Metastatic Breast Cancer: Experience with the Combination Paclitaxel Plus Epirubicin

ABSTRACT: This study evaluated the safety and feasibility of the combination of paclitaxel (Taxol) and epirubicin, the 4¢-epimer of doxorubicin, in women with metastatic breast cancer. A total of 85 patients with histologically proven metastatic breast cancer were treated in two cohorts; epirubicin 60 mg/m² IV infused over 1 hour, followed by paclitaxel 175 mg/m² IV infused over 3 hours (group A), and epirubicin 90 mg/m² IV via a 1-hour infusion, followed by paclitaxel 175 mg/m² IV via a 3-hour infusion (group B). Of the 85 patients, 68 were evaluable for response and toxicity (43 in group A and 25 in group B). The combination was generally well tolerated. The higher epirubicin dose induced more severe neutropenia and one case of cardiotoxicity. Nonhematologic toxicities were mild, with no severe mucositis or peripheral neuropathy reported. Overall, 68% of patients in group A and 68% of patients in group B responded. A phase III trial comparing paclitaxel, 175 mg/m², plus epirubicin, 60 mg/m², with the standard combination of epirubicin, 60 mg/m², and cyclophosphamide (Cytoxan, Neosar), 600 mg/m², is currently in progress.ONCOLOGY 12(Suppl 1):36-39, 1998]

Paclitaxel (Taxol) is one of the few active drugs for the treatment of metastatic breast cancer. One of the most important observations made in the earliest studies of the drug by Holmes et al[1] and Reichman et al[2] was that clinical resistance to doxorubicin does not predict resistance to paclitaxel. This observation suggests the feasibility of evaluating the combination of paclitaxel and anthracyclines, which are also active in metastatic breast cancer.

Holmes et al[3] performed a phase I study in which paclitaxel was administered as a 24-hour intravenous infusion, followed by doxorubicin given as a 48-hour continuous infusion. The dose-limiting toxicity in this study was mucositis, which occurred with relatively low doses of both drugs. Sledge et al[4]described a phase I trial that used the same regimen but with the reverse sequence. The doxorubicin infusion was followed, after 4 hours, by a 24-hour paclitaxel infusion. The rate of severe mucositis associated with this schedule was very low. The maximum tolerated doses were 50 mg/m² of doxorubicin and 150 mg/m² of paclitaxel.

Dombernowski et al[5] and Gianni et al[6a] reported high response rates in patients with previously untreated metastatic breast cancer who received paclitaxel (via a 3-hour infusion) combined with doxorubicin. In these studies, the main toxicities were neutropenia and febrile neutropenia. Both studies described severe cardiac toxicities in 15% to 25% of patients. It was then showed that by limiting the cumulative dose of doxorubicin to 360 mg/m² or administering the two drugs with a more prolonged interval, the cardiac toxicity of the combination was limited to an incidence of 5%.[6b,6c]

Epirubicin, the 4¢-epimer of doxorubicin, is as effective as its parent compound but less cardiotoxic.[7] A literature search revealed eight trials in which doxorubicin and epirubicin were compared in patients with metastatic breast cancer. In three trials, identical doses of doxorubicin and epirubicin produced identical response rates.[8-10] In five others, the dose ratio of doxorubicin to epirubicin was 1.4.[11-15] The response rate was similar in all of these trials, independent of dose ratio. Mouridsen et al[16] reported that the two drugs have similar pharmacodynamics, antitumor spectrum, and levels of clinical efficacy.

The aim of this phase II study was to evaluate the safety and feasibility of combining paclitaxel and epirubicin in patients with metastatic breast cancer, focusing specifically on cardiac side effects.

Patients and Methods

Eligibility Criteria—Only patients with histologically proven metastatic breast cancer were recruited to participate in this study. To be eligible, patients were not allowed to have received prior chemotherapy for metastatic disease, but they could have received one prior regimen of adjuvant chemotherapy or hormone therapy, or one palliative hormone therapy. If the patient had received prior anthracycline therapy, the total allowable dose was 300 mg/m².

Other eligibility criteria included measurable metastasis and normal hematologic, renal, and hepatic function, as well as age between 18 and 70 years and a life expectancy of more than 12 weeks. Patients who did not meet these criteria were not eligible for the study. Patients with congenital heart failure also could not participate.

Study Design—Patients were treated in two cohorts. Group A received epirubicin 60 mg/m² IV infused over 1 hour, followed by paclitaxel 175 mg/m² IV infused over 3 hours. Group B received epirubicin 90 mg/m² IV via a 1-hour infusion, followed by paclitaxel 175 mg/m² IV via a 3-hour infusion. Both groups were premedicated with dexamethasone 20 mg PO for two doses, one dose 12 hours and the other 6 hours before paclitaxel. In addition, patients received clemastine 2 mg IV, and ranitidine 50 mg IV, 30 minutes before paclitaxel.

Left-ventricular ejection fraction was assessed prior to treatment and after every second cycle by echocardiography or multiple-gated acquisition (MUGA) scanning.

Paclitaxel dose escalation (without granulocyte colony-stimulating factor support) was permissible to a dose of 225 mg/m², in 25-mg/m² steps, as long as the neutrophil count nadir was ³ 1 ´ 10⁹/L and peripheral neuropathy was lower than World Health Organization (WHO) toxicity grade 2. In cases of higher toxicity grades, the paclitaxel dose could be reduced to 135 or 110 mg/m².

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