title: High-dose consolidation chemotherapy with Idarubicin and alkylating agents following induction with gemcitabine-epirubicin-paclitaxel in metastatic breast cancer: a dose finding study.
abstract: 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/m(2) days 1 and 4, epirubicin 90 mg/m(2) day 1, taxol 175 mg/m(2) 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/m(2) (three patients), 50 mg/m(2) (three patients), 60 mg/m(2) (five patients) and 70 mg/m(2) (three patients). Mucositis was the dose-limiting toxicity and the MTD was 60 mg/m(2). C(max) of Idarubicin and idarubicinol were 7.7+/-2.0 and 26.3+/-9.7 ng/ml at 40 mg/m(2) and increased to 14.8+3.0 and 47.4+12.6 ng/ml at 70 mg/m(2). AUCt(0-264) of idarubicin and idarubicinol increased from 423.2+/-111.6 and 2581+/-606 hng/ml at 40 mg/m(2) to 732.8+/-140.2 and 4590+/-1258 hng/ml at 70 mg/m(2). 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.
authors.affiliation: Division of Medical Oncology, St Chiara University Hospital, Pisa, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Bengala
authors.forename: R
authors.initials: R
authors.lastname: Danesi
authors.forename: V
authors.initials: V
authors.lastname: Guarneri
authors.forename: I
authors.initials: I
authors.lastname: Pazzagli
authors.forename: S
authors.initials: S
authors.lastname: Donati
authors.forename: C
authors.initials: C
authors.lastname: Favre
authors.forename: S
authors.initials: S
authors.lastname: Fogli
authors.forename: O
authors.initials: O
authors.lastname: Biadi
authors.forename: F
authors.initials: F
authors.lastname: Innocenti
authors.forename: M
authors.initials: M
authors.lastname: Del Tacca
authors.forename: M
authors.initials: M
authors.lastname: Mariani
authors.forename: P F
authors.initials: PF
authors.lastname: Conte
mesh_terms: D000328:Adult; D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000473:pathology / Q000628:therapy*; D003630:Daunorubicin / Q000031:analogs & derivatives* / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics / Q000627:therapeutic use; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D018450:Disease Progression; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D015251:Epirubicin / Q000008:administration & dosage; D005260:Female; D006801:Humans; D015255:Idarubicin / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008558:Melphalan / Q000008:administration & dosage; D008875:Middle Aged; D009362:Neoplasm Metastasis; D017239:Paclitaxel / Q000008:administration & dosage; D012074:Remission Induction; D043823:Taxoids; D013852:Thiotepa / Q000008:administration & dosage; D013997:Time Factors; D019172:Transplantation Conditioning / Q000379:methods; D016896:Treatment Outcome
chemical_list: D018906:Antineoplastic Agents, Alkylating; D043823:Taxoids; D003841:Deoxycytidine; D015251:Epirubicin; C054440:idarubicinol; D013852:Thiotepa; D017239:Paclitaxel; D008558:Melphalan; D015255:Idarubicin; D003630:Daunorubicin