Suppression of the stress system in children who received synthetic stress hormones for acute lymphoblastic leukaemia
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).
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.
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.
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.