Methotrexate-induced neurotoxicity in oncology: Current issues for a classic drug

Methotrexate (MTX) is an antimetabolite with immunosuppressive and antineoplastic properties extensively used in cancer treatment. It is administered through various routes, including intravenous and intrathecal. MTX inhibits the dihydrofolate reductase, thereby disrupting folic acid metabolism and impending DNA synthesis. Despite its efficacy, MTX administration can result in significant toxicity, affecting multiple organs and leading to potential side effects like myelosuppression, hepatotoxicity, renal failure, mucositis and neurotoxicity. MTX-induced neurotoxicity is a critical problem, with manifestations varying from hours to years post-administration, ranging from transient and reversible to severe presentations. Several risk factors may contribute to MTX-induced neurotoxicity, including genetic predisposition, drug interactions, renal impairment and concurrent radiotherapy. Management strategies in preventing and mitigating neurotoxicity are based on supportive measures such as hydration, leucovorin rescue and the use of glucarpidase. This review focusses on the neurotoxic effects of MTX, a global health issue in the growing cancer population.