title: Hydrocortisone as an Intervention for Dexamethasone-Induced Adverse Effects in Pediatric Patients With Acute Lymphoblastic Leukemia: Results of a Double-Blind, Randomized Controlled Trial.
abstract: Dexamethasone is a key component in the treatment of pediatric acute lymphoblastic leukemia (ALL), but can induce serious adverse effects. Recent studies have led to the hypothesis that neuropsychological adverse effects may be a result of cortisol depletion of the cerebral mineralocorticoid receptors. We examined whether including a physiologic dose of hydrocortisone in dexamethasone treatment can reduce neuropsychologic and metabolic adverse effects in children with ALL.
  
  
  
  We performed a multicenter, double-blind, randomized controlled trial with a crossover design. Of 116 potentially eligible patients (age 3 to 16 years), 50 were enrolled and were treated with two consecutive courses of dexamethasone in accordance with Dutch Childhood Oncology Group ALL protocols. Patients were randomly assigned to receive either hydrocortisone or placebo in a circadian rhythm (10 mg/m(2)/d) during both dexamethasone courses. Primary outcome measure was parent-reported Strength and Difficulties Questionnaire in Dutch, which assesses psychosocial problems. Other end points included questionnaires, neuropsychological tests, and metabolic parameters.
  
  
  
  Of 48 patients who completed both courses, hydrocortisone had no significant effect on outcome; however, a more detailed analysis revealed that in 16 patients who developed clinically relevant psychosocial adverse effects, addition of hydrocortisone substantially reduced their Strength and Difficulties Questionnaire in Dutch scores in the following domains: total difficulties, emotional symptoms, conduct problems, and impact of difficulties. Moreover, in nine patients who developed clinically relevant, sleep-related difficulties, addition of hydrocortisone reduced total sleeping problems and disorders of initiating and maintaining sleep. In contrast, hydrocortisone had no effect on metabolic parameters.
  
  
  
  Our results suggest that adding a physiologic dose of hydrocortisone to dexamethasone treatment can reduce the occurrence of serious neuropsychological adverse effects and sleep-related difficulties in pediatric patients with ALL.
authors.affiliation: Lidewij T. Warris, Marry M. van den Heuvel-Eibrink, Femke K. Aarsen, Saskia M.F. Pluijm, Christian M. Zwaan, Rob Pieters, and Erica L.T. van den Akker, Erasmus MC-Sophia Children's Hospital, Rotterdam; Cor van den Bos, Academic Medical Center-Emma Children's Hospital; Margreet A. Veening, Vrije Universiteit Medical Center; Helene H. Thygesen, Netherlands Cancer Institute, Amsterdam; Marc B. Bierings, University Medical Center Utrecht-Wilhelmina Children's Hospital; Lidewij T. Warris, Marry M. van den Heuvel-Eibrink, Marc B. Bierings, and Rob Pieters, Princess Máxima Center for Pediatric Oncology, Utrecht; Wim J.E. Tissing, University Medical Center Groningen, Groningen, the Netherlands. l.warris@erasmusmc.nl.
authors.forename: Lidewij T
authors.initials: LT
authors.lastname: Warris
authors.affiliation: Lidewij T. Warris, Marry M. van den Heuvel-Eibrink, Femke K. Aarsen, Saskia M.F. Pluijm, Christian M. Zwaan, Rob Pieters, and Erica L.T. van den Akker, Erasmus MC-Sophia Children's Hospital, Rotterdam; Cor van den Bos, Academic Medical Center-Emma Children's Hospital; Margreet A. Veening, Vrije Universiteit Medical Center; Helene H. Thygesen, Netherlands Cancer Institute, Amsterdam; Marc B. Bierings, University Medical Center Utrecht-Wilhelmina Children's Hospital; Lidewij T. Warris, Marry M. van den Heuvel-Eibrink, Marc B. Bierings, and Rob Pieters, Princess Máxima Center for Pediatric Oncology, Utrecht; Wim J.E. Tissing, University Medical Center Groningen, Groningen, the Netherlands.
authors.forename: Marry M
authors.initials: MM
authors.lastname: van den Heuvel-Eibrink
authors.affiliation: Lidewij T. Warris, Marry M. van den Heuvel-Eibrink, Femke K. Aarsen, Saskia M.F. Pluijm, Christian M. Zwaan, Rob Pieters, and Erica L.T. van den Akker, Erasmus MC-Sophia Children's Hospital, Rotterdam; Cor van den Bos, Academic Medical Center-Emma Children's Hospital; Margreet A. Veening, Vrije Universiteit Medical Center; Helene H. Thygesen, Netherlands Cancer Institute, Amsterdam; Marc B. Bierings, University Medical Center Utrecht-Wilhelmina Children's Hospital; Lidewij T. Warris, Marry M. van den Heuvel-Eibrink, Marc B. Bierings, and Rob Pieters, Princess Máxima Center for Pediatric Oncology, Utrecht; Wim J.E. Tissing, University Medical Center Groningen, Groningen, the Netherlands.
authors.forename: Femke K
authors.initials: FK
authors.lastname: Aarsen
authors.affiliation: Lidewij T. Warris, Marry M. van den Heuvel-Eibrink, Femke K. Aarsen, Saskia M.F. Pluijm, Christian M. Zwaan, Rob Pieters, and Erica L.T. van den Akker, Erasmus MC-Sophia Children's Hospital, Rotterdam; Cor van den Bos, Academic Medical Center-Emma Children's Hospital; Margreet A. Veening, Vrije Universiteit Medical Center; Helene H. Thygesen, Netherlands Cancer Institute, Amsterdam; Marc B. Bierings, University Medical Center Utrecht-Wilhelmina Children's Hospital; Lidewij T. Warris, Marry M. van den Heuvel-Eibrink, Marc B. Bierings, and Rob Pieters, Princess Máxima Center for Pediatric Oncology, Utrecht; Wim J.E. Tissing, University Medical Center Groningen, Groningen, the Netherlands.
authors.forename: Saskia M F
authors.initials: SM
authors.lastname: Pluijm
authors.affiliation: Lidewij T. Warris, Marry M. van den Heuvel-Eibrink, Femke K. Aarsen, Saskia M.F. Pluijm, Christian M. Zwaan, Rob Pieters, and Erica L.T. van den Akker, Erasmus MC-Sophia Children's Hospital, Rotterdam; Cor van den Bos, Academic Medical Center-Emma Children's Hospital; Margreet A. Veening, Vrije Universiteit Medical Center; Helene H. Thygesen, Netherlands Cancer Institute, Amsterdam; Marc B. Bierings, University Medical Center Utrecht-Wilhelmina Children's Hospital; Lidewij T. Warris, Marry M. van den Heuvel-Eibrink, Marc B. Bierings, and Rob Pieters, Princess Máxima Center for Pediatric Oncology, Utrecht; Wim J.E. Tissing, University Medical Center Groningen, Groningen, the Netherlands.
authors.forename: Marc B
authors.initials: MB
authors.lastname: Bierings
authors.affiliation: Lidewij T. Warris, Marry M. van den Heuvel-Eibrink, Femke K. Aarsen, Saskia M.F. Pluijm, Christian M. Zwaan, Rob Pieters, and Erica L.T. van den Akker, Erasmus MC-Sophia Children's Hospital, Rotterdam; Cor van den Bos, Academic Medical Center-Emma Children's Hospital; Margreet A. Veening, Vrije Universiteit Medical Center; Helene H. Thygesen, Netherlands Cancer Institute, Amsterdam; Marc B. Bierings, University Medical Center Utrecht-Wilhelmina Children's Hospital; Lidewij T. Warris, Marry M. van den Heuvel-Eibrink, Marc B. Bierings, and Rob Pieters, Princess Máxima Center for Pediatric Oncology, Utrecht; Wim J.E. Tissing, University Medical Center Groningen, Groningen, the Netherlands.
authors.forename: Cor
authors.initials: C
authors.lastname: van den Bos
authors.affiliation: Lidewij T. Warris, Marry M. van den Heuvel-Eibrink, Femke K. Aarsen, Saskia M.F. Pluijm, Christian M. Zwaan, Rob Pieters, and Erica L.T. van den Akker, Erasmus MC-Sophia Children's Hospital, Rotterdam; Cor van den Bos, Academic Medical Center-Emma Children's Hospital; Margreet A. Veening, Vrije Universiteit Medical Center; Helene H. Thygesen, Netherlands Cancer Institute, Amsterdam; Marc B. Bierings, University Medical Center Utrecht-Wilhelmina Children's Hospital; Lidewij T. Warris, Marry M. van den Heuvel-Eibrink, Marc B. Bierings, and Rob Pieters, Princess Máxima Center for Pediatric Oncology, Utrecht; Wim J.E. Tissing, University Medical Center Groningen, Groningen, the Netherlands.
authors.forename: Christian M
authors.initials: CM
authors.lastname: Zwaan
authors.affiliation: Lidewij T. Warris, Marry M. van den Heuvel-Eibrink, Femke K. Aarsen, Saskia M.F. Pluijm, Christian M. Zwaan, Rob Pieters, and Erica L.T. van den Akker, Erasmus MC-Sophia Children's Hospital, Rotterdam; Cor van den Bos, Academic Medical Center-Emma Children's Hospital; Margreet A. Veening, Vrije Universiteit Medical Center; Helene H. Thygesen, Netherlands Cancer Institute, Amsterdam; Marc B. Bierings, University Medical Center Utrecht-Wilhelmina Children's Hospital; Lidewij T. Warris, Marry M. van den Heuvel-Eibrink, Marc B. Bierings, and Rob Pieters, Princess Máxima Center for Pediatric Oncology, Utrecht; Wim J.E. Tissing, University Medical Center Groningen, Groningen, the Netherlands.
authors.forename: Helene H
authors.initials: HH
authors.lastname: Thygesen
authors.affiliation: Lidewij T. Warris, Marry M. van den Heuvel-Eibrink, Femke K. Aarsen, Saskia M.F. Pluijm, Christian M. Zwaan, Rob Pieters, and Erica L.T. van den Akker, Erasmus MC-Sophia Children's Hospital, Rotterdam; Cor van den Bos, Academic Medical Center-Emma Children's Hospital; Margreet A. Veening, Vrije Universiteit Medical Center; Helene H. Thygesen, Netherlands Cancer Institute, Amsterdam; Marc B. Bierings, University Medical Center Utrecht-Wilhelmina Children's Hospital; Lidewij T. Warris, Marry M. van den Heuvel-Eibrink, Marc B. Bierings, and Rob Pieters, Princess Máxima Center for Pediatric Oncology, Utrecht; Wim J.E. Tissing, University Medical Center Groningen, Groningen, the Netherlands.
authors.forename: Wim J E
authors.initials: WJ
authors.lastname: Tissing
authors.affiliation: Lidewij T. Warris, Marry M. van den Heuvel-Eibrink, Femke K. Aarsen, Saskia M.F. Pluijm, Christian M. Zwaan, Rob Pieters, and Erica L.T. van den Akker, Erasmus MC-Sophia Children's Hospital, Rotterdam; Cor van den Bos, Academic Medical Center-Emma Children's Hospital; Margreet A. Veening, Vrije Universiteit Medical Center; Helene H. Thygesen, Netherlands Cancer Institute, Amsterdam; Marc B. Bierings, University Medical Center Utrecht-Wilhelmina Children's Hospital; Lidewij T. Warris, Marry M. van den Heuvel-Eibrink, Marc B. Bierings, and Rob Pieters, Princess Máxima Center for Pediatric Oncology, Utrecht; Wim J.E. Tissing, University Medical Center Groningen, Groningen, the Netherlands.
authors.forename: Margreet A
authors.initials: MA
authors.lastname: Veening
authors.affiliation: Lidewij T. Warris, Marry M. van den Heuvel-Eibrink, Femke K. Aarsen, Saskia M.F. Pluijm, Christian M. Zwaan, Rob Pieters, and Erica L.T. van den Akker, Erasmus MC-Sophia Children's Hospital, Rotterdam; Cor van den Bos, Academic Medical Center-Emma Children's Hospital; Margreet A. Veening, Vrije Universiteit Medical Center; Helene H. Thygesen, Netherlands Cancer Institute, Amsterdam; Marc B. Bierings, University Medical Center Utrecht-Wilhelmina Children's Hospital; Lidewij T. Warris, Marry M. van den Heuvel-Eibrink, Marc B. Bierings, and Rob Pieters, Princess Máxima Center for Pediatric Oncology, Utrecht; Wim J.E. Tissing, University Medical Center Groningen, Groningen, the Netherlands.
authors.forename: Rob
authors.initials: R
authors.lastname: Pieters
authors.affiliation: Lidewij T. Warris, Marry M. van den Heuvel-Eibrink, Femke K. Aarsen, Saskia M.F. Pluijm, Christian M. Zwaan, Rob Pieters, and Erica L.T. van den Akker, Erasmus MC-Sophia Children's Hospital, Rotterdam; Cor van den Bos, Academic Medical Center-Emma Children's Hospital; Margreet A. Veening, Vrije Universiteit Medical Center; Helene H. Thygesen, Netherlands Cancer Institute, Amsterdam; Marc B. Bierings, University Medical Center Utrecht-Wilhelmina Children's Hospital; Lidewij T. Warris, Marry M. van den Heuvel-Eibrink, Marc B. Bierings, and Rob Pieters, Princess Máxima Center for Pediatric Oncology, Utrecht; Wim J.E. Tissing, University Medical Center Groningen, Groningen, the Netherlands.
authors.forename: Erica L T
authors.initials: EL
authors.lastname: van den Akker
mesh_terms: D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D018592:Cross-Over Studies; D003907:Dexamethasone / Q000009:adverse effects*; D004311:Double-Blind Method; D006801:Humans; D006854:Hydrocortisone / Q000627:therapeutic use*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000523:psychology; D012890:Sleep / Q000187:drug effects
chemical_list: D003907:Dexamethasone; D006854:Hydrocortisone