It should be noted that the phenotype of attention problems in ALL survivors appears to differ from developmental attention-deficit disorder, as few survivors demonstrate significant hyperactivity/impulsivity. By contrast, impairments in cognitive efficiency (information processing and short-term memory) and executive functioning (organization and planning) have been more often observed among ALL survivors treated with cranial radiation therapy, and have been observed in children at lower frequency among those treated with chemotherapy alone.
ALL and chemotherapy–only CNS therapy
Most studies of chemotherapy-only CNS-directed treatment display good neurocognitive long-term outcomes. However, one review suggests modest effects on processes of attention, speed of information processing, memory, verbal comprehension, visual-spatial skills, and visual-motor functioning; global intellectual function was found to be preserved.[23,29,33,34,35] Few longitudinal studies evaluating long-term neurocognitive outcome report adequate data for a decline in global IQ after treatment with chemotherapy alone.[34,36] The academic achievement of ALL survivors in the long term seems to be generally average for reading and spelling with deficits mainly affecting arithmetic performance.[29,37,38] Further risk factors for poor neurocognitive outcome after chemotherapy-only CNS-directed treatment are younger age and female gender.[36,39] Time since diagnosis or treatment does not appear to have a similar influence on neurocognitive functioning as observed following cranial irradiation.
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.