Leukoencephalopathy, a Frequent Complication After High-Dose Methotrexate in Treatment of Osteosarcoma

Methotrexate-associated leukoencephalopathy is poorly documented in osteosarcoma. Since 2007, our institution has monitored osteosarcoma patients with sequential magnetic resonance imaging (MRI) and neuropsychological evaluations during treatment and follow-up.

We analyzed data from consecutive osteosarcoma patients younger than 25 years enrolled at Gustave Roussy in the OS2006 study (2007-2015) and treated with high-dose methotrexate (MTX) and etoposide-ifosfamide. Eligible patients received four or more MTX courses and at least one brain MRI. MTX-related neurotoxicity was defined as neurological symptoms attributed to MTX after excluding other causes.

MTX-related neurotoxicity occurred in seven (13%) of 53 eligible patients. Additionally, 12 had severe depression, nine reported attention/memory deficits, and 25 had headaches during MTX infusion. Acute symptoms resolved in all but one. Forty-nine patients had an MRI during treatment, and 47 after. Leukoencephalopathy was found in 44 (83%): Grade 1 in six, Grade 2 in 15, and Grade 3 in 23. Grade 2-3 leukoencephalopathy was more frequent in patients with severe depression (p = 0.02) and those receiving more than 12 MTX courses (p = 0.03); no association was found with age, sex, MTX-related neurotoxicity, or cognitive complaints. Among 24 patients with MRI ≥3 years post-treatment, 20 still showed leukoencephalopathy (12 Grade 1, eight Grade 2). Neurocognitive evaluations showed IQ scores consistent with norms, except for lower processing speed, which improved post-treatment. At last follow-up (median 8.5 years), most patients had integrated into school or work.

MTX-associated leukoencephalopathy is frequent in osteosarcoma, even in asymptomatic patients, and often persists after treatment. Serious neurocognitive sequelae appear uncommon, but long-term cognitive monitoring is essential to detect subtle deficits.