Methotrexate area under the curve is an important outcome predictor in patients with primary CNS lymphoma: A pharmacokinetic-pharmacodynamic analysis from the IELSG no. 20 trial

M. Joerger, A. D R Huitema, S. Krähenbühl, J. H M Schellens, T. Cerny, M. Reni, E. Zucca, F. Cavalli, A. J M Ferreri

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Abstract

Background: This analysis was initiated to define the predictive value of the area under the curve of high-dose methotrexate (AUCHD-MTX) in patients with primary central nervous system lymphoma (PCNSL).Patients and Methods:We included 55 patients with PCNSL and available pharmacokinetic (PK) data from the International Extranodal Lymphoma Study Group (IELSG) no. 20 trial, randomised to HD-MTX (n=30) or HD-MTX and high-dose cytarabine (HD-AraC) (n=25). Individual AUCHD-MTX from population PK analysis was tested on drug toxicity and clinical outcome using multivariate logistic regression analysis and Cox hazards modelling.results: AUC HD-MTX, the IELSG score and treatment group were significant predictors for treatment response (complete or partial) in the adjusted model. The AUCHD-MTX did not predict toxicity, with the exception of liver toxicity and neutropaenia. A high AUC HD-MTX was associated with better event-free survival (EFS) (P=0.01) and overall survival (OAS) (P=0.02). Both the AUCHD-MTX and the IELSG score were significant predictors of EFS and OAS in the adjusted model, with a hazard ratio of 0.82 and 0.73, respectively, per 100μ mol l-1 h-1 increase in AUC HD-MTX. Conclusions Individualised dosing of HD-MTX might have the potential to improve clinical outcome in patients with PCNSL, even when administered concurrently with HD-AraC. In the future, this could be carried out by using first-cycle PK modelling with determination of potential dose adaptations for later cycles using Bayesian analysis.

Original languageEnglish
Pages (from-to)673-677
Number of pages5
JournalBritish Journal of Cancer
Volume102
Issue number4
DOIs
Publication statusPublished - Feb 2010

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Keywords

  • CNS lymphoma
  • Cytarabine
  • High-dose chemotherapy
  • Methotrexate
  • Pharmacokinetics

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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