Dose-intensified epirubicin versus standard-dose epirubicin/cyclophosphamide followed by CMF in breast cancer patients with 10 or more positive lymph nodes: Results of a randomised trial (GABG-IV E-93) – The German Adjuvant Breast Cancer Group

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Abstract

To compare dose-intensified epirubicin monotherapy with a standard sequential regimen, patients with primary breast cancer and ⩾10 involved axillary nodes were randomised to either four 21-day cycles of epirubicin 120 mg/m2 (E120; n = 202) or four 21-day cycles of epirubicin 90 mg/m2 plus cyclophosphamide 600 mg/m2 (EC) followed by three 28-day cycles of cyclophosphamide, methotrexate and 5-fluorouracil (CMF; n = 209). Simultaneous hormonal treatment was applied in both arms. At 5 years’ median follow-up, the 5-year event-free survival (EFS) rates were 47.7% (95% confidence interval [CI], 40.2–55.2%) for E120 and 45.9% (38.5–53.3%) for EC-CMF. E120 was as effective as EC-CMF with regard to EFS (hazard ratio [HR] for E120 versus EC-CMF 1.04; 95% CI, 0.79–1.36; p = 0.79) and overall survival (HR 1.06; 95% CI 0.77–1.46; p = 0.72). The data demonstrate that 4 cycles of dose-intensified epirubicin monotherapy can be as effective as 7 cycles of standard sequential polychemotherapy in high-risk breast cancer patients with ⩾10 positive lymph nodes, despite treatment with a single agent and a shorter treatment duration.

Introduction

Randomised trials in early breast cancer have assessed the long-term effects of various systemic adjuvant therapies on breast cancer recurrence and survival. The use of adjuvant polychemotherapy and the implementation of anthracycline for the treatment of breast cancer could improve event-free survival (EFS) and overall survival (OS). High-risk patients with ⩾10 positive lymph nodes also derive significant benefit from adjuvant chemotherapy, but these patients exhibit a high recurrence rate at 5 years, with an EFS of less than 50%.1

In 1993 the German Adjuvant Breast Cancer Group (GABG) started a series of trials which enrolled patients according to their menopausal, hormone-receptor and lymph-node status.2, 3, 4 The GABG trial IV E-93 was designed for patients with ⩾10 positive lymph nodes. In the standard arm a sequential chemotherapy of four cycles of epirubicin and cyclophosphamide (EC) followed by three cycles of cyclophosphamide, methotrexate and fluorouracil (CMF) was applied; in the experimental treatment arm, four cycles of dose-intensified epirubicin (120 mg/m2) were chosen. The study design was based on the earlier trials, which showed a benefit of sequential doxorubicin/CMF application in women with extensive nodal involvement,1 equal efficacy but lower toxicity for epirubicin compared with doxorubicin,5 comparable efficacy of three versus six cycles of CMF,6 and evidence that 120 mg/m2 epirubicin every 3 weeks was reasonably well tolerated, associated with promising activity and its simplicity.7

The study was conducted in parallel as an alternative to another trial comparing the same standard arm with a high-dose regimen requiring autologous stem-cell support.8 Here we present the results of the GABG trial IV E-93 at 5 years’ median follow-up; preliminary results have been reported previously.9

Section snippets

Study design

Patients with ⩾10 positive axillary lymph nodes were randomised to either four 21-day cycles of epirubicin 120 mg/m2 intravenously (E120) or four 21-day cycles of epirubicin 90 mg/m2 and cyclophosphamide 600 mg/m2 intravenously followed by three 28-day cycles of cyclophosphamide 500 mg/m2, methotrexate 40 mg/m2 and 5-fluorouracil 600 mg/m2 intravenously on days 1 and 8 (EC-CMF).

Chemotherapy and endocrine therapies (goserelin 3.6 mg subcutaneously every 28 days for 2 years in premenopausal women,

Patients included

Four-hundred and eleven patients were randomised in 54 centres across Germany between March 1993 and December 2000, 209 patients to EC-CMF and 202 to E120. Overall, the patients in the two treatment groups were well matched for baseline clinical characteristics, with slightly more hormone receptor-positive patients allocated to the EC-CMF arm. The patients in the E120 group tended to have smaller tumours but higher tumour grade compared with those randomised to EC-CMF, therefore, the NPI was

Discussion

GABG trial IV E-93 demonstrated the efficacy and feasibility of dose-intensified epirubicin monotherapy application without severe toxicity issues. It showed that breast cancer patients with ⩾10 positive lymph nodes can benefit equally from the monotherapy (4 cycles) and the standard-dose chemotherapy regimen consisting of four cycles of epirubicin and cyclophosphamide followed by three cycles of CMF. With 5 years’ median follow-up, the HR of E120 versus EC-CMF was approximately 1 for both EFS

List of collaborators and their affiliations

Prof. Dr. G. Geier (Kreiskrankenhaus Albstadt); Dr. K.-J. Winzer (Universitätsklinikum Charité, Chirurgie, Berlin); Prof. Dr. J.R. Strecker (Krankenhaus Reinickendorf, Berlin); Dr. C. Kempter (Waldfriede Krankenhaus, Berlin); Dr. I. Schulz-Im Busch (St. Josefshospital Cloppenburg); Dr. D. Kress (Klinikum Deggendorf); Dr. O. Aga (Kreiskrankenhaus Eggenfelden); Prof. Dr. M. Kaufmann (J.W. Goethe Universität Frankfurt); Frau Dr. Kissel (Universitätsklinikum Freiburg); PD Dr. de Gregorio

Conflict of interest statement

The following potential conflicts of interest were declared: W. Eiermann (consultant, honoraria from Astra Zeneca), G. von Minckwitz (honoraria and research funding from Astra Zeneca) and M. Kaufmann (honoraria from Pfizer). The other authors declared no conflict of interest.

Acknowledgements

This study was supported by the Deutsche Krebshilfe; Pharmacia, Germany and Astra Zeneca, Germany.

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    This report presents the final analysis of trial GABG-IV E-93. Preliminary results were reported at the ASCO Annual Meeting in 2001.

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