High-dose consolidation chemotherapy with idarubicin and alkylating agents following induction with gemcitabine-epirubicin-paclitaxel in metastatic breast cancer: A dose finding study

Preliminary randomized studies have failed to show a survival benefit of high-dose chemotherapy with alkylators in advanced breast cancer. Idarubicin is an active agent in breast cancer and is suitable for dose escalation. We designed a dose finding study with escalating high-dose idarubicin (HD-Ida) followed by fixed high-dose thiotepa + melphalan (HD-TM) with peripheral blood progenitor cells (PBPC) in MBC patients with stable disease or in partial response after six courses of induction chemotherapy with gemcitabine 1000 mg/m² days 1 and 4, epirubicin 90 mg/m² day 1, taxol 175 mg/m² day 1 (GET). Aims of the study were to identify the maximum tolerated dose (MTD) of idarubicin, to evaluate the cardiac safety and activity of HD-Ida and HD-TM after GET and to study the pharmacokinetic profile of idarubicin and idarubicinol. A total of 14 patients were treated. Idarubicin was administered as a 48 h continuous i.v. infusion at the following dose levels: 40 mg/m² (three patients), 50 mg/m² (three patients), 60 mg/m² (five patients) and 70 mg/m² (three patients). Mucositis was the dose-limiting toxicity and the MTD was 60 mg/m². C_max of Idarubicin and idarubicinol were 7.7 ± 2.0 and 26.3 ± 9.7 ng/ml at 40 mg/m² and increased to 14.8 + 3.0 and 47.4 + 12.6 ng/ml at 70 mg/m². AUCt_o-264 of idarubicin and idarubicinol increased from 423.2 ± 111.6 and 2581 ± 606 hng/ml at 40 mg/m² to 732.8 ± 140.2 and 4590 ± 1258 hng/ml at 70 mg/m². Conversion rates after HD-Ida and HD-TM were 28.6 and 38.5%, respectively. No episodes of cardiac toxicity were observed. We conclude that HD-Ida followed by HD-TM is feasible and devoid of cardiac toxicity. Moreover, the activity of HD-Ida after a epirubicin-containing regimen suggests incomplete cross-resistance between the two drugs.