Beyond CMF: The Use of Doxorubicin and Taxane-Containing Regimens

In the chemotherapy overview analysis, 11 trials included women who were randomized to receive CMF versus an anthracycline-containing regimen (either doxorubicin or, in European trials, epirubicin). There was a small but significant reduction in the risk of recurrence with the anthracycline-containing regimen (12% ± 4) as compared to CMF, which translated into a small benefit in overall survival (Fig. 8.4).

The use of doxorubicin-containing chemotherapy is now commonly employed for the treatment of patients with lymph node-positive disease. Doxorubicin is generally more toxic, such that women experience more frequent side effects, including alopecia, nausea, vomiting and mucositis. In addition, women can develop symptoms of congestive heart failure which occurs in approximately 1% of patients in the adjuvant dose range (<300mg/m²).

Recently, a link has been established between doxorubicin use and an increased incidence of acute myelogenous leukemia. Patients with anthracycline-induced AML typically have a specific chromosomal translocation (11q23), which is characteristic of drugs that inhibit the enzyme topoisomerase II. Thus, the benefits of doxorubicin in improving disease-free and overall survival must be carefully weighed against the side effects of these regimens.

The use of escalating doses of doxorubicin (60, 75 and 90 mg/m² ) in combination with cyclophosphamide (referred to as AC) and the sequential addition of paclitaxel (Taxol®) to this regimen (AC followed by T) has recently been tested in the adjuvant setting.

Paclitaxel is a chemotherapeutic drug that causes stabilization of the microtubule assembly and has proven to be an effective agent in the treatment of metastatic disease. After a median follow-up of 18 months, no differences in either disease-free or overall survival were seen with increasing doses of doxorubicin; however, the addition of paclitaxel to AC was slightly but significantly superior to AC alone in both disease-free and overall survival (improved disease-free survival from 86 to 90%, RR 22%, p=0.0077 and overall survival from 95 to 97%, RR 26%, p=0.0390).

Fig. 8.4. Absolute effects of anthracycline-containing regimens compared with CMF. Values at 5 years and absolute differences in outcome (with SDs, and log-rank p-values for whole period) given beside each pair of lines. Years 0-4 include 90% of all recurrences and 81% of all deaths in these trials. Reprinted with permission from Lancet 1998; 352:930-942. Additional follow-up is required to confirm these early results, which have recently been reported in abstract form. The use of taxanes, however, appear to be promising additions to adjuvant treatment, and ongoing trials are investigating the use of both paclitaxel- and docetaxel-containing (Taxotere®) regimens.