Paclitaxel in doxorubicin-refractory or mitoxantrone-refractory breast cancer: a phase I/II trial of 96-hour infusion

J Clin Oncol. 1994 Aug;12(8):1621-9. doi: 10.1200/JCO.1994.12.8.1621.


Purpose: 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.

Patients and 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.

Conclusion: 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.

Publication types

  • Clinical Trial
  • Clinical Trial, Phase I
  • Clinical Trial, Phase II

MeSH terms

  • Adult
  • Aged
  • Agranulocytosis / chemically induced
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / mortality
  • Doxorubicin / therapeutic use
  • Drug Administration Schedule
  • Drug Resistance / genetics
  • Female
  • Humans
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / metabolism
  • Lymphoma / drug therapy*
  • Lymphoma / metabolism
  • Male
  • Middle Aged
  • Mitoxantrone / therapeutic use
  • Mouth Mucosa
  • Paclitaxel / administration & dosage*
  • Paclitaxel / adverse effects
  • Paclitaxel / pharmacokinetics
  • Stomatitis / chemically induced


  • Doxorubicin
  • Mitoxantrone
  • Paclitaxel