Phase I/II clinical trial of epirubicin and paclitaxel followed by granulocyte colony-stimulating factor in a 2-week schedule in patients with advanced or metastatic breast cancer.

Anthracyclines and taxanes are the most potent cytotoxic agents available for treating breast cancer. With combined therapy (either epirubicin or doxorubicin with paclitaxel [Taxol; Bristol-Myers Squibb Company, Princeton, NJ]), response rates of 70% to 90% have been reported. To achieve a maximal dose intensity per week, we decided to combine epirubicin 100 mg/m2 with escalating doses of paclitaxel, at successive dose levels of 135, 150, 165, and 180 mg/m2 in a 2-week schedule, with administration of subcutaneous granulocyte colony-stimulating factor 5 microg/kg from days 2 through 10. To date, 16 patients have been included, with six patients treated at level 1 (100/135 mg/m2 epirubicin/paclitaxel), four at level 2 (100/150 mg/m2), four at level 3 (100/165 mg/m2), and two at level 4 (100/180 mg/m2). The median age of all subjects is 55 years (range, 41 to 65 years). Five patients had received chemotherapy in the adjuvant setting. Of 79 treatment courses, 78 are evaluable for toxicity. The mean number of courses per patient is six (range, two to six courses). At dose level 1, one episode of febrile neutropenia with grade 4 thrombocytopenia occurred. No grade 4 extrahematologic adverse event has been noted so far. At dose level 2, we achieved a dose intensity per week of epirubicin 50 mg/m2 and paclitaxel 75 mg/m2, as expected. At dose level 3, the dose intensity per week was 47.5 mg/m2 and 78.8 mg/m2, respectively (expected 50 and 82.5 mg/m2). The current response rate, evaluated in 14 of 16 patients, is four complete remissions and eight partial remissions, for an overall response rate of 85%. Two patients had stable disease. Granulocyte colony-stimulating factor following epirubicin/paclitaxel on a 2-week schedule permits a very high dose intensity per week for both drugs and produces a high response rate in patients with advanced or metastatic breast cancer.

Second malignancies following adjuvant chemotherapy: 6-year results from a Belgian randomized study comparing cyclophosphamide, methotrexate and 5-fluorouracil (CMF) with an anthracycline-based regimen in adjuvant treatment of node-positive breast cancer patients.

BACKGROUND: Alkylating agents and topoisomerase-II inhibitors have been associated with the occurrence of secondary leukemias and myelodysplastic syndromes in breast cancer patients treated with adjuvant chemotherapy. Conversely, data on the occurrence of second solid malignancies in this setting are scarce. PATIENTS AND METHODS: This study retrospectively evaluates the occurrence of second hematological and solid malignancies in the context of a prospective multicenter phase III trial comparing epirubicin-cyclophosphamide at intermediate doses (EC), or at full doses (HEC), with classical cyclophosphamide, methotrexate and 5-fluorouracil (CMF) in 777 patients with early breast cancer. RESULTS: At a median follow-up of 73 months, the following 8-year actuarial rates of second solid primaries were observed: CMF 5.5% [95% confidence interval (CI) 1.5% to 9.5%], EC 4.1% (95% CI 0.1% to 8.1%), and HEC 7.2% (95% CI 3.2% to 11.2%) (P = 0.79 by log rank test). Three secondary acute myeloid leukemias (AML) were reported, all in the HEC arm (incidence = 1.2%, 95% CI 0.0% to 2.5%), which by a three arm comparison allows us to conclude that HEC is statistically different (borderline significance) from CMF and EC (P = 0.05). CONCLUSIONS: HEC, as delivered in this trial, cannot be recommended in clinical practice because of the lack of superiority over classic CMF and because of the increased risk of AML observed in this arm. Prolongation of conventional anthracycline-based treatment beyond the current standard of four to six cycles is not recommended in clinical practice.