Because of its penetrance into the CNS, systemic methotrexate has been used in a variety of low-dose and high-dose regimens for leukemia CNS prophylaxis. Systemic methotrexate in high doses and combined with radiation therapy can lead to an infrequent but well-described leukoencephalopathy, in which severe neurocognitive deficits are obvious.
The type of steroid used for ALL systemic treatment does not affect cognitive functioning. This is based on long-term neurocognitive testing in 92 children with a history of standard-risk ALL who had received either dexamethasone or prednisone during treatment that observed no meaningful differences in cognitive functioning based on corticosteroid randomization.
Treatment intensity and duration can also adversely affect cognitive performance, because of absences from school and interruption of studies. In the Childhood Cancer Survivor Study (CCSS), treatment-related neurocognitive impairment resulted in decreased educational attainment and greater utilization of special education services. Those ALL survivors who were provided with special educational services had comparable educational attainment to siblings, whereas those not reporting use of special education had lower educational attainment.
Infants with ALL
Infants with ALL are considered to be at high risk for CNS disease. In the past, infants diagnosed before age 2 years were treated with cranial irradiation. As a result, significant deficits in overall intellectual function were noted as compared with cancer controls. Currently, most ALL treatment protocols do not specify cranial irradiation for infants or very young children. When cranial radiation is avoided, neurodevelopmental outcome improves. One long-term study of infants who received high-dose systemic methotrexate combined with intrathecal cytarabine and methotrexate for CNS leukemia prophylaxis and were tested 3 to 9 years posttreatment showed cognitive function was in the average range.
Neurocognitive abnormalities have been reported in other groups of cancer survivors besides patients with CNS tumors and ALL. In a study of adult survivors of childhood non-CNS cancers (including ALL, n = 5,937), 13% to 21% of survivors had impairment in task efficiency, organization, memory, or emotional regulation. This rate of impairment was approximately 50% higher than that in the sibling comparison. Factors such as diagnosis before age 6 years, female gender, cranial radiation therapy, and hearing impediment were associated with impairment.