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☆
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.
References (30)
- et al.
CMF versus goserelin as adjuvant therapy for node-negative, hormone-receptor-positive breast cancer in premenopausal patients: a randomised trial (GABG trial IV-A-93)
Eur J Cancer
(2006) - et al.
A randomised trial of goserelin versus control after adjuvant, risk-adapted chemotherapy in premenopausal patients with primary breast cancer – GABG-IV B-93
Eur J Cancer
(2007) - et al.
Quantification of the completeness of follow-up
Lancet
(2002) - et al.
The effect of endocrine responsiveness on high-risk breast cancer treated with dose-intensive chemotherapy: results of International Breast Cancer Study Group Trial 15-95 after prolonged follow-up
Ann Oncol
(2009) - et al.
Randomized trial of high-dose chemotherapy and hematopoietic progenitor-cell support in operable breast cancer with extensive lymph node involvement: final analysis with 7 years follow-up
Ann Oncol
(2002) - et al.
Adjuvant chemotherapy with doxorubicin plus cyclophosphamide, methotrexate and fluorouracil in the treatment of resectable breast cancer with more than three positive axillary nodes
J Clin Oncol
(1991) - et al.
Tamoxifen versus control after adjuvant, risk-adapted chemotherapy in postmenopausal, receptor-negative patients with breast cancer: a randomized trial (GABG-IV D-93) – the German Adjuvant Breast Cancer Group
J Clin Oncol
(2005) A prospective randomized phase III trial comparing combination chemotherapy with cyclophosphamide, fluorouracil and either doxorubicin or epirubicin
J Clin Oncol
(1988)- et al.
Randomized 2 × 2 trial evaluating hormonal treatment and the duration of chemotherapy in node-positive breast cancer patients
J Clin Oncol
(1994) - et al.
High-dose epirubicin as primary chemotherapy in advanced breast carcinoma: a phase II study
Cancer Chemother Pharmacol
(1991)
High-dose chemotherapy with autologous haematopoietic stem-cell support vs. standard-dose chemotherapy in breast cancer patients with 10 or more positive lymph nodes: First result of a randomised trial
J Clin Oncol
High-dose epirubicin vs. standard-dose epirubicin–cyclophosphamide followed by CMF in breast cancer patients with 10 or more positive lymph nodes: first results of a randomised trial of the German Adjuvant Breast Cancer Group (GABG)
Proc ASCO
A prognostic index in primary breast cancer
Brit J Cancer
The Nottingham Prognostic Index for invasive carcinoma of the breast
Pathol Oncol Res
Long-term follow-up of patients in four prospective studies of the German Breast Cancer Study Group (GBSG): a summary of key results
Onkologie
Cited by (3)
Epirubicin: Is it like doxorubicin in breast cancer? A clinical review
2012, BreastCitation Excerpt :At 5 years, the data demonstrated that 4 cycles of dose-intensified epirubicin monotherapy could be as effective as 7 cycles of standard sequential polychemotherapy in this population with EFS rates of 47.7% for E120 and 45.9% for EC-CMF. The E120 regimen was as effective as EC-CMF with regard to 5 year OS rates, 64.1% in the E120 group versus 63.5% in the EC-CMF group.56 In a head to head comparison of adjuvant eprirubicin with docurubicin regimes, Burnell et al. showed that AC followed by paclitaxel (ACP; n = 702) is significantly inferior to CEF or dose-dense EC followed by paclitaxel dd EC-P; n = 701) in terms of RFS in node-positive and high-risk node-negative breast cancer.
Breast cancer follow-up strategies in randomized phase III adjuvant clinical trials: A systematic review
2013, Journal of Experimental and Clinical Cancer Research
- ☆
This report presents the final analysis of trial GABG-IV E-93. Preliminary results were reported at the ASCO Annual Meeting in 2001.