Metastatic breast cancer: treatment with fluorouracil-based combinations

During the 1990s, one in nine women in the western world will be diagnosed with breast cancer, and more than 58,000 will die of the disease each year in Europe alone. Recent changes in the primary therapy of operable breast cancer have not altered patient prognosis. Adjuvant therapy delays systemic recurrence and improves survival for only a fairly selected fraction of these patients. Therapy for metastatic breast cancer has not improved significantly in recent years. While combination chemotherapy may prolong survival in selected patients, few if any achieve cure. Standard chemotherapy regimens used to treat metastatic breast cancer, such as CMF (cyclophosphamide/methotrexate/fluorouracil), FAC (5-FU/Adriamycin/cyclophosphamide), and FEC (5-FU/epirubicin/cyclophosphamide), were developed over a decade ago. Current efforts to improve therapeutic efficacy have concentrated on decreasing drug toxicity and increasing drug doses (e.g., high-dose chemotherapy with peripheral stem cell support). An important alternative to increasing therapeutic efficacy by such approaches is altering the administration schedules of well-known chemotherapeutic agents and introducing active new cytotoxic agents. One of the most frequently used cytotoxic drugs, 5-FU has documented activity in a variety of malignancies, most notably in breast cancer and gastrointestinal tract cancers. However, despite broad clinical experience, our knowledge of mechanisms of resistance in relation to various 5-FU schedules is limited. In vitro data and clinical experience show that resistance to one schedule of 5-FU can be overcome by using an alternative schedule, most often a protracted infusion.