title: Hypothalamic-pituitary-adrenal (HPA) axis suppression after treatment with glucocorticoid therapy for childhood acute lymphoblastic leukaemia.
abstract: BACKGROUND
  Glucocorticoids play a major role in the treatment of acute lymphoblastic leukaemia (ALL). However, supraphysiological doses may cause suppression of the hypothalamic-pituitary-adrenal (HPA) axis. HPA axis suppression resulting in reduced cortisol response may cause an impaired stress response and an inadequate host defence against infections, which remains a cause of morbidity and death. The exact occurrence and duration of HPA axis suppression after glucocorticoid therapy for childhood ALL are unclear.
  
  
  OBJECTIVE
  To examine the occurrence and duration of HPA axis suppression after (each cycle of) glucocorticoid therapy for childhood ALL.
  
  
  METHODS
  We searched the Cochrane Central Register of Controlled Trials (in The Cochrane Library, issue 3, 2010), MEDLINE/PubMed (from 1945 to July 2010) and EMBASE/Ovid (from 1980 to July 2010). In addition, we searched reference lists of relevant articles, conference proceedings and ongoing trial databases.
  
  
  METHODS
  All study designs, except case reports and patient series with fewer than 10 patients, examining the effect of glucocorticoid therapy for childhood ALL on the HPA axis function.
  
  
  METHODS
  Two review authors independently performed the study selection. One review author performed the data extraction and 'Risk of bias' assessment, which was checked by another review author.
  
  
  RESULTS
  We identified seven studies (total number of participants = 189), including one randomised controlled trial (RCT), which assessed the adrenal function. None of the studies assessed the HPA axis at the level of the hypothalamus, pituitary, or both. Due to substantial differences between studies, results could not be pooled. All studies had some methodological limitations. The included studies demonstrated that adrenal insufficiency occurs in nearly all patients in the first days after cessation of glucocorticoid treatment for childhood ALL. The majority of patients recovered within a few weeks, but a small amount of patients had ongoing adrenal insufficiency lasting up to 34 weeks. In the RCT, the occurrence and duration of adrenal insufficiency did not differ between the prednisolone and dexamethasone arms. In one study included in the review it appeared that treatment with fluconazole prolonged the duration of adrenal insufficiency.
  
  
  CONCLUSIONS
  Based on the available evidence, we conclude that adrenal insufficiency commonly occurs in the first days after cessation of glucocorticoid therapy for childhood ALL, but the exact duration is unclear. Since no data on the level of the hypothalamus and the pituitary were available we cannot make any conclusions regarding those outcomes. Clinicians should consider prescribing glucocorticoid replacement therapy during periods of serious stress in the first weeks after cessation of glucocorticoid therapy for childhood ALL, to reduce the risk of life-threatening complications. However, more high-quality research is needed for evidence-based guidelines for glucocorticoid replacement therapy.Special attention should be paid to patients receiving fluconazole therapy, and perhaps similar antifungal drugs, as this may prolong the duration of adrenal insufficiency.
authors.affiliation: Department of Pediatrics, Division of Oncology/Hematology, VU University Medical Center, Amsterdam, Netherlands.ms.gordijn@vumc.nl.
authors.forename: Maartje S
authors.initials: MS
authors.lastname: Gordijn
authors.forename: Reinoud Jbj
authors.initials: RJ
authors.lastname: Gemke
authors.forename: Elvira C
authors.initials: EC
authors.lastname: van Dalen
authors.forename: Joost
authors.initials: J
authors.lastname: Rotteveel
authors.forename: Gertjan Jl
authors.initials: GJ
authors.lastname: Kaspers
mesh_terms: D000309:Adrenal Insufficiency / Q000139:chemically induced*; D018931:Antineoplastic Agents, Hormonal / Q000008:administration & dosage / Q000009:adverse effects; D002648:Child; D015331:Cohort Studies; D003907:Dexamethasone / Q000008:administration & dosage / Q000009:adverse effects; D005938:Glucocorticoids / Q000008:administration & dosage / Q000009:adverse effects*; D006801:Humans; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects*; D010913:Pituitary-Adrenal System / Q000187:drug effects*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy*; D011239:Prednisolone / Q000008:administration & dosage / Q000009:adverse effects; D016032:Randomized Controlled Trials as Topic
chemical_list: D018931:Antineoplastic Agents, Hormonal; D005938:Glucocorticoids; D003907:Dexamethasone; D011239:Prednisolone