title: Phase I and pharmacologic study of sequences of paclitaxel and cyclophosphamide supported by granulocyte colony-stimulating factor in women with previously treated metastatic breast cancer.
abstract: OBJECTIVE
  Pacltaxel is active in metastatic breast cancer, but limited information is available on combinations of this agent with other cytotoxic agents. Study aims were to determine the maximum-tolerated doses (MTDs) of paclitaxel (24-hour infusion) and cyclophosphamide (1-hour infusion) administered every 21 days with granulocyte colony-stimulating factor (G-CSF, filgrastim) to determine the effect of drug sequence on toxicity and pharmacology and to evaluate the activity of this combination in women with anthracycline-resistant disease.
  
  
  METHODS
  Thirty-seven women with metastatic breast cancer were treated. Starting doses were paclitaxel 135 mg/m2 and cyclophosphamide 750 mg/m2, with filgrastim 5 microG/kg/d subcutaneously beginning 24 hours after chemotherapy. Four patients were treated at each dose level. The sequence of drug administration was alternated between sequential patients, and with subsequent courses of therapy in each patient, to enable evaluation of effects of drug sequence on toxicity and pharmacology. Patients were treated every 21 days and disease status was reevaluated every two courses.
  
  
  RESULTS
  Paclitaxel 200 mg/m2 and cyclophosphamide 1,250 mg/m2 is the MTD for this combination on this schedule. The hematopoietic toxicity of therapy was sequence-dependent. Paired analysis of toxicity data indicated more severe toxicity in courses in which paclitaxel was administered first. Sequence-dependent pharmacologic effects did not account for this phenomenon. Responses were noted in 29% of patients with anthracycline-resistant disease.
  
  
  CONCLUSIONS
  Paclitaxel 200 mg/m2 and cyclophosphamide 1,250 mg/m2 with filgrastim administered every 21 days are the doses recommended for further study.
authors.affiliation: The Johns Hopkins Oncology Center, Baltimore, MD, 21287, USA.
authors.forename: M J
authors.initials: MJ
authors.lastname: Kennedy
authors.forename: M L
authors.initials: ML
authors.lastname: Zahurak
authors.forename: R C
authors.initials: RC
authors.lastname: Donehower
authors.forename: D A
authors.initials: DA
authors.lastname: Noe
authors.forename: S
authors.initials: S
authors.lastname: Sartorius
authors.forename: T L
authors.initials: TL
authors.lastname: Chen
authors.forename: K
authors.initials: K
authors.lastname: Bowling
authors.forename: E K
authors.initials: EK
authors.lastname: Rowinsky
mesh_terms: D000328:Adult; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects; D001943:Breast Neoplasms / Q000188:drug therapy*; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000009:adverse effects; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor / Q000008:administration & dosage; D006801:Humans; D008875:Middle Aged; D009503:Neutropenia / Q000139:chemically induced; D017239:Paclitaxel / Q000008:administration & dosage / Q000009:adverse effects; D012074:Remission Induction; D013921:Thrombocytopenia / Q000139:chemically induced
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D016179:Granulocyte Colony-Stimulating Factor; D003520:Cyclophosphamide; D017239:Paclitaxel