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

Br J Cancer. 2010 Feb 16;102(4):673-7. doi: 10.1038/sj.bjc.6605559. Epub 2010 Feb 2.

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).

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 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.

Publication types

  • Multicenter Study
  • Randomized Controlled Trial

MeSH terms

  • Antimetabolites, Antineoplastic / administration & dosage
  • Antimetabolites, Antineoplastic / therapeutic use
  • Area Under Curve
  • Central Nervous System Neoplasms / diagnosis*
  • Central Nervous System Neoplasms / drug therapy*
  • Central Nervous System Neoplasms / metabolism
  • Central Nervous System Neoplasms / mortality
  • Cytarabine / administration & dosage
  • Cytarabine / pharmacokinetics
  • Dose-Response Relationship, Drug
  • Female
  • Humans
  • International Cooperation
  • Lymphoma / diagnosis*
  • Lymphoma / drug therapy*
  • Lymphoma / metabolism
  • Lymphoma / mortality
  • Male
  • Methotrexate / administration & dosage
  • Methotrexate / pharmacokinetics*
  • Middle Aged
  • Prognosis
  • Survival Analysis
  • Treatment Outcome

Substances

  • Antimetabolites, Antineoplastic
  • Cytarabine
  • Methotrexate