31 Risk factors: a systematic review 2 INTRODUCTION Glucocorticoids, such as prednisone and dexamethasone, were among the first drug classes successfully used in the treatment of childhood acute lymphoblastic leukemia (ALL) and are still regarded as cornerstones of ALL therapy.1 These drugs have contributed substantially to the current 5-year overall survival of more than 90% in developed countries.2 However, glucocorticoids can also cause severe side effects, such as osteonecrosis, hyperlipidemia, hyperglycemia, altered body composition, and thromboembolisms.3 Besides these physical toxicities, steroid treatment can cause severe adverse psychological reactions (APRs). These include mood swings, behavioral changes, but also anxiety, psychosis and depression.4,5 Steroid related APRs in ALL are experienced as the most detrimental contributor to impaired health-related quality of life (HRQoL) by both patients and parents.6 Reports on estimated frequencies of steroid-induced APRs in children range from 5% to 75%.5,7-10 Closely related to APRs and also common in children with ALL, are sleep problems, with an estimated prevalence of 19% to 87%.9,11 Steroid-induced APRs and sleep problems are often studied and reported as separate phenomena in pediatric ALL literature.9,12,13 However, sleep problems interrelate with APRs by being both a symptom of certain APRs, such as depression or psychosis, as well as a risk factor to develop APRs.14 Additionally, during ALL steroid-treatment sleep problems significantly impact the quality of life of children.15 An important step to handle both APRs and sleep problems is to identify potential risk factors, making early recognition of susceptible patients possible. This may allow implementation of early intervention strategies to potentially prevent or overcome APRs and sleep problems and their related HRQoL impairments. This was recently acknowledged by the International Psycho-Oncology Society Pediatrics Special Interest Group, which published a call for awareness of sleep problems in pediatric oncology. One of their recommendations was to identify risk factors.16 In adults (both with and without cancer diagnosis), a higher steroid dose as well as past psychiatric history increases the risk of APRs.17,18 In children, only the use of dexamethasone (in comparison to prednisone) appears to influence the occurrence of steroid-induced APRs.19 Known risk factors for sleep problems in the general population are female sex, familial (genetic) predisposition, history of sleep problems, personality type or having a parent with depression.20-23 Although some possible risk factors for APRs and sleep problems have been described, findings in pediatric oncology are often conflicting or not specific for steroid-induced problems.5,24,25
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