Comparison of long-term neurocognitive outcomes in young children with acute lymphoblastic leukemia treated with cranial radiation or high-dose or very high-dose intravenous methotrexate.
OBJECTIVE
Cranial radiation therapy (CRT) is associated with neurocognitive morbidity in survivors of childhood acute lymphoblastic leukemia (ALL). For most patients, CRT has been replaced with intensified systemic and intrathecal chemotherapy, often including methotrexate (MTX). The impact of chemotherapy-only protocols on neurocognitive outcomes is unclear, and the importance of systemic MTX dose has not been established.


METHODS
Seventy nine of 120 eligible children diagnosed with high-risk ALL between the ages of 1.0 and 4.9 years participated in this retrospective cohort study. All patients were treated on a uniform chemotherapy protocol with one of three modalities of CNS prophylaxis, depending on their treatment era. In addition to intrathecal therapy, CNS-directed therapy consisted of CRT (18 Gy in 10 fractions) in 25 patients, high-dose intravenous (IV) MTX (8 g/m2 x 3 doses) in 32 patients and very high-dose IV MTX (33.6 g/m2 x 3 doses) in 22 patients. Participants completed tests of intelligence, academic achievement, attention, and memory.


RESULTS
Neurocognitive assessment was conducted at least 5 years after diagnosis (mean, 10.5 years, standard deviation, 2.7 years). No difference was detected on any neurocognitive measure between children treated with high-dose or very high-dose IV MTX. The combined MTX groups scored near the population mean on 17/18 measures. Children treated with CRT performed more poorly than the MTX group on most measures.


CONCLUSIONS
Treatment strategies for young children with ALL that avoid CRT are associated with good long-term neurocognitive outcomes. In this cohort, the dose of IV MTX did not influence these outcomes.
Spiegler
Brenda J
BJ
Department of Paediatrics, Division of Haematology/Oncology, The Hospital for Sick Children, The University of Toronto, Toronto, Ontario, Canada. brenda.spiegler@sickkids.ca
Kennedy
Kimberly
K
Maze
Ronnen
R
Greenberg
Mark L
ML
Weitzman
Sheila
S
Hitzler
Johann K
JK
Nathan
Paul C
PC
D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001288:Attention / Q000187:drug effects / Q000528:radiation effects; D001932:Brain Neoplasms / Q000517:prevention & control / Q000556:secondary; D002675:Child, Preschool; D003071:Cognition / Q000187:drug effects* / Q000528:radiation effects*; D015331:Cohort Studies; D016371:Cranial Irradiation / Q000009:adverse effects*; D019583:Dose Fractionation, Radiation; D004522:Educational Status; D005260:Female; D006801:Humans; D007223:Infant; D007262:Infusions, Intravenous; D007361:Intelligence Tests; D008297:Male; D008568:Memory / Q000187:drug effects / Q000528:radiation effects; D008727:Methotrexate / Q000008:administration & dosage* / Q000009:adverse effects*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000532:radiotherapy*; D012189:Retrospective Studies
D000964:Antimetabolites, Antineoplastic; D008727:Methotrexate