179 Hydrocortisone as an intervention (RCT) 6 INTRODUCTION The introduction of dexamethasone for the treatment of pediatric acute lymphoblastic leukemia (ALL) significantly contributed to the current overall 5-year survival rate of more than 90%.1 However, dexamethasone may cause severe adverse effects, of which emotional or behavioral disturbances and sleep problems are experienced as detrimental with respect to health-related quality of life (HRQoL) by both patients and parents.2,3 Currently, in most pediatric ALL treatment protocols, dexamethasone is administered in monthly 5-day courses, during at least one and a half year of maintenance treatment, thereby significantly impacting well-being of child and family for a substantial amount of time. Children and parents can be supported through psychological interventions; however, no effective treatment to overcome dexamethasone-induced neurobehavioral problems exists to date.4,5 The pathophysiology of dexamethasone-induced neurobehavioral problems is complex. Previous studies emphasized that both the mineralocorticoid receptor (MR) and the glucocorticoid receptor (GR) in the brain play an important role in the regulation of mood, behavior, and sleep.6,7 The MR and GR are activated by binding of endo- and exogenous glucocorticoids. Dexamethasone has a high affinity for the GR, but in contrast to other glucocorticoids, binds the MR to a minimal extent.8 Simultaneously, the endogenous production of cortisol, which has a high affinity for the MR, is suppressed due to the supra-physiological dose of dexamethasone.9 Dexamethasone treatment may therefore lead to a relatively insufficient activation of the MR, and this can lead, as shown in preclinical studies in MR knockout mice, to increased anxiety behaviour.7 In adults with major depression, treatment with MR antagonists was associated with impaired cognitive function and sleep.7 Our hypothesis was that the relatively underactivated MR contributes to the dexamethasone-induced neurobehavioral side-effects observed in ALL patients.6,7,10 Based on this hypothesis, we previously performed a double-blind, randomized placebocontrolled trial (RCT) in which we investigated whether neurobehavioral side-effects could be ameliorated by adding physiological dosages of hydrocortisone, to activate the MR in the brain.10 The intervention suggested a beneficial effect of hydrocortisone, however only for the subset of children who suffered most from dexamethasone-induced neurobehavioral side-effects.10 Since the results of this study were based on a relatively small number of patients with clinically relevant side-effects, we aimed to validate this finding in a larger targeted patient cohort. The current study therefore aimed to validate that hydrocortisone decreases dexamethasone-induced neurobehavioral problems in an independent cohort of children with ALL who suffer from these problems. Our secondary aims were to examine whether adding hydrocortisone could reduce dexamethasone-induced sleep problems and feeling of hunger, and improve patient HRQoL and parental stress.11
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