Growth hormone deficiency in adult survivors of childhood brain tumors treated with radiation

in Endocrine Connections
Authors:
Mette Marie BaunsgaardDepartment of Clinical Medicine, Aarhus University, Aarhus, Denmark
Department of Pediatrics and Adolescent Medicine, Aarhus University Hospital, Aarhus, Denmark

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https://orcid.org/0000-0002-2373-5195
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Anne Sophie Lind HelligsoeDepartment of Clinical Medicine, Aarhus University, Aarhus, Denmark
Department of Pediatrics and Adolescent Medicine, Aarhus University Hospital, Aarhus, Denmark

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Louise Tram HenriksenDepartment of Clinical Medicine, Aarhus University, Aarhus, Denmark
Department of Pediatrics and Adolescent Medicine, Aarhus University Hospital, Aarhus, Denmark

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Torben Stamm MikkelsenDepartment of Clinical Medicine, Aarhus University, Aarhus, Denmark
Department of Pediatrics and Adolescent Medicine, Aarhus University Hospital, Aarhus, Denmark

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Michael CallesenDepartment of Paediatrics, Odense University Hospital, Odense, Funen, Denmark

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Britta WeberThe Danish Center for Particle Therapy, Aarhus University Hospital, Aarhus, Denmark

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Henrik HasleDepartment of Clinical Medicine, Aarhus University, Aarhus, Denmark
Department of Pediatrics and Adolescent Medicine, Aarhus University Hospital, Aarhus, Denmark

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Niels BirkebækDepartment of Clinical Medicine, Aarhus University, Aarhus, Denmark
Department of Pediatrics and Adolescent Medicine, Aarhus University Hospital, Aarhus, Denmark
Steno Diabetes Center Aarhus, Aarhus University Hospital, Aarhus, Denmark

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Correspondence should be addressed to M Baunsgaard: metbau@rm.dk
Open access

Objective

Growth hormone deficiency (GHD) is the most common endocrine late effect in irradiated survivors of childhood brain tumors. This study aimed to determine the prevalence of GHD in adults treated with proton or photon irradiation for a brain tumor in childhood and to detect undiagnosed GHD.

Design

This study is a cross-sectional study.

Methods

We investigated GHD in 5-year survivors from two health regions in Denmark treated for childhood brain tumors with cranial or craniospinal irradiation in the period 1997–2015. Medical charts were reviewed for endocrinological and other health data. Survivors without a growth hormone (GH) test at final height were invited to a GH stimulation test.

Results

Totally 41 (22 females) survivors with a median age of 21.7 years (range: 15.1–33.8 years) at follow-up and 14.8 years (range: 5.1–23.4 years) since diagnosis were included; 11 were treated with proton and 30 with photon irradiation; 18 of 21 survivors were previously found to have GHD; 16 of 20 survivors with no GH test at final height were tested, 8 (50 %) had GHD. In total, 26 of 41 patients (63%) had GHD. Insulin-like growth factor-1 (IGF-1) is associated poorly with the insulin tolerance test (ITT).

Conclusion

This study identified a high prevalence of undiagnosed GHD in survivors with no GH test at final height. The results stress the importance of screening for GHD at final height in survivors of childhood brain tumors with prior exposure to cranial irradiation, irrespective of radiation modality and IGF-1.

Significance statement

This cross-sectional study reports a prevalence of 63% of GHD in irradiated childhood brain tumor survivors. Furthermore, the study identified a considerable number of long-term survivors without a GH test at final height, of whom, 50% subsequently were shown to have undiagnosed GHD. Additionally, this study confirmed that a normal serum IGF-1 measurement cannot exclude the diagnosis of GHD in irradiated survivors. This illustrates the need for improvements in the diagnostic approach to GHD after reaching final height in childhood brain tumor survivors at risk of GHD. In summary, our study stresses the need for GHD testing in all adult survivors treated with cranial irradiation for a brain tumor in childhood irrespective of radiation modality.

Abstract

Objective

Growth hormone deficiency (GHD) is the most common endocrine late effect in irradiated survivors of childhood brain tumors. This study aimed to determine the prevalence of GHD in adults treated with proton or photon irradiation for a brain tumor in childhood and to detect undiagnosed GHD.

Design

This study is a cross-sectional study.

Methods

We investigated GHD in 5-year survivors from two health regions in Denmark treated for childhood brain tumors with cranial or craniospinal irradiation in the period 1997–2015. Medical charts were reviewed for endocrinological and other health data. Survivors without a growth hormone (GH) test at final height were invited to a GH stimulation test.

Results

Totally 41 (22 females) survivors with a median age of 21.7 years (range: 15.1–33.8 years) at follow-up and 14.8 years (range: 5.1–23.4 years) since diagnosis were included; 11 were treated with proton and 30 with photon irradiation; 18 of 21 survivors were previously found to have GHD; 16 of 20 survivors with no GH test at final height were tested, 8 (50 %) had GHD. In total, 26 of 41 patients (63%) had GHD. Insulin-like growth factor-1 (IGF-1) is associated poorly with the insulin tolerance test (ITT).

Conclusion

This study identified a high prevalence of undiagnosed GHD in survivors with no GH test at final height. The results stress the importance of screening for GHD at final height in survivors of childhood brain tumors with prior exposure to cranial irradiation, irrespective of radiation modality and IGF-1.

Significance statement

This cross-sectional study reports a prevalence of 63% of GHD in irradiated childhood brain tumor survivors. Furthermore, the study identified a considerable number of long-term survivors without a GH test at final height, of whom, 50% subsequently were shown to have undiagnosed GHD. Additionally, this study confirmed that a normal serum IGF-1 measurement cannot exclude the diagnosis of GHD in irradiated survivors. This illustrates the need for improvements in the diagnostic approach to GHD after reaching final height in childhood brain tumor survivors at risk of GHD. In summary, our study stresses the need for GHD testing in all adult survivors treated with cranial irradiation for a brain tumor in childhood irrespective of radiation modality.

Introduction

Brain tumors are the most common solid neoplasm in children (1) with an annual incidence rate of 42 per million in the Nordic countries (2). Survival rates for children with brain tumors have improved significantly over the last 5 decades (3, 4), due to treatment improvements with targeted cranial radiotherapy (CR) in combination with chemotherapy and improved surgery techniques (5). The overall 5-year survival rate is now approaching 83% in the Nordic countries (6). With more children surviving a brain tumor, it is evident that survivorship comes with a cost.

Childhood brain tumor survivors have an increased risk of long-term and possibly lifelong morbidity affecting multiple organ systems (4). Compared to survivors of other childhood cancers, childhood brain tumor survivors are among those at highest risk of both cognitive and physical sequelae (7, 8, 9, 10, 11, 12, 13, 14). Endocrine complications are, however, some of the most frequent physical chronic late effects (15) with growth hormone deficiency (GHD) being the most common endocrinopathy (16) followed by thyroid-stimulating hormone deficiency (17).

CR is the most significant risk factor for the development of GHD (18). Irradiation-induced GHD is dose-dependent (19), might occur even after low radiation doses (20), and can evolve over time years after treatment has been completed (21).

The consequences of GHD are many: reduced linear growth in children, decreased bone mineral density, an adverse lipid profile, abdominal adiposity, reduced lean muscle mass, and fatigue (22, 23). Lifelong periodic clinical assessment for GHD in brain tumor survivors exposed to CR of more than 18 Gy is recommended (21). In childhood, GHD can be monitored by linear growth. However, assessment of linear growth is of no use when final height has been reached. Furthermore, insulin-like growth factor 1 (IGF-1) has been questioned as a reliable biochemical proxy marker of GHD in CR patients (21, 24). Therefore, children treated with CR are recommended a growth hormone (GH) stimulation test after reaching final height (21, 25). One of the most sensitive and specific tests for GHD in youths is the insulin tolerance test (ITT) (26, 27).

The primary objectives of this study were to determine the prevalence of GHD in adult long-term survivors after proton or photon CR for a brain tumor in childhood and to unveil undiagnosed GHD. The secondary objective was to evaluate the diagnostic value of IGF-1 regarding GHD in adult childhood brain tumor survivors treated with CR.

Materials and methods

Study design and recruitment

Survivors for this cross-sectional study were recruited from the Central and Northern Region of Denmark and have been treated for a primary brain tumor at Aarhus University Hospital or Aalborg University Hospital in the period from January 1997 to December 2015. Clinical data from the medical charts were extracted from October 2020 to April 2021 and the GHD testing was conducted from May to September 2021 at the Medical Research Laboratory, Aarhus University Hospital.

Study cohort

Inclusion criteria were (i) children diagnosed with a primary brain tumor from January 1 1997, to December 31, 2015, in the Central and Northern Region of Denmark, (ii) age below 15 years at diagnosis, (iii) 5 years since diagnosis, (iv) age above 15 years at inclusion, and (v) children treated with CR. Patients, who met all those criteria, were included in the main study cohort.

A subgroup of survivors from the main cohort was invited to a GH stimulation test. To be invited to a GH stimulation test, the participants had to fulfill one of the following criteria: (i) no GH stimulation test performed at final height or (ii) previously treated with recombinant human growth hormone and no stimulation test performed after end of treatment. Childhood brain tumor survivors currently treated with recombinant human growth hormone due to an abnormal GH stimulation test after having reached final height were included in the main study cohort but were not retested.

Exclusion criteria were (i) a CNS tumor diagnosed after the age of 15 years, (ii) spinal cord tumors, (iii) a GH-producing pituitary adenoma, or (iv) disease progression at time of inclusion.

Using the Danish Childhood Cancer Registry, a total of 241 children were retrospectively identified with a primary brain tumor treated in the Central and Northern Region of Denmark and diagnosed between January 1, 1997, and December 31, 2015 (Fig. 1). Of these 241 children, 74 children died. Of the remaining 167 children, 126 were excluded due to age below 15 at time of inclusion (n  = 37), intraspinal tumor/spinal cord tumor (n  = 9), disease progression (n  = 2), GH-producing pituitary adenoma (n  = 1), and no CR (n  =77). Hence, the main study cohort consisted of 41 survivors who had been treated with CR (Fig. 1).

Figure 1
Figure 1

Flowchart of the study cohort.

Citation: Endocrine Connections 12, 2; 10.1530/EC-22-0365

The medical charts of the 41 survivors were scrutinized. Fifteen survivors had had a GH stimulation test performed after having reached final height, five survivors had more than two hormonal deficiencies in addition to GHD and hence continued their GH treatment into adulthood without further GH testing (21) and one survivor moved out of the region. Twenty survivors had not had a GH stimulation test performed at final height and were invited to an ITT or if contraindication for ITT, a growth hormone-releasing hormone (GHRH)-arginine stimulation test (Fig. 2) (28).

Figure 2
Figure 2

Flowchart for the GH test participants.

Citation: Endocrine Connections 12, 2; 10.1530/EC-22-0365

Data extraction

Demographics, tumor-related characteristics, and treatment were retrieved from the medical charts. Further, endocrine data including growth data and hormone replacement therapy were retrieved from the charts. When calculating the cumulative CNS irradiation doses, both whole brain irradiation and boost irradiation were included, and the median cumulative CNS irradiation doses therefore correlate to the irradiation doses received in the boost area.

Growth hormone stimulation tests

Both the ITTs and the GHRH-arginine stimulation tests were carried out in the morning after an overnight fast. For the ITT, a peak GH response < 5 ng/mL was interpreted as being diagnostic of GHD in adulthood (29). A peak GH > 5 ng/mL was interpreted as a normal response.

The cut-off values for the GHRH-arginine stimulation test were adjusted for BMI. A peak GH below 11 ng/mL (BMI < 25), 8 ng/mL (BMI: 25–30), or 4 ng/mL (BMI > 30) was interpreted as diagnostic of GHD (28).

Statistical analyses

Continuous variables are shown as median and range, whereas categorical variables are shown as absolute numbers and percentage. Serum IGF-1 values were converted to s.d. scores using the formula by Bidlingmaier et al. (30). Height was converted into an age- and sex-adjusted height s.d. score using national growth charts for participants younger than 20 years (31). For participants aged ≥ 20 years, Z-score data for age 20 years was applied. Target height was calculated as: ((height of father (cm) + height of mother (cm))/2) ± 6.5 cm (male/female). Statistical analyses were carried out using Stata version 17.

Ethics

The study was approved by the Danish Data Protection Agency (#1-16-02-118-19) and by the National Committee on Health Research, Denmark (#1-10-72-65-19). The protocol conforms to the ethical standards of the Helsinki Declaration revised in 2008. All test participants gave written informed consent after full explanation of the purpose and nature of all procedures used.

Results

Patient characteristics of the main cohort

The median age at follow-up was 21.7 years (range: 15.1–33.8 years), and the median time since brain tumor diagnosis was 14.8 years (range: 5.1–23.4 years). The median age at diagnosis was 8.5 years (range: 0.4–14.6 years) with 13 (32%) diagnosed between 0 and 4 years and 16 (39%) diagnosed between 5 and 10 years and 12 (29%) diagnosed between 10 and 14 years. The most common tumor location was in cerebellum/fourth ventricle (44%, n = 18) and the most common tumor types were medulloblastoma (n  = 12) and astrocytoma (n  = 8) (Table 1).

Table 1

Patient demographics for irradiated childhood brain tumor survivors in the Middle and Northern Region of Denmark (n  =41) and for the sub-population invited to a growth hormone stimulation test (n  = 20).

Main study group n = 41 % Invited to GH stimulation test n  =20 %
Sex
 Female 22 54 10 50
 Male 19 46 10 50
Treatment center
 Aarhus 26 63 14 70
 Aalborg 15 37  6 30
Age at brain tumor diagnosis, years
 Median (range) 8.5 (0.4–14.6) 9.4 (2.1–14.6)
 0–4 13 32  6 30
 5–9 16 39  5 25
 10–15 12 29  9 45
Age at follow-up, years
 Median (range) 21.7 (15.1–33.8) 23.9 (15.4–33.8)
 15–19 13 32  5 25
 20–25 12 29  6 30
 >25 16 39  9 45
Time since diagnosis, years
 Median (range) 14.8 (5.1–23.4) 15.6 (5.1–23.4)
Tumor location
 Cerebellum/fourth ventricle 18 44  7 35
 Cerebral hemisphere  5 12  2 10
 Chiasma/optical nerve  5 12  1  5
 Brainstem  3  7  3 15
 Hypothalamus  3 10  2 10
 Pituitary gland  2 2  0  0
 Supratentorial central  1 2  1  5
 Pineal gland  4 10  4 20
Histology
 Medulloblastoma 12 29  2 10
 Astrocytoma  8 20  6 30
 Germ cell tumor  5 12  5 25
 Ependymoma  3  7  3 15
 DNET  1  2  0  0
 Craniopharyngioma  2  5  0  0
 Choroid plexus tumors  1  2  1  5
 Brainstem glioma  2  5  2 10
 Chiasma  1  2  1  5
 Opticus glioma  2  5  0  0
 Pituitary adenoma  1  2  0  0
 Schwannoma  1  2  0  0
 PNET  2  5  0  0

DNET, dysembryoplastic neuroepithelial tumor; PNET, primitive neuro-ectodermal tumors.

Treatment modalities of the main cohort

The median age at the start of irradiation was 8.8 years (range: 1.3–18.8 years); 30 (73%) had received photon radiation and 11 (27%) had received proton radiation. The median cumulative CNS irradiation doses was 54 Gy (range: 12–61 Gy). A total of 28 (68%) had received focal CR, whereas 13 (32%) had received craniospinal irradiation. Furthermore, 23 (56%) had received chemotherapy as part of their treatment, and of these, 5 had received gonadotoxic chemotherapy (cyclophosphamide with median dose of 2400 mg/m2 (range: 2400–12,587 mg/m2). In total, 37 (88%) had undergone surgery (Table 2).

Table 2

Treatment characteristics for irradiated childhood brain tumor survivors in the Middle and Northern Region of Denmark (n  = 41) and for the sub-population invited to a growth hormone stimulation test (n  = 20).

Irradiated n =  41 % Invited to GH stimulation test n  =20 %
Received chemotherapy
 Yes 23 56 10 50
 No 18 44 10 50
Received gonadotoxic chemotherapy (cyclophosphamide) n = 23 n = 10
 Yes  5 22  0  0
 No 18 78 10 100
Cumulative cyclophosphamide dose, mg/m2
Median (range) 2400 (2400–12,587)
Undergone surgery
 Yes 36 88 17 85
 No  5 12  3 15
Current GH treatment
 Yes 18 44  0  0
 No 23 56 20 100
Previously treated with GH before reaching final height and no stimulation test after end of treatment
 Yes  4 10  4 20
 No 37 90 16 80
Age at start of GH treatment, years
Median (range) 11 (2.4–15.2) 12.7 (12.5–12.9)
Current hormone replacement therapy other that GH
 Sex hormonesa 12 29  1  5
 Desmopressin  3  7  0  0
 Thyroid hormone 18 44  1  5
 Hydrocortisone  8 20  0  0
Age at radiotherapy, years
 Median (range) 8.8 (1.3–18.8) 9.5 (2.3–18.8)
 0–4  8 20  2 10
 5–9 21 51  9 45
 >10 12 29  9 45
Type of irradiation
 Photon 30 73 14 70
 Proton 11 27  6 30
Irradiation technique
 Focal cranial irradiation 28 68 16 80
 Craniospinal irradiation 13 32  4 20
Cumulative CNS irradiation dose, Gy

Median (range)
54 (12–61) 54 (40–56)
Time from irradiation to GH treatment, years

Median (range)
2.6 (0.5–7.9) 5.6 (1.2–7.9)

aIncludes estrogen and testosterone.

GH, growth hormone; ITT, insulin tolerance test.

Endocrinopathies of the main cohort

A total of 18 of 41 (44%) survivors treated with CR were receiving GH replacement therapy at the time of the study (Table 2). The median age at start of GH treatment was 11 years (range: 2.4–15.2 years).

Additionally, 18 (44%) were currently treated with thyroid hormone, 8 (20%) with hydrocortisone, and 12 (29%) with sex steroids (Table 2). In total, 15% (n  = 6), 7% (n  = 3), and 7% (n  = 3) had two, three, and four hormonal deficiencies, respectively, excluding GHD.

Patient characteristics of the GH test participants

A total of 20 survivors had not had a GH test performed after final height had been reached and were invited to a GH test. The median age at follow-up was 22.9 years (range: 15.9–34.2 years), the median time since brain tumor diagnosis was 14.8 years (range: 5.5–23.7 years), and the median time since CR was 14 years (range: 4.3–23.6 years) (Table 3).

Table 3

Patient demographics, treatment characteristics, and test results of the growth hormone stimulation test for the GH test participants (n  = 16), for the GH test participants found to have GHD (n  = 8), and for the GH test participants without GHD (n  = 8).

Test participants n  =16 (%) Test participants with GHD n  =8 (%) Test participants without GHD n  =8 (%)
Test type
 ITT 15 94  7 87 8 100
 GHRH-arginine test  1  6  1 13 0  0
Sex
 Female  9 56  4 50 5 63
 Male  7 44  4 50 3 37
Age at GH-test, years
Median (range) 22.9 (15.9–34.2) 20.8 (17.6–28.6) 28.3 (15.9–34.2)
 15–19  6 38  4 50 2 25
 20–25  4 25  2 25 2 25
 >25  6 38  2 25 4 50
Time since diagnosis, years
Median (range) 14.8 (5.5–23.7) 13.8 (7.6–20) 19.1 (5.5–23.7)
BMI
Median (range) 25.3 (18.4–34) 27.5 (20.7–34) 22.3 (18.4–34)
 <18.5  1  6  0  0 1 13
 18.5–24.9  6 38  2 25 4 50
 ≥25  9 56  6 75 3 37
HSDS
Median (range) 0.2 (−2; 2.5) −0.3 (−1.8; 2) 0.2 (−2;2,5)
Reached target heighta
 Yes 10 63  4 50 6 75
 No  6 37  4 50 2 25
Have had children
 Yes  3 19  0  0 3 37
 No 13 81  8 100 5 63
Spontaneous menarche n = 9 n = 4 n = 5
 Yes 9 100 4 100 5 100
 No 0  0 0  0 0 0
Regular period n = 9 n = 4 n = 5
 Yes  8 89  4 100 4 80
 No  1 11  0  0 1 20
Type of irradiation
 Photon 10 63  5 62 5 63
 Proton  6 38  3 38 3 37
Cumulative CNS irradiation dose, Gy
Median (range) 54 (45–56) 54 (45–54) 54 (54–56)
Irradiation technique
 Focal cranial irradiation 13 81  7 88 6 75
 Craniospinal irradiation  3 19  1 12 2 25
Age at radiotherapy, years
 Median (range) 9.5 (2.3–16.5) 10.2 (2.3–16.5) 9.5 (5.8–14.8)
 0–4  2 13  2 25 0 0
 5–9  7 44  2 25 5 63
 >10  7 44  4 50 3 37
Time since irradiation, years
 Median (range) 14 (4.3–23.6) 12.5 (4.3–19.8) 16.9 (5.3–23.6)
Test peak GH
 GHD  8 50  8 100 0 0
 No GHD  8 50  0  0 8 100
IGF-1 s.d.
Median (range) 0.3 (−1.3; 2.5) −0.2 (−1.3; 2.5) 0.5 (−0.1; 1.8)
 Median (range) IFG-1 s.d. if GHD -0.2 (−1.3; 2.5) −0.2 (−1.3; 2.5)
 Median (range) IFG-1 s.d. if no GHD 0.5 (−0.1; 1.8) .

aTarget height calculated as ((height of father (cm) + height of mother (cm))/2) ± 6.5 cm (male/female). GHD defined as peak GH < 5 ng/mL at the ITT and a peak GH <11.5 ng/mL (BMI < 25) at the GHRH-arginine test.

GH, growth hormone; GHD, growth hormone deficiency; GHRH, growth hormone-releasing hormone; HSDS, height standard deviation score; IGF-1, insulin-like growth factor-1; ITT, insulin tolerance test.

The median height s.d. score was 0.2 s.d. (range: −2.5; 2.5 s.d.). The median BMI was 25.3 (range: 18.4–34). Six of the 16 GH test participants (38%) had received proton irradiation.

The GH tests

Three survivors declined to participate in an ITT and in one case, testing was not possible due to dysregulated diabetes, yielding a participation rate of 80% (16/20). A total of 15 survivors completed the ITT, and 1 completed the GHRH-arginine test, due to epilepsy (Fig. 2).

Two ITT test participants were retested due to insufficient primary test.

Eight (50%) of the 16 GH test participants had GHD; 7 had a peak GH < 5 ng/mL at the ITT and 1 had a peak GH <11.5 ng/mL (BMI < 25) at the GHRH-arginine test (Table 3). The three patients, who did not accept a GH stimulation test and the one patient, where a GH stimulation test was contraindicated, had received a median cumulative CNS irradiation dose of 50 Gy (range: 40–55 Gy).

Peak GH and IGF-1

The median IGF-1 s.d. for the 16 irradiated GH test participants were 0.3 s.d. (range: −1.3 to 2.5 s.d.). For the irradiated participants with GHD (peak GH < 5 ng/mL), the median IGF-1 was −0.2 s.d. (range: −1.3 to 2.5 s.d.), and for the irradiated test participants with a normal test result (peak GH > 5 ng/mL), the median IGF-1 were 0.5 s.d. (range: −0.1 to 1.8 s.d.) (Table 3 and Fig. 3).

Figure 3
Figure 3

Box plot of IGF-1 s.d. measured at the GH stimulation tests, grouped by the categories; GHD (peak GH < 5 ng/mL) and no GHD (peak GH > 5 ng/mL).

Citation: Endocrine Connections 12, 2; 10.1530/EC-22-0365

Prevalence of growth hormone deficiency in the cohort

In the main cohort of 41 survivors, 18 survivors had GHD and were on GH treatment. Combined with the 8 GH test participants found to have GHD as described above, the true prevalence of adult GHD in the whole cohort was 26 of 41 survivors (63 %) (Table 2 and 3). Of the 41 irradiated survivors in the cohort, 18 of 30 (60 %) of the photon irradiated survivors had GHD, while 8 of 11 (73 %) of the survivors treated with proton irradiation had GHD.

Of the eight, GH test participants found to have undiagnosed GHD, two (25 %) have decided to start on recombinant human growth hormone treatment until now.

Discussion

In this cross-sectional study, we report a GHD prevalence of 63% in irradiated childhood brain tumor survivors. A considerable number of adult long-term survivors without a GH test performed at final height was identified, and 50% of those subsequently had undiagnosed GHD. Furthermore, GHD was observed in survivors treated with photon as well as proton irradiation. Finally, IGF-1 was not found to be a reliable marker of GHD.

The prevalence of GHD in irradiated survivors is in line with previous studies (32, 33). However, both higher (34, 35) and lower (20, 36, 37) frequencies of GHD in irradiated childhood brain tumor survivors have been reported. Differences in irradiation modality, irradiation dose, histology, tumor localization, age at diagnosis, age at irradiation, time from irradiation to GH evaluation, and different GH test modalities could explain this discrepancy in previously reported GHD prevalence studies in childhood brain tumor survivors treated with CR. Moreover, the use of different GHD assays and cut-off values for GHD in adults from 3 to 7 ng/mL (21, 28, 29, 38) might also influence the prevalence. We followed an endocrine society guideline (29) and used a cut-off value of 5 ng/mL, whereas other studies applied a higher cut-off, which would lead to a lower prevalence and the risk of missing the diagnosis.

This study reveals a considerable number of undiagnosed GHD with 50% of the participants having GHD. One reason for this high percentage of undiagnosed GHD in the cohort of survivors invited to GH stimulation tests could be that some of them had reached their target height before developing GHD. Another reason may be that IGF-1 is still used in the screening of GHD in childhood brain tumor survivors treated with radiation, and therefore, survivors with a normal IGF-1 might not be referred to GH stimulation test. We confirm previous research that IGF-1 is not a reliable indicator of GHD in cranial irradiated survivors (24, 38, 39). The use of IGF-1 as a screening tool for GHD is not recommended in irradiated patients (21, 29). All survivors previously treated with CR with less than two hormonal deficiencies in addition to GHD should have a growth hormone stimulation test conducted (21, 29).

As IGF-1 is an unreliable marker of GHD in children treated with radiation so is the fact that the survivor has reached their target height. The median height in the eight GH test participants found to have undiagnosed GHD were −0.3 s.d., and 50% had reached their target height. This could indicate that some of the participants had developed GHD after reaching their final height, which might explain why GHD was not suspected. The fact that a survivor has reached their genetic target height should therefore not be used to rule out GHD, and a normal IGF-1 is an unreliable proxy marker for GHD in brain-radiated patients.

The frequency of GHD after final height showed no trends between survivors treated with photons vs protons. However, due to the relatively small sample size, we lack the possibility to conclude on differences in prevalence of GHD in survivors treated with protons vs photons. Survivors treated with protons report fewer late effects regarding, for example, neurocognition (40), but importantly, endocrinological late effects are also observed in survivors of childhood brain tumor treated with protons in our study as well as in others (32, 33).

Strengths

Major strengths of this study are first that we recruited the participants through a national register with full coverage. Secondly, the fact that we used dynamic testing such as ITT, which is the golden standard in the diagnostic process of GHD in adults. Thirdly, the follow-up time from diagnosis was very long and often more than the 5 years required. GHD can develop several years after the end of cancer treatment with irradiation, and a long follow-up time is crucial to detect GHD (16, 36, 41). However, it is likely that with a longer follow-up time, the prevalence of undiagnosed GHD would have been even higher, since radiation-induced GHD can develop years after the end of treatment.

Limitations

However, there were also limitations in the study. The relatively small study cohort was identified, but despite this, we found a high prevalence of survivors without a GH stimulation test at final height. Another limitation was that one patient was tested with another test than ITT due to contraindication (29). Finally, three survivors treated with a CR dose of more than 40 Gy did not want to have a GH stimulation test performed. Due to the high radiation dose, one or more of them might have GHD, and the prevalence of GHD in the main study group would have been even higher than 63%.

Conclusion

To conclude, this study reports a high prevalence of GHD in irradiated adult long-term survivors after treatment for a brain tumor in childhood, in line with previous studies. Furthermore, a high prevalence of undiagnosed GHD in adult survivors treated with CR was identified. We observed similar prevalence of GHD in survivors treated with proton and photon irradiation; and the study confirmed that a normal serum IGF-1 measurement cannot exclude the diagnosis of GHD in irradiated survivors. In summary, our study illustrates that there is room for improvements regarding the diagnostic process of GHD and stresses the need for GH testing in adult radiated brain tumor survivors with less than two hormonal deficiencies in addition to GHD, irrespective of IGF-1 and radiation modality.

Declaration of interest

We declare that no author has any conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

Funding

This work was supported by the Aarhus University (grant number AUFF-F-2019-FLS-1-3) and Dagmar Marshalls Fond (grant number 500020).

Acknowledgements

The authors would like to thank all survivors who participated in this study. The authors would also like to thank Steen Rosthøj, MD, Department of Pediatrics, Aalborg University Hospital, Denmark, for his valuable help and knowledge and Pia Buchtrup Hornbek, medical laboratory technician, Medical Research Laboratory, Aarhus University Hospital, Denmark for her experience and guidance in GH testing.

References

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    Figure 1

    Flowchart of the study cohort.

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    Figure 2

    Flowchart for the GH test participants.

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    Figure 3

    Box plot of IGF-1 s.d. measured at the GH stimulation tests, grouped by the categories; GHD (peak GH < 5 ng/mL) and no GHD (peak GH > 5 ng/mL).

  • 1

    Gurney JG, Davis S, Severson RK, Fang JY, Ross JA, Robison LL. Trends in cancer incidence among children in the U.S. Cancer 1996 78 532541. (https://doi.org/10.1002/(SICI)1097-0142(19960801)78:3<532::AID-CNCR22>3.0.CO;2-Z)

    • Search Google Scholar
    • Export Citation
  • 2

    Schmidt LS, Schmiegelow K, Lahteenmaki P, Träger C, Stokland T, Grell K, Gustafson G, Sehested A, Raashou-Nielsen O & Johansen C et al.Incidence of childhood central nervous system tumors in the Nordic countries. Pediatric Blood and Cancer 2011 56 6569. (https://doi.org/10.1002/pbc.22585)

    • Search Google Scholar
    • Export Citation
  • 3

    Ward E, DeSantis C, Robbins A, Kohler B, Jemal A. Childhood and adolescent cancer statistics, 2014. CA: a Cancer Journal for Clinicians 2014 64 83103. (https://doi.org/10.3322/caac.21219)

    • Search Google Scholar
    • Export Citation
  • 4

    Bhakta N, Liu Q, Ness KK, Baassiri M, Eissa H, Yeo F, Chemaitilly W, Ehrhardt MJ, Bass J & Bishop MW et al.The cumulative burden of surviving childhood cancer: an initial report from the St Jude Lifetime Cohort Study (SJLIFE). Lancet 2017 390 25692582. (https://doi.org/10.1016/S0140-6736(1731610-0)

    • Search Google Scholar
    • Export Citation
  • 5

    Green DM, Kun LE, Matthay KK, Meadows AT, Meyer WH, Meyers PA, Spunt SL, Robison LL, Hudson MM. Relevance of historical therapeutic approaches to the contemporary treatment of pediatric solid tumors. Pediatric Blood and Cancer 2013 60 10831094. (https://doi.org/10.1002/pbc.24487)

    • Search Google Scholar
    • Export Citation
  • 6

    Helligsoe ASL, Kenborg L, Henriksen LT, Udupi A, Hasle H, Winther JF. Incidence and survival of childhood central nervous system tumors in Denmark. Cancer Medicine 2022 11 245256. (https://doi.org/10.1002/cam4.4429)

    • Search Google Scholar
    • Export Citation
  • 7

    de Fine Licht S, Rugbjerg K, Gudmundsdottir T, Bonnesen TG, Asdahl PH, Holmqvist AS, Madanat-Harjuoja L, Tryggvadottir L, Wesenberg F & Hasle H et al.Long-term inpatient disease burden in the Adult Life after Childhood Cancer in Scandinavia (ALiCCS) study: a cohort study of 21,297 childhood cancer survivors. PLoS Medicine 2017 14 e1002296. (https://doi.org/10.1371/journal.pmed.1002296)

    • Search Google Scholar
    • Export Citation
  • 8

    Gudmundsdottir T, Winther JF, de Fine Licht S, Bonnesen TG, Asdahl PH, Tryggvadottir L, Anderson H, Wesenberg F, Malila N & Hasle H et al.Cardiovascular disease in Adult Life after Childhood Cancer in Scandinavia: a population-based cohort study of 32,308 one-year survivors. International Journal of Cancer 2015 137 11761186. (https://doi.org/10.1002/ijc.29468)

    • Search Google Scholar
    • Export Citation
  • 9

    Kenborg L, Winther JF, Linnet KM, Kroyer A, Albieri V, Holmqvist AS, Tryggvadottir L, Madanat-Harjuoja LM, Stovall M & Hasle H et al.Neurologic disorders in 4858 survivors of central nervous system tumors in childhood-an Adult Life after Childhood Cancer in Scandinavia (ALiCCS) study. Neuro-Oncology 2019 21 125136. (https://doi.org/10.1093/neuonc/noy094)

    • Search Google Scholar
    • Export Citation
  • 10

    Ellenberg L, Liu Q, Gioia G, Yasui Y, Packer RJ, Mertens A, Donaldson SS, Stovall M, Kadan-Lottick N & Armstrong G et al.Neurocognitive status in long-term survivors of childhood CNS malignancies: a report from the Childhood Cancer Survivor Study. Neuropsychology 2009 23 705717. (https://doi.org/10.1037/a0016674)

    • Search Google Scholar
    • Export Citation
  • 11

    Heikens J, Ubbink MC, van der Pal HP, Bakker PJ, Fliers E, Smilde TJ, Kastelein JJ, Trip MD. Long term survivors of childhood brain cancer have an increased risk for cardiovascular disease. Cancer 2000 88 21162121. (https://doi.org/10.1002/(SICI)1097-0142(20000501)88:9<2116::AID-CNCR18>3.0.CO;2-U)

    • Search Google Scholar
    • Export Citation
  • 12

    Olsen JH, Moller T, Anderson H, Langmark F, Sankila R, Tryggvadottir L, Winther JF, Rechnitzer C, Jonmundsson G & Christensen J et al.Lifelong cancer incidence in 47,697 patients treated for childhood cancer in the Nordic countries. Journal of the National Cancer Institute 2009 101 806813. (https://doi.org/10.1093/jnci/djp104)

    • Search Google Scholar
    • Export Citation
  • 13

    Kaleyias J, Manley P, Kothare SV. Sleep disorders in children with cancer. Seminars in Pediatric Neurology 2012 19 2534. (https://doi.org/10.1016/j.spen.2012.02.013)

    • Search Google Scholar
    • Export Citation
  • 14

    Lund LW, Winther JF, Dalton SO, Cederkvist L, Jeppesen P, Deltour I, Hargreave M, Kjaer SK, Jensen A & Rechnitzer C et al.Hospital contact for mental disorders in survivors of childhood cancer and their siblings in Denmark: a population-based cohort study. Lancet. Oncology 2013 14 971980. (https://doi.org/10.1016/S1470-2045(1370351-6)

    • Search Google Scholar
    • Export Citation
  • 15

    Chemaitilly W, Li Z, Huang S, Ness KK, Clark KL, Green DM, Barnes N, Armstrong GT, Krasin MJ & Srivastava DK et al.Anterior hypopituitarism in adult survivors of childhood cancers treated with cranial radiotherapy: a report from the St Jude Lifetime Cohort study. Journal of Clinical Oncology 2015 33 492500. (https://doi.org/10.1200/JCO.2014.56.7933)

    • Search Google Scholar
    • Export Citation
  • 16

    Mulder RL, Kremer LC, van Santen HM, Ket JL, van Trotsenburg AS, Koning CC, Schouten-van Meeteren AY, Caron HN, Neggers SJ, van Dalen EC. Prevalence and risk factors of radiation-induced growth hormone deficiency in childhood cancer survivors: a systematic review. Cancer Treatment Reviews 2009 35 616632. (https://doi.org/10.1016/j.ctrv.2009.06.004)

    • Search Google Scholar
    • Export Citation
  • 17

    van Iersel L, Li Z, Srivastava DK, Brinkman TM, Bjornard KL, Wilson CL, Green DM, Merchant TE, Pui CH & Howell RM et al.Hypothalamic-pituitary disorders in childhood cancer survivors: prevalence, risk factors and long-term health outcomes. Journal of Clinical Endocrinology and Metabolism 2019 104 61016115. (https://doi.org/10.1210/jc.2019-00834)

    • Search Google Scholar
    • Export Citation
  • 18

    Gleeson HK, Shalet SM. The impact of cancer therapy on the endocrine system in survivors of childhood brain tumours. Endocrine-Related Cancer 2004 11 589602. (https://doi.org/10.1677/erc.1.00779)

    • Search Google Scholar
    • Export Citation
  • 19

    Littley MD, Shalet SM, Beardwell CG, Robinson EL, Sutton ML. Radiation-induced hypopituitarism is dose-dependent. Clinical Endocrinology 1989 31 363373. (https://doi.org/10.1111/j.1365-2265.1989.tb01260.x)

    • Search Google Scholar
    • Export Citation
  • 20

    Clement SC, Schouten-van Meeteren AY, Boot AM, Claahsen-van der Grinten HL, Granzen B, Sen Han K, Janssens GO, Michiels EM, van Trotsenburg AS & Vandertop WP et al.Prevalence and risk factors of early endocrine disorders in childhood brain tumor survivors: a nationwide, multicenter study. Journal of Clinical Oncology 2016 34 43624370. (https://doi.org/10.1200/JCO.2016.67.5025)

    • Search Google Scholar
    • Export Citation
  • 21

    Sklar CA, Antal Z, Chemaitilly W, Cohen LE, Follin C, Meacham LR, Murad MH. Hypothalamic-pituitary and growth disorders in survivors of childhood cancer: an Endocrine Society clinical practice guideline. Journal of Clinical Endocrinology and Metabolism 2018 103 27612784. (https://doi.org/10.1210/jc.2018-01175)

    • Search Google Scholar
    • Export Citation
  • 22

    Spaziani M, Tarantino C, Tahani N, Gianfrilli D, Sbardella E, Isidori AM, Lenzi A, Radicioni AF. Clinical, diagnostic, and therapeutic aspects of growth hormone deficiency during the transition period: review of the literature. Frontiers in Endocrinology 2021 12 634288. (https://doi.org/10.3389/fendo.2021.634288)

    • Search Google Scholar
    • Export Citation
  • 23

    Shalet S Stepping into adulthood: the transition period. Hormone Research 2004 62(Supplement 4) 1522. (https://doi.org/10.1159/000080904)

    • Search Google Scholar
    • Export Citation
  • 24

    Cattoni A, Clarke E, Albanese A. The predictive value of insulin-like growth factor 1 in irradiation-dependent growth hormone deficiency in childhood cancer survivors. Hormone Research in Paediatrics 2018 90 314325. (https://doi.org/10.1159/000495760)

    • Search Google Scholar
    • Export Citation
  • 25

    Gleeson HK, Gattamaneni HR, Smethurst L, Brennan BM, Shalet SM. Reassessment of growth hormone status is required at final height in children treated with growth hormone replacement after radiation therapy. Journal of Clinical Endocrinology and Metabolism 2004 89 662666. (https://doi.org/10.1210/jc.2003-031224)

    • Search Google Scholar
    • Export Citation
  • 26

    Richards GE, Silverman BL, Winter RJ, Edidin DV. Dose dependency of time of onset of radiation-induced growth hormone deficiency. Journal of Pediatrics 1991 119 502503. (https://doi.org/10.1016/s0022-3476(0582077-3)

    • Search Google Scholar
    • Export Citation
  • 27

    Sfeir JG, Kittah NEN, Tamhane SU, Jasim S, Chemaitilly W, Cohen LE, Murad MH. Diagnosis of GH deficiency as a late effect of radiotherapy in survivors of childhood cancers. Journal of Clinical Endocrinology and Metabolism 2018 103 27852793. (https://doi.org/10.1210/jc.2018-01204)

    • Search Google Scholar
    • Export Citation
  • 28

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