Farina Hellmann (1), Gareth Veal (2), Georg Hempel (1)
(1) Department of Pharmaceutical and Medical Chemistry, University of Muenster, Germany; (2) Northern Institute for Cancer Research, Newcastle University, United Kingdom
Introduction: Ewing sarcoma is a very aggressive bone tumour, which often occurs in adolescents or young adulthood [1]. The incidence of treatment-associated toxicity varies significantly between children, adolescents and adults [2]. These toxicities are often worse in young children and reduce with advancing age. Furthermore, survival rates differ between age groups, with younger patients generally having a better outcome as compared to older patients [3]. The standard induction therapy of Ewing sarcoma patients includes the drugs vincristine (V), ifosfamide (I), doxorubicin (D), etoposide (E) and cyclophosphamide (C). Population pharmacokinetic (popPK) modelling of these drugs can help to further elucidate age-dependent differences in toxicity and survival of Ewing sarcoma patients and therefore potentially improve therapy.
Objectives:
- Investigation of a possible age-dependency in the clearance of vincristine, ifosfamide, doxorubicin, etoposide and cyclophosphamide in Ewing sarcoma patients
- Analysis of possible predictors of treatment-associated toxicity in Ewing sarcoma patients such as age and gender
- Development of improved strategies regarding toxicity and survival for the treatment of Ewing sarcoma patients
Methods: The Northern Institute for Cancer Research (NICR) at Newcastle University is conducting a clinical pharmacology study to investigate differences in drug disposition between Ewing sarcoma patients of different ages and early drug toxicity in this patient population (short title: PK 2013 01; EUDRACT Number: 2013-000052-17). In total, 120 Ewing sarcoma patients treated with standard dose induction chemotherapy (VIDE or VDC/IE), will be recruited to the study. Blood samples are collected from patients at defined time points for quantification of plasma drug concentrations on a single course of VIDE or VDC/IE treatment. So far, data obtained from over 60 patients are available for these drugs for the development of popPK models using NONMEM®.
Results: Appropriate popPK models have been developed and the effects of covariates including age and gender on the PK parameters have been analysed. Based on the preliminary analysis, there are no differences in the PK of vincristine, ifosfamide, doxorubicin and etoposide with age or gender. Furthermore, the PK parameters of the different drugs are tested for potential correlations between drugs. In this patient population, vincristine clearance correlates significantly with doxorubicin clearance (r=0.407, p=0.009).
Conclusions: Preliminary data suggest that there are no differences in the PK of vincristine, ifosfamide, doxorubicin and etoposide with age or gender. Once data are available for all patients the models will be revised and both the covariate analysis and the potential relations between PK parameters of the different drugs will be renewed. These analyses could help to further elucidate the differences in toxicity and survival of Ewing sarcoma patients and therefore potentially serve to develop strategies to improve future therapy.
References:
[1] Lawlor E R, Sorensen P H (2015) Twenty Years on: What Do We Really Know about Ewing Sarcoma and What Is the Path Forward? Crit Rev Oncog 20(3-4): 155–171
[2] Juergens C, Weston C, Lewis I et al (2006) Safety assessment of intensive induction with vincristine, ifosfamide, doxorubicin, and etoposide (VIDE) in the treatment of Ewing tumors in the EURO-E.W.I.N.G. 99 clinical trial. Pediatr Blood Cancer 47(1): 22–29
[3] Ladenstein R, Pötschger U, Le Deley M C et al (2010) Primary disseminated multifocal Ewing sarcoma: results of the Euro-EWING 99 trial. J Clin Oncol 28(20): 3284–3291
Reference: PAGE () Abstr 9380 [www.page-meeting.org/?abstract=9380]
Poster: Drug/Disease Modelling - Oncology