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

Niki Rensen; Reinoud JBJ Gemke; Elvira C van Dalen; Joost Rotteveel; Gertjan JL Kaspers

doi:10.1002/14651858.CD008727.pub4

Cochrane Database of Systematic Reviews

Supresión del eje hipotalámico‐hipofisario‐suprarrenal (HHS) después del tratamiento con glucocorticoides para la leucemia linfoblástica aguda en niños

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DOI:

https://doi.org/10.1002/14651858.CD008727.pub4 Copiar DOI

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Cochrane Database of Systematic Reviews

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06 noviembre 2017see what's new

Tipo:

Intervention

Etapa:

Review

Grupo Editorial Cochrane:

Grupo Cochrane de Cáncer infantil

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Copyright © 2017 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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Autores

Niki Rensen

Correspondencia a: Department of Pediatrics, Division of Oncology/Hematology, VU University Medical Center, Amsterdam, Netherlands

[email protected]
Reinoud JBJ Gemke

Department of Pediatrics, Division of General Pediatrics and other subspecialties, VU University Medical Center, Amsterdam, Netherlands
Elvira C van Dalen

Department of Paediatric Oncology, Emma Children's Hospital/Academic Medical Center, Amsterdam, Netherlands
Joost Rotteveel

Department of Pediatrics, Division of Endocrinology, VU University Medical Center, Amsterdam, Netherlands
Gertjan JL Kaspers

Department of Pediatrics, Division of Oncology/Hematology, VU University Medical Center, Amsterdam, Netherlands

Contributions of authors

Niki Rensen:

identified studies meeting the inclusion criteria;
searched for unpublished and ongoing studies;
performed data extraction and 'Risk of bias' assessment of included studies;
analysed data and interpreted results of analysis; and
revised the manuscript.

Reinoud Gemke and Gertjan Kaspers:

identified studies meeting the inclusion criteria;
checked data extraction and 'Risk of bias' assessment of included studies;
contributed to interpretation of results; and
critically reviewed the protocol and the manuscript.

Elvira van Dalen:

contributed to analysis of data and interpretation of results; and
critically reviewed the manuscript.

Joost Rotteveel contributed to interpretation of results and critically reviewed the protocol and the manuscript.

All review authors approved the final report.

Sources of support

Internal sources

No sources of support supplied

External sources

Dutch Cancer Society, Netherlands.
‘Stichting Kinderen Kankervrij’ (KiKa), Netherlands.

Declarations of interest

None.

Acknowledgements

We would like to acknowledge the Editorial Base of Cochrane Childhood Cancer for advice and support provided. We thank Leontien Kremer for assistance in preparing the protocol of this review; Peter van de Ven for statistical advice; and Y. Loke and S. Neggers ‐ peer reviewers for the first version of this review ‐ whose comments have improved this paper. We also would like to thank Anna Font Gonzalez for assistance in translating one of the articles. Maartje S. Gordijn was a co‐author of the protocol for this systematic review, the original version, and the first update; we thank her for her valuable input. Finally, we thank all study authors for providing additional information upon request.

The Editorial Base of Cochrane Childhood Cancer is funded by ‘Stichting Kinderen Kankervrij’ (KiKa), the Netherlands.

Version history

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Authors

Version

2017 Nov 06

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

Review

Niki Rensen, Reinoud JBJ Gemke, Elvira C van Dalen, Joost Rotteveel, Gertjan JL Kaspers

https://doi.org/10.1002/14651858.CD008727.pub4

2015 Aug 17

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

Review

Maartje S Gordijn, Niki Rensen, Reinoud JBJ Gemke, Elvira C van Dalen, Joost Rotteveel, Gertjan JL Kaspers

https://doi.org/10.1002/14651858.CD008727.pub3

2012 May 16

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

Review

Maartje S Gordijn, Reinoud JBJ Gemke, Elvira C van Dalen, Joost Rotteveel, Gertjan JL Kaspers

https://doi.org/10.1002/14651858.CD008727.pub2

2010 Oct 06

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

Protocol

Maartje S Gordijn, Reinoud JBJ Gemke, Elvira C van Dalen, Joost Rotteveel, Gertjan JL Kaspers

https://doi.org/10.1002/14651858.CD008727

Differences between protocol and review

In addition to our primary objective of examining the occurrence of hypothalamic‐pituitary‐adrenal (HPA) axis suppression after treatment with glucocorticoids for childhood acute lymphoblastic leukaemia (ALL), as stated in the protocol, we studied the duration of HPA axis suppression.

One review author performed data extraction and 'Risk of bias' assessment of included studies, and two other review authors independently checked this information. This approach differed from that stated in the protocol, which indicated that two independent review authors would extract data and assess ‘Risk of bias’.

In the second update, we searched an additional conference proceeding (ASPHO) (which is a new policy of Cochrane Childhood Cancer). We also searched an additional ongoing trials register (ICTRP/WHO). Furthermore, Cochrane Childhood Cancer adjusted the search strategy for children; as opposed to the earlier version, this is a validated strategy. We did include a new secondary outcome measure based on advancing knowledge of the topic: other possible risk factors (such as fluconazole and presence of infection/stress). Finally, since performing the first update, Cochrane Childhood Cancer has slightly changed the risk of bias criteria for observational studies: Risk estimation should now be assessed only for studies evaluating risk factors. We made the necessary changes for all included studies.

Keywords

MeSH

Medical Subject Headings (MeSH) Keywords

Medical Subject Headings Check Words

Child; Humans;

PICO

Population

Intervention

Comparison

Outcome

El uso y la enseñanza del modelo PICO están muy extendidos en el ámbito de la atención sanitaria basada en la evidencia para formular preguntas y estrategias de búsqueda y para caracterizar estudios o metanálisis clínicos. PICO son las siglas en inglés de cuatro posibles componentes de una pregunta de investigación: paciente, población o problema; intervención; comparación; desenlace (outcome).

Para saber más sobre el uso del modelo PICO, puede consultar el Manual Cochrane.

Figure 1

Study flow diagram.

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Table 1. 'Risk of bias' assessment criteria for observational studies

	Internal validity	External validity
Study group	Selection bias (representative: yes/no): if it consisted of more than 90% of the original cohort of children with ALL treated with glucocorticoids; or if it was a random sample with respect to treatment.	Reporting bias (well defined: yes/no): if treatment protocol was mentioned; and if (cumulative) dose of glucocorticoid treatment was mentioned; and if type of glucocorticoid treatment was mentioned; and if duration of glucocorticoid treatment was mentioned; and if method of cessation of glucocorticoid treatment was mentioned.
Follow‐up	Attrition bias (adequate: yes/no): if outcome was assessed at end date of the study for 60% to 90% of study group; or if outcome was assessed for more than 90% of the study group but with an unknown end date.	Reporting bias (well defined: yes/no): if length of follow‐up was mentioned; and if frequency of measuring outcomes was mentioned.
Outcome	Detection bias (blinding: yes/no): if outcome assessor was blinded to glucocorticoid treatment.	Reporting bias (well defined: yes/no): if methods of detection were described; and if outcome definition was objective and precise.
Risk estimation	Confounding (adjustment for other factors: yes/no): if important prognostic factors (i.e. age, sex, cotreatment) or follow‐up was taken adequately into account.	Analysis (well defined: yes/no): if risk ratio, odds ratio, attributable risk, linear or logistic regression model, mean difference, or Chi² statistic was calculated.
ALL: acute lymphoblastic leukaemia.

Table 1. 'Risk of bias' assessment criteria for observational studies

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Table 2. 'Risk of bias' assessment criteria for randomised controlled trials

Selection bias

Sequence generation (adequate: yes/no):

if the rule for allocating interventions to participants was based on some chance (random) process.

Allocation concealment (adequate: yes/no):

if the randomisation method did not allow investigator and child to know or influence allocation of treatment before eligible children entered the study.

Performance bias
Blinding of care providers (yes/no):

if knowledge of the allocated intervention was adequately prevented during the study.

Blinding of participants (yes/no):

if knowledge of the allocated intervention was adequately prevented during the study.

Detection bias
Blinding of outcome assessors (yes/no; assessed for each outcome separately):

if knowledge of the allocated intervention was adequately prevented during the study.

Attrition bias
Incomplete outcome data (adequate: yes/no; assessed for each outcome separately):

if incomplete outcome (attrition and exclusions) data have been adequately addressed.

Reporting bias
Selective outcome reporting (yes/no):

if reports of the study were free of the suggestion of selective outcome reporting.

Other bias
Other bias (yes/no):

if the study was free of other problems (i.e. potential source of bias related to specific study design, premature termination of the study due to some data‐dependent process, extreme baseline imbalance) that could put it at high risk of bias.

Table 2. 'Risk of bias' assessment criteria for randomised controlled trials

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Table 3. Risk of bias in included observational studies

Study	Representative study group	Complete follow‐up assessment	Blinded outcome assessor	Adjustment for important confounders	Well‐defined study group	Well‐defined follow‐up	Well‐defined outcome	Well‐defined risk estimation
Cunha 2004	No, based on additional information provided by trial authors, the study group described did not consist of more than 90% of the original cohort and was not a random sample.	Yes, outcome was assessed for 60% to 90% of the study group at the end date of the study.	Unclear whether outcome assessor was blinded to glucocorticoid treatment		Yes, treatment protocol and (cumulative) dose, type, duration, and form of cessation of glucocorticoid treatment were mentioned.	Yes, length of follow‐up and frequency of measuring were mentioned.	Yes, methods of detection were described, and outcome definition was objective and precise.
Felner 2000	Yes, based on additional information provided by trial authors, the study group described consisted of more than 90% of the original cohort.	Yes, outcome was assessed for 60% to 90% of the study group at the end date of the study.	Unclear whether outcome assessor was blinded to glucocorticoid treatment		No, treatment protocol was not mentioned.	Yes, length of follow‐up and frequency of measuring were mentioned.	Yes, methods of detection were described, and outcome definition was objective and precise.
Kuperman 2001	Yes, based on additional information provided by trial authors, the study group described consisted of more than 90% of the original cohort.	Yes, outcome was assessed for 60% to 90% of the study group at the end date of the study.	Unclear whether outcome assessor was blinded to glucocorticoid treatment		No, treatment protocol was not mentioned.	Yes, length of follow‐up and frequency of measuring were mentioned.	Yes, methods of detection were described, and outcome definition was objective and precise.
Mahachoklertwattana 2004	Unclear whether the study group consisted of more than 90% of the original cohort, or if it was a random sample	Yes, outcome was assessed for 60% to 90% of the study group at the end date of the study.	Unclear whether outcome assessor was blinded to glucocorticoid treatment		Yes, treatment protocol and (cumulative) dose, type, duration, and form of cessation of glucocorticoid treatment were mentioned.	Yes, length of follow‐up and frequency of measuring were mentioned.	Yes, methods of detection were described, and outcome definition was objective and precise.
Perdomo‐Ramírez 2016	Unclear whether the study group consisted of more than 90% of the original cohort, or if it was a random sample	Yes, outcome was assessed for 60% to 90% of the study group at the end date of the study.	No, outcome assessor was not blinded to glucocorticoid treatment. This information was based on additional information provided by trial authors.		Yes, treatment protocol and (cumulative) dose, type, and duration of glucocorticoid therapy were mentioned.	Yes, length of follow‐up and frequency of measuring were mentioned.	Yes, methods of detection were described, and outcome definition was objective and precise.	Yes, mean difference was calculated.
Petersen 2003	Yes, the study group described consisted of more than 90% of the original cohort.	Yes, outcome was assessed for 60% to 90% of the study group at the end date of the study.	Unclear whether outcome assessor was blinded to glucocorticoid treatment.	Yes, important prognostic factors or follow‐up was taken into account.	Yes, treatment protocol and (cumulative) dose, type, and duration of glucocorticoid treatment were mentioned. Information on the method of cessation of glucocorticoid treatment was based on additional information provided by trial authors.	Yes, length of follow‐up and frequency of measuring were mentioned.	Yes, methods of detection were described, and outcome definition was objective and precise.	No, risk ratio, odds ratio, attributable risk, linear or logistic regression model, mean difference, or Chi² statistic was not calculated.
Rix 2005	Yes, the study group described consisted of more than 90% of the original cohort.	Yes, outcome was assessed for 60% to 90% of the study group at the end date of the study.	No, outcome assessor was not blinded to glucocorticoid treatment.		Yes, treatment protocol and (cumulative) dose, type, and duration of glucocorticoid treatment were mentioned. Information on the method of cessation of glucocorticoid treatment was based on additional information provided by trial authors.	Yes, length of follow‐up and frequency of measuring were mentioned.	Yes, methods of detection were described, and outcome definition was objective and precise.
Salem 2015	Unclear whether the study group consisted of more than 90% of the original cohort, or if it was a random sample	Unclear whether outcome was assessed for 60% to 90% at the end date of the study.	Unclear whether outcome assessor was blinded to glucocorticoid treatment	Yes, important prognostic factors or follow‐up was taken into account.	No, duration of tapering of glucocorticoid treatment was not mentioned.	Yes, length of follow‐up and frequency of measuring were mentioned.	Yes, methods of detection were described, and outcome definition was objective and precise.	Yes, mean difference was calculated.

Table 3. Risk of bias in included observational studies

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Table 4. Risk of bias in included randomised controlled trials

Study	Adequate sequence generation?	Adequate allocation concealment?	Blinding?	Incomplete outcome data addressed?	Free of selective reporting?	Free of other bias?
Einaudi 2008	Yes, according to additional information provided by trial authors, the rule for allocating interventions to children was based on some chance (random) process.	Yes, according to additional information provided by trial authors, the randomisation method did not allow investigator and child to know or influence allocation of treatment before eligible children entered the study.	Based on additional information provided by trial authors, care providers, children, and outcome assessors were not blinded.	Yes, no outcome data were missing.	No, "adrenal function completely recovered in the 12 children evaluated with subsequent low‐dose ACTH test (in 4, 3, and 5 patients after 4, 8, and 10 weeks, respectively)". However, it was not reported which of these children received prednisone and which received dexamethasone. Therefore, not all of the study's prespecified primary outcomes were reported.	Yes
Kuperman 2012	Yes, the rule for allocating interventions to children was based on some chance (random) process.	Yes, according to additional information provided by trial authors, the randomisation method did not allow investigator and child to know or influence allocation of treatment before eligible children entered the study.	Yes, based on additional information provided by trial authors, care providers, children, and outcome assessors were all blinded.	Outcomes were assessed for 83% to 93% of the study population.	Yes	Yes
ACTH: adrenocorticotropic hormone.

Table 4. Risk of bias in included randomised controlled trials

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Table 5. Prevalence and duration of adrenal insufficiency evaluated by an ACTH stimulation test

Felner et al	Therapy: dexamethasone (cumulative dose 168 mg/m²)
Time after cessation	Before	1 day	4 weeks	8 weeks
n insufficient/n total	0/10	10/10	3/10	0/10
Petersen et al (1)	Therapy: prednisolone (cumulative dose 2257.5 mg/m²)^a
Time after cessation	1 week	3 weeks	7 weeks	End of follow‐up: 10, 11, 11, and 19 weeks, respectively
n insufficient/n total	7/10	6/10	4/10	4/10
Petersen et al (2)	Therapy: dexamethasone (cumulative dose 236.25 mg/m²)^b
Time after cessation	1 week	3 weeks	7 weeks	End of follow‐up: 16, 33, and 34 weeks, respectively
n insufficient/n total	5/7	4/7	3/7	3/7
ACTH: adrenocorticotropic hormone. ^a One child received additional 840 mg/m² prednisolone during the period of adrenal insufficiency. ^b These children received prednisolone 2257.5 mg/m² as induction therapy before. Three high‐risk patients received an additional 560 mg/m² prednisolone in advance. Furthermore, owing to persistent adrenal insufficiency, one of these high‐risk children received an additional 420 mg/m² prednisolone during the period of insufficiency, and the other two high‐risk children received an additional 1260 mg/m² prednisolone during that period.

Table 5. Prevalence and duration of adrenal insufficiency evaluated by an ACTH stimulation test

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Table 6. Prevalence and duration of adrenal insufficiency evaluated by a low‐dose ACTH stimulation test

Mahachoklertwattana et al	Therapy: prednisolone (cumulative dose 1120 mg/m²)^a
Time after cessation	2 weeks	4 weeks	8 weeks	12 weeks	20 weeks
n insufficient/n total^b	11/24	9/24	7/24	3/24	3/24
Rix et al (1)	Therapy: prednisolone (cumulative dose 2257.5 mg/m²)
Time after cessation	Before	1 day	3 days	5 days	‐
n insufficient/n total^b	0/13	16/17	8/15	8/17	‐
Rix et al (2)	Therapy: prednisolone (cumulative dose 420 mg/m²)^c
Time after cessation	Before	2 days	‐	‐	‐
n insufficient/n total^b	2/13	13/13	‐	‐	‐
Rix et al (3)	Therapy: dexamethasone (cumulative dose 236.25 mg/m²)^c
Time after cessation	Before	1 day	3 days	7 days	‐
n insufficient/n total^b	0/5	2/2	3/5	1/5	‐
Einaudi et al (1)	Therapy: prednisone (cumulative dose 1477.5 mg/m²)^d
Time after cessation	1 day	7 to 14 days	28 days	42 days	10 weeks
n insufficient/n total^b	32/40	8/32	5/8	5/5	0/5
Einaudi et al (2)	Therapy: dexamethasone (cumulative dose 246.25 mg/m²)^d
Time after cessation	1 day	7 to 14 days	28 days	42 days	10 weeks
n insufficient/n total^b	20/24	4/20	3/4	3/3	0/3
Kuperman et al 2012 (1)	Therapy: prednisone (cumulative dose 1120 mg/m²)
Time after cessation	Before (4 weeks after start of glucocorticoid treatment)	1 week	2 weeks	3 weeks	4 weeks
n insufficient/n total^b	5/14	3/13	4/14	5/14	4/15
Kuperman et al 2012 (2)	Therapy: dexamethasone (cumulative dose 168 mg/m²)
Time after cessation	Before (4 weeks after start of glucocorticoid treatment)	1 week	2 weeks	3 weeks	4 weeks
n insufficient/n total^b	1/12	3/13	5/11	3/10	3/12
Perdomo‐Ramírez et al 2015	Therapy: prednisone (cumulative dose 1837.5 mg/m²)
Time after cessation	Before	3 days	1 week	2 weeks	4 weeks
n insufficient/n total^b	0/40	29/40	11/28	3/11	0/3
Salem et al 2015 (1) (both induction and reinduction phases)	Therapy: dexamethasone (cumulative dose unknown)
Time after cessation	Before (at diagnosis)	1 day to 18 weeks			20 weeks
n insufficient/n total^b	5/20	No data on patient level were available.			All children recovered.^e
Salem et al 2015 (2) (both induction and reinduction phases)	Therapy: prednisone (cumulative dose unknown)
Time after cessation	Before (at diagnosis)	1 day to 18 weeks			20 weeks
n insufficient/n total^b	6/20	No data on patient level were available.			All children recovered.^e
ACTH, adrenocortiotropic hormone. ^a Four weeks after completion of induction therapy, children received maintenance therapy consisting of a 7‐day course of high‐dose dexamethasone 8 mg/m²/d every 4 weeks. Cumulative dose depended on how long the child had been followed up. ^b If not all children were tested at all time points, then "n total" = n tested. ^c All children first received prednisolone (cumulative dose 2257.5 mg/m²). ^d After 7 days of prednisone (60 mg/m²/d, cumulative dose 420 mg/m²). ^eFrom 4 weeks after cessation of glucocorticoid therapy, only children who were adrenal insufficient at that time point underwent further low‐dose ACTH testing every 2 weeks until adrenal recovery. Therefore it is unknown how many children were tested at 20 weeks (in both induction and reinduction phases).

Table 6. Prevalence and duration of adrenal insufficiency evaluated by a low‐dose ACTH stimulation test

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Table 7. Prevalence and duration of adrenal insufficiency evaluated by basal morning cortisol values

Cunha et al	No data on patient levels were available.
Time after cessation
n insufficient/n total
Kuperman et al 2001	Therapy: dexamethasone (cumulative dose 252 mg/m²)^a
Time after cessation	Before	1 week	2 weeks
n insufficient/n total	0/15	4/15	4/14
^a Results based on basal cortisol levels; cutoff level 7 µg/dL = 194 nmol/L.

Table 7. Prevalence and duration of adrenal insufficiency evaluated by basal morning cortisol values

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Supresión del eje hipotalámico‐hipofisario‐suprarrenal (HHS) después del tratamiento con glucocorticoides para la leucemia linfoblástica aguda en niños

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Medical Subject Headings Check Words

PICO

PICO

Population

Intervention

Comparison

Outcome

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Keywords

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Medical Subject Headings Check Words

PICO

PICO

Population

Intervention

Comparison

Outcome

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