title: Predicting the neurobehavioral side effects of dexamethasone in pediatric acute lymphoblastic leukemia.
abstract: Although dexamethasone is an effective treatment for acute lymphoblastic leukemia (ALL), it can induce a variety of serious neurobehavioral side effects. We hypothesized that these side effects are influenced by glucocorticoid sensitivity at the tissue level. We therefore prospectively studied whether we could predict the occurrence of these side effects using the very low-dose dexamethasone suppression test (DST) or by measuring trough levels of dexamethasone. Fifty pediatric patients (3-16 years of age) with acute lymphoblastic leukemia (ALL) were initially included during the maintenance phase (with dexamethasone) of the Dutch ALL treatment protocol. As a marker of glucocorticoid sensitivity, the salivary very low-dose DST was used. A post-dexamethasone cortisol level <2.0nmol/L was considered a hypersensitive response. The neurobehavioral endpoints consisted of questionnaires regarding psychosocial and sleeping problems administered before and during the course of dexamethasone (6mg/m(2)), and dexamethasone trough levels were measured during dexamethasone treatment. Patients with a hypersensitive response to dexamethasone had more behavioral problems (N=11), sleeping problems, and/or somnolence (N=12) (P<0.05 for all three endpoints). The positive predictive values of the DST for psychosocial problems and sleeping problems were 50% and 30%, respectively. Dexamethasone levels were not associated with neurobehavioral side effects. We conclude that neither the very low-dose DST nor measuring dexamethasone trough levels can accurately predict dexamethasone-induced neurobehavioral side effects. However, patients with glucocorticoid hypersensitivity experienced significantly more symptoms associated with dexamethasone-induced depression. Future studies should elucidate further the mechanisms by which neurobehavioral side effects are influenced by glucocorticoid sensitivity.
authors.affiliation: Department of Pediatric Oncology, Erasmus MC - Sophia Children's Hospital, P.O. Box 2060, 3000 CB, Rotterdam, The Netherlands; Department of Pediatric Endocrinology, Erasmus MC - Sophia Children's Hospital, P.O. Box 2060, 3000 CB, Rotterdam, The Netherlands. Electronic address: l.warris@erasmusmc.nl.
authors.forename: Lidewij T
authors.initials: LT
authors.lastname: Warris
authors.affiliation: Department of Pediatric Endocrinology, Erasmus MC - Sophia Children's Hospital, P.O. Box 2060, 3000 CB, Rotterdam, The Netherlands. Electronic address: e.l.t.vandenakker@erasmusmc.nl.
authors.forename: Erica L T
authors.initials: EL
authors.lastname: van den Akker
authors.affiliation: Department of Child and Adolescent Psychiatry/Psychology, Erasmus MC - Sophia Children's Hospital, P.O. Box 2060, 3000 CB, Rotterdam, The Netherlands. Electronic address: f.aarsen@erasmusmc.nl.
authors.forename: Femke K
authors.initials: FK
authors.lastname: Aarsen
authors.affiliation: Department of Pediatric Oncology, University Medical Center Utrecht - Wilhelmina Children's Hospital, Lundlaan 6, 3584 EA, Utrecht, The Netherlands. Electronic address: m.bierings@umcutrecht.nl.
authors.forename: Marc B
authors.initials: MB
authors.lastname: Bierings
authors.affiliation: Department of Pediatric Oncology, Academic Medical Center - Emma Children's Hospital, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands. Electronic address: c.vandenbos@amc.uva.nl.
authors.forename: Cor
authors.initials: C
authors.lastname: van den Bos
authors.affiliation: Department of Pediatric Oncology, University Medical Center Groningen, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands. Electronic address: w.j.e.tissing@umcg.nl.
authors.forename: Wim J E
authors.initials: WJ
authors.lastname: Tissing
authors.affiliation: Department of Pediatric Oncology, Erasmus MC - Sophia Children's Hospital, P.O. Box 2060, 3000 CB, Rotterdam, The Netherlands. Electronic address: s.sassen@erasmusmc.nl.
authors.forename: Sebastiaan D T
authors.initials: SD
authors.lastname: Sassen
authors.affiliation: Department of Pediatric Oncology, VU Medical Center, De Boelelaan 1118, 1081 HZ, Amsterdam, The Netherlands. Electronic address: ma.veening@vumc.nl.
authors.forename: Margreet A
authors.initials: MA
authors.lastname: Veening
authors.affiliation: Department of Pediatric Oncology, Erasmus MC - Sophia Children's Hospital, P.O. Box 2060, 3000 CB, Rotterdam, The Netherlands. Electronic address: c.m.zwaan@erasmusmc.nl.
authors.forename: Christian M
authors.initials: CM
authors.lastname: Zwaan
authors.affiliation: Department of Pediatric Oncology, Erasmus MC - Sophia Children's Hospital, P.O. Box 2060, 3000 CB, Rotterdam, The Netherlands; Princess Máxima Center for Pediatric Oncology, P.O. Box 85090, 3508 AB, Utrecht, The Netherlands. Electronic address: l.warris@erasmusmc.nl.
authors.forename: Rob
authors.initials: R
authors.lastname: Pieters
authors.affiliation: Department of Pediatric Oncology, Erasmus MC - Sophia Children's Hospital, P.O. Box 2060, 3000 CB, Rotterdam, The Netherlands; Princess Máxima Center for Pediatric Oncology, P.O. Box 85090, 3508 AB, Utrecht, The Netherlands. Electronic address: l.warris@erasmusmc.nl.
authors.forename: Marry M
authors.initials: MM
authors.lastname: van den Heuvel-Eibrink
mesh_terms: D000293:Adolescent; D000294:Adolescent Behavior / Q000187:drug effects*; D018931:Antineoplastic Agents, Hormonal / Q000009:adverse effects*; D002648:Child; D002652:Child Behavior / Q000187:drug effects*; D002675:Child, Preschool; D003863:Depression / Q000139:chemically induced*; D003907:Dexamethasone / Q000009:adverse effects*; D005260:Female; D006801:Humans; D006854:Hydrocortisone / Q000378:metabolism*; D008297:Male; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy*; D011237:Predictive Value of Tests; D000066553:Problem Behavior; D012893:Sleep Wake Disorders / Q000139:chemically induced*
chemical_list: D018931:Antineoplastic Agents, Hormonal; D003907:Dexamethasone; D006854:Hydrocortisone
keywords: Acute lymphoblastic leukemia; Dexamethasone; Dexamethasone suppression test; Neurobehavioral problems; Pediatrics; Predictors