190 Chapter 6 DISCUSSION Our study showed that hydrocortisone, when compared to placebo, had no additional effect in reducing clinically relevant dexamethasone-induced neurobehavioral problems in children with ALL. Similarly, hydrocortisone was not better in reducing dexamethasoneinduced sleep problems, feeling of hunger, parental distress or improving quality of life as compared to placebo. The finding that, when compared to placebo, hydrocortisone did not significantly reduce dexamethasone-induced neurobehavioral problems was surprising, since our previous RCT suggested a beneficial effect of hydrocortisone.10 Several choices in the current study design may have contributed to this different outcome. First, we selected patients with a rise of ≥5 points on the SDQ during a ‘dexamethasone only’ course, whereas the previous study did a post-hoc analysis on selected patients with a rise of ≥5 points during a placebo course. The results of the previous study may have been based on regression to the mean, rather than an effect of hydrocortisone. Second, we increased the inclusion age to 18 years, compared to 16 in the former study. This may have influenced our results, since older children may have a lower risk of behavioral problems.26 Nevertheless, only three patients older than 16 were included in our study. A third difference was the presence of two courses hydrocortisone and placebo instead of one, by which we aimed to mimic the repetitive dexamethasone courses with an often changing burden of side-effects. We accounted for the presence of repeated measurements by using a generalized mixed model to estimate the effect of hydrocortisone on the outcomes. This is a different analysis than the previously published study where the Wilcoxon-signedrank test was used. Due to our nationalized pediatric cancer care, more extensive information about sideeffects of dexamethasone and experiences from other patients and parents may have influenced our results, illustrated by the fact that 66% of the included patients experienced clinically significant side-effects, in contrast to 35% in our previous study.10 Previous negative experiences, worrisome information, mistaken beliefs and negative expectations induced by verbal suggestions are known to increase or even cause side-effects, and are described as nocebo-effects.27-29 This nocebo-effect (by proxy)30 of dexamethasone may have played an important role in our findings. In children, nocebo-effects can be severe and often anticipatory.31 Behavioral and anticipatory adjustment of both child and family, may give rise to intensified behavioral changes. Hence, despite the fact that informing parents and children regarding side-effects is standard of care, overextended information may provoke non-intended adverse effects.
RkJQdWJsaXNoZXIy MTk4NDMw