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You B.,University of Lyon | You B.,Center Dinvestigation Of Therapeutiques En Oncologie Et Hematologie Of Lyon Citohl | Salles G.,Institute Of Cancerologie Des Hospices Civils Of Lyon Ic Hcl | Salles G.,University of Lyon | And 14 more authors.
Cancer Chemotherapy and Pharmacology | Year: 2015

Background: Relationships between pharmacokinetic (PK) parameters of etoposide and toxicity survivals were reported in cancer patients treated at standard doses. The clinical impact of PK variations of etoposide high doses has never been explored in lymphoma patients. Patients and methods: The primary objective of LYMPK study was to prospectively assess the impact of etoposide PK parameters on outcomes in lymphoma patients receiving high-dose chemotherapy regimen (carmustine, cytarabine, etoposide and melphalan) followed by autologous stem cell transplant (ASCT). Individual etoposide PK parameters were estimated with a previously reported bi-compartment model using NONMEM® program. The impact of PK parameters on toxicity and survival was assessed using univariate/multivariate analyses. Results: A total of 91 patients with malignant lymphoma [non-Hodgkin's lymphoma (NHL): 79; Hodgkin's lymphoma: 12] at first line (n = 49) or relapse (n = 42) were enrolled in five centers. Large inter-individual variabilities in individual PK values were found for the same administration doses. In NHL patients, cumulative higher trough concentrations over the eight administrations of the first cycle (TotC min, categorized by the median 58.71 mg/L) had significant prognostic value regarding the 5-year progression-free survival (PFS: 73.6 vs 46.5 %, P = 0.015) and 5-year overall survival (OS: 74.0 vs 52.2 %, P = 0.034). Using a Cox model analysis, integrating disease settings (first line vs recurrent disease), simplified IPI and other prognostic factors, TotC min was the only significant independent prognostic factor influencing PFS, disease-specific survival and OS. Conclusion: This prospective study suggests survival of NHL patients treated with BEAM regimen and ASCT might be improved by increasing etoposide administration dose, or plasma concentration-based adjustment. © 2015 Springer-Verlag Berlin Heidelberg.

Lignet F.,University of Lyon | Lignet F.,Ecole Normale Superieure de Lyon | Benzekry S.,Tufts University | Wilson S.,Ecole Normale Superieure de Lyon | And 13 more authors.
Journal of Theoretical Biology | Year: 2013

Antiangiogenic drugs were developed with the aim to inhibit the formation of intratumoral blood vessels and in consequence the growth of solid tumors. As these drugs are generally combined with classical cytotoxic drugs in the treatment of cancer patients, finding the optimal combinations remains a complex challenge due to possible interactions of the antiangiogenic compound with the hemodynamic property of the treated tumor. To analyze this problem, we developed a multi-scale model of vascular tumor growth combining a molecular model of VEGF signaling pathways and a tissue model of the tumor expansion including the dynamics of cellular and tissue processes of tumor growth and response to treatments. We addressed the potential impact of antiangiogenic drug by defining a new index of vasculature quality which depends on the balance between stable and unstable vessels within the tumor mass. Our goal was to investigate the interactions between a chemotherapy and a antiangiogenic treatment, and, by simulating the model, to identify the optimal delay of chemotherapy delivery after the administration of the antiangiogenic compound. This theoretical analysis could be used in the future to optimize antiangiogenic drug delivery in preclinical settings and to facilitate the translation from preclinical to clinical studies. © 2012 Elsevier Ltd.

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