title: Phase I/II study of 72-hour infusional paclitaxel and doxorubicin with granulocyte colony-stimulating factor in patients with metastatic breast cancer.
abstract: OBJECTIVE
  We conducted a phase I/II trial of concurrently administered 72-hour infusional paclitaxel and doxorubicin in combination with granulocyte colony-stimulating factor (G-CSF) in patients with previously untreated metastatic breast cancer and bidimensionally measurable disease.
  
  
  METHODS
  We defined the maximum-tolerated dose (MTD) of concurrent paclitaxel and doxorubicin administration and then studied potential pharmacokinetic interactions between the two drugs. Forty-two patients who had not received prior chemotherapy for metastatic breast cancer received 296 total cycles of paclitaxel and doxorubicin with G-CSF.
  
  
  RESULTS
  The MTD was determined to be paclitaxel 180 mg/m2 and doxorubicin 60 mg/m2 each by 72-hour infusion with G-CSF. Diarrhea was the dose-limiting toxicity (DLT) of this combination, with three of three patients developing abdominal computed tomographic (CT) scan evidence of typhlitis (cecal thickening) at the dose level above the MTD. All patients developed grade 4 neutropenia (absolute neutrophil count [ANC] < 500 microL), generally less than 5 days in duration. This combination was generally safely administered at dose levels at or below the MTD. The overall response rate was 72% (28 of 39 patients; 95% confidence interval [CI], 55% to 85%), with 8% complete responses (CRs) (three of 39; 95% CI, 2% to 21%) and a median response duration of 9 months. The median overall survival time for all patients is 23 months, with a median follow-up duration of 28 months. Pharmacokinetic studies showed that administration of paclitaxel and doxorubicin together by 72-hour infusion did not affect the steady-state concentrations of either drug.
  
  
  CONCLUSIONS
  Concurrent 72-hour infusional paclitaxel and doxorubicin can be administered safely, but is associated with significant toxicity. The overall response rate of this combination in untreated metastatic breast cancer patients is similar to that achieved with other doxorubicin-based combination regimens. The modest complete response rate achieved suggests that this schedule of paclitaxel and doxorubicin administration does not produce significant additive or synergistic cytotoxicity against breast cancer.
authors.affiliation: Medicine Branch, Cancer Therapy Evaluation Program, National Cancer Institute, Clinical Center, National Institutes of Health, Bethesda, MD, USA.
authors.forename: J S
authors.initials: JS
authors.lastname: Fisherman
authors.forename: K H
authors.initials: KH
authors.lastname: Cowan
authors.forename: M
authors.initials: M
authors.lastname: Noone
authors.forename: A
authors.initials: A
authors.lastname: Denicoff
authors.forename: S
authors.initials: S
authors.lastname: Berg
authors.forename: D
authors.initials: D
authors.lastname: Poplack
authors.forename: F
authors.initials: F
authors.lastname: Balis
authors.forename: D
authors.initials: D
authors.lastname: Venzon
authors.forename: M
authors.initials: M
authors.lastname: McCabe
authors.forename: B
authors.initials: B
authors.lastname: Goldspiel
authors.forename: C
authors.initials: C
authors.lastname: Chow
authors.forename: F P
authors.initials: FP
authors.lastname: Ognibene
authors.forename: J
authors.initials: J
authors.lastname: O'Shaughnessy
mesh_terms: D000328:Adult; D000368:Aged; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000493:pharmacokinetics; D003967:Diarrhea / Q000139:chemically induced; D018572:Disease-Free Survival; D004317:Doxorubicin / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D004334:Drug Administration Schedule; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor / Q000008:administration & dosage; D006321:Heart / Q000187:drug effects; D006801:Humans; D008875:Middle Aged; D017239:Paclitaxel / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D013921:Thrombocytopenia / Q000139:chemically induced
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D016179:Granulocyte Colony-Stimulating Factor; D004317:Doxorubicin; D017239:Paclitaxel