J Alexandre1, E Rey2, V Girre3, S Grabar4, A Tran2, V Montheil5, F Rabillon5, V Dieras3, V Jullien2, P Hérait5, G Pons2, J-M Treluyer2, F Goldwasser5. 1. Department of Medical Oncology, Groupe Hospitalier Cochin St Vincent de Paul, Université Paris 5, Assistance Publique-Hôpitaux de Paris, Paris, France; Department of Molecular Pathology, University of Texas, MD Anderson Cancer Center, Houston, USA. Electronic address: jalexand@mdanderson.org. 2. Department of Clinical Pharmacology, Groupe Hospitalier Cochin St Vincent de Paul, Université Paris 5, Assistance Publique-Hôpitaux de Paris, Paris. 3. Department of Medical Oncology, Institut Curie, Paris. 4. Department of Biostatistics, Groupe Hospitalier Cochin St Vincent de Paul, Université Paris 5, Assistance Publique-Hôpitaux de Paris, Paris, France. 5. Department of Medical Oncology, Groupe Hospitalier Cochin St Vincent de Paul, Université Paris 5, Assistance Publique-Hôpitaux de Paris, Paris, France.
Abstract
BACKGROUND: We hypothesized that cancer-related inflammation might increase the risk of febrile neutropenia (FN) induced by docetaxel (DCX, Taxotere), by both affecting the exposure to DCX and the tissue sensitivity. PATIENTS AND METHODS: Advanced cancer patients with normal liver function, performance status (PS)<3, were included. Cytochrome P450 3A (CYP 3A) activity was estimated before the first cycle of DCX by a single determination of midazolam plasma concentration, 4 hours after 0.015 mg/kg i.v. bolus. Following the first cycle of 75-100 mg/m2 DCX, clearance and area under the concentration versus time curve (AUC) were estimated using a limited sampling strategy. RESULTS: Among 56 assessable patients, 7 FNs occurred after first cycle (13%). In univariate analysis, high midazolam concentration and free DCX AUC were associated with severe neutropenia and FN. In addition to DCX exposure-related parameters, the risk of FN was also correlated with poor PS, baseline lymphopenia and lung cancer, while high ferritin level, indicator of an inflammatory state, reached borderline significance (P=0.07). By multivariate analysis, total DCX AUC and baseline lymphopenia were associated with FN. High midazolam concentration was correlated with elevated ferritin level (r=0.32; P=0.02). CONCLUSION: Inflammatory status and lymphocyte count should be included in the evaluation of the benefice/risk ratio before the initiation of DCX.
BACKGROUND: We hypothesized that cancer-related inflammation might increase the risk of febrile neutropenia (FN) induced by docetaxel (DCX, Taxotere), by both affecting the exposure to DCX and the tissue sensitivity. PATIENTS AND METHODS: Advanced cancerpatients with normal liver function, performance status (PS)<3, were included. Cytochrome P450 3A (CYP 3A) activity was estimated before the first cycle of DCX by a single determination of midazolam plasma concentration, 4 hours after 0.015 mg/kg i.v. bolus. Following the first cycle of 75-100 mg/m2 DCX, clearance and area under the concentration versus time curve (AUC) were estimated using a limited sampling strategy. RESULTS: Among 56 assessable patients, 7 FNs occurred after first cycle (13%). In univariate analysis, high midazolam concentration and free DCX AUC were associated with severe neutropenia and FN. In addition to DCX exposure-related parameters, the risk of FN was also correlated with poor PS, baseline lymphopenia and lung cancer, while high ferritin level, indicator of an inflammatory state, reached borderline significance (P=0.07). By multivariate analysis, total DCX AUC and baseline lymphopenia were associated with FN. High midazolam concentration was correlated with elevated ferritin level (r=0.32; P=0.02). CONCLUSION: Inflammatory status and lymphocyte count should be included in the evaluation of the benefice/risk ratio before the initiation of DCX.
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