Abstract
Background: The mitoxantrone combination CNF and the epirubicin combination CEF have shown similar activity and less toxicity than the standard CAF combination in metastatic breast cancer (MBC). A prospective randomised study was started to compare safety and activity between CEF and CNF administered using a classical chemotherapeutic schedule in MBC.
Patients and methods: From December 1987 to June 1993, 151 patients were randomised to receive cyclophosphamide (C) 100 mg m−2 p.o. days 1–14, fluorouracil (F) 500 mg m−2 i.v. days 1 and 8, and epirubicin (E) 30 mg m−2 i.v. days 1 and 8, or mitoxantrone (N) 6 mg m−2 i.v. days 1 and 8, every 4 weeks. Seventy‐three patients were eligible for CEF and 72 for CNF.
Results: Objective responses were observed in 61.6 of the CEF group and 44.4 in CNF group (p=0.004). The median duration of response was 64 weeks in CEF and 50 weeks in CNF group (p=0.02) and median time to progression was 51 and 33 weeks, respectively (p=0.0004). At the time of analysis, all except six patients (one in CNF and five in CEF) had died and the median survival time in the CEF group was longer than in CNF (74.4 weeks vs 51.4 weeks; log-rank χ2 test p=0.015). CNF produced more hematologic toxicity than CEF (WHO scale; grades 2–4): leucopenia 84% vs 68% (p=0.03) and trombocytopenia 17% vs 4.5% (p=0.01); CEF caused more grade 2 and 3 alopecia: 93% vs 70% (p=0.00 1).
Conclusion: The combination CEF using this schedule and dosage in metastatic breast cancer is more effective with less toxicity than CNF, except for alopecia, and was associated with longer survival.
Similar content being viewed by others
References
Smalley RV, Carpenter J, Bartolucci A, et al.: A comparison of cyclophosphamide, adriamycin, 5–fluorouracil (CAF) and cyclophosphamide, methotrexate, 5–fluorouracil, vincristine, prednisone (CMFVP) in patients with metastatic breast cancer. Cancer 40: 625–632, 1977
Bull JM, Tormey DC, Li S, et al.: A randomized comparative trial of adriamycin versus methotrexate in combination drug therapy. Cancer 41: 1649–1657, 1978
Falkson G, Gelman R, Tormey DC, et al.: The Eastern Cooperative Oncology Group experience with cyclophosphamide, Adriamycin, and 5–fluorouracil (CAF) in patients with metastatic breast cancer. Cancer 56: 219–224, 1985
Brambilla C, Rossi A, Bonfante V, et al.: Phase II study of doxorubicin versus epirubicin in advanced breast cancer. Cancer Treat Rep 70: 261–266, 1986
Hayat M, Chauvergne J, Fargeot P, et al.: Phase III Chemotherapy comparing FAC versus FEC in advanced breast cancer: Preliminary results. Proc Am Soc Clin Oncol: C-460, 1984
Intini C, Zingali G, de Micheli P, et al.: FEC versus FAC in advanced breast cancer. Results of an Italian cooperative study. Cancer Chemother Pharmacol 18 (Suppl 1): A38, 149, 1986
Bennett JM, Muss HB, Doroshow JH, et al.: A randomized multicenter trial comparing mitoxantrone, cyclophosphamide, and fluorouracil with doxorubicin, cyclophosphamide, and fluorouracil in therapy of metastatic breast carcinoma. J Clin Oncol 6: 1611–1620, 1988
Henderson IC, Wolff S, Allegra J, et al.: Mitoxantrone versus doxorubicin in advanced breast cancer: a randomized trial in 220 patients. Third European Conference on Clinical Oncology and Cancer Nursing. ECCO 3. Novantrone Satellite Symposium. Stockholm, 19 June, 1985, Abstract Book, 4
Neidhart JA, Gochnour D, Roach R, et al.: A comparison of mitoxantrone and doxorubicin in breast cancer. J Clin Oncol 4: 672–677, 1986
Alexander J, Daimak N, Berber HJ, et al.: Serial assessement of doxorubicin cardiotoxicity with quantitative radionuclide angiocardiography. N Engl J Med 300: 278–283, 1979
Miller AB, Hoogstraten B, Staquet M, et al.: Reporting results of cancer treatment. Cancer 47: 207–214, 1981
Hayward JL, Carbone PP, Heuson JC, et al.: Assessment of response to therapy in advanced breast cancer. Eur J Cancer Cli Oncol 13: 89–94, 1977
Cochran WG: The chi-square test of goodness of fit. Ann Math Stat 23: 315–345, 1952
Winer BJ: Statistical Principles in Experimental Design. McGraw-Hill, London, England, 1970
Mehta CR, Patel NR: A network algorithm for performing Fisher's exact test in r x c contingency tables. J Am Stat Assoc 78: 427–434, 1983
Kaplan EL, Meier P: Non-parametric estimation from incomplete observations. J Am Stat Assoc 53: 457–481, 1958
Peto R, Pike MC: Conservation of the approximation 6.O-E/2/E in the log-rank test for survival data or tumor incidence data. Biometrics 29: 579–584, 1973
Allegra JC, Woodcock T, Woolf S, et al.: A randomized trial comparing mitoxantrone with doxorubicin in patients with stage IV breast cancer. Invest New Drugs 3: 153–161, 1985
Henderson IC, Allegra JC, Woodcock T, et al.: Randomized clinical trial comparing mitoxantrone with doxorubicin in previously treated patients with metastatic breast cancer. J Clin Oncol 7: 560–571, 1989
Cowan JD, Neidhart J, McClude S, et al.: Randomized trial of doxorubicin, bisantrene, and mitoxantrone in advanced breast cancer: a Southwest Oncology Group study. J Natl Cancer Inst 83: 1077–1084, 1991
Lawton PA, Spittle MF, Ostrowski MJ, et al.: A comparison of doxorubicin, epirubicin and mitozantrone as single agents in advanced breast carcinoma. Clin Oncol (R. Coll Radiol) 5(2): 80–84, 1993
Follezou JY, Palangie T, Feuilhade F, et al.: Essai randomise comparant la mitoxantrone a l'adriamycine dans les cancers du sein evolves. La presse medicale 16(16): 765–768, 1987
Periti P, Pannuti F, Della Cuna GR, et al.: Combination chemotherapy with cyclophosphamide, fluorouracil, and either epirubicin or mitoxantrone: a comparative randomized multicenter study in metastatic breast cancer. Cancer Invest 9: 249–255, 1991
Taguchi T, Sakai K, Terasawa T, et al.: Result of clinical trials with a CAF (cyclophosphamide, adriamycin, and 5–fluorouracil) regimen versus a CMITF (cyclophosphamide, mitoxantrone and 5–fluorouracil) regimen in advanced relapsed breast cancer. Jpn J Cancer Chemother 13: 2820–2828 1986
Buyukunal E, Derman U, Serdengecti S, et al.: A clinical trial of mitoxantrone versus doxorubicin in combination chemotherapy for metastatic breast cancer. Chemioterapia 6: 377–379, 1987
Heidemann E, Steinke B, Hartlapp J, et al.: Randomized clinical trial comparing mitoxantrone with epirubicin and with doxorubicin, each combined with cyclophosphamide in the first-line treatment of patients with metastatic breast cancer. Onkologie 13:24–27, 1990
Alonso MC, Tabernero JM, Ojeda B, et al.: A phase III randomized trial of cyclophosphamide, mitoxantrone, and 5–fluorouracil versus cyclophosphamide, adriamycin, and 5–fluorouracil in patients with metastatic breast cancer. Breast Cancer Res Treat 34: 15–24, 1995
Stewart DJ, Evans WK, Shepherd FA, et al.: Cyclophosphamide and fluorouracil combined with mitoxantrone versus doxorubicin for breast cancer: superiority of doxorubicin. J Clin Oncol 15: 1897–1905, 1997
Hausmaninger H, Lehnert M, Steger G, et al.: Vindesineepirubicin versus vindesine-mitoxantrone in metastatic breast cancer. Onkologie 12: 225–229, 1989
Rahman ZU, Frye DK, Smith TL, et al.: Results and long term followup for 1581 patients with metastatic breast carcinoma treated with standard dose doxorubicin-containing chemotherapy. Cancer 85: 104–111, 1999
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Esteban, E., Lacave, A., Fernández, J. et al. Phase III trial of cyclophosphamide, epirubicin, fluorouracil (CEF) versus cyclophosphamide, mitoxantrone, fluorouracil (CNF) in women with metastatic breast cancer. Breast Cancer Res Treat 58, 141–150 (1999). https://doi.org/10.1023/A:1006387801960
Issue Date:
DOI: https://doi.org/10.1023/A:1006387801960