title: Phase I and pharmacokinetic study of docetaxel in combination with epirubicin and cyclophosphamide in advanced cancer: dose escalation possible with granulocyte colony-stimulating factor, but not with prophylactic antibiotics.
abstract: BACKGROUND
  The objective of this phase I trial was to determine the maximally tolerated doses of the combination of docetaxel, epirubicin and cyclophosphamide.
  
  
  METHODS
  Patients with advanced cancer, World Health Organization (WHO) performance status 0 to 2, who had received up to one prior chemotherapy regimen were treated with docetaxel, epirubicin and cyclophosphamide repeated every 21 days. The cyclophosphamide dose was fixed at 600 mg/m(2) and the dose levels studied were: docetaxel/epirubicin; 60/60, 75/60, 75/75, 75/90, 85/90 and 85/105 mg/m(2). There was provision for the addition of prophylactic ciprofloxacin and granulocyte colony-stimulating factor (G-CSF) in separate steps if dose-limiting toxicity (DLT) was neutropenia related.
  
  
  RESULTS
  Forty-three patients were entered and all were assessable for toxicity. Dose-limiting toxicity, predominantly febrile neutropenia, was surprisingly seen at the first dose level. The addition of prophylactic ciprofloxacin did not permit dose escalation, but dose escalation was possible with the addition of G-CSF. The highest administered dose level with G-CSF was docetaxel 85 mg/m(2) and epirubicin 105 mg/m(2) with DLTs in five of six patients. Treatment was well tolerated in 10 patients treated at the recommended dose level (85/90) with only one patient experiencing DLT. Responses were seen in a range of malignancies including breast and anaplastic thyroid cancers. No significant pharmacokinetic interaction was observed, but a transient increase in epirubicinol plasma concentration occurred during and after docetaxel infusion.
  
  
  CONCLUSIONS
  The recommended dose level of docetaxel 85 mg/m(2), epirubicin 90 mg/m(2) and cyclophosphamide 600 mg/m(2) with G-CSF support has a favorable toxicity profile and is suitable for further investigation in phase II and III trials.
authors.affiliation: Division of Haematology and Medical Oncology and Statistical Centre, Peter MacCallum Cancer Institute, Melbourne, Austtralia. drischin@petermac.unimelb.edu.au
authors.forename: D
authors.initials: D
authors.lastname: Rischin
authors.forename: S P
authors.initials: SP
authors.lastname: Ackland
authors.forename: J
authors.initials: J
authors.lastname: Smith
authors.forename: M B
authors.initials: MB
authors.lastname: Garg
authors.forename: S
authors.initials: S
authors.lastname: Clarke
authors.forename: M J
authors.initials: MJ
authors.lastname: Millward
authors.forename: G C
authors.initials: GC
authors.lastname: Toner
authors.forename: J
authors.initials: J
authors.lastname: Zalcberg
mesh_terms: D000328:Adult; D000368:Aged; D019072:Antibiotic Prophylaxis; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D001707:Biopsy, Needle; D016001:Confidence Intervals; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000493:pharmacokinetics; D000077143:Docetaxel; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D015251:Epirubicin / Q000008:administration & dosage / Q000493:pharmacokinetics; D005260:Female; D005500:Follow-Up Studies; D016179:Granulocyte Colony-Stimulating Factor / Q000008:administration & dosage*; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009367:Neoplasm Staging; D009369:Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology*; D017239:Paclitaxel / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D011336:Probability; D018570:Risk Assessment; D012680:Sensitivity and Specificity; D015996:Survival Rate; D043823:Taxoids; D016896:Treatment Outcome
chemical_list: D043823:Taxoids; D016179:Granulocyte Colony-Stimulating Factor; D000077143:Docetaxel; D015251:Epirubicin; D003520:Cyclophosphamide; D017239:Paclitaxel