Supresión del eje hipotalámico‐hipofisario‐suprarrenal (HHS) después del tratamiento con glucocorticoides para la leucemia linfoblástica aguda en niños
Referencias
References to studies included in this review
References to studies excluded from this review
References to studies awaiting assessment
Additional references
References to other published versions of this review
Characteristics of studies
Characteristics of included studies [ordered by study ID]
| Methods | Study type: prospective multi‐centre study | |
| Participants | 35 children (median age at diagnosis/first HPA axis function test 6.9 years (range 1.2 to 14.4 years); 17 boys and 18 girls) with ALL | |
| Interventions | Treatment according to the Brazilian Group for Treatment of ALL, 1993 protocol (GBTLI‐93). Specific medication not defined No control intervention | |
| Outcomes | Specific HPA axis function test: ovine CRH stimulus test at 8 a.m. (after an overnight fasting period), including cortisol basal morning value Moment of testing: before introduction of dexamethasone, on 8th and 28th days of dexamethasone use, and 48 hours and 1 month after cessation of dexamethasone. Tests were performed during treatment for ALL. | |
| Notes | 7 children were lost to follow‐up at testing on the 8th and 28th days of dexamethasone use, 1 more child at 48 hours after cessation of dexamethasone, and 7 more children at 1 month after cessation of dexamethasone. Length of follow‐up after glucocorticoid therapy: 1 month Funding source: Fundação de Amparo à Pesquisa do Estado de Minas Gerais (FAPEMIG) Declaration of interest among primary researchers: not mentioned | |
| Methods | Study type: multi‐centre RCT | |
| Participants | 64 children (24 who received dexamethasone: mean age at diagnosis 4 years 11 months (range 1 year 2 months to 12 years 1 month), 11 boys and 13 girls; 40 children who received prednisone: mean age at diagnosis 6 years 9 months (range 1 year 2 months to 17 years 6 months), 18 boys and 22 girls) with ALL. This information was based on additional information provided by trial authors. | |
| Interventions | Treatment according to the AIEOP ALL 2000 study. Induction phase 1A: prednisone (from day 8 randomisation prednisone or dexamethasone), vincristine, daunorubicin, Escherichia coli L‐asparaginase, and IT methotrexate. Induction phase 1B: 6‐mercaptopurine, cyclophosphamide, cytosine‐arabinoside, and IT methotrexate | |
| Outcomes | Specific HPA axis function test: basal cortisol between 8 and 9 a.m. at diagnosis and low‐dose ACTH test between 8 and 11 a.m. (1 µg/1.74 m2 of tetracosactrin (Synacthen, Novartis, Basel, Switzerland), basal morning value cortisol, after 30 and 60 minutes) Moment of testing: at diagnosis, basal cortisol was determined. The first low‐dose ACTH stimulation test was performed 24 hours after the last tapering dose of glucocorticoid (on day 39), which was given as a single dose in the morning. Tests were performed during treatment for ALL. This study addressed type of glucocorticoid as a risk factor. | |
| Notes | 0 children were lost to follow‐up. Length of follow‐up after glucocorticoid therapy: Children with suppressed levels underwent further low‐dose ACTH testing between 7 and 14 days from the last glucocorticoid dose and every 2 weeks thereafter until cortisol levels were normalised. Total follow‐up duration was 10 weeks. Funding source: not mentioned Declaration of interest among primary researchers: not mentioned | |
| Methods | Study type: prospective single‐centre study | |
| Participants | 10 children (mean age at diagnosis 5.3 ± 2.9 years (range 2.0 to 9.9 years); 7 boys and 3 girls) with early B‐cell lineage ALL | |
| Interventions | Induction therapy: dexamethasone, vincristine, L‐asparaginase, and daunorubicin. High‐risk therapy: 1 additional lumbar puncture with IT chemotherapy during induction No control intervention | |
| Outcomes | Specific HPA axis function test: 250 µg cosyntropin stimulation test (synthetic corticotrophin 1‐24/ACTH test) IV between 8 and 10 a.m. (Cortrosyn, Organon) (basal morning value cortisol and after 45 minutes) Moment of testing: at diagnosis (baseline), 24 hours after completion of the dexamethasone course, and every 4 weeks thereafter until normalisation of adrenal function. Tests were performed during treatment for ALL. | |
| Notes | 0 children were lost to follow‐up. Length of follow‐up after glucocorticoid therapy: Children with suppressed levels underwent further testing every 4 weeks thereafter until cortisol levels were normalised. Total follow‐up duration was 8 weeks. Funding source: National Institutes of Health grants Declaration of interest among primary researchers: not mentioned | |
| Methods | Study type: prospective single‐centre study | |
| Participants | 15 children with ALL (age at diagnosis 5 months to 12 years; 5 boys and 10 girls) | |
| Interventions | Dexamethasone, daunomycin, vincristine, L‐asparaginase, and cytosine arabinoside No control intervention | |
| Outcomes | Specific HPA axis function test: 1 µg/kg ovine CRH stimulation test IV, after an 8‐hour fast, between 8 and 9 a.m. (basal morning value cortisol and after 15, 30, 60, and 90 minutes) Moment of testing: before dexamethasone therapy (baseline), 7 and 14 days after last dose of dexamethasone. It was not defined whether tests were performed during treatment for ALL. | |
| Notes | Additional information provided by trial authors revealed that 1 child was lost to follow‐up 14 days after administration of dexamethasone. Length of follow‐up after glucocorticoid therapy: 14 days Funding source: not mentioned Declaration of interest among primary researchers: not mentioned | |
| Methods | Study type: randomised double‐blind comparative study Setting: Instituto da Criança (Children’s Institute), São Paulo University Medical School Hospital, Brazil. This information was based on additional information provided by trial authors. | |
| Participants | 29 children (16 children who received prednisone: mean age at diagnosis 8.0 ± 4.4 years; 3 boys and 13 girls; 13 children who received dexamethasone: mean age at diagnosis 5.3 ± 3.6 years, 9 boys and 4 girls) with ALL. Control group for determining cutoff peak cortisol level: 16 children (mean age at HPA axis function test 8.1 ± 2.7 years; 7 boys and 9 girls) suspected of having any endocrinopathy other than adrenal insufficiency | |
| Interventions | Treatment according to the Brazilian Childhood Leukemia Protocol 99. Standard remission induction phase: vincristine, L‐asparaginase, daunorubicin, methotrexate (IT), cytarabine (IT), and dexamethasone (IT). This information was based on additional information provided by trial authors. Type of glucocorticoid therapy: remission induction phase: Children were randomised to receive prednisone (40 mg/m2/d) or dexamethasone (6 mg/m2/d), both divided into 3 daily doses for 28 days, without tapering. Cumulative dose of glucocorticoid therapy: prednisone 1120 mg/m2 or dexamethasone 168 mg/m2 Duration of glucocorticoid therapy: 28 days Methods of cessation of glucocorticoid therapy: abrupt | |
| Outcomes | Specific HPA axis function test: low‐dose ACTH test between 8 and 9 a.m. (1.0 µg/m2 of cosyntropin, basal cortisol and after 30 minutes) Moment of testing: intervention groups: before remission induction and subsequently every week after 28 days of glucocorticoid therapy, over a total period of 8 weeks Cutoff limits were defined by the control group: basal cortisol: not defined. Low‐dose ACTH test: normal response ≥ 14.2 µg/dL (≥ 392 nmol/L) after 30 minutes (control group’s mean peak cortisol level minus 1.96 standard deviation) This study addressed type of glucocorticoid and presence of infection/stress (defined as hospitalisation due to fever with or without neutropenia) as risk factors. | |
| Notes | 2 children were lost to follow‐up at final measurement. Moreover, not all children underwent the low‐dose ACTH test every week after remission induction. Information on individual testing schedules and on adrenal recovery per child was not provided. Funding source: research grant from the Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) Declaration of interest among primary researchers: Researchers declared that they had no conflicts of interest. | |
| Methods | Study type: prospective single‐centre study | |
| Participants | 24 children (median age at diagnosis 3.5 years (range 1 to 14 years); 13 boys and 11 girls) with newly diagnosed ALL | |
| Interventions | According to modification of St. Jude Children's Research Hospital Total XIII Protocol for ALL: standard induction therapy: prednisolone, vincristine, L‐asparaginase, doxorubicin, etoposide, and cytosine arabinoside No control intervention | |
| Outcomes | Specific HPA axis function test: serum cortisol level at 8 a.m., at diagnosis (baseline); low‐dose ACTH stimulation test (1 µg cosyntropin (Cortrosyn, Organon, West Orange, NJ)) at 8 a.m. after an overnight fast (basal cortisol and after 30 minutes) Moment of testing: Baseline adrenal function was assessed by determination of serum cortisol level at 8 a.m. before induction therapy. The first low‐dose ACTH stimulation test was performed 2 weeks after discontinuation of prednisolone. Children with adrenal insufficiency underwent repeated ACTH testing 4 weeks after completion of the prednisolone course and every 4 weeks thereafter in the morning of the day on which children were admitted for the next course of maintenance chemotherapy until normalisation. Tests were performed during treatment for ALL. | |
| Notes | 0 children were lost to follow‐up. Length of follow‐up after glucocorticoid therapy: up to 20 weeks Funding source: not mentioned Declaration of interest among primary researchers: not mentioned | |
| Methods | Study type: prospective single‐centre study Setting: Hospital La Misericordia, Bogota, Colombia Information was based on additional information provided by trial authors. | |
| Participants | 40 children with newly diagnosed ALL (mean age at diagnosis 8.5 years (range 2 to 17 years); 21 boys and 19 girls) | |
| Interventions | According to the Berlin‐Frankfurt‐Münster (BFM) protocol: prednisone, vincristine, daunorubicin, L‐asparaginase Type of glucocorticoid therapy: induction phase: prednisone 60 mg/m2 for 28 consecutive days with 9 days of tapering No control intervention | |
| Outcomes | Specific HPA axis function test: basal cortisol and ACTH levels at baseline; low‐dose ACTH test (1 µg Synacthen) between 7 and 8 a.m. at time points after cessation of glucocorticoid therapy (see below). This information was based on additional information provided by trial authors. Moment of testing: Baseline adrenal function was assessed by basal cortisol and ACTH levels before induction therapy. The first low‐dose ACTH stimulation test was performed 3 days after cessation of prednisone. Children with adrenal insufficiency underwent repeated low‐dose ACTH testing 7, 14, and 30 days after cessation of glucocorticoid therapy until normalisation of adrenal function. Tests were performed during treatment for ALL. Cutoff limits defined by original studies: basal cortisol: 6 to 30 µg/dL, baseline ACTH: 4.4 to 22 pmol/L. Low‐dose ACTH test: normal response ≥ 18 µg/dL (≥ 500 nmol/L) | |
| Notes | One child died during follow‐up. Length of follow‐up after glucocorticoid therapy: up to 30 days. Funding source: Premio de Investigación (Research award), Josefa Cualla de Barberi Declaration of interest among primary researchers: Researchers declared that they had no conflicts of interest. | |
| Methods | Study type: prospective single‐centre study | |
| Participants | 17 children (median age at diagnosis 5.4 years (range 2 to 15 years)) with ALL | |
| Interventions | According to risk groups by NOPHO ALL‐1992 or ALL‐2000 protocol. Ten children were studied after receiving prednisolone, weekly vincristine, 4 doses of IT methotrexate, L‐asparaginase, and doxorubicin. Seven additional children were studied following reinduction therapy with dexamethasone, weekly vincristine and daunorubicin, 4 doses of L‐asparaginase, and IT methotrexate. No control intervention | |
| Outcomes | Specific HPA axis function test: ACTH stimulation test (250 µg tetracosactide (Synacthen, Novartis)) between 8 and 11 a.m. (basal cortisol and after 30 and 60 minutes) Moment of testing: Adrenal function was assessed by an ACTH stimulation test within 2 weeks after discontinuation of glucocorticoid therapy. Testing was repeated every 3 to 5 weeks until recovery or end of follow‐up. Tests were performed during treatment for ALL. Fluconazole therapy was evaluated as a risk factor for adrenal insufficiency. | |
| Notes | 0 children were lost to follow‐up. Length of follow‐up after glucocorticoid therapy: fluctuating Funding source: not mentioned Declaration of interest among primary researchers: not mentioned | |
| Methods | Study type: prospective multi‐centre study | |
| Participants | 24 children (median age at diagnosis 4.5 years (range 1.8 to 14.6 years); 17 boys and 7 girls) with newly diagnosed ALL. 12 had standard‐risk ALL according to Nordic risk criteria, 7 had intermediate‐risk ALL, and 5 had high‐risk ALL. | |
| Interventions | According to NOPHO ALL‐92 protocol: No control intervention | |
| Outcomes | Specific HPA axis function test: low‐dose ACTH stimulation test (1 µg tetracosactide (Synacthen, Novartis) between 8 and 10 a.m. (basal cortisol and after 30 minutes)) Moment of testing: for each child: before 5‐week course of prednisolone (weeks 1 to 5) and on days 1, 3, and 5 after tapering was completed. Before 1‐week course of prednisolone (weeks 14 (standard risk), 28 (high risk), and 37 (intermediate risk)) and on day 2 after cessation. Before 3‐week course of dexamethasone (weeks 25 to 27 (intermediate risk) or 36 to 38 (high risk)), before tapering, and on days 1, 3, and 7 after tapering was completed. Tests were performed during treatment for ALL. Cutoff limits defined by original studies: low‐dose ACTH test: normal response > 500 nmol/L | |
| Notes | Based on additional information provided by trial authors, 5 children were lost to follow‐up. Length of follow‐up after glucocorticoid therapy: varied Funding source: research grants from the Danish Cancer Society Declaration of interest among primary researchers: not mentioned | |
| Methods | Study type: prospective single‐centre study Setting: Pediatric Hematology/Oncology Unit, Children's Hospital, Ain Shams University, Cairo, Egypt | |
| Participants | 40 children (mean age at diagnosis unknown; 22 girls and 18 boys) with newly diagnosed standard‐risk ALL. | |
| Interventions | Induction and reinduction therapy according to CCG‐1991 protocol (dexamethasone, vincristine, L‐asparaginase, daunomycin) or modified BFM‐1990 protocol (prednisone, vincristine, L‐asparaginase, daunomycin), depending on time of diagnosis (before or during and after the year 2006). 20 children were treated according to CCG‐1991 protocol, and 20 children followed the modified BFM‐1990 protocol. Type of glucocorticoid therapy: induction phase CCG‐1991 protocol: dexamethasone 6 mg/m2 for 28 consecutive days, reinduction phase: dexamethasone 6 mg/m2 for 21 consecutive days, both followed by a tapering phase of unknown duration. Induction phase modified BFM‐1990 protocol: prednisone 60 mg/m2 for 28 consecutive days, reinduction phase: prednisone 60 mg/m2 for 21 consecutive days, both followed by a tapering phase of unknown duration Cumulative dose of glucocorticoid therapy: unknown Duration of glucocorticoid therapy: induction phase 28 days, reinduction phase 21 days, both followed by a tapering phase of unknown duration Methods of cessation of glucocorticoid therapy: tapering, duration unknown | |
| Outcomes | Specific HPA axis function test: low‐dose ACTH stimulation test (1 µg tetracosactide (Synacthen, Novartis) between 8 and 11 a.m. (basal cortisol and after 30 minutes)) Moment of testing: at diagnosis, and during both induction and reinduction at the following time points: immediately after last steroid course, 2 weeks after end of glucocorticoid treatment, 4 weeks after end of glucocorticoid treatment, and every 2 weeks thereafter until HPA axis recovery was reached. Additionally, adrenal function was tested at the time of an infectious event. Tests were performed during treatment for ALL. Cutoff limits defined by original studies: low‐dose ACTH test: normal response > 18 µg/dL (> 500 nmol/L) Type of glucocorticoid, fluconazole therapy, and presence of infection (study authors stated: The duration and frequency of hospitalisation for septic episodes, number of days with neutropenia > 500/mm³ were recorded. Infectious events were graded from mild to severe according to whether febrile neutropenic patients were managed as outpatients or needed hospitalisation for antimicrobial coverage. We recorded data about whether fluconazole (FCZ) was used or not in the febrile event and the dose given (< 10 mg/kg/d or more)) were evaluated as risk factors for (prolonged) adrenal insufficiency. | |
| Notes | Children lost to follow‐up: unknown Length of follow‐up after glucocorticoid therapy: up to 20 weeks Funding source: none Declaration of interest among primary researchers: Researchers declared that they had no conflicts of interest. | |
ACTH: adrenocorticotropic hormone.
AIEOP: Associazione Italiana Ematologia e Oncologia.
ALL: acute lymphoblastic leukaemia.
CRH: corticotrophin‐releasing hormone.
HPA: hypothalamic‐pituitary‐adrenal.
IT: intrathecal.
IV: intravenous.
NOPHO: Nordic Society of Pediatric Hematology and Oncology.
RCT: randomised controlled trial.
Characteristics of excluded studies [ordered by study ID]
| Study | Reason for exclusion |
| HPA axis was not examined. | |
| No data on intervention (dose, duration, methods of cessation of glucocorticoid therapy) | |
| HPA axis function was examined only during glucocorticoid treatment. | |
| No clinical study (but a response to the article of Vestergaard 2011) | |
| Children received cranial irradiation. | |
| Children received cranial irradiation. | |
| Double publication of Cunha 2004 | |
| Some of the included children received cranial irradiation. |
HPA: hypothalamic‐pituitary‐adrenal.
Characteristics of studies awaiting assessment [ordered by study ID]
| Methods | Study type: retrospective single‐centre study Setting: Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada |
| Participants | 176 paediatric patients with ALL during maintenance phase of treatment |
| Interventions | Treatment protocol: unknown Type of glucocorticoid therapy: unknown Methods of cessation of glucocorticoid therapy: unknown |
| Outcomes | Specific HPA axis function test: unknown Moment of testing: unknown Cutoff limits defined by original studies: unknown |
| Notes | This study has not been published in full text (search conducted 12 December 2016) but was presented to the ASPHO 2016 conference. It is not yet clear whether this study is eligible for inclusion in this review. |
ALL: acute lymphoblastic leukaemia.
ASPHO: American Society of Pediatric Hematology/Oncology.
HPA: hypothalamic‐pituitary‐adrenal.
Study flow diagram.
| Internal validity | External validity | |
| Study group | Selection bias (representative: yes/no):
| Reporting bias (well defined: yes/no):
|
| Follow‐up | Attrition bias (adequate: yes/no):
| Reporting bias (well defined: yes/no):
|
| Outcome | Detection bias (blinding: yes/no):
| Reporting bias (well defined: yes/no):
|
| Risk estimation | Confounding (adjustment for other factors: yes/no):
| Analysis (well defined: yes/no):
|
| ALL: acute lymphoblastic leukaemia. | ||
| Selection bias Sequence generation (adequate: yes/no):
Allocation concealment (adequate: yes/no):
|
| Performance bias
Blinding of participants (yes/no):
|
| Detection bias
|
| Attrition bias
|
| Reporting bias
|
| Other bias
|
| 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 |
| 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. | |||
| 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. | |||
| 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. | |||
| 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. | |||
| 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. | ||
| 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. | |
| 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. | |||
| 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. |
| Study | Adequate sequence generation? | Adequate allocation concealment? | Blinding? | Incomplete outcome data addressed? | Free of selective reporting? | Free of other bias? |
| 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 | |
| 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. | ||||||
| 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. 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. | ||||
| 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 totalb | 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 totalb | 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 totalb | 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 totalb | 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 totalb | 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 totalb | 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 totalb | 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 totalb | 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 totalb | 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 totalb | 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 totalb | 6/20 | No data on patient level were available. | All children recovered.e | ||
| ACTH, adrenocortiotropic hormone. 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). | |||||
| 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. | |||
