title: Paclitaxel in doxorubicin-refractory or mitoxantrone-refractory breast cancer: a phase I/II trial of 96-hour infusion.
abstract: OBJECTIVE
  A phase I study of paclitaxel infused over 96-hours was performed to determine toxicity, maximum-tolerated dose (MTD), and pharmacokinetics in patients with incurable lymphomas and solid tumors. A phase II study was performed at the MTD of paclitaxel in patients with doxorubicin/mitoxantrone-refractory metastatic breast cancer.
  
  
  METHODS
  In the phase I study, paclitaxel dose levels ranged from 120 to 160 mg/m2, administered on a 21-day cycle. Patients with metastatic breast cancer who had either no response or a partial response (PR) to doxorubicin or mitoxantrone and had measurable disease were eligible for the phase I and II studies. Expression of the multidrug resistance (mdr-1) gene was determined in tumor biopsies by mRNA quantitative polymerase chain reaction.
  
  
  RESULTS
  Twelve patients received a total of 73 cycles of paclitaxel on the phase I study. Dose-limiting mucositis and/or grade IV granulocytopenia was reached at 160 mg/m2, and 140 mg/m2 was selected as the phase II dose. Thirty-six consecutive patients with metastatic breast cancer were treated, of whom three were not assessable. The median age was 49 years, with disease in the liver and/or lung in 76%. Patients received a median of two prior regimens for metastatic disease, and 73% had no response to prior doxorubicin or mitoxantrone. Of 33 patients treated with paclitaxel, 16 patients (48%) achieved a PR and five (15%) achieved a minor response (MR). With a median potential follow-up duration of 60 weeks, the median progression-free and overall survival durations were 27 and 43 weeks, respectively. No correlation was found between extent of prior treatment or prior response to doxorubicin/mitoxantrone, and response to paclitaxel. Paclitaxel pharmacokinetics showed a correlation between both granulocyte and mucosal toxicity, and serum steady-state concentrations (Css) more than 0.07 mumol/L. Patients with liver metastases had significantly decreased paclitaxel clearance and higher paclitaxel Css. Levels of mdr-1 were uniformly low in all tumor biopsies studied.
  
  
  CONCLUSIONS
  The recommended phase II dose of paclitaxel is 140 mg/m2 in patients without liver metastases and 105 mg/m2 in patients with liver metastases. Ninety-six-hour infusions of paclitaxel were effective and well tolerated in patients with doxorubicin/mitoxantrone-refractory breast cancer. Prolonged infusion schedules may be more effective than shorter schedules and deserve further study.
authors.affiliation: Medicine Branch, National Cancer Institute, Bethesda, MD 20892.
authors.forename: W H
authors.initials: WH
authors.lastname: Wilson
authors.forename: S L
authors.initials: SL
authors.lastname: Berg
authors.forename: G
authors.initials: G
authors.lastname: Bryant
authors.forename: R E
authors.initials: RE
authors.lastname: Wittes
authors.forename: S
authors.initials: S
authors.lastname: Bates
authors.forename: A
authors.initials: A
authors.lastname: Fojo
authors.forename: S M
authors.initials: SM
authors.lastname: Steinberg
authors.forename: B R
authors.initials: BR
authors.lastname: Goldspiel
authors.forename: J
authors.initials: J
authors.lastname: Herdt
authors.forename: J
authors.initials: J
authors.lastname: O'Shaughnessy
mesh_terms: D000328:Adult; D000368:Aged; D000380:Agranulocytosis / Q000139:chemically induced; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000401:mortality; D004317:Doxorubicin / Q000627:therapeutic use; D004334:Drug Administration Schedule; D004351:Drug Resistance / Q000235:genetics; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D008223:Lymphoma / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D008942:Mitoxantrone / Q000627:therapeutic use; D009061:Mouth Mucosa; D017239:Paclitaxel / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D013280:Stomatitis / Q000139:chemically induced
chemical_list: D004317:Doxorubicin; D008942:Mitoxantrone; D017239:Paclitaxel