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Delayed methotrexate excretion in infants and young children with primary central nervous system tumors and postoperative fluid collections

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Abstract

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.

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Acknowledgments

This work was supported in part by the National Cancer Institute Grants CA21765, CA098543, CA096832, CA154619, and CA081457; Musicians Against Childhood Cancer; the Noyes Brain Tumor Foundation; and the American Lebanese Syrian Associated Charities.

Conflict of interest

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

Ethical Standards

The study was approved by the St. Jude Institutional Review Board and therefore performed with the ethical standards laid down in the 1964 Declaration of Helsinki and it subsequent amendments. All involved patients’ parents gave their informed consents prior to the child’s inclusion in the study.

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Authors and Affiliations

  1. 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 D. Wright, Ibrahim Qaddoumi, Alberto Broniscer, Giles Robinson & Amar Gajjar

  2. Department of Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, TN, USA

    John C. Panetta & Clinton F. Stewart

  3. Department of Biostatistics, St. Jude Children’s Research Hospital, Memphis, TN, USA

    Arzu Onar-Thomas

  4. Department of Radiological Sciences, St. Jude Children’s Research Hospital, Memphis, TN, USA

    Wilburn E. Reddick & Zoltan Patay

  5. Department of Neurosurgery, Le Bonheur Children’s Medical Center, Memphis, TN, USA

    Frederick A. Boop & Paul Klimo Jr.

  6. Department of Pharmaceutical Services, St. Jude Children’s Research Hospital, Memphis, TN, USA

    Deborah Ward

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  1. Karen D. Wright
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Correspondence to Karen D. Wright.

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Wright, K.D., Panetta, J.C., Onar-Thomas, A. et al. Delayed methotrexate excretion in infants and young children with primary central nervous system tumors and postoperative fluid collections. Cancer Chemother Pharmacol 75, 27–35 (2015). https://doi.org/10.1007/s00280-014-2614-6

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  • DOI: https://doi.org/10.1007/s00280-014-2614-6

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