Adjuvant cyclophosphamide, methotrexate, and fluorouracil in premonopausal patients with node-positive breast cancer: Indirect comparison of dose and schedule in DBCG trials 77, 82, and 89

Abstract

A significant reduction in the risk of recurrence and death was achieved three decades ago with adjuvant chemotherapy in patients with operable breast. The major pivotal trials used oral cyclophosphamide (C) days 1–14 with intravenous methotrexate (M) and fluorouracil (F) on days 1 and 8, repeated every 28 days. The classical CMF has later been modified as concerns dose and schedule, without formal comparisons in randomised trials between the classical CMF and the modifications. Material and methods. Classical CMF was used in the first adjuvant chemotherapy trial performed by the Danish Breast Cancer Cooperative Group (DBCG), and two succeeding randomised trials in premenopausal patients with node positive breast cancer used three-weekly or four-weekly intravenous CMF in one of the treatment arms. Results. Between November 1977 and January 2001 these trials included 2 213 patients who in addition to surgery and radiotherapy received CMF. Ten-year disease-free survival (DFS) rates were 48% following classical CMF, 45% following four-weekly and 47% following three-weekly CMF. Major differences in patient characteristics were observed across these three cohorts, and a multivariate analysis was performed adjusting for the known prognostic factors. In the adjusted analysis a 30% increase in the risk of recurrence was observed for two the intravenous regimens as compared to classical CMF. As concerns survival a significant 40% increase in the risk of death was observed with the four-weekly regimen, while a similar risk of death was observed with the three-weekly intravenous. Classical CMF was associated with a higher risk of amenorrhoea, and this may at least in part explain an observed interaction between age and efficacy. Discussion. This cross trial comparison suggests a detrimental effect in premenopausal patients with node positive breast cancer when shifting from classical CMF to intravenous regimens with lower dose-intensity. Caution is required in the interpretation of these results due to the non-experimental study design.