249 General discussion 8 GENERAL DISCUSSION AND FUTURE PERSPECTIVES The aims of this thesis were threefold. First, we aimed to increase current knowledge on the prevalence and determinants of dexamethasone-induced side effects in children with acute lymphoblastic leukemia (ALL). Second, we aimed to validate the finding that hydrocortisone addition to dexamethasone treatment leads to a significant reduction of clinically relevant dexamethasone-induced neurobehavioral and sleep problems. Third, we aimed to describe the role of the mineralocorticoid receptor in steroid-induced cytotoxicity. The findings described in this thesis are relevant for the identification, possible prevention and treatment of the burdensome side effects of dexamethasone in children with ALL, as discussed in this chapter. Table 1 provides an overview of studies and the main findings of this thesis. Prevalence and measurement of dexamethasone-induced side effects Neurobehavioral problems This thesis showed that 67% of ALL patients who received dexamethasone during maintenance treatment experienced clinically relevant dexamethasone-induced neurobehavioral problems (Chapter 4). Previous prospective studies in children with ALL which used validated measurement tools, reported adverse psychological reactions between 38% and 86%.1-5 This wide range may partly be due to the differences in outcome measurement tools. We consider the used strengths and difficulties questionnaire (SDQ) very valuable since it is validated in children from 3 to 18 years.6 However, this 25-item questionnaire is not fitting for the evaluation of other more specific adverse psychological reactions, such as depressive symptoms or psychosis, which occur more often in older children.7,8 A validated questionnaire which evaluates both behavioral problems in young children and (e.g.) depressive symptoms in older children is currently not available. A promising future option would be to use a patient-reported outcome measures information system (PROMIS) which measures patient-reported specific outcomes with highly accurate, precise and short measures.9,10 Combining short forms (4-items each) for anxiety, depression and anger, as recently specified by the Outcome-Based Healthcare Program Working Group Generic PROMs,11 could provide more insight in the different psychological reactions which occur during dexamethasone treatment. Preferably, these measurements should be self-reported when possible, since children are known to report less (severe) side effects than their parents.12
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