Journal of Clinical Oncology, Vol 12, 1621-1629, Copyright © 1994 by American Society of Clinical Oncology
Paclitaxel in doxorubicin-refractory or mitoxantrone-refractory breast cancer: a phase I/II trial of 96-hour infusion
WH Wilson, SL Berg, G Bryant, RE Wittes, S Bates, A Fojo, SM Steinberg, BR Goldspiel, J Herdt and J O'Shaughnessy
Medicine Branch, National Cancer Institute, Bethesda, MD 20892.
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.
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