Lessons From the Initial Adjuvant Cyclophosphamide, Methotrexate, and Fluorouracil Studies in Operable Breast Cancer
Authors: Gianni Bonadonna, Pinuccia Valagussa, Umberto Veronesi
Journal: Journal of Clinical Oncology (2008)

In 1975, we presented our first report on the efficacy of cyclophosphamide, methotrexate, and fluorouracil (CMF) delivered in 1-month cycles for 12 months as adjuvant treatment for nodepositive breast cancer. These results, along with those reported in a similar patient population by the National Surgical Adjuvant Breast and Bowel Project, raised hopes that chemotherapy could have a more central role in the primary management of this common cancer, and were of seminal importance for all the studies on adjuvant systemic therapy conducted throughout the world. Among the numerous questions to be answered after the first CMF study was the optimal duration of treatment. In fact, a relatively short-term effective adjuvant chemotherapy would spare the patients a considerable amount of toxicity. For this reason, in September 1975, we started a new randomized study with the intent of evaluating the possibility of reducing the duration of CMF without compromising its therapeutic effects. The 5-year results of the study showed that 1-month cycles for 6 months of CMF yielded results that were identical to those obtained with 12 cycles. The long-term analysis after a median follow-up of 25 years confirmed that a longer duration of the same drug regimen was unable to improve treatment outcome. The pattern of relapse-free survival was superimposable in the two treatment groups, the estimated relapse-free survival rates were 39% after 12 cycles and 38% after six cycles of CMF, and the overall survival rates were 40% in both treatment arms. In the multivariate analysis, the only variable able to influence treatment outcome was the extent of axillary node involvement; patients with more than three involved nodes were at a significantly higher risk of disease relapse and death (hazard rate, 2.3; P .0001). Neither estrogen-receptor status nor size of the primary tumor was able to affect therapeutic outcome significantly. In response to the early results observed in the abovementioned study, in the early 1980s our own research group tested in a random fashion whether the inclusion of a non– crossresistant agent such as doxorubicin (DOX) could be of benefit in patients with positive nodes. The choice of DOX was based on its great efficacy in metastatic and locally advanced breast cancer and on the low reported incidence of congestive heart failure when the total dose was less than 400 mg/m of the body-surface area. In women at high risk of disease relapse because of extended axillary involvement ( three positive nodes), we reasoned that DOX, either given first and followed sequentially by CMF or interspersed with CMF, had the potential to improve treatment outcome. A 20-year analysis confirmed the superiority of the sequential delivery of DOX as first treatment for four cycles followed by intravenous CMF (DOXCMF) compared with the alternating delivery of the same regimens (CMF/DOX). In fact, after DOXCMF, the risk of developing disease relapse was reduced by approximately 32% (P .0017) and the risk of dying as a result of all causes was reduced by approximately 26% (P .018). The improved outcome in the sequential arm was not impaired by the occurrence of congestive heart failure. It is important to note that the 5-year joint efficacy analysis of the National Epirubicin Adjuvant Trial and of the Scottish Cancer Trials Breast Group reported a highly significant benefit in favor of the sequential administration of epirubicin for four cycles followed by CMF compared with CMF alone, supporting the hypothesis that single-agent anthracyclines given first, before CMF, can indeed improve treatment outcome. In patients with one to three involved axillary nodes, we randomly assessed whether the addition of single-agent DOX for four cycles administered after intravenous CMF given for approximately 6 months could overcome resistance putatively induced by the alkylating regimen alone. The 20-year analysis showed that approximately half of the patients in this study were alive and disease free regardless of whether they received CMF alone or CMF sequentially followed by DOX. Although available long-term results failed to detect any statistically significant difference from the addition of DOX in the overall population of patients enrolled onto the study, a retrospective analysis on the predictive relevance of the status of human epidermal growth factor receptor (HER2) showed a trend for an increased benefit of the DOX combination in patients with HER2-positive tumors. This observation further emphasizes the need for a priori characterization of markers predicting for response, and for eventually tailoring adjuvant treatment to individual patients—a goal that is currently being pursued, but was inconceivable at the time when the study protocol was designed. JOURNAL OF CLINICAL ONCOLOGY C E L E B R A T I N G 2 5 Y E A R S O F J C O VOLUME 26 NUMBER 3 JANUARY 2