title: 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.
abstract: BACKGROUND
  This analysis was initiated to define the predictive value of the area under the curve of high-dose methotrexate (AUC(HD-MTX)) in patients with primary central nervous system lymphoma (PCNSL).
  
  
  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 AUC(HD-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 AUC(HD-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 AUC(HD-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 micromol 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.
authors.affiliation: Department of Oncology and Hematology, Cantonal Hospital, Switzerland. markus.joerger@kssg.ch
authors.forename: M
authors.initials: M
authors.lastname: Joerger
authors.forename: A D R
authors.initials: AD
authors.lastname: Huitema
authors.forename: S
authors.initials: S
authors.lastname: Krähenbühl
authors.forename: J H M
authors.initials: JH
authors.lastname: Schellens
authors.forename: T
authors.initials: T
authors.lastname: Cerny
authors.forename: M
authors.initials: M
authors.lastname: Reni
authors.forename: E
authors.initials: E
authors.lastname: Zucca
authors.forename: F
authors.initials: F
authors.lastname: Cavalli
authors.forename: A J M
authors.initials: AJ
authors.lastname: Ferreri
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000627:therapeutic use; D019540:Area Under Curve; D016543:Central Nervous System Neoplasms / Q000175:diagnosis* / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality; D003561:Cytarabine / Q000008:administration & dosage / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007391:International Cooperation; D008223:Lymphoma / Q000175:diagnosis* / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008875:Middle Aged; D011379:Prognosis; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D000964:Antimetabolites, Antineoplastic; D003561:Cytarabine; D008727:Methotrexate