title: Neurocognitive and neuroradiologic central nervous system late effects in children treated on Pediatric Oncology Group (POG) P9605 (standard risk) and P9201 (lesser risk) acute lymphoblastic leukemia protocols (ACCL0131): a methotrexate consequence? A report from the Children's Oncology Group.
abstract: Concerns about long-term methotrexate (MTX) neurotoxicity in the 1990s led to modifications in intrathecal (IT) therapy, leucovorin rescue, and frequency of systemic MTX administration in children with acute lymphoblastic leukemia. In this study, neurocognitive outcomes and neuroradiologic evidence of leukoencephalopathy were compared in children treated with intense central nervous system (CNS)-directed therapy (P9605) versus those receiving fewer CNS-directed treatment days during intensive consolidation (P9201). A total of 66 children from 16 Pediatric Oncology Group institutions with "standard-risk" acute lymphoblastic leukemia, 1.00 to 9.99 years at diagnosis, without evidence of CNS leukemia at diagnosis were enrolled on ACCL0131: 28 from P9201 and 38 from P9605. Magnetic resonance imaging scans and standard neuropsychological tests were performed ≥2.6 years after the end of treatment. Significantly more P9605 patients developed leukoencephalopathy compared with P9201 patients (68%, 95% confidence interval 49%-83% vs. 22%, 95% confidence interval 5%-44%; P=0.001) identified as late as 7.7 years after the end of treatment. Overall, 40% of patients scored <85 on either Verbal or Performance IQ. Children on both studies had significant attention problems, but P9605 children scored below average on more neurocognitive measures than those treated on P9201 (82%, 14/17 measures vs. 24%, 4/17 measures). This supports ongoing concerns about intensive MTX exposure as a major contributor to CNS late effects.
authors.affiliation: *Department of Neurology, University at Buffalo School of Medicine ∥Department of Pediatrics, Roswell Park Cancer Institute, Buffalo, NY †Department of Pediatrics, University of Miami Miller School of Medicine and Holtz Children's Hospital, Miami, FL ‡Statistics and Data Center, Children's Oncology Group, Monrovia, CA §Department of Radiological Sciences, St Jude Children's Research Hospital, Memphis, TN ¶Department of Pediatrics, Georgia Health Science Center, Augusta, GA #Department of Pediatrics, West Virginia University Health Science Center, Charleston, WV.
authors.forename: Patricia K
authors.initials: PK
authors.lastname: Duffner
authors.forename: Floyd Daniel
authors.initials: FD
authors.lastname: Armstrong
authors.forename: Lu
authors.initials: L
authors.lastname: Chen
authors.forename: Kathleen J
authors.initials: KJ
authors.lastname: Helton
authors.forename: Martin L
authors.initials: ML
authors.lastname: Brecher
authors.forename: Beverly
authors.initials: B
authors.lastname: Bell
authors.forename: Allen R
authors.initials: AR
authors.lastname: Chauvenet
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects; D002648:Child; D002675:Child, Preschool; D003072:Cognition Disorders / Q000139:chemically induced* / Q000453:epidemiology / Q000473:pathology; D005260:Female; D006801:Humans; D007223:Infant; D007361:Intelligence Tests; D056784:Leukoencephalopathies / Q000139:chemically induced* / Q000453:epidemiology / Q000473:pathology; D008279:Magnetic Resonance Imaging; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage / Q000009:adverse effects*; D009483:Neuropsychological Tests; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy*; D015995:Prevalence; D012307:Risk Factors; D016896:Treatment Outcome
chemical_list: D000964:Antimetabolites, Antineoplastic; D008727:Methotrexate