Journal of Clinical Oncology, Vol 12, 1659-1666, Copyright © 1994 by American Society of Clinical Oncology
Comparative study of the pharmacokinetics and toxicity of high-dose epirubicin with or without dexrazoxane in patients with advanced malignancy
RL Basser, MM Sobol, G Duggan, J Cebon, MA Rosenthal, G Mihaly and MD Green
Department of Hematology and Medical Oncology, Royal Melbourne Hospital, Parkville, Victoria Australia.
PURPOSE: We evaluated the toxicity and pharmacokinetics of the combination
of dexrazoxane with epirubicin at dexrazoxane/epirubicin dose ratios of 5
to 9:1 in a controlled, crossover phase I study in patients with advanced
malignancy. PATIENTS AND METHODS: Thirty-eight patients with a variety of
malignancies were enrolled. Assessable patients received two cycles of
chemotherapy consisting of epirubicin alone and in combination with
dexrazoxane. Comparisons were made between the toxicity and
pharmacokinetics of epirubicin in the two treatment arms, using each
patient as his or her own control. Dexrazoxane and epirubicin were
delivered at dose levels of 600/120 mg/m2, 900/120 mg/m2, 900/135 mg/m2,
900/150 mg/m2, and 1,200/135 mg/m2, respectively. Twenty-six patients
completed two cycles of chemotherapy and were therefore assessable.
RESULTS: The maximum- tolerated doses (MTDs) of dexrazoxane/epirubicin were
1,200/135 mg/m2, with the dose-limiting toxicities being neutropenia,
infection, and stomatitis. There was no difference in the nadir neutrophil
or platelet counts between single-agent and combination treatment at any of
the dose levels. Severe vomiting and stomatitis occurred less frequently
following administration of epirubicin and dexrazoxane when compared with
epirubicin alone (P = .01 and .02, respectively). Prior administration of
higher doses (900 mg/m2 and 1,200 mg/m2) of dexrazoxane increased the
systemic clearance of epirubicin, resulting in a decrease in the area under
the curve (AUC). Elimination half-life, maximum plasma concentration
(Cmax), and apparent volume of distribution of epirubicin were not
significantly affected by dexrazoxane. Left ventricular ejection fraction
(LVEF) decreased by greater than 10% in two patients, but neither developed
clinical or radiologic evidence of cardiac failure. CONCLUSION: This study
demonstrates that dexrazoxane can be safely combined with escalating doses
of epirubicin at dose ratios of 5 to 9:1 without having an adverse impact
on toxicity. Studies are need to determine the optimal dose ratio for
cardioprotection and to explore further the pharmacokinetic interactions of
the two drugs at increasing doses of epirubicin supported by hematopoietic
growth factors.
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