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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.

Joerger M, Huitema AD, Krähenbühl S, Schellens JH, Cerny T, Reni M, Zucca E, Cavalli F, Ferreri AJ - Br. J. Cancer (2010)

Bottom Line: 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).

View Article: PubMed Central - PubMed

Affiliation: Department of Oncology and Hematology, Cantonal Hospital, Switzerland. markus.joerger@kssg.ch

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.

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Related in: MedlinePlus

Goodness-of-fit plots of the final population pharmacokinetic model (all data log-transformed, drug concentration as μmol l−1). Observed MTX concentrations vs model predictions (A) and vs individual Bayesian predictions (B).
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fig1: Goodness-of-fit plots of the final population pharmacokinetic model (all data log-transformed, drug concentration as μmol l−1). Observed MTX concentrations vs model predictions (A) and vs individual Bayesian predictions (B).

Mentions: The inclusion of patient age, BSA or concurrent administration of HD-AraC did not improve the model fit. The goodness-of-fit plots supported a good data fit of the final model (Figure 1).


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.

Joerger M, Huitema AD, Krähenbühl S, Schellens JH, Cerny T, Reni M, Zucca E, Cavalli F, Ferreri AJ - Br. J. Cancer (2010)

Goodness-of-fit plots of the final population pharmacokinetic model (all data log-transformed, drug concentration as μmol l−1). Observed MTX concentrations vs model predictions (A) and vs individual Bayesian predictions (B).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2837574&req=5

fig1: Goodness-of-fit plots of the final population pharmacokinetic model (all data log-transformed, drug concentration as μmol l−1). Observed MTX concentrations vs model predictions (A) and vs individual Bayesian predictions (B).
Mentions: The inclusion of patient age, BSA or concurrent administration of HD-AraC did not improve the model fit. The goodness-of-fit plots supported a good data fit of the final model (Figure 1).

Bottom Line: 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).

View Article: PubMed Central - PubMed

Affiliation: Department of Oncology and Hematology, Cantonal Hospital, Switzerland. markus.joerger@kssg.ch

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.

Show MeSH
Related in: MedlinePlus