Review question
We reviewed the evidence for suppression of the stress system/hypothalamic-pituitary-adrenal (HPA) axis (how often does it happen? how long does the suppression persist?) after treatment with synthetic stress hormones/glucocorticoids in children with acute lymphoblastic leukaemia (ALL).
Background
ALL is the most frequent type of cancer among children. Glucocorticoids, such as prednisone and dexamethasone, play a very important role in the treatment of ALL. However, high-dose glucocorticoids can cause suppression of the stress axis (in medical terms, the hypothalamic-pituitary-adrenal (HPA) axis). Suppression of the stress or HPA axis results in inadequate cortisol production. Cortisol is the natural stress hormone found in humans. When this hormone is produced insufficiently, response to stressors (e.g. trauma, surgery, inflammation) may be impaired and defence against infections may be inadequate. Therefore, insufficient production of cortisol 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.
Study characteristics
This systematic review included eight cohort studies and two randomised studies with a total number of 298 patients. All studies assessed adrenal function in paediatric patients treated with glucocorticoids for ALL. The evidence is current to December 2016. None of these studies assessed the HPA axis at the level of the hypothalamus, the pituitary, or both. We could not combine the results of different studies because of heterogeneity.
Key results
Adrenal insufficiency occurred in nearly all children during the first days after completion of glucocorticoid therapy. Most children recovered within a few weeks, but a small number had ongoing adrenal insufficiency lasting up to 34 weeks. Three studies looked into differences in duration of adrenal insufficiency between children who received prednisone and those who were given dexamethasone (two types of glucocorticoids). Two of these three studies found no differences. In the other study, children who received prednisone recovered earlier than those who received dexamethasone. Also, treatment with a certain antifungal drug (fluconazole) seemed to prolong the duration of adrenal insufficiency. Two studies investigated this. Finally, two studies evaluated the presence of infection/stress as a risk factor for adrenal insufficiency. One study found no relationship. The other study reported that increased infection was associated with a longer duration of adrenal insufficiency.
More high-quality research is needed to define the exact occurrence and duration of HPA axis suppression. Then adequate guidelines for glucocorticoid replacement therapy can be formulated.
Quality of the evidence
All of the included studies had some risk of bias issues.
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. No data were available on the levels of the hypothalamus and the pituitary; therefore, we could draw no conclusions regarding these outcomes. Clinicians may 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, additional high-quality research is needed to inform evidence-based guidelines for glucocorticoid replacement therapy.
Special attention should be paid to patients receiving fluconazole therapy, and perhaps similar antifungal drugs, as these treatments may prolong the duration of adrenal insufficiency, especially when administered at a dose higher than 10 mg/kg/d.
Finally, it would be relevant to investigate further the relationship between present infection/stress and adrenal insufficiency in a larger, separate study specially designed for this purpose.
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 infection, which remain 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 the second update of a previously published Cochrane review.
To examine the occurrence and duration of HPA axis suppression after (each cycle of) glucocorticoid therapy for childhood ALL.
We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 11), MEDLINE/PubMed (from 1945 to December 2016), and Embase/Ovid (from 1980 to December 2016). 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 up to and including 2016, and the American Society of Pediatric Hematology/Oncology from 2014 up to and including 2016), and ongoing trial databases (the International Standard Registered Clinical/Social Study Number (ISRCTN) register via http://www.controlled-trials.com, the National Institutes of Health (NIH) register via www.clinicaltrials.gov, and the International Clinical Trials Registry Platform (ICTRP) of the World Health Organization (WHO) via apps.who.int/trialsearch) on 27 December 2016.
All study designs, except case reports and patient series with fewer than 10 children, examining effects of glucocorticoid therapy for childhood ALL on HPA axis function.
Two review authors independently performed study selection. One review author extracted data and assessed 'Risk of bias'; another review author checked this information.
We identified 10 studies (total of 298 children; we identified two studies for this update) including two randomised controlled trials (RCTs) that assessed adrenal function. None of the included studies assessed the HPA axis at the level of the hypothalamus, the pituitary, or both. Owing to substantial differences between studies, we could not pool results. All studies had risk of bias issues. Included studies demonstrated that adrenal insufficiency occurs in nearly all children during the first days after cessation of glucocorticoid treatment for childhood ALL. Most children recovered within a few weeks, but a small number of children had ongoing adrenal insufficiency lasting up to 34 weeks.
Included studies evaluated several risk factors for (prolonged) adrenal insufficiency. First, three studies including two RCTs investigated the difference between prednisone and dexamethasone in terms of occurrence and duration of adrenal insufficiency. The RCTs found no differences between prednisone and dexamethasone arms. In the other (observational) study, children who received prednisone recovered earlier than children who received dexamethasone. Second, treatment with fluconazole appeared to prolong the duration of adrenal insufficiency, which was evaluated in two studies. One of these studies reported that the effect was present only when children received fluconazole at a dose higher than 10 mg/kg/d. Finally, two studies evaluated the presence of infection, stress episodes, or both, as a risk factor for adrenal insufficiency. In one of these studies (an RCT), trial authors found no relationship between the presence of infection/stress and adrenal insufficiency. The other study found that increased infection was associated with prolonged duration of adrenal insufficiency.