Preventing and Managing Toxicities of High-Dose Methotrexate

• Type of Material: Article
• Authors: Scott C. Howard, University of Memphis; John McCormick, St. Jude Children’s Research Hospital; Ching-Hon Pui, St. Jude Children’s Research Hospital; Randall K. Buddington, University of Memphis; R Donald Harvey, Emory University
• Language: English
• Date: 2016-12-01
• Publisher: AlphaMed Press: Oncologist
• Publication Version: Final Published Version
• Copyright Statement: ©AlphaMed Press
• Final Published Version (URL): http://dx.doi.org/10.1634/theoncologist.2015-0164
• Title of Journal or Parent Work: Oncologist
• ISSN: 1083-7159
• Volume: 21
• Issue: 12
• Start Page: 1471
• End Page: 1482
• Grant/Funding Information: We thank Thomas King, M.P.H. (BTG International Inc.) for preparation of key figures and editorial assistance. Funding was provided in part by the National Institutes of Health Cancer Center Support Core Grant (CA-21765) and the American Lebanese Syrian Associated Charities. Dr. Pui is an American Cancer Society professor.
• Keywords: PEDIATRIC-ONCOLOGY-GROUP; Glucarpidase; GLUCARPIDASE CARBOXYPEPTIDASE G2; ACUTE LYMPHOBLASTIC-LEUKEMIA; LEUCOVORIN RESCUE; PRIMARY CNS LYMPHOMA; DRUG-DRUG INTERACTION; INDUCED ORAL MUCOSITIS; LONG-TERM; Methotrexate; HIGH-FLUX HEMODIALYSIS; Acute kidney injury; Science & Technology; Pharmacokinetics; Life Sciences & Biomedicine; INDUCED RENAL DYSFUNCTION; High-dose methotrexate; Oncology; Leucovorin
• Research Categories: Health Sciences, Oncology; Health Sciences, General

Abstract

High-dose methotrexate (HDMTX), defined as a dose higher than 500 mg/m2, is used to treat a range of adult and childhood cancers. Although HDMTX is safely administered to most patients, it can cause significant toxicity, including acute kidney injury (AKI) in 2%-12% of patients. Nephrotoxicity results from crystallization of methotrexate in the renal tubular lumen, leading to tubular toxicity. AKI and other toxicities of high-dose methotrexate can lead to significant morbidity, treatment delays, and diminished renal function. Risk factors for methotrexate-associated toxicity include a history of renal dysfunction, volume depletion, acidic urine, and drug interactions. Renal toxicity leads to impaired methotrexate clearance and prolonged exposure to toxic concentrations, which further worsen renal function and exacerbate nonrenal adverse events, including myelosuppression, mucositis, dermatologic toxicity, and hepatotoxicity. Serum creatinine, urine output, and serum methotrexate concentration are monitored to assess renal clearance, with concurrent hydration, urinary alkalinization, and leucovorin rescue to prevent and mitigate AKI and subsequent toxicity. When delayed methotrexate excretion or AKI occurs despite preventive strategies, increased hydration, high-dose leucovorin, and glucarpidase are usually sufficient to allow renal recovery without the need for dialysis. Prompt recognition and effective treatment of AKI and associated toxicities mitigate further toxicity, facilitate renal recovery, and permit patients to receive other chemotherapy or resume HDMTX therapy when additional courses are indicated. IMPLICATIONS FOR PRACTICE: High-dose methotrexate (HDMTX), defined as a dose higher than 500 mg/m2, is used for a range of cancers. Although HDMTX is safely administered to most patients, it can cause significant toxicity, including acute kidney injury (AKI), attributable to crystallization of methotrexate in the renal tubular lumen, leading to tubular toxicity. When AKI occurs despite preventive strategies, increased hydration, high-dose leucovorin, and glucarpidase allow renal recovery without the need for dialysis. This article, based on a review of the current associated literature, provides comprehensive recommendations for prevention of toxicity and, when necessary, detailed treatment guidance to mitigate AKI and subsequent toxicity.