Dexamethasone and neurocognitive outcomes in survivors of childhood acute lymphoblastic leukemia

Abstract

Altered brain development and neurocognitive impairment in survivors of childhood acute lymphoblastic leukemia (ALL) is the result of multiple factors that interact with one another and evolve over the lifespan. Within the first 10 years of survival, direct effects of neurotoxic therapies (i.e., cranial irradiation, intrathecal chemotherapy) appear most pronounced, though over the lifespan the impact of other therapies can begin to have indirect effects on brain integrity and function. For example, thoracic radiation increases risk for cardiopulmonary dysfunction,1 and this dysfunction can impact brain integrity and neurocognitive function in adult survivors.2 Both the direct and indirect effects of ALL and therapy can be modified by health behaviors, such as physical fitness and sleep quality.3,4 In the article by Phillips et al. within this issue, evidence is presented that suggests the direct effects of chemotherapy on brain function are not uniform, but rather may have differential impact on brain regions based on the sex of the survivors and the density of receptors for the specific neurotoxic chemotherapy agentwithin that region. As reported by the authors, glucocorticoid receptors are not uniformly distributed throughout the brain. Rather, the cerebellum and hippocampi seem tohave higher concentrations of these receptors and when the brain is exposed to glucocorticoids, such as dexamethasone, these regions with higher concentrations may be more affected than other regions. This principle does not necessarily apply just to glucocorticoids but may explain some of the variability in response to other chemotherapy agents andmay be further modified by sex. Phillips et al. demonstrated sex differences in brain structures, including smaller subcortical volumes and thinner cortices associated with higher dexamethasone exposure. All differences were adjusted for intracranial volume, which itself did not differ between survivors and same-sex controls. The fact that intracranial volume was similar but regional volumes were smaller in survivors compared with controls suggests overall brain growth was not suppressed, because brain growth determines cranium size, but rather development of specific regions was selectively altered. Although not presented in the brief report, smaller volume in the subcortical hippocampi and anterior thalamic regions and thinner cortices in medial and lateral frontal regions were also associated with poorer neurocognitive outcomes (P < 0.05). However, these associations appear influenced by sex, because female survivors with smaller hippocampi demonstrated poorer performance on measures of inhibition, cognitive flexibility, and processing speed, while male survivors did not demonstrate this pattern. We have previously reported that higher methotrexate exposure was associated with poorer performance on measures of executive function and processing speed.5 There is now ample evidence that glucocorticoids are also associated with neurocognitive problems. This has been established in children with chronic disease,6–8 as well as in a large epidemiological study in long-term survivors of childhood cancer.9 However, controversy remains regarding the type and dose of glucocorticoid associated with neurocognitive impairment. Survivors of theDana-Farber Cancer Institute 91-01 protocol were treatedwith either 6 or 18 mg/m2/day dexamethasone and, although no major differenceswere noted between these doses, bothwere found to demonstrate poorer performance on neurocognitive measures compared with children treated with prednisone.10 A subsequent study examining outcomes in children randomized to dexamethasone or prednisone during induction on the Children’s Cancer Group 1922 protocol found that children who received 6 mg/m2/day dexamethasone demonstrated marginally lower scores on word reading compared with those treated with prednisone, though no differences in neurocognitive or other academic measures were noted.11 The survivors included in the