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. 2015 Jan;75(1):27-35.
doi: 10.1007/s00280-014-2614-6. Epub 2014 Oct 24.

Delayed Methotrexate Excretion in Infants and Young Children With Primary Central Nervous System Tumors and Postoperative Fluid Collections

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Delayed Methotrexate Excretion in Infants and Young Children With Primary Central Nervous System Tumors and Postoperative Fluid Collections

Karen D Wright et al. Cancer Chemother Pharmacol. .
Free PMC article


Purpose: 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.

Conflict of interest statement

Conflicts: The authors have no conflicts of interest to disclose and maintain control of all primary data. To that end, the journal may review data as requested.


Figure 1
Figure 1
(Left) T2-weighted image as acquired during the MR examination demonstrating bilateral extra-axial fluid collections (subdural hygromas) over cerebral hemispheres and ventriculomegaly. (Right) T2-weighted image after extraction of the brain and surrounding fluid. The segmented fluid volume is shown in orange and demonstrates the exclusion of CSF within the ventricles
Figure 2
Figure 2
Variation in methotrexate (MTX) clearance (a) and volume of distribution with age (b)
Figure 3
Figure 3
Relation between MTX intercompartmental clearance term (Q) and intracranial fluid volume

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