title: Dose-finding study and pharmacokinetics of epirubicin and paclitaxel over 3 hours: a regimen with high activity and low cardiotoxicity in advanced breast cancer.
abstract: OBJECTIVE
  To determine the maximum-tolerated dose (MTD) of paclitaxel over 3 hours with a fixed dose of epirubicin, to investigate the plasma pharmacokinetics of this combination, and to evaluate the toxicity and the activity in previously untreated metastatic breast cancer patients.
  
  
  METHODS
  Fifty patients with metastatic breast cancer, measurable disease, and normal left ventricular ejection fraction (LVEF) were eligible. Epirubicin was administered as an intravenous (I.V.) bolus at the fixed dose of 90 mg/m2 before the infusion of paclitaxel over 3 hours. The initial dose of paclitaxel was 135 mg/m2 and was increased by 20 mg/m2 in subsequent cohorts of six patients until dose-limiting toxicity (DLT). Plasma pharmacokinetics of paclitaxel and epirubicin was performed at cycle 1 in at least two patients per dose level of paclitaxel (175 up to 225 mg/m2).
  
  
  RESULTS
  The DLT of this combination was febrile neutropenia in two of eight patients who received paclitaxel at 225 mg/m2. The mean peak plasma concentration of paclitaxel ranged between 5.1 and 6.2 micromol/L at doses of 175 to 225 mg/m2. The concentration of epirubicinol decreased from 47.3 +/- 9.4 to 37.9 +/- 7.5 ng/mL in patients treated with paclitaxel 175 and 225 mg/m2. The most relevant toxicity was grade 4 neutropenia (61% of all courses). The pharmacokinetic data of paclitaxel, in particular the time above the threshold level of 0.05 micromol/L, were not significantly related to myelosuppression. Cardiac toxicity was mild: three patients (6%) developed mild congestive heart failure that was responsive to therapy. Among 49 assessable patients, 41 responses (84%; 95% confidence interval [CI], 70% to 92%) were observed, and nine (18%) of these were complete.
  
  
  CONCLUSIONS
  Our study demonstrates that (1) the MTD is epirubicin 90 mg/m2 and paclitaxel 200 mg/m2; (2) no clear relationship exists between pharmacokinetic data of paclitaxel and myelosuppression, while the increase in the dose of paclitaxel is associated with a reduction in epirubicinol plasma levels; and (3) the association is feasible, with low cardiotoxicity, and has a high activity in metastatic breast cancer.
authors.affiliation: Division of Medical Oncology, Oncologia Medica, Ospedale S. Chiara, Pisa, Italy.
authors.forename: P F
authors.initials: PF
authors.lastname: Conte
authors.forename: E
authors.initials: E
authors.lastname: Baldini
authors.forename: A
authors.initials: A
authors.lastname: Gennari
authors.forename: A
authors.initials: A
authors.lastname: Michelotti
authors.forename: B
authors.initials: B
authors.lastname: Salvadori
authors.forename: C
authors.initials: C
authors.lastname: Tibaldi
authors.forename: R
authors.initials: R
authors.lastname: Danesi
authors.forename: F
authors.initials: F
authors.lastname: Innocenti
authors.forename: A
authors.initials: A
authors.lastname: Gentile
authors.forename: R
authors.initials: R
authors.lastname: Dell'Anna
authors.forename: O
authors.initials: O
authors.lastname: Biadi
authors.forename: M
authors.initials: M
authors.lastname: Mariani
authors.forename: M
authors.initials: M
authors.lastname: Del Tacca
mesh_terms: D000328:Adult; D000368:Aged; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000493:pharmacokinetics; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000493:pharmacokinetics; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D001943:Breast Neoplasms / Q000097:blood*; D004334:Drug Administration Schedule; D015251:Epirubicin / Q000008:administration & dosage / Q000493:pharmacokinetics; D005260:Female; D006331:Heart Diseases / Q000139:chemically induced / Q000503:physiopathology / Q000517:prevention & control*; D006801:Humans; D016018:Least-Squares Analysis; D008875:Middle Aged; D009503:Neutropenia / Q000139:chemically induced; D017239:Paclitaxel / Q000008:administration & dosage / Q000493:pharmacokinetics; D011446:Prospective Studies; D013318:Stroke Volume; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D000903:Antibiotics, Antineoplastic; D000972:Antineoplastic Agents, Phytogenic; D015251:Epirubicin; D017239:Paclitaxel