ABSTRACT: Influence of Amifostine on the Toxicity and Pharmacokinetics
of Docetaxel in Metastatic Breast Cancer Patients
Preclinical studies suggest that amifostine could protect against
toxicities induced by taxoids. We conducted a clinical and pharmacokinetic
pilot study to assess the feasibility and toxicity of the docetaxel
plus amifostine combination and the absence of influence of amifostine
on docetaxel pharmacokinetics. We included 18 previously treated
women with metastatic breast cancer (median age, 58.5 years;
range, 34-74) in this single-center study. They were to
receive a first course of docetaxel at 100 mg/m2 i.v. as a 1-h
infusion, then subsequent courses of docetaxel at 100 mg/m2 preceded
by amifostine at 910 mg/m2 given as a 15-min i.v. infusion. Treatment
was given every 3 weeks until disease progression or occurrence
of unacceptable toxicity. We focused on neutrophils nadir (NN),
time to nadir occurrence, and time to recovery of a neutrophil
count >2 x 109/liter, means of which were compared between
cycle 1 and each of the other cycles by paired Student's t test.
The total number of administered cycles was 84 (median number/patient,
4; range, 1-8). One patient received only the first course
of docetaxel and was therefore not evaluable for amifostine effect.
Neutropenia grade >2 occurred in 16 patients and was febrile
in only 1. Other hematological and nonhematological toxicities
were mild and manageable. Amifostine had no obvious influence
on docetaxel-induced myelotoxicity as expressed by NN, time to
nadir occurrence, and time to recovery. The mean NN (1 x 106/liter)
was 345 (18 patients) for cycle 1, then 318 (17 patients), 330
(13 patients), 340 (11 patients), 470 (8 patients), 200 (8 patients),
680 (5 patients), and 545 (4 patients) for cycles 2, 3, 4, 5,
6, 7, and 8, respectively (P >0.2). Individual pharmacokinetic
(PK) parameters of docetaxel estimated in 11 patients undergoing
blood sampling showed no influence of amifostine on the PK profile
of docetaxel. Mean clearances (liter/h/m2) and peak concentration
(Cpeak; ng/ml) were 29.9 at cycle 1 versus 32.8 at cycle 2 (not
significant) and 2849.9 at cycle 1 versus 2542.5 at cycle 2 (not
significant), respectively. The population analysis including
those 11 patients and 49 additional patients receiving docetaxel
in other studies confirmed those findings.
This study does not support evidence for amifostine cytoprotection
against docetaxel-induced myelosuppression and shows that there
is no major influence of amifostine on docetaxel PK parameters.
For the other toxicities, which are usually cumulative, the present
study has design limitations and further comparative trials are warranted.
[01/22/2002; Clinical Cancer Research]
Ann's NOTE: Amifostine is a synthetic (analogue) of antioxidants. We need to know which ones and a lot more information on how it works.
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