99 Study protocol 3 BACKGROUND Dexamethasone, a highly effective drug for the treatment of pediatric acute lymphoblastic leukemia (ALL),1-3 can induce serious neurobehavioral side effects. These side effects are experienced as particularly detrimental to health-related quality of life (HRQoL) by patients and parents.4 Recent studies emphasize that the mineralocorticoid receptor (MR) in the brain plays an important role in the regulation of mood, behavior and sleep.5,6 Both the glucocorticoid receptor (GR) and MR are important for the binding of endo- and exogenous glucocorticoids.5 In animals as well as humans it has been shown that the MR plays an important role in behavior, cognition and psychiatric diseases.6-11 Besides MR expression in the brain, cortisol affinity and MR:GR balance are thought to be associated with behavior. It has been shown, that the MR has a tenfold greater affinity for endogenous cortisol than the GR.12 Synthetic glucocorticoids mostly have the GR as their therapeutic target: dexamethasone has a high potency to activate GRs, but does not bind MRs.13 In patients treated with glucocorticoids the production of endogenous cortisol is suppressed. Therefore, in patients treated with high doses dexamethasone, the hypothesis is that the GR in the brain is stimulated, whereas the MR is underactivated. The disturbance of this GR:MR balance conceivably deregulates the stress-system and enhances vulnerability to stress-related problems.5 Consequently, we previously hypothesized that pediatric ALL patients who receive dexamethasone treatment, cortisol depletion of the MR in the brain may be responsible for attendant neurobehavioral problems. We therefore performed a randomized controlled trial (RCT), the DexaDays-1 trial, to investigate whether these side effects could be ameliorated by adding a physiological dose of hydrocortisone which stimulates the MRs in the brain in a physiological way.14 No beneficial effect of hydrocortisone on neurobehavioral problems could be shown in the complete group of 46 patients. However, in a small subgroup of patients with clinically relevant dexamethasone-induced neurobehavioral or sleeping problems (n = 16 and n = 9 respectively), hydrocortisone addition had a significant beneficial effect.14 Our results suggest that neurobehavioral and sleeping problems can be reduced in children who are most affected. Before implementing this into standard clinical practice, we felt that the results require replication in a larger patient cohort with clinically relevant dexamethasone-induced neurobehavioral problems. Hence, we initiated the DexaDays-2 trial in 2018. Several factors may be associated to neurobehavioral side effects during dexamethasone treatment which warrant further study.
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