Fluorouracil-Based Combinations in the Treatment of Metastatic Breast Cancer

ABSTRACT: Although combination chemotherapy regimens may prolong survival for selected patients with metastatic breast cancer, few, if any, are cured. The standard regimens used in treatment, eg, CMF (cyclophosphamide, methotrexate, and fluorouracil [5-FU]), FAC (5-FU, Adriamycin, and cyclophosphamide), and FEC (5-FU, epirubicin, and cyclophosphamide), were developed over a decade ago. Current efforts to improve therapeutic efficacy have concentrated on decreasing drug toxicity and increasing drug doses (eg, high-dose chemotherapy with peripheral stem-cell support). An important alternative approach to increasing therapeutic efficacy focuses on altering the administration schedules of well-known chemotherapeutic agents and introducing active new agents. One of the most frequently used cytotoxic drugs, fluorouracil (5-FU), has documented activity in a variety of malignancies, most notably, breast cancer and gastrointestinal tract cancers. However, despite broad clinical experience with 5-FU, our knowledge about the mechanisms of resistance to the various administration schedules used is limited. In vitro data and clinical experience show that resistance to one schedule of 5-FU can be overcome by using alternative schedules, in particular, a protracted infusion. This article discusses our clinical experience with weekly high-dose 24-hour infusions of 5-FU in combination with folinic acid (leucovorin) alone and together with paclitaxel (Taxol) for the treatment of advanced breast cancer.[ONCOLOGY 12(Suppl 1):31-35, 1998]

During the 1990s, one in nine women in the western world will be diagnosed with breast cancer in their lifetime, and more than 58,000 will die of the disease each year in Europe alone. Recent changes in the primary treatment of operable breast cancer have not altered patient prognosis. Adjuvant therapy delays systemic recurrence and improves survival for only a select fraction of these patients.

Therapy for metastatic breast cancer has not improved significantly in recent years. Although many combination chemotherapy regimens result in high response rates, complete remissions occur in fewer than 20% of patients, and median survival is generally 2 years. In women who do not respond to primary therapy for metastatic disease, complete remissions are infrequent, with overall response rates for most regimens ranging from 10% to 35%.[1] Given the dearth of active agents capable of inducing durable remissions in metastatic breast cancer, there is clearly a need for new therapeutic strategies, as well as the incorporation of new drugs into these strategies.

Results of studies have suggested that fluorouracil (5-FU) administered by continuous infusion has significant clinical activity in heavily pretreated breast cancer patients, with reported response rates of 25% to 40%.[2-4] A substantial body of experimental data indicates that the addition of pharmacologic concentrations of reduced folates to human tumor cells in vitro enhances both the duration and degree of thymidylate synthase inhibition produced by 5-FU.[10-12]

Studies have shown that folinic acid (leucovorin) enhances the therapeutic activity of 5-FU, especially in colorectal carcinoma.[5-8] In order to extend this area of biochemical modulation and build on the results obtained with a monthly schedule of 5-FU/folinic acid in advanced colorectal carcinoma, several groups performed phase II trials using this combination in patients with previously treated metastatic breast cancer.[1,9] The results of these studies indicated that the combination has a significant therapeutic effect and can be administered with an acceptable level of toxicity in this palliative situation.

Moreover, several phase II trials have shown that 5-FU plus folinic acid is active in breast cancer patients pretreated with anthracycline-containing regimens.[1,13-15] In these trials, folinic acid and 5-FU were usually administered by bolus injection. However, phase II studies in colorectal cancer have suggested that weekly administration of high-dose folinic acid in combination with high-dose 5-FU given as a continuous 24-hour IV infusion induces higher overall response rates.[16] Similarly, our in vitro and clinical data indicate higher activity when this combination is given as a protracted infusion.[2-4,32]

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