Abstract C129: Relation between long-term blood pharmacokinetics, pharmacogenomics, and severe neurotoxicity in patients undergoing an oxaliplatin-based regimen
Authors: Bastian Gérard , Chibaudel Benoist , Maindrault-Goebel Frederique , Garcia-Hejl Carine , Bonnetain Franck , Maillard Emilie , Rebischung Christine , Hebbar Mohamed , André Thierry , Gil-Delgado Marian , Collery Philippe , Yataghene Youssef , Maral Jean , de Gramont Aimery 
Published: June 2012

Abstract
The aim of the study was to investigate the residual blood level of O before each cycle of various oxaliplatin (O) based protocols, and to explore its predictive value for potential occurrence of a severe neurotoxicity.
Methods: Between 11/2005 and 06/2008, 220 Pts were included in a prospective cohort, in 7 French centers. Patients received a minimum of 7 cycles of O.
Blood samples were taken before each cycle with a maximum of 12 cycles. In parallel neurotoxicity was assessed by the modified Levi score (grade 0 to 3) and by the Von Frey filament exam. Saliva was collected before the first cycle for genomics analysis. The O concentration was obtained by Atomic Absorption Spectrometry assay after nitric digestion of total blood. Polymorphism of different targets were investigated (carrier proteins: MRP2, OCT1, OCT2, GSTP1, adducts repair system: ERCC1, ERCC2). Time to first severe neurotoxicity occurrence (TTSN Events: Grade 2 or3) was estimated using Kaplan-Meier. Predictive value of severe neurotoxicity was explored using univariate and multivariate logistic or Cox regressions. Harrel C index was produced.
Results: 206 pts with gastro-intestinal cancer had, at the time of analysis, completed follow-up and 201 pts (91.3%) were eligible for pharmacokinetics. (85%) received FOLFOX regimen (85mg/m2every 2 weeks), the others GEMOX or XELOX (100mg/m2 every 3 weeks). The mean total dose of O received for all pts was 1.18 ± 0.4 g.
After cycle 1, 2 and 10, median residual level of O was respectively 0.31 mg/L, 0.43 mg/L and 0.60 mg/L. The maximal concentration was obtained between cycle 5 and cycle 9. Respectively 89 Pts (44%) and 15 pts (7%) had a Gr2 and a Gr3 neurotoxicity. Median time TTSN was 141 days (95% CI: 132 – 161). O concentration before 2nd cure (HR = 1.39, p &lt; 0.0001) is associated with TTSN (cure N°2 for Gr0 and Gr1, cure N° 7 for Gr2 and Gr3) but not with the frequency. Multivariate logistic and Cox analyses confirmed these results.
Conclusions: 1. The mean residual blood level of O before the second cure is correlated with the occurrence of Gr2 or Gr3 neurotoxicity (p Mann-Whitney = 0.0007)
2. The residual blood level of O before the second O cure is correlated with the delay of occurrence of a Gr2 or Gr3 neurotoxicity in patients receiving an O based-regimen (Harrel C=0.54, p=0.021). Further statistical analyses will be done to analyse the data from the Von Frey filaments and the gene polymorphism and will be presented at the meeting. An O posology adaptation or infusion duration modification based on Platinum residual level of cure 1 have to be considered in future clinical trial in order to avoid severe Gr2 or Gr3 neurotoxicity.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C129.