title: Factors Affecting the Upper Limit of the Methotrexate (MTX) CSF Levels Achievable in Children With Brain Tumors Treated With High-dose Intravenous MTX.
abstract: Little has been published in the medical literature on serum and cerebrospinal fluid (CSF) methotrexate (MTX) levels in children with brain tumors.
  
  
  
  Matched 24-hour serum and CSF MTX levels were studied after 113 treatments in 35 brain tumors patients.
  
  
  
  A correlation between the 24-hour serum levels of MTX and MTX dosage was observed after 113 treatments in all 35 patients (r=0.39, P<0.001) but no statistical difference was found between CSF MTX levels in the irradiated and nonirradiated groups (P=0.12). Nonirradiated children received a lower dose of MTX (12.3±4.8 cf 14.8±3.7) (P=0.002). The 24-hour MTX CSF levels of these 2 groups were also found to be different (the nonirradiated group 7.6±9.8 cf 12.5±0.15.3). Using the Levene test for variances we found that these variances were not equal and therefore we used the Welch test which resulted in a P-value of 0.04. However, when an analysis of covariance was performed looking at evidence of CSF disease and MTX dose the radiation difference was no longer significant (P=0.15). The 24-hour CSF MTX levels in children without evidence of active CSF disease were consistently lower than those with active disease using a mixed-model analysis (P=0.002). Although a 24-hour CSF MTX level of at least 1 μM was observed after infusions of >5 g/m MTX in previously irradiated children and after infusion of ≥10 g/m in nonirradiated children this difference did not reach statistical significance. CSF MTX levels plateau at doses of MTX 15 g/m putting in doubt the value of administering even higher doses of MTX.
  
  
  
  The 24-hour MTX CSF levels are higher in patients with active CSF disease. Doses of <10 gm/m in children with brain tumors may not achieve a guaranteed 24-hour MTX CSF level of 1 μM. There may be little value in a given dose of >15 g/m MTX as CSF levels plateau at this dose.
authors.affiliation: *Department of Pediatric Hematology-Oncology, Schneider Children's Medical Center of Israel ‡Recanati Center for Medicine and Research and Clinical Pharmacology Unit, Rabin Medical Center-Beilinson Hospital, Petach Tikva †Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Vered
authors.initials: V
authors.lastname: Shkalim Zemer
authors.forename: Helen
authors.initials: H
authors.lastname: Toledano
authors.forename: Shifra
authors.initials: S
authors.lastname: Ash
authors.forename: Eytan
authors.initials: E
authors.lastname: Cohen
authors.forename: Isaac
authors.initials: I
authors.lastname: Yaniv
authors.forename: Ian J
authors.initials: IJ
authors.lastname: Cohen
mesh_terms: D000293:Adolescent; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000134:cerebrospinal fluid / Q000188:drug therapy* / Q000401:mortality; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D008727:Methotrexate / Q000097:blood / Q000134:cerebrospinal fluid / Q000627:therapeutic use*; D055815:Young Adult
chemical_list: D000964:Antimetabolites, Antineoplastic; D008727:Methotrexate