IMPROVING CANCER THERAPY BY DOCETAXEL AND GRANULOCYTE COLONY-STIMULATING FACTOR (G-CSF)

摘要

Neutropenia is the dose-limiting toxicity of the tri-weekly docetaxel (Taxotere®) schedule. Here, we evaluate in Metastatic Breast Cancer (MBC) patients (N = 38) a computerized method for predicting docetaxel-induced neutropenia, and use the model to identify improved docetaxel and Granulocyte Colony Stimulating Factor (G-CSF) regimens. Pharmacokinetics/pharmacodynamics (PK/PD) models were created and simulated concomitantly with a mathematical granulopoiesis model. Individual baseline neutrophil counts and docetaxel schedules served as inputs. Our trial validated the model accuracy in predicting nadir timings (r = 0.99), grade 3/4 neutropenia (86% success) and neutrophil profiles (r = 0.62). Model was robust to CYP3A-induced variability, except for slightly less accurate grade 3/4 neutropenia predictions. Simulations confirm smaller toxicity of the weekly docetaxel regimen than the tri-weekly one, and suggest an optimal G-CSF support for alleviating neutropenia, 60 µg/day QD x 3, 6-7 days post-docetaxel, administered tri- and bi-weekly, and 4 days post weekly docetaxel >33 mg/m2.