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A pharmacologically-based approach to high dose methotrexate administration to investigate nephrotoxicity and acute kidney injury biomarkers in children and adolescents with newly diagnosed osteosarcoma

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Abstract

Purpose

High dose methotrexate (HDMTX) acute kidney injury (AKI) results in prolonged hospitalization and treatment delays. Using a pharmacologically-based approach, HDMTX was administered with standard combination therapy to patients with osteosarcoma; nephrotoxicity was assessed.

Methods

Patients were randomized by cycle to 4 h or 12 h HDMTX (12 g/m2) infusions administered with hydration, alkalization and leucovorin rescue. Urinalysis, AKI biomarkers, and estimated glomerular filtration rate using serum creatinine or cystatin C (GFRCr or GFRcysC) were obtained. Serum and urine methotrexate concentrations [MTX] were measured.

Results

Patients (n = 12), median (range) age 12.4 (5.7–19.2) years were enrolled; 73 MTX infusions were analyzed. Median (95% Confidence Interval) serum and urine [MTX] were 1309 (1190, 1400) µM and 16.4 (14.7, 19.4) mM at the end of 4 h infusion and 557 (493, 586) µM and 11.1 (9.9, 21.1) mM at the end of 12 h infusion. Time to serum [MTX] < 0.1 µM was 83 (80.7, 90.7) h and 87 (82.8, 92.4) h for 4 and 12 h infusions. GFRCr was highly variable, increased after cisplatin, and exceeded 150 ml/min/1.73 m2. GFRcysC was less variable and decreased at the end of therapy. AKI biomarkers were elevated indicating acute tubular dysfunction, however, did not differ between 4 and 12 h infusions. Radiographic and histological response were similar for patients receiving 4 h or 12 h infusions; the median percent tumor necrosis was > 95%.

Conclusions

Reducing peak serum and urine MTX concentration by prolonging the infusion duration did not alter risk of acute kidney injury. GFRcysC was decreased at the end of therapy. Proteinuria and elevations in AKI biomarkers indicate that direct tubular damage contributes to HDMTX nephrotoxicity.

Clinical Trial

NCT01848457.

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Acknowledgements

This work was funded by Gateway for Cancer Research Foundation and Alex's Lemonade Stand Center of Excellence.

Funding

This clinical trial was funded by the Gateway for Cancer Research and Alex's Lemonade Stand Center of Excellence.

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Authors and Affiliations

  1. Children’s Hospital of Philadelphia, Philadelphia, PA, 19104, USA

    Elizabeth Fox, Christine Busch, Alexander DeBernardo, Blair Segers, Joseph Gottschalk, Richard Womer, Naomi Balamuth, Rochelle Bagatell & Frank Balis

  2. St Jude Children’s Research Hospital, Memphis, TN, 38105, USA

    Elizabeth Fox & Blair Segers

  3. School of Dentistry, University of Texas Health Science Center, Houston, TX, USA

    Alexander DeBernardo

  4. University of New England College of Osteopathic Medicine, Biddeford, ME, USA

    Joseph Gottschalk

Authors
  1. Elizabeth Fox
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  2. Christine Busch
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  3. Alexander DeBernardo
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  4. Blair Segers
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  5. Joseph Gottschalk
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  6. Richard Womer
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  9. Frank Balis
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Correspondence to Elizabeth Fox.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Fox, E., Busch, C., DeBernardo, A. et al. A pharmacologically-based approach to high dose methotrexate administration to investigate nephrotoxicity and acute kidney injury biomarkers in children and adolescents with newly diagnosed osteosarcoma. Cancer Chemother Pharmacol 87, 807–815 (2021). https://doi.org/10.1007/s00280-021-04248-8

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  • DOI: https://doi.org/10.1007/s00280-021-04248-8

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