55 Risk factors: a systematic review 2 some APRs are better recognized in different age groups, or that younger children might not have developed the skills necessary to control their behavior. Age differences also differ per investigated domain of sleep problems, for example when measured in circadian parameters no differences were found, but when measured in sleep parameters, older children appear to have more sleep problems. Another source of heterogeneity complicating the generalization of conclusions, is the methodology of measuring APRs and sleep problems, which differed considerably between studies. Several large randomized controlled trials37,38,42,46 reported APRs as part of toxicity registration. This could potentially give an underestimation of the problem, since usually only extreme cases (toxicity grade III or IV) are reported. Nevertheless, grade II/IV toxicities include side effects that are clinically relevant. These studies found an APR incidence of 0,1-6,0% in their population, remarkably lower than the reported 19-86% in prospective studies which used validated questionnaires to measure APRs as primary outcome parameter.4,9,41,48,52 Sleep problems were not registered as toxicity in any of the trials, which recently led to a call for action to start screening for sleep problems.16 Since dexamethasone is more potent and penetrates the central nervous system better than prednisone,63 and as dexamethasone has a higher affinity for the GR, it is conceivable that more APRs or sleep problems may be expected with dexamethasone treatment. Contrary to this expectation, results were conflicting. Most (6/8) studies of which four of higher quality did not find a difference between dexamethasone and prednisone with regard to developing APRs.4,25,37,38,43,47,51 This is in line with a previous review investigating neuropsychological side effects of dexamethasone versus prednisone.10 Oppositely, two other high quality studies did find more APRs during dexamethasone treatment46,52 and one described significantly more dexamethasone related sleep problems.12 Despite being a possible risk factor, dexamethasone has a higher anti-leukemic activity and will probably remain the preferred steroid in the treatment of ALL. Although it was expected that a higher steroid dose might predispose for APRs or sleep problems as well, this was not reported. Steroid dose was not related to APRs in four studies of which one of high quality.25,47-49 This is surprising, since in adults dosage appears to be the most significant risk factor.64 Evidence is contradictory in children with chronic diseases, though dexamethasone levels and pharmacokinetics may play a role in the occurrence of steroidinduced toxicities. Dexamethasone clearance is known to be higher in younger children, which might explain the inter-patient variability.65 Furthermore, even the lowest steroid dose children with ALL receive during their treatment is very high compared to adults or other pediatric patients with diseases such as asthma. This could possibly explain why we did not find a difference comparing steroid dose in the occurrence of APRs in children with ALL.
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