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In the course of MTX therapy, a variety of disorders can occur, resulting from either increased patient susceptibility to toxicity or excessive administration. The clinical manifestations of MTX toxicity include stomatitis, esophagitis, kidney failure, myelosuppression, hepatitis, and central nervous system dysfunction. In a group of 23 patients who received 45 courses of high-dose MTX therapy with leucovorin rescue, the most commonly observed signs included increased aspartate aminotransferase (AST) or alanine aminotransferase (ALT) (81%), nausea and vomiting (66%), mucositis (33%), dermatitis (18%), leukopenia (11%), thrombocytopenia (9%), and creatinine elevation (7%).55
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Nausea and vomiting, considered rare after low-dose cancer therapy (40 mg/m2), typically begin 2 to 4 hours after high-dose therapy (1000 mg/m2)and last for about 6 to 12 hours. Mucositis, characterized by mouth soreness, stomatitis, or diarrhea, usually occurs in the first week of therapy, continues to evolve in the second week of therapy, and can last for 4 to 7 days. Other GI effects resulting from MTX therapy include pharyngitis, anorexia, GI hemorrhage, and toxic megacolon.6 Hepatocellular toxicity, as identified as increased AST (>1000 IU/L) or ALT (>1000 IU/L), and hyperbilirubinemia, can occur with both acute and chronic therapy.47,49 It is usually associated with high dose regimens. Laboratory abnormalities improve within 1 to 2 weeks of discontinuation of MTX. The mechanism is incompletely understood, but toxicity is attributed to reduced liver folate stores.7 Factors associated with hepatotoxicity include sustained high serum concentrations, increased cumulative dosages, chronic therapy, and host factors such as an increase in age, obesity, diabetes, and alcoholism.71
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Pancytopenia usually occurs within the first 2 weeks after an acute exposure. Pancytopenia can also occur with chronic MTX therapy for rheumatoid arthritis and psoriasis.16,40,47,57
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When used in low-dose IV doses of 40 to 60 mg/m2, MTX is not associated with appreciable nephrotoxicity. However, at doses greater than 5000 mg/m2 (~130 mg/kg for an adult), several investigators report severe kidney damage, with oliguria, azotemia, and kidney failure.8 The kidney function can normalize over time. Patients at risk for nephrotoxicity include elderly adults; those with underlying kidney disease defined as a glomerular filtration rate of less than 50 mL/min; and those who receive concurrent drug therapy that can delay MTX excretion, which includes xenobiotics that reduce renal blood flow such as NSAIDs, nephrotoxins such as cisplatin and the aminoglycosides, and weak organic acids such as salicylates and piperacillin that inhibit renal secretion.32,65
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The neurologic complications associated with either high-dose systemic MTX therapy or intrathecal administration are the most consequential manifestations. The incidence of neurologic toxicity from high-dose MTX therapy is approximately 5% to 15%.35 The manifestations of toxicity usually occur from hours to days after the initiation of therapy and include hemiparesis, paraparesis, quadraparesis, seizures, and dysreflexia.35,46,66,69 These events are reversible to varying degrees.2 Clinical findings occurring within several hours (usually within 12 hours) of therapy are attributed to chemical arachnoiditis, and they include acute onset of fever, meningismus, pleocytosis, and increased cerebrospinal fluid (CSF) protein concentration.28 Leukoencephalopathy is associated with the onset of behavioral disorders and progressive dementia from months to years after treatment and is irreversible, although manifestations presenting soon after treatment can be reversible depending on the extent of involvement.5,74 Patients with increased age and prior cranial radiation are at increased risk for this disorder.23 Patients with leukoencephalopathy have findings consistent with edema and demyelination or necrosis of the white matter on computed tomography (CT) and magnetic resonance imaging (MRI) of the brain.5