Hypothalamic-pituitary-adrenal (HPA) axis suppression after treatment with glucocorticoid therapy for childhood acute lymphoblastic leukaemia

Acute lymphoblastic leukaemia (ALL) is the most frequent type of cancer to occur in children. Glucocorticoids, like prednisone and dexamethasone, play a major role in the treatment of ALL. However, high-dose glucocorticoids can cause HPA axis suppression. Suppression of the HPA axis resulting in inadequate cortisol production may cause an impaired response to stressors (for example trauma, surgery, or inflammation) and an inadequate host defence against infections, and remains a cause of morbidity and death in childhood. The occurrence and duration of HPA axis suppression after glucocorticoid therapy for childhood ALL are unclear.

This systematic review included six cohort studies and two randomised studies that assessed the adrenal function. None of the studies assessed the HPA axis at the level of the hypothalamus, pituitary, or both. All of the studies had some methodological limitations, and we could not pool results because of the heterogeneity. Adrenal insufficiency occurred in nearly all of the children in the first days after cessation of glucocorticoid therapy. The majority of children recovered within a few weeks, but a small number of children had ongoing adrenal insufficiency lasting up to 34 weeks. More high-quality research is needed to assess the exact occurrence and duration of HPA axis suppression in order to formulate adequate guidelines for glucocorticoid replacement therapy.

Authors' conclusions: 

We concluded 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.

Finally, it would be relevant to further investigate the relationship between present infection/stress and adrenal insufficiency in a larger, separate study specially designed for this purpose.

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Background: 

Glucocorticoids play a major role in the treatment of acute lymphoblastic leukaemia (ALL). However, supraphysiological doses can suppress 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. Suppression commonly occurs in the first days after cessation of glucocorticoid therapy, but the exact duration is unclear. This review is an update of a previously published Cochrane review.

Objectives: 

To examine the occurrence and duration of HPA axis suppression after (each cycle of) glucocorticoid therapy for childhood ALL.

Search strategy: 

We searched the Cochrane Central Register of Controlled Trials (CENTRAL; Issue 6, 2014), MEDLINE/PubMed (from 1945 to June 2014), and EMBASE/Ovid (from 1980 to June 2014). In addition, we searched reference lists of relevant articles, conference proceedings (the International Society for Paediatric Oncology and the American Society of Clinical Oncology from 2005 to 2013), and ongoing trial databases (the ISRCTN register and the NIH register via http://www.controlled-trials.com in June 2014).

Selection criteria: 

All study designs, except case reports and patient series with fewer than 10 children, examining the effect of glucocorticoid therapy for childhood ALL on the HPA axis function.

Data collection and analysis: 

Two review authors independently performed the study selection. One review author performed the data extraction and 'Risk of bias' assessment, which another review author checked.

Main results: 

We identified eight studies (total of 218 children), including two randomised controlled trials (RCTs), that 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, we could not pool results. All of the studies had some methodological limitations. The included studies demonstrated that adrenal insufficiency occurs in nearly all children in the first days after cessation of glucocorticoid treatment for childhood ALL. The majority of children recovered within a few weeks, but a small number of children had ongoing adrenal insufficiency lasting up to 34 weeks. In the RCTs, the occurrence and duration of adrenal insufficiency did not differ between the prednisone and dexamethasone arms. In one study, it appeared that treatment with fluconazole prolonged the duration of adrenal insufficiency. Furthermore, one of the studies evaluated the presence of infections or stress episodes, or both as a risk factor for adrenal insufficiency. The authors found no relationship between the presence of infection/stress and adrenal insufficiency.

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