdur, R. et al. Phase I trial of combined irinotecan and oxaliplatin given every three weeks to patients with metastatic colorectal cancer. Invest New Drugs 22, 307–313 (2004). https://doi.org/10.1023/B:DRUG.0000026257.31142.41

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/B:DRUG.0000026257.31142.41

Search

Navigation