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Pediatric Oncology

Understanding and Managing Methotrexate Nephrotoxicity

^a Pediatric Oncology Branch, National Cancer Institute, Bethesda, Maryland, USA; ^b Division of Clinical Pharmacology & Therapeutics, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA

Key Words. Methotrexate toxicity • Renal dysfunction • Carboxypeptidase-G₂ • Hemodialysis • Hemoperfusion • Thymidine • High-dose chemotherapy • Rescue agents

Correspondence: Brigitte C. Widemann, M.D., Pediatric Oncology Branch, National Cancer Institute, 10 Center Drive, Building 10 CRC Room 1-5750, Bethesda, Maryland 20892-1101, USA. Telephone: 301-496-2783; Fax: 301-480-2308; e-mail: widemanb{at}mail.nih.gov

Methotrexate (MTX) is one of the most widely used anti-cancer agents, and administration of high-dose methotrexate (HDMTX) followed by leucovorin (LV) rescue is an important component in the treatment of a variety of childhood and adult cancers. HDMTX can be safely administered to patients with normal renal function by the use of alkalinization, hydration, and pharmacokinetically guided LV rescue. Despite these measures, HDMTX-induced renal dysfunction continues to occur in approximately 1.8% of patients with osteosarcoma treated on clinical trials. Prompt recognition and treatment of MTX-induced renal dysfunction are essential to prevent potentially life-threatening MTX-associated toxicities, especially myelosuppression, mucositis, and dermatitis. In addition to conventional treatment approaches, dialysis-based methods have been used to remove MTX with limited effectiveness. More recently carboxypeptidase-G₂ (CPDG₂), a recombinant bacterial enzyme that rapidly hydrolyzes MTX to inactive metabolites, has become available for the treatment of HDMTX-induced renal dysfunction. CPDG₂ administration has been well tolerated and resulted in consistent and rapid reductions in plasma MTX concentrations by a median of 98.7% (range, 84%–99.5%). The early administration of CPDG₂ in addition to LV may be beneficial for patients with MTX-induced renal dysfunction and significantly elevated plasma MTX concentrations.

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