Skip to main content

Advertisement

SpringerLink
Log in

A multicenter phase II study of irinotecan (CPT-11) alternated with 5-fluorouracil and leucovorin as first-line treatment of patients with metastatic colorectal cancer

  • Original Article
  • Published:
Cancer Chemotherapy and Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

In this multicenter phase II study the efficacy and safety of the alternating schedule of irinotecan (CPT-11) with bolus 5-fluorouracil (5-FU) and leucovorin (LV) were assessed as first-line chemotherapy in patients with metastatic colorectal cancer (CRC).

Patients and methods

Enrolled in the study were 43 patients with advanced CRC. They received CPT-11 350 mg/m2 i.v. on day 1, alternating with LV 20 mg/m2 i.v. and 5-FU 425 mg/m2 i.v. daily for five consecutive days, on days 22–26 (Mayo Clinic regimen). One cycle consisted of 6 weeks.

Results

A total of 179 cycles were administered with a median of four per patient (range one to nine). Efficacy was analyzed on an intention-to-treat basis. The overall objective response rate was 30% (95% CI 16–44), with four complete responses and nine partial responses, whereas 20 patients (4%) showed stable disease. The median time to disease progression was 9.0 months and median survival was 18.5 months. Grade 3/4 diarrhea was mainly related to CPT-11 rather than to 5-FU (9.3% vs 4.7% of patients), whereas grade 3/4 neutropenia was higher during 5-FU administration (16.3% vs 7.0% of patients).

Conclusions

The alternating schedule of CPT-11 with 5 days bolus of 5-FU and low-dose LV showed a clinical benefit in terms of tumor growth control as first-line treatment of patients with metastatic CRC. The overall safety data confirmed this alternating combination as a well-tolerated treatment.

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

Fig. 1.
Fig. 2.

Similar content being viewed by others

References

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

    PubMed  Google Scholar 

  2. Barone C, Pozzo C, Starkhammar H, et al (1997) A multicentre phase II study in first-line chemotherapy (CT) of metastatic colorectal cancer (CRC): preliminary results. Proc Am Soc Clin Oncol 16:270a

    Google Scholar 

  3. Benhammouda A, Bastian G, Rixe O, et al (1997) A phase I and pharmacokinetic study of CPT-11 an 5-FU combination. Proc Am Soc Clin Oncol 1:202a

    Google Scholar 

  4. Berg D (1998) Managing the side effects of chemotherapy for colorectal cancer. Semin Oncol 25:53–59

    CAS  Google Scholar 

  5. Bleiberg H, Hendlisz A (2002) Advanced colorectal cancer treatment in Europe: what have we achieved? Anticancer Drugs 13:461–471

    Google Scholar 

  6. Cao S, Rustum YM (2000) Synergistic antitumor activity of irinotecan in combination with 5- fluorouracil in rats bearing advanced colorectal cancer: role of drug sequence and dose. Cancer Res 60:3717–3721

    CAS  PubMed  Google Scholar 

  7. Conti JA, Kemeny NE, Saltz LB, Huang Y, Tong WP, Chou TC, Sun M, Pulliam S, Gonzalez C (1996) Irinotecan is an active agent in untreated patients with metastatic colorectal cancer. J Clin Oncol 14:709–715

    PubMed  Google Scholar 

  8. Cunningham D, Pyrhonen S, James RD, Punt CJ, Hickish TF, Heikkila R, Johannesen TB, Starkhammar H, Topham CA, Awad L, Jacques C, Herait P (1998) Randomised trial of irinotecan plus supportive care versus supportive care alone after fluorouracil failure for patients with metastatic colorectal cancer. Lancet 352:1413–1418

    PubMed  Google Scholar 

  9. 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 (2000) Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomised trial. Lancet 355:1041–1047

    PubMed  Google Scholar 

  10. Goldberg RM, Erlichman C (1998) Irinotecan plus 5-FU and leucovorin in advanced colorectal cancer: North American trials. Oncology (Huntingt) 12:59–63

  11. Guichard S, Cussac D, Hennebelle I, Bugat R, Canal P (1997) Sequence-dependent activity of the irinotecan-5FU combination in human colon-cancer model HT-29 in vitro and in vivo. Int J Cancer 73:729–734

    Google Scholar 

  12. Haller DG (2001) Update on chemotherapy for advanced colorectal cancer. Oncology (Huntingt) 15:11–15

  13. Isacoff WH, Borud K (1997) Chemotherapy for the treatment of patients with metastatic colorectal cancer: an overview. World J Surg 21:748–762

    Article  CAS  PubMed  Google Scholar 

  14. Khayat D, Gil-Delgado M, Antoine EC, Coeffic D, Benhammouda A, Grapin JP, Bastian G (1998) European experience with irinotecan plus fluorouracil/folinic acid or mitomycin. Oncology (Huntingt) 12:64–67

    Google Scholar 

  15. Miller AB, Hoogstraten B, Staquet M, Winkler A (1981) Reporting results of cancer treatment. Cancer 47:207–214

    PubMed  Google Scholar 

  16. Moertel CG (1994) Chemotherapy for colorectal cancer. N Engl J Med 330:1136–1142

    Article  CAS  PubMed  Google Scholar 

  17. Pavillard V, Formento P, Rostagno P, Formento JL, Fischel JL, Francoual M, Etienne MC, Milano G (1998) Combination of irinotecan (CPT11) and 5-fluorouracil with an analysis of cellular determinants of drug activity. Biochem Pharmacol 56:1315–1322

    Article  CAS  PubMed  Google Scholar 

  18. 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 (1997) Phase II trial of irinotecan in patients with metastatic colorectal carcinoma. J Clin Oncol 15:2910–2919

    PubMed  Google Scholar 

  19. Rosati G, Rossi A, Reggiardo G, Manzione L (2002) A phase II study of irinotecan alternated with a weekly schedule of high-dose leucovorin and 48-hour 5-fluorouracil infusion in patients with metastatic colorectal cancer. Oncology 62:209–215

    Article  CAS  PubMed  Google Scholar 

  20. Rothenberg ML (1998) Efficacy and toxicity of irinotecan in patients with colorectal cancer. Semin Oncol 25:39–46

    CAS  Google Scholar 

  21. Rothenberg ML, Pazdur R, Rowinsky EK, et al (1997) A phase II multicenter trial of alternating cycles of irinotecan (CPT-11) and 5-FU/LV in patients with previously untreated metastatic colorectal cancer (CRC). Proc Am Soc Clin Oncol 16:266a

    Google Scholar 

  22. Rothenberg ML, Feun LC, Gralla RJ, et al (1998) Phase II study of irinotecan (CPT-11) 250 mg/m2 given every-other-week in previously treated colorectal cancer patients. Proc Am Soc Clin Oncol 17:284a

    Google Scholar 

  23. Rougier P, Bugat R, Douillard JY, Culine S, Suc E, Brunet P, Becouarn Y, Ychou M, Marty M, Extra JM, Bonneterre J, Adenis A, Seitz JF, Ganem G, Namer M, Conroy T, Negrier S, Merrouche Y, Burki F, Mousseau M, Herait P, Mahjoubi M (1997) Phase II study of irinotecan in the treatment of advanced colorectal cancer in chemotherapy-naive patients and patients pretreated with fluorouracil-based chemotherapy. J Clin Oncol 15:251–260

    PubMed  Google Scholar 

  24. Saltz LB, Kanowitz J, Kemeny NE, Schaaf L, Spriggs D, Staton BA, Berkery R, Steger C, Eng M, Dietz A, Locker P, Kelsen DP (1996) Phase I clinical and pharmacokinetic study of irinotecan, fluorouracil, and leucovorin in patients with advanced solid tumors. J Clin Oncol 14:2959–2967

    CAS  PubMed  Google Scholar 

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

    Google Scholar 

  26. Schmoll HJ, Buchele T, Grothey A, Dempke W (1999) Where do we stand with 5-fluorouracil? Semin Oncol 26:589–605

    Google Scholar 

  27. Sobrero A, Kerr D, Glimelius B, Van Cutsem E, Milano G, Pritchard DM, Rougier P, Aapro M (2000) New directions in the treatment of colorectal cancer: a look to the future. Eur J Cancer 36:559–566

    PubMed  Google Scholar 

  28. Tebbutt NC, Cattell E, Midgley R, Cunningham D, Kerr D (2002) Systemic treatment of colorectal cancer. Eur J Cancer 38:1000–1015

    Article  CAS  PubMed  Google Scholar 

  29. Van Cutsem E, Pozzo C, Starkhammar H, Dirix L, Terzoli E, Cognetti F, Humblet Y, Garufi C, Filez L, Gruia G, Cote C, Barone C (1998) A phase II study of irinotecan alternated with five days bolus of 5-fluorouracil and leucovorin in first-line chemotherapy of metastatic colorectal cancer. Ann Oncol 9:1199–1204

    Article  PubMed  Google Scholar 

  30. Vanhoefer U, Harstrick A, Kohne CH, Achterrath W, Rustum YM, Seeber S, Wilke H (1999) Phase I study of a weekly schedule of irinotecan, high-dose leucovorin, and infusional fluorouracil as first-line chemotherapy in patients with advanced colorectal cancer. J Clin Oncol 17:907–913

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Hospital Juan Ramón Jiménez, Huelva, Spain

    Juan José Reina

  2. Hospital Universitario La Fe, Valencia, Spain

    Jorge Aparicio

  3. Hospital Virgen del Rocío, Sevilla, Spain

    Javier Salvador & José Andrés Moreno-Nogueira

  4. Hospital Infanta Cristina, Badajoz, Spain

    José María Puerto Pica

  5. Hospital Puerta del Mar, Cádiz, Spain

    Antonio Rueda

  6. Hospital Puerto Real, Cádiz, Spain

    Antonio Lorenzo

  7. Hospital El Tomillar, Sevilla, Spain

    Carlos González de la Puente

  8. Hospital San Pedro de Alcántara, Cáceres, Spain

    Pablo Borrega

  9. Servicio de Oncología Médica, Hospital Virgen del Rocío, Avda. Manuel Siurot, s/n, 41013, Seville, Spain

    José Andrés Moreno-Nogueira

Authors
  1. Juan José Reina
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jorge Aparicio
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Javier Salvador
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. José María Puerto Pica
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Antonio Rueda
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Antonio Lorenzo
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Carlos González de la Puente
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Pablo Borrega
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. José Andrés Moreno-Nogueira
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to José Andrés Moreno-Nogueira.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Reina, J.J., Aparicio, J., Salvador, J. et al. A multicenter phase II study of irinotecan (CPT-11) alternated with 5-fluorouracil and leucovorin as first-line treatment of patients with metastatic colorectal cancer. Cancer Chemother Pharmacol 52, 339–345 (2003). https://doi.org/10.1007/s00280-003-0601-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00280-003-0601-4

Keywords

Search

Navigation