title: Delayed methotrexate excretion in infants and young children with primary central nervous system tumors and postoperative fluid collections.
abstract: OBJECTIVE
  High-dose methotrexate (HD-MTX) has been used to treat children with central nervous system tumors. Accumulation of MTX within pleural, peritoneal, or cardiac effusions has led to delayed excretion and increased risk of systemic toxicity. This retrospective study analyzed the association of intracranial post-resection fluid collections with MTX plasma disposition in infants and young children with brain tumors.
  
  
  METHODS
  Brain MRI findings were analyzed for postoperative intracranial fluid collections in 75 pediatric patients treated with HD-MTX and for whom serial MTX plasma concentrations (MTX) were collected. Delayed plasma excretion was defined as (MTX) ≥1 μM at 42 hours (h). Leucovorin was administered at 42 h and then every 6 h until (MTX) <0.1 μM. Population and individual MTX pharmacokinetic parameters were estimated by nonlinear mixed-effects modeling.
  
  
  RESULTS
  Fifty-eight patients had intracranial fluid collections present. Population average (inter-individual variation) MTX clearance was 96.0 ml/min/m² (41.1 CV %) and increased with age. Of the patients with intracranial fluid collections, 24 had delayed excretion; only 2 of the 17 without fluid collections (P < 0.04) had delayed excretion. Eleven patients had grade 3 or 4 toxicities attributed to HD-MTX. No significant difference was observed in intracranial fluid collection, total leucovorin dosing, or hydration fluids between those with and without toxicity.
  
  
  CONCLUSIONS
  Although an intracranial fluid collection is associated with delayed MTX excretion, HD-MTX can be safely administered with monitoring of infants and young children with intracranial fluid collections. Infants younger than 1 year may need additional monitoring to avoid toxicity.
authors.affiliation: Division of Neuro-oncology, Department of Oncology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Mail Stop 260, Memphis, TN, 38105, USA, karen.wright@stjude.org.
authors.forename: Karen D
authors.initials: KD
authors.lastname: Wright
authors.forename: John C
authors.initials: JC
authors.lastname: Panetta
authors.forename: Arzu
authors.initials: A
authors.lastname: Onar-Thomas
authors.forename: Wilburn E
authors.initials: WE
authors.lastname: Reddick
authors.forename: Zoltan
authors.initials: Z
authors.lastname: Patay
authors.forename: Ibrahim
authors.initials: I
authors.lastname: Qaddoumi
authors.forename: Alberto
authors.initials: A
authors.lastname: Broniscer
authors.forename: Giles
authors.initials: G
authors.lastname: Robinson
authors.forename: Frederick A
authors.initials: FA
authors.lastname: Boop
authors.forename: Paul
authors.initials: P
authors.lastname: Klimo
authors.forename: Deborah
authors.initials: D
authors.lastname: Ward
authors.forename: Amar
authors.initials: A
authors.lastname: Gajjar
authors.forename: Clinton F
authors.initials: CF
authors.lastname: Stewart
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects / Q000378:metabolism / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001202:Ascitic Fluid / Q000187:drug effects / Q000378:metabolism; D016543:Central Nervous System Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism / Q000601:surgery; D002675:Child, Preschool; D015331:Cohort Studies; D003131:Combined Modality Therapy / Q000009:adverse effects; D015536:Down-Regulation; D004322:Drainage; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D002955:Leucovorin / Q000627:therapeutic use*; D008297:Male; D008657:Metabolic Clearance Rate; D008727:Methotrexate / Q000009:adverse effects / Q000378:metabolism / Q000493:pharmacokinetics* / Q000627:therapeutic use; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D010490:Pericardial Effusion / Q000378:metabolism / Q000517:prevention & control; D016066:Pleural Effusion, Malignant / Q000378:metabolism / Q000517:prevention & control; D011183:Postoperative Complications / Q000378:metabolism / Q000517:prevention & control*; D012189:Retrospective Studies; D013353:Subdural Effusion / Q000378:metabolism / Q000517:prevention & control*
chemical_list: D000964:Antimetabolites, Antineoplastic; D018696:Neuroprotective Agents; D002955:Leucovorin; D008727:Methotrexate