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
Open Access
- 2 February 2010
- journal article
- research article
- Published by Springer Science and Business Media LLC in British Journal of Cancer
- Vol. 102 (4), 673-677
- https://doi.org/10.1038/sj.bjc.6605559
Abstract
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). 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. AUCHD-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 AUCHD-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 100 μmol l−1 h−1 increase in AUCHD-MTX. 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.Keywords
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