DOSE-RESPONSE EFFECT OF ADJUVANT CYCLOPHOSPHAMIDE, METHOTREXATE, 5-FLUOROURACIL (CMF) IN NODE-POSITIVE BREAST-CANCER

There is evidence in the literature of a relationship between dose and response to adjuvant chemotherapy for breast cancer, although publish ed results are conflicting. We therefore retrospectively analysed the role of dose response in patients included in four adjuvant trials of the International Breast Cancer Study Group (IBCSG, formerly the Ludwi g Breast Cancer Study Group (trials I, II, III and V), all using 'clas sical' cyclophosphamide, methotrexate, and 5-fluorouracil (CMF). A tot al of 1385 node-positive patients were treated with oral cyclophospham ide, and intravenous methotrexate plus 5-fluorouracil (CMF) for at lea st six 4 week courses. 1350 of these were included in 6 month landmark treatment outcome analyses. A total of 1029 patients were premenopaus al, 321 were postmenopausal; 800 had one to three and 550 more than th ree involved axillary nodes at surgery. The median follow-up ranged fr om 12 years for trial V to 15 years for trials I-III. Patients were gr ouped according to three prospectively defined dose levels based on th e percentage of the protocol prescribed dose that was actually adminis tered (level I greater than or equal to 85%, level II 65-84%, level II I < 65%). Patients who received dose level II had a higher disease-fre e (P = 0.07) and overall survival (P = 0.03) than those who received a higher (level I) or lower (level III) percentage. The 10 year overall survival was 60% for dose level II, 56% for dose level I, 51% for dos e level III. The results were generally consistent within trial, menop ausal status, and oestrogen receptor status groups. The results within nodal groups showed a large difference among the dose levels for the group with one to three positive nodes (P = 0.02), but no difference f or the group with four or more positive nodes. Our results indicate th at the dose-response effect remains a crucial factor in adjuvant chemo therapy of breast cancer. Reductions larger than 35% in the dose admin istered of oral CMF adversely influenced the outcome of breast cancer patients and should be avoided. The better outcome of the intermediate dose group indicates the need to investigate other aspects involved i n the cytotoxicity of adjuvant CMF chemotherapy. (C) 1998 Elsevier Sci ence Ltd. All rights reserved.