Methotrexate is eliminated primarily unchanged in the urine.3 This means that a patient’s renal function is a critical factor in predicting the magnitude and duration of methotrexate levels following high-dose administration.
Very high levels of methotrexate may lead to precipitation of the drug in the renal tubules. This can cause methotrexate-induced nephrotoxicity, with increased serum creatinine and the potential for acute renal failure.1,3 Once methotrexate-induced nephrotoxicity occurs, a vicious cycle is initiated. Nephrotoxicity with impaired renal function leads to even more delayed clearance of methotrexate, with further impairment of renal function and high sustained methotrexate levels in the blood.
Severe toxicity may occur when the renal clearance of high-dose methotrexate is delayed. This often manifests as myelosuppression and mucositis, with potentially fatal outcomes.1,6 The incidence of severe toxicity resulting from methotrexate-induced nephrotoxicity has been reported to be 1.8%, with a mortality rate in these patients of 4.4%.7
Conventional treatment options for delayed methotrexate clearance include high doses of leucovorin rescue, intravenous hydration with urinary alkalinization to reduce the likelihood that methotrexate will precipitate in the renal tubules, and in severe cases, hemodialysis.1,3
Use of HD-MTX in Cancer
The 4 cancers that incorporate high-dose methotrexate into standard treatment regimens are osteosarcoma (also known as osteogenic sarcoma), acute lymphoblastic leukemia (or ALL) (also known as acute lymphocytic leukemia), some aggressive subtypes of non-Hodgkin lymphoma (or NHL), and primary central nervous system lymphoma.2
Other cancer types that may be treated with high-dose methotrexate therapy include chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL), Burkitt lymphoma, lymphoblastic lymphoma, AIDS-related B-cell lymphoma, peripheral T-cell lymphoma, adult T-cell leukemia/lymphoma, and leptomeningeal metastases (from breast cancer or lymphoma).4,5
1. Chabner BA, Allegra CJ. Antifolates. In: Chabner BA, Longo DL, eds. Cancer Chemotherapy and Biotherapy: Principles and Practice. 5th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2011:109-138.
2. Ackland SP, Schilsky RL. High-dose methotrexate: a critical reappraisal. J Clin Oncol. 1987;5(12):2017-2031.
3. Methotrexate injection [package insert]. Bedford, OH: Bedford Laboratories Inc; 2005.
4. National Comprehensive Cancer Network (NCCN). Clinical practice guidelines in oncology: central nervous system cancer v.1.2012. NCCN Web site. www.nccn.org/professionals/physician_gls/pdf/cns.pdf. Updated February 22, 2012. Accessed February 22, 2012.
5. National Comprehensive Cancer Network (NCCN). Clinical practice guidelines in oncology: non-Hodgkin’s lymphoma v.2.2012. NCCN Web site. www.nccn.org/professionals/physician_gls/pdf/nhl.pdf. Updated February 23, 2012. Accessed February 23, 2012.
6. Buchen S, Ngampolo D, Melton RG, et al. Carboxypeptidase G2 rescue in patients with methotrexate intoxication and renal failure. Br J Cancer. 2005;92:480-487.
7. Widemann BC, Adamson PC. Understanding and managing methotrexate nephrotoxicity. Oncologist. 2006;11:694-703.
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