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.