title: The prognostic value of serum methotrexate area under curve in elderly primary CNS lymphoma patients.
abstract: Studies on pharmacokinetics and pharmacodynamics of high-dose methotrexate chemotherapy (HD-MTX) in elderly primary central nervous system lymphoma (PCNSL) patients are rare. MTX exposure time has recently been proposed as an outcome determining factor in PCNSL. We investigated 49 immunocompetent PCNSL patients (female N=30, male N=19, median age 73 years) who were treated according to HD-MTX-based protocols. A two-compartment pharmacokinetic model was used to describe the MTX clearance. Response to treatment was assessed by MRI. We used multivariable models to investigate the association between MTX exposure and tumor response as well as survival. Dose normalized MTX peak serum levels [C (max), μmol/L g] and dose normalized area under the curve [AUC(dn), μmol h/L g] were higher in females than in males, respectively [59.4 (f) vs. 48.1 (m), P<0.001; 373.2 (f) vs. 271.9 (m), P=0.008]. Increasing AUC was inversely correlated with tumor response. AUC values above 2,126 h μmol/L were independently associated with shorter overall and progression-free survival [hazard ratio (HR), 4.56, 95 % CI 1.74-11.94; HR 2.87, 95 % CI 1.18-7.00]. Exceedingly high MTX AUC levels can have a negative impact on progression-free and overall survivals in elderly PCNSL patients.
authors.affiliation: Department of Hematology and Oncology, University Medical Center Freiburg, Hugstetterstrasse 5, 79106 Freiburg, Germany.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Kasenda
authors.forename: Marcel
authors.initials: M
authors.lastname: Rehberg
authors.forename: Petra
authors.initials: P
authors.lastname: Thürmann
authors.forename: Melanie
authors.initials: M
authors.lastname: Franzem
authors.forename: Hendrik
authors.initials: H
authors.lastname: Veelken
authors.forename: Kristina
authors.initials: K
authors.lastname: Fritsch
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Schorb
authors.forename: Jürgen
authors.initials: J
authors.lastname: Finke
authors.forename: Dirk
authors.initials: D
authors.lastname: Lebiedz
authors.forename: Gerald
authors.initials: G
authors.lastname: Illerhaus
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic / Q000032:analysis / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D019540:Area Under Curve; D001682:Biological Availability; D016543:Central Nervous System Neoplasms / Q000097:blood / Q000175:diagnosis* / Q000188:drug therapy / Q000378:metabolism; D005260:Female; D006801:Humans; D008223:Lymphoma / Q000097:blood / Q000175:diagnosis* / Q000188:drug therapy / Q000378:metabolism; D008297:Male; D008727:Methotrexate / Q000032:analysis / Q000097:blood* / Q000493:pharmacokinetics / Q000627:therapeutic use; D008875:Middle Aged; D011237:Predictive Value of Tests; D011379:Prognosis; D016896:Treatment Outcome
chemical_list: D000964:Antimetabolites, Antineoplastic; D008727:Methotrexate