1. ¹European Institute of Oncology, Milan, Italy
2. ²IBCSG Statistical Center, Dana-Farber Cancer Institute and Frontier Science and Technology Research Foundation, Boston, Massachusetts, USA
3. ³IBCSG Coordination Center, Bern, Switzerland
4. ⁴Institute of Medical Biometry and Medical Informatics, University Hospital of Freiburg, Freiburg, Germany
5. ⁵The Cancer Council Australia and University of Sydney, Sydney, Australia
6. ⁶Department of Gynaecology, Marien Hospital Essen-Altenessen, Essen, Germany
7. ⁷Department of Gynaecology, University Hospital of Heidelberg, Heidelberg, Germany
8. ⁸Western Sweden Breast Cancer Study Group, Sahlgrenska University Hospital, Göteborg, Sweden
9. ⁹Institute of Oncology, Ljubljana, Slovenia
10. ¹⁰Anti-Cancer Council of Victoria, Melbourne, Australia
11. ¹¹Kantonsspital, St. Gallen, Switzerland
12. ¹²Centro di Riferimento Oncologico, Aviano, Italy
13. ¹³Department of Gynaecology, Kreiskrankenhaus Kronach, Kronach, Germany
14. ¹⁴Oncology Institute of Southern Switzerland, Lugano, Switzerland

Correspondence: M Colleoni, Department of Medicine, Division of Medical Oncology, European Institute of Oncology, via Ripamonti 435, Milan, 20141, Italy. E-mail: marco.colleoni@ieo.it

Received 26 April 2001; Revised 1 March 2002; Accepted 8 April 2002.

Abstract

Cyclophosphamide, methotrexate and fluorouracil adjuvant combination chemotherapy for breast cancer is currently used for the duration of six monthly courses. We performed a joint analysis of two studies on the duration of adjuvant cyclophosphamide, methotrexate and fluorouracil in patients with node-positive breast cancer to investigate whether three courses of cyclophosphamide, methotrexate and fluorouracil might suffice. The International Breast Cancer Study Group Trial VI randomly assigned 735 pre- and perimenopausal patients to receive 'classical' cyclophosphamide, methotrexate and fluorouracil for three consecutive cycles, or the same chemotherapy for six consecutive cycles. The German Breast Cancer Study Group randomised 289 patients to receive either three or six cycles of i.v. cyclophosphamide, methotrexate and fluorouracil day 1, 8. Treatment effects were estimated using Cox regression analysis stratified by clinical trial without further adjustment for covariates. The 5-year disease-free survival per cents (s.e.) were 542% for three cycles and 552% for six cycles (n=1024; risk ratio (risk ratio: CMF 3/CMF 6), 1.00; 95% confidence interval, 0.85 to 1.18; P=0.99). Use of three rather than six cycles was demonstrated to be adequate in both studies for patients at least 40-years-old with oestrogen-receptor-positive tumours (n=594; risk ratio, 0.86; 95% confidence interval, 0.68 to 1.08; P=0.19). In fact, results slightly favoured three cycles over six for this subgroup, and the 95% confidence interval excluded an adverse effect of more than 2% with respect to absolute 5-year survival. In contrast, three cycles appeared to be possibly inferior to six cycles for women less than 40-years-old (n=190; risk ratio, 1.25; 95% confidence interval, 0.87 to 1.80; P=0.22) and for women with oestrogen-receptor-negative tumours (n=302; risk ratio, 1.15; 95% confidence interval, 0.85 to 1.57; P=0.37). Thus, three initial cycles of adjuvant cyclophosphamide, methotrexate and fluorouracil chemotherapy were as effective as six cycles for older patients (40-years-old) with oestrogen-receptor-positive tumours, while six cycles of adjuvant cyclophosphamide, methotrexate and fluorouracil might still be required for other cohorts. Because endocrine therapy with tamoxifen and GnRH analogues is now available for younger women with oestrogen-receptor-positive tumours, the need for six cycles of cyclophosphamide, methotrexate and fluorouracil is unclear and requires further investigation.