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Journal of Clinical Oncology, Vol 23, No 18 (June 20), 2005: pp. 4237-4238 © 2005 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.01.0207
Weekly Epirubicin Plus Tamoxifen Versus Tamoxifen Alone As Adjuvant Treatment of Operable, Node-Positive, Elderly Breast Cancer PatientsHematology/Oncology Division, General Hospital of Annemasse, Annemasse, France To the Editor: I read with interest the report of a randomized phase III study by Fargeot et al1 in the December 1, 2004, issue of the Journal of Clinical Oncology comparing weekly epirubicin (30 mg, full dose) plus tamoxifen (30 mg/day) with tamoxifen alone as adjuvant treatment for node-positive, elderly breast cancer patients. Although a longer disease-free survival has been obtained by the combination treatment, there are several points to discuss. Conducting a clinical trial in an elderly population is an exploit, and 10 years have been necessary to recruit 338 women from 19 institutions. Thus, the population is extremely heterogeneous, and favors patients younger than 70 years, who comprise half of the recruited patients. Can we treat similarly a woman of 65 years and a woman older than 80 years? Combination chemotherapy should remain an option in the patients younger than 70 years as much as 5-hydroxytryptamine subtype-3 receptor antagonists (and from now on neurokinin subtype-1 receptor antagonists), granulocyte colony-stimulating factors (prohibited in the study), erythropoietin, or serotonin reuptake inhibitors favor tolerance as well as dose reduction of tamoxifen to 20 mg/day. It must be underlined that approximately 40% of the patients had more than three positive lymph nodes, requiring optimal systemic therapy. In this line, single-agent chemotherapy also must be discussed as much as the dose-intensity of weekly epirubicin (22.5 mg/week) was lower to that administered to patients with a body surface of 1.5 m2 or more treated with the FEC50 regimen (fluorouracil, epirubicin 50 mg/m2, and cyclophosphamide). The Early Breast Cancer Trialists' Collaborative Group (EBCTCG) overview had revealed an absolute gain of 4% in recurrence and survival at 10 years in the node-positive subset of patients treated with anthracyclines when compared with the combination of cyclophosphamide, methotrexate, and fluorouracil (CMF).2,3 Nevertheless, this advantage is found almost exclusively with regimens comprising at least three drugs.4-6 In this study, estrogen receptor–positive patients 60 to 69 years of age who received chemotherapy demonstrated a risk reduction in recurrence of 18% and 8% in mortality. The largest (2,691 patients) randomized comparison of FAC (5-fluorouracil, doxorubicin, 50 mg/m2, and cyclophosphamide) and CMF resulted in a modest superiority of FAC for both disease-free and overall survivals at 5 years (86% v 84% and 92% v 91%, respectively).7 A recent European Organisation for Research and Treatment of Cancer randomized trial showed no superiority of eight cycles of the combination of epirubicin 100 mg/m2 and cyclophosphamide over six cycles of CMF.8 A previous randomized comparison of weekly epirubicin (30 mg/m2 x 16 weeks) and six cycles of CMF in stage I and II pre- and postmenopausal women showed a superiority of CMF in patients with four to nine positive nodes.9 Consequently, although dose reduction of epirubicin to 30 mg probably is adequate in the oldest patients, this regimen probably has been suboptimal in a vast proportion of patients among the youngest. Adapted combination chemotherapy including doxorubicin remains feasible since a retrospective study revealed that 67 patients age 65 to 78 years who were treated at The M.D. Anderson Cancer Center (Houston, TX) between 1975 and 1988 had received either FAC or ACVFP (doxorubicin, cyclophosphamide, vincristine, fluorouracil, prednisone) with cyclophosphamide 400 mg/m2, fluorouracil 400 mg/m2, and doxorubicin 40 mg/m2 every four weeks.10 Moreover, 26 of these patients received maintenance therapy with CMF for a total duration of chemotherapy of 2 years and the total cumulative dose of doxorubicin reached up to 400 mg/m2 in the subset of node-positive patients. A Dutch prospective study11 in patients older than 70 years with advanced breast cancer has shown that CMF with a dose reduction of 25% (with further dose reduction in case of severe renal failure) also is feasible. Hormonotherapy with 3 years of tamoxifen also is suboptimal as aromatase inhibitors become the standard. Approximately 10% of the patients were hormone receptor-negative and consequently received absolutely no systemic therapy in the tamoxifen arm. Logically, a subset analysis has shown that the benefit of the combined arm was particularly significant in hormone receptor–negative patients. The EBCTCG meta-analysis has revealed mortality reductions of 26% and 17% with 5 years versus 2 years of tamoxifen respectively.12 A large randomized trial revealed a 23% reduction in the risk of relapse after prolonged treatment with tamoxifen (mean duration, 6 years) comparatively to a treatment of 3 years.13 Weekly chemotherapy also may lead to constraints in terms of quality of life and mobilization of resources since the patients have had to be hospitalized 18 times. There is no precision about the use of indwelling catheters, which may be dangerous in elderly patients. Full doses of alternative drugs such as vinorelbine, gemcitabine, or new fluoropyrimidines, but above all oral administration, should be considered. Given that only 1% of patients older than 70 years receive adjuvant chemotherapy in general practice, classical large randomized studies in elderly populations are probably condemned to obsolete results. Author's Disclosures of Potential Conflicts of Interest The author indicated no potential conflicts of interest. REFERENCES 1. Fargeot P, Bonneterre J, Roché H, et al: Disease-free survival advantage of weekly epirubicin plus tamoxifen versus tamoxifen alone as adjuvant treatment of operable, node-positive, elderly breast cancer patients: 6-year follow-up results of the French Adjuvant Study Group 08 trial. J Clin Oncol 22:4622-4630, 2004 2. Early Breast Cancer Trialists' Cooperative Group: Polychemotherapy for early breast cancer: An overview of the randomised trials. Lancet 352:930-942, 1998[CrossRef][Medline] 3. Early Breast Cancer Trialists' Cooperative Group: 2000 analysis overview results. Fifth Meeting of the Early Breast Cancer Trialists Collaborative Group, Oxford, UK, September 21-23, 2000
4. Misset JL, di Palma M, Delgado M, et al: Adjuvant treatment of node-positive breast cancer with cyclophosphamide, doxorubicin, fluorouracil, and vincristine versus cyclophosphamide, methotrexate, and fluorouracil: Final report after a 16-year median follow-up duration. J Clin Oncol 14:1136-1145, 1996
5. Martin M, Villar A, Sole-Calvo A, et al: Doxorubicin in combination with fluorouracil and cyclophosphamide (i.v. FAC regimen, day 1, 21) versus methotrexate in combination with fluorouracil and cyclophosphamide (i.v. CMF regimen, day 1, 21) as adjuvant chemotherapy for operable breast cancer: A study by the GEICAM group. Ann Oncol 14:833-842, 2003 6. Mouridsen HT, Andersen J, Anderson M, et al: Adjuvant anthracycline in breast cancer: Improved outcome in premenopausal patients following substitution of methotrexate in the CMF combination with epirubicin. Proc Am Soc Clin Oncol 18:68, 1999 (abstr 254) 7. Hutchins L, Green S, Ravdin P, et al: CMF versus CAF with and without tamoxifen in high-risk node-negative breast cancer patients and a natural history follow-up study in low-risk node-negative patients: Update of tamoxifen results. Breast Cancer Res Treat 57:25, 1999
8. Piccart MJ, Di Leo A, Beauduin M, et al: Phase III trial comparing two dose levels of epirubicin combined with cyclophosphamide, methotrexate, and fluorouracil in node-positive breast cancer. J Clin Oncol 19:3103-3110, 2001 9. Colozza M, Bisagni G, Mosconi AM, et al: Epirubicin versus CMF as adjuvant therapy for stage I and II breast cancer: A prospective randomised study. Eur J Cancer 38:2279-2288, 2002
10. Ibrahim NK, Buzdar AU, Asmar L, et al: Doxorubicin-based adjuvant chemotherapy in elderly breast cancer patients: The M.D. Anderson experience, with long-term follow-up. Ann Oncol 11:1597-1601, 2000 11. Beex LV, Hermus AR, Pieters GF, et al: Dose intensity of chemotherapy with cyclophosphamide, methotrexate and 5-fluorouracil in the elderly with advanced breast cancer. Eur J Cancer 28:686-690, 1992 12. Early Breast Cancer Trialist's Collaborative Group: Tamoxifen for early breast cancer: An overview of the randomized trials. Lancet 351:1451-1467, 1998[CrossRef][Medline]
13. Delozier T, Spielmann M, Mace-Lesec'h J, et al: Tamoxifen adjuvant treatment duration in early breast cancer: Initial results of a randomized study comparing short-term treatment with long term treatment. J Clin Oncol 18:3507-3512, 2000
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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