Annals of Oncology Advance Access originally published online on October 23, 2006
Annals of Oncology 2007 18(1):168-172; doi:10.1093/annonc/mdl321
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© 2006 European Society for Medical Oncology
supportive care |
Relationship between cytochrome 3A activity, inflammatory status and the risk of docetaxel-induced febrile neutropenia: a prospective study
1 Department of Medical Oncology, Groupe Hospitalier Cochin St Vincent de Paul, Université Paris 5, Assistance Publique—Hôpitaux de Paris, Paris, France
2 Department of Molecular Pathology, University of Texas, MD Anderson Cancer Center, Houston, USA
3 Department of Clinical Pharmacology, Groupe Hospitalier Cochin St Vincent de Paul, Université Paris 5, Assistance Publique—Hôpitaux de Paris, Paris
4 Department of Medical Oncology, Institut Curie, Paris
5 Department of Biostatistics, Groupe Hospitalier Cochin St Vincent de Paul, Université Paris 5, Assistance Publique—Hôpitaux de Paris, Paris, France
* Correspondence to: Dr J. Alexandre, Department of Molecular Pathology, unit 951, University of Texas, MD Anderson Cancer Center, PO Box 301429, Houston, TX 77230-1429, USA. Tel: +1-713-834-6070; Fax: +1-713-834-6084; E-mail: jalexand{at}mdanderson.org
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.
Key words: cytochrome 3A, docetaxel, febrile neutropenia, lymphocytopenia midazolam