title: Phase I study of paclitaxel in combination with cyclophosphamide and granulocyte colony-stimulating factor in metastatic breast cancer patients.
abstract: OBJECTIVE
  In vitro data suggest that prolonged exposure to paclitaxel enhances breast cancer cytotoxicity. Our objective in this phase I study was to determine the tolerability of paclitaxel administered by 72-hour continuous intravenous (i.v.) infusion (CIVI) in combination with high-dose cyclophosphamide and granulocyte colony-stimulating factor (G-CSF) in the ambulatory setting to metastatic breast cancer patients.
  
  
  METHODS
  Paclitaxel was administered over 72 hours by CIVI and cyclophosphamide was given daily by i.v. bolus on days 1, 2, and 3, followed by G-CSF every 21 days. The availability of ambulatory infusion pumps and paclitaxel-compatible tubing permitted outpatient administration.
  
  
  RESULTS
  Fifty-five patients with metastatic breast cancer who had been previously treated with a median of two prior chemotherapy regimens were entered onto the study. Dose-limiting toxicity of grade 4 neutropenia for longer than 5 days and grade 4 thrombocytopenia occurred in three of five patients treated with paclitaxel 160 mg/m2 CIVI and cyclophosphamide 3,300 mg/m2 followed by G-CSF. The maximum-tolerated dose (MTD) was paclitaxel 160 mg/m2 CIVI and cyclophosphamide 2,700 mg/m2 in divided doses with G-CSF. Nonhematologic toxicities were moderate and included diarrhea, mucositis, and arthalgias. Although hemorrhagic cystitis developed in six patients, recurrence was prevented with i.v. and oral mesna, which permitted continued outpatient delivery. One hundred seventy-four cycles were safely administered in the ambulatory setting using infusional pumps and tubing. Objective responses occurred in 23 (one complete and 22 partial) of 42 patients with bidimensionally measurable disease (55%; 95% confidence interval, 38% to 70%), with a response rate of 73% (11 of 15) seen at the highest dose levels.
  
  
  CONCLUSIONS
  Paclitaxel by 72-hour CIVI with daily cyclophosphamide followed by G-CSF can be administered safely in the ambulatory setting, has acceptable toxicity, and is an active regimen in the treatment of metastatic breast cancer.
authors.affiliation: Medicine Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: A W
authors.initials: AW
authors.lastname: Tolcher
authors.forename: K H
authors.initials: KH
authors.lastname: Cowan
authors.forename: M H
authors.initials: MH
authors.lastname: Noone
authors.forename: A M
authors.initials: AM
authors.lastname: Denicoff
authors.forename: D R
authors.initials: DR
authors.lastname: Kohler
authors.forename: B R
authors.initials: BR
authors.lastname: Goldspiel
authors.forename: C S
authors.initials: CS
authors.lastname: Barnes
authors.forename: M
authors.initials: M
authors.lastname: McCabe
authors.forename: M R
authors.initials: MR
authors.lastname: Gossard
authors.forename: J
authors.initials: J
authors.lastname: Zujewski
authors.forename: J A
authors.initials: JA
authors.lastname: O'Shaughnessy
mesh_terms: D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D001772:Blood Cell Count / Q000187:drug effects; D001943:Breast Neoplasms / Q000473:pathology* / Q000628:therapy*; D003520:Cyclophosphamide / Q000008:administration & dosage; D003967:Diarrhea / Q000139:chemically induced; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004342:Drug Hypersensitivity / Q000188:drug therapy / Q000209:etiology; D004868:Equipment Failure; D017707:Erythrocyte Transfusion; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor / Q000008:administration & dosage; D006402:Hematologic Diseases / Q000097:blood / Q000139:chemically induced / Q000628:therapy; D006417:Hematuria / Q000139:chemically induced / Q000188:drug therapy; D018718:Home Infusion Therapy / Q000295:instrumentation; D006801:Humans; D015080:Mesna / Q000627:therapeutic use; D008875:Middle Aged; D009362:Neoplasm Metastasis; D017239:Paclitaxel / Q000008:administration & dosage*
chemical_list: D016179:Granulocyte Colony-Stimulating Factor; D003520:Cyclophosphamide; D015080:Mesna; D017239:Paclitaxel