Although low-, standard-, and most high-risk patients currently are treated with chemotherapy-only protocols, the described neurocognitive effects for ALL patients are based on a heterogeneous treatment group of survivors in the past who were treated with combinations (simultaneously or sequentially) of intrathecal chemotherapy, radiation, and high-dose chemotherapy making it difficult to differentiate the impact of the individual components. In the future, more accurate data will be available about the neurocognitive effects on survivors of childhood ALL treated with chemotherapy only.
In a large prospective study (N = 555) of neurocognitive outcomes in children with newly diagnosed ALL randomly assigned to CNS-directed therapy according to risk group (low: intrathecal methotrexate vs. high-dose methotrexate; high: high-dose methotrexate vs. cranial radiation therapy), a significant reduction in IQ scores (4 to 7 points) was observed between all patient groups when compared with controls (P < .002), regardless of the CNS treatment delivered. Children younger than 5 years at diagnosis were more likely than children older than 5 years at diagnosis to have IQs below 80 at 3 years posttherapy, irrespective of treatment allocation, suggesting that younger children are more vulnerable to treatment-related neurologic toxic effects.
In the St. Jude Total XV (NCT00137111) trial, which omitted prophylactic cranial irradiation, comprehensive cognitive testing of 243 participants at week 120 revealed higher risk for below-average performance on a measure of sustained attention but not on measures of intellectual functioning, academic skills, or memory. The risk of cognitive deficits correlated with treatment intensity but not with age at diagnosis or gender. These results underscore the need for longitudinal follow-up to better characterize the prevalence and magnitude of cognitive deficits after CNS-directed therapy with chemotherapy alone.
ALL and cranial radiation
In survivors of ALL, cranial radiation therapy does lead to identifiable neurodevelopment late sequelae. Although these abnormalities are mild in some patients (overall IQ fall of approximately 10 points), those who have received higher doses at a young age may have significant learning difficulties.[27,28] Deficits in neuropsychological functions, such as visual-motor integration, processing speed, attention, and short-term memory are reported in children treated with 18 Gy to 24 Gy.[29,30,31] Girls and younger children are more vulnerable to cranial irradiation.[32,33,34] The decline in intellectual functioning appears to be progressive, showing more impairment of cognitive function with increasing time since radiation therapy.[35,36] When the neurocognitive outcome of radiation therapy and chemotherapy-only CNS regimens are directly compared, the evidence suggests a better outcome for those treated with chemotherapy alone although some studies show no significant difference.[37,38,39]