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