Risk of Meningioma in European Patients Treated With Growth Hormone in Childhood: Results From the SAGhE Cohort

The Journal of Clinical Endocrinology & Metabolism, Mar 2019

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Risk of Meningioma in European Patients Treated With Growth Hormone in Childhood: Results From the SAGhE Cohort

Abstract Context There has been concern that GH treatment of children might increase meningioma risk. Results of published studies have been inconsistent and limited. Objective To examine meningioma risks in relation to GH treatment. Design Cohort study with follow-up via cancer registries and other registers. Setting Population-based. Patients A cohort of 10,403 patients treated in childhood with recombinant GH in five European countries since this treatment was first used in 1984. Expected rates from national cancer registration statistics. Main Outcome Measures Risk of meningioma incidence. Results During follow-up, 38 meningiomas occurred. Meningioma risk was greatly raised in the cohort overall [standardized incidence ratio (SIR) = 75.4; 95% CI: 54.9 to 103.6], as a consequence of high risk in subjects who had received radiotherapy for underlying malignancy (SIR = 658.4; 95% CI: 460.4 to 941.7). Risk was not significantly raised in patients who did not receive radiotherapy. Risk in radiotherapy-treated patients was not significantly related to mean daily dose of GH, duration of GH treatment, or cumulative dose of GH. Conclusions Our data add to evidence of very high risk of meningioma in patients treated in childhood with GH after cranial radiotherapy, but suggest that GH may not affect radiotherapy-related risk, and that there is no material raised risk of meningioma in GH-treated patients who did not receive radiotherapy. Since 1957 GH has been used to treat GH deficiency and short stature, initially using a human pituitary extract but since 1985 using solely recombinant GH (r-hGH). GH causes increased serum concentrations of IGF-1. IGF-1 is antiapoptotic and mitogenic in vitro, and levels in adults have been associated in several studies with risks of subsequent malignancies (1). As a consequence, and because of early case reports and some findings in humans, there has been concern as to whether GH therapy might increase cancer risks (1, 2). Meningiomas express GH receptors, and in vitro activation of the GH/IGF-1 axis increases the growth rate of meningiomas (3). In an in vivo model, downregulation of the GH/IGF-1 axis reduced meningioma growth (4). In the US Childhood Cancer Survivors Study cohort, second malignancy was significantly more common among GH-treated than non–GH-treated patients, and meningioma was much the most common second malignancy in the GH-treated group, accounting for 40% of all second neoplasms (5). A UK study (6) found meningiomas more common in GH-treated, brain-irradiated cancer patients than in matched, brain-irradiated cancer controls, but based on small numbers, and a later analysis from the US cohort did not find raised meningioma risk (7). The published results, however, have been based on relatively small numbers: 338 GH-treated patients in the US study (7) and 110 in the only other analysis, in the UK (6). To analyze the risk with much greater power, we therefore analyzed meningioma risks in the Safety and Appropriateness of Growth Hormone Treatments in Europe (SAGhE) study, a large cross-European cohort study of patients treated with r-hGH since 1984. Materials and Methods The SAGhE study is a coordinated cohort study in eight European countries of patients treated with r-hGH at pediatric ages since such treatment was first used (1984 to 1986, depending on the country), and never treated with human pituitary GH. Details of the assembly of the cohort and methods of data collection have been described previously (8). Ethics committee agreement was obtained in every country, and for each patient either written informed consent was obtained, or the ethics committee stated that consent was not required. Only three patients in the cohort died of meningioma during follow-up, so we have only undertaken incidence analyses, not mortality analyses, for meningioma in this paper. Cancer incidence follow-up was via cancer registration and highly complete in Belgium, the Netherlands, Sweden, Switzerland, and the United Kingdom, and therefore analyses of incidence are restricted to these countries. The cohorts were national and population based, or virtually so, in Belgium, the Netherlands, Sweden, and the United Kingdom and clinic based and subnational in Switzerland. We obtained data on demographic and GH-related variables from existing databases and from case notes. Subjects were followed for mortality via national population-based registries in Belgium, the Netherlands, Sweden, and the United Kingdom, and by municipal registers and other means in Switzerland. In all countries, follow-up was independent of pharmaceutical companies. Vital status follow-up was highly complete. We excluded from analysis, individuals with certain conditions that both lead to GH therapy and are themselves very strong predisposing factors for malignancy [e.g., type 1 neurofibromatosis, Fanconi syndrome (9)]. In addition, we also excluded from the cohort, subjects (n = 1) whose original diagnosis leading to GH treatment was meningioma. We calculated person-years at risk for meningioma in the cohort by sex, 5-year age group, single calendar year, and country, commencing on the date of first treatment with GH and ending at whichever occurred earliest of: diagnosis of meningioma, death, loss to follow-up, or a fixed end date for each country (the date to which follow-up in that country was considered complete at the time the follow-up data were obtained). In Switzerland, cancer incidence follow-up was censored at age 16 or 21, depending on the canton, because cancer incidence data were from the Swiss Childhood Cancer Registry, which only covered these ages. Meningiomas were taken as tumors coded to International Classification of Diseases 10 codes C70 (malignant), D32 (benign), and D42 (uncertain and unknown behavior) (10) and equivalents in International Classification of Diseases 9. Observed numbers of cancers and deaths in the cohort were compared with expectations derived from application of sex, age, country, and year-specific rates in the general population of each country to the person-years at risk in these categories in the cohort, to provide standardized incidence ratios (SIRs). Absolute excess rates were calculated by subtracting expected from observed numbers of cases, dividing by person-years at risk and multiplying by 10,000. Trends in risk with variables such as duration of GH treatment were tested as described by Breslow and Day (11); P values are all two sided. As well as analyses of risks in the cohort overall, we also analyzed the data in subdivisions by initial diagnosis, whether radiotherapy was received, and cumulative dose, mean daily dose, and duration of GH treatment. To be able to explore potential surveillance bias in the diagnosis of meningiomas in the cohort, we endeavored to discover from clinical sources for each UK patient, the pathway that had led to diagnosis of the meningioma. Results Of 10,786 patients recorded as treated with r-hGH in the five study countries, 257 had to be excluded from analysis because of lack of permission for cancer incidence follow-up or lack of data, and 126 because of an underlying diagnosis at high risk of cancer or an underlying diagnosis of meningioma as the reason for GH treatment. This left 10,403 who formed the study cohort. Just over one-half were male and four-fifths were aged 5 to 14 years at first treatment (Table 1). The most common underlying diagnoses were isolated growth failure (n = 3952), and malignancy (n = 1830). Table 1. Descriptive Characteristics of Patients in the SAGhE Cohort Followed for Risk of Meningioma Characteristic No.     % Sex    Male 5530 53.2  Female 4873 46.8 Country    Belgium 1325 12.7  Netherlands 1685 16.2  Sweden 2822 27.1  Switzerland 737 7.1  United Kingdom 3834 36.9 Age started GH treatment, y    0–4 1130 10.9  5–9 3632 34.9  10–14 4834 46.5  15–19 807 7.8 Year started GH treatment    <1990 2070 19.9  1990–1994 3976 38.2  1995–1999 2840 27.3  ≥2000 1517 14.6 Diagnosis leading to GH treatment    CNS tumor 1307 12.6  Non-CNS solid tumor 97 0.9  Hematological malignancy 426 4.1  Chronic renal failure and renal diseases 139 1.3  Turner syndrome 1721 16.5  Other syndromes and chronic diseases 1003 9.6  Multiple pituitary hormone deficiency organic 1343 12.9  Skeletal dysplasias 286 2.8  Isolated growth failurea 3952 38.0  Nonclassifiable 129 1.2 Total 10,403 100.0  Characteristic No.     % Sex    Male 5530 53.2  Female 4873 46.8 Country    Belgium 1325 12.7  Netherlands 1685 16.2  Sweden 2822 27.1  Switzerland 737 7.1  United Kingdom 3834 36.9 Age started GH treatment, y    0–4 1130 10.9  5–9 3632 34.9  10–14 4834 46.5  15–19 807 7.8 Year started GH treatment    <1990 2070 19.9  1990–1994 3976 38.2  1995–1999 2840 27.3  ≥2000 1517 14.6 Diagnosis leading to GH treatment    CNS tumor 1307 12.6  Non-CNS solid tumor 97 0.9  Hematological malignancy 426 4.1  Chronic renal failure and renal diseases 139 1.3  Turner syndrome 1721 16.5  Other syndromes and chronic diseases 1003 9.6  Multiple pituitary hormone deficiency organic 1343 12.9  Skeletal dysplasias 286 2.8  Isolated growth failurea 3952 38.0  Nonclassifiable 129 1.2 Total 10,403 100.0  a Including isolated GH deficiency, idiopathic short stature, and small for gestational age. View Large Table 1. Descriptive Characteristics of Patients in the SAGhE Cohort Followed for Risk of Meningioma Characteristic No.     % Sex    Male 5530 53.2  Female 4873 46.8 Country    Belgium 1325 12.7  Netherlands 1685 16.2  Sweden 2822 27.1  Switzerland 737 7.1  United Kingdom 3834 36.9 Age started GH treatment, y    0–4 1130 10.9  5–9 3632 34.9  10–14 4834 46.5  15–19 807 7.8 Year started GH treatment    <1990 2070 19.9  1990–1994 3976 38.2  1995–1999 2840 27.3  ≥2000 1517 14.6 Diagnosis leading to GH treatment    CNS tumor 1307 12.6  Non-CNS solid tumor 97 0.9  Hematological malignancy 426 4.1  Chronic renal failure and renal diseases 139 1.3  Turner syndrome 1721 16.5  Other syndromes and chronic diseases 1003 9.6  Multiple pituitary hormone deficiency organic 1343 12.9  Skeletal dysplasias 286 2.8  Isolated growth failurea 3952 38.0  Nonclassifiable 129 1.2 Total 10,403 100.0  Characteristic No.     % Sex    Male 5530 53.2  Female 4873 46.8 Country    Belgium 1325 12.7  Netherlands 1685 16.2  Sweden 2822 27.1  Switzerland 737 7.1  United Kingdom 3834 36.9 Age started GH treatment, y    0–4 1130 10.9  5–9 3632 34.9  10–14 4834 46.5  15–19 807 7.8 Year started GH treatment    <1990 2070 19.9  1990–1994 3976 38.2  1995–1999 2840 27.3  ≥2000 1517 14.6 Diagnosis leading to GH treatment    CNS tumor 1307 12.6  Non-CNS solid tumor 97 0.9  Hematological malignancy 426 4.1  Chronic renal failure and renal diseases 139 1.3  Turner syndrome 1721 16.5  Other syndromes and chronic diseases 1003 9.6  Multiple pituitary hormone deficiency organic 1343 12.9  Skeletal dysplasias 286 2.8  Isolated growth failurea 3952 38.0  Nonclassifiable 129 1.2 Total 10,403 100.0  a Including isolated GH deficiency, idiopathic short stature, and small for gestational age. View Large During follow-up, 326 patients died, 175 were lost to follow-up, 38 were diagnosed with meningioma (30 benign, one malignant, and seven of uncertain behavior), and 9864 survived without meningioma to the end of the follow-up period. A total of 154,795 person-years at risk were accrued, an average of 14.9 years per patient. The SIR for meningioma in the cohort overall was 75.4 (95% CI: 54.9 to 103.6) (Table 2), and the absolute excess rate was 2.4 per 10,000 (not in Table). Relative risks were similar in males and females, and greatly raised in the Netherlands, Sweden, and the United Kingdom. There were no cases in Belgium and Switzerland but expected numbers were small (0.04 and 0.01, respectively) and 95% CIs included the all-country SIR. All but one of the meningiomas occurred in patients whose initial diagnosis was cancer [SIR = 466.3 (95% CI: 337.8 to 643.5)]; the risk was not significantly raised in patients whose initial diagnosis was not cancer [SIR = 2.4 (95% CI: 0.3 to 16.7)]. Risks were over 300-fold raised for patients whose initial diagnoses were central nervous system (CNS) tumor; hematological malignancy; or non-CNS solid tumor (Table 2). Table 2. Risk of Meningioma in the Cohort in Relation to Sex, Country of Residence, and Initial Diagnosis Leading to GH Treatment  All Initial Diagnoses Initial Diagnosis Cancer Initial Diagnosis Noncancer  n SIR (95% CI) n SIR (95% CI) n SIR (95% CI) Sex        Male 18 83.7 (52.7, 132.8)a 18 464.9 (292.9, 737.8)a 0 0.0 (0.0, 20.5)  Female 20 69.2 (44.7, 107.3)a 19 467.6 (298.3, 733.1)a 1 4.0 (0.6, 28.6) Country of residence        Belgium 0 0.0 (0.0, 92.2) 0 0.0 (0.0, 368.9) 0 0.0 (0.0, 92.2)  Netherlands 9 84.4 (43.9, 162.2)a 9 503.4 (261.9, 967.5)a 0 0.0 (0.0, 41.0)  Sweden 7 40.5 (19.3, 85.0)a 7 385.6 (183.8, 808.8)a 0 0.0 (0.0, 24.6)  Switzerland 0 0.0 (0.0, 368.9) 0 0.0 (0.0, 6148.1) 0 0.0 (0.0, 368.9)  United Kingdom 22 126.8 (83.5, 192.6)a 21 593.5 (387.0, 910.3)a 1 7.2 (1.0, 51.4) Diagnosis leading to GH treatment        CNS tumor 29 533.7 (370.9, 768.0)a 29 533.7 (370.9, 768.0)a — —  Hematological malignancy 7 319.2 (152.2, 669.5)a 7 319.2 (152.2, 669.5)a — —  Non-CNS solid tumor 1 324.1 (45.6, 2300.6)b 1 324.1 (45.6, 2300.6)b — —  Turner syndrome 1 9.2 (1.3, 65.0)c — — 1 9.2 (1.3, 65.0)c  Isolated growth failure 0 0.0 (0.0, 19.4) — — 0 0.0 (0.0, 19.4)  Other noncancer 0 0.0 (0.0, 30.7) — — 0 0.0 (0.0, 30.7) Total 38 75.4 (54.9, 103.6)a 37 466.3 (337.8, 643.5)a 1 2.4 (0.3, 16.7)   All Initial Diagnoses Initial Diagnosis Cancer Initial Diagnosis Noncancer  n SIR (95% CI) n SIR (95% CI) n SIR (95% CI) Sex        Male 18 83.7 (52.7, 132.8)a 18 464.9 (292.9, 737.8)a 0 0.0 (0.0, 20.5)  Female 20 69.2 (44.7, 107.3)a 19 467.6 (298.3, 733.1)a 1 4.0 (0.6, 28.6) Country of residence        Belgium 0 0.0 (0.0, 92.2) 0 0.0 (0.0, 368.9) 0 0.0 (0.0, 92.2)  Netherlands 9 84.4 (43.9, 162.2)a 9 503.4 (261.9, 967.5)a 0 0.0 (0.0, 41.0)  Sweden 7 40.5 (19.3, 85.0)a 7 385.6 (183.8, 808.8)a 0 0.0 (0.0, 24.6)  Switzerland 0 0.0 (0.0, 368.9) 0 0.0 (0.0, 6148.1) 0 0.0 (0.0, 368.9)  United Kingdom 22 126.8 (83.5, 192.6)a 21 593.5 (387.0, 910.3)a 1 7.2 (1.0, 51.4) Diagnosis leading to GH treatment        CNS tumor 29 533.7 (370.9, 768.0)a 29 533.7 (370.9, 768.0)a — —  Hematological malignancy 7 319.2 (152.2, 669.5)a 7 319.2 (152.2, 669.5)a — —  Non-CNS solid tumor 1 324.1 (45.6, 2300.6)b 1 324.1 (45.6, 2300.6)b — —  Turner syndrome 1 9.2 (1.3, 65.0)c — — 1 9.2 (1.3, 65.0)c  Isolated growth failure 0 0.0 (0.0, 19.4) — — 0 0.0 (0.0, 19.4)  Other noncancer 0 0.0 (0.0, 30.7) — — 0 0.0 (0.0, 30.7) Total 38 75.4 (54.9, 103.6)a 37 466.3 (337.8, 643.5)a 1 2.4 (0.3, 16.7)  a P < 0.001. b P < 0.01. c P < 0.05. View Large Table 2. Risk of Meningioma in the Cohort in Relation to Sex, Country of Residence, and Initial Diagnosis Leading to GH Treatment  All Initial Diagnoses Initial Diagnosis Cancer Initial Diagnosis Noncancer  n SIR (95% CI) n SIR (95% CI) n SIR (95% CI) Sex        Male 18 83.7 (52.7, 132.8)a 18 464.9 (292.9, 737.8)a 0 0.0 (0.0, 20.5)  Female 20 69.2 (44.7, 107.3)a 19 467.6 (298.3, 733.1)a 1 4.0 (0.6, 28.6) Country of residence        Belgium 0 0.0 (0.0, 92.2) 0 0.0 (0.0, 368.9) 0 0.0 (0.0, 92.2)  Netherlands 9 84.4 (43.9, 162.2)a 9 503.4 (261.9, 967.5)a 0 0.0 (0.0, 41.0)  Sweden 7 40.5 (19.3, 85.0)a 7 385.6 (183.8, 808.8)a 0 0.0 (0.0, 24.6)  Switzerland 0 0.0 (0.0, 368.9) 0 0.0 (0.0, 6148.1) 0 0.0 (0.0, 368.9)  United Kingdom 22 126.8 (83.5, 192.6)a 21 593.5 (387.0, 910.3)a 1 7.2 (1.0, 51.4) Diagnosis leading to GH treatment        CNS tumor 29 533.7 (370.9, 768.0)a 29 533.7 (370.9, 768.0)a — —  Hematological malignancy 7 319.2 (152.2, 669.5)a 7 319.2 (152.2, 669.5)a — —  Non-CNS solid tumor 1 324.1 (45.6, 2300.6)b 1 324.1 (45.6, 2300.6)b — —  Turner syndrome 1 9.2 (1.3, 65.0)c — — 1 9.2 (1.3, 65.0)c  Isolated growth failure 0 0.0 (0.0, 19.4) — — 0 0.0 (0.0, 19.4)  Other noncancer 0 0.0 (0.0, 30.7) — — 0 0.0 (0.0, 30.7) Total 38 75.4 (54.9, 103.6)a 37 466.3 (337.8, 643.5)a 1 2.4 (0.3, 16.7)   All Initial Diagnoses Initial Diagnosis Cancer Initial Diagnosis Noncancer  n SIR (95% CI) n SIR (95% CI) n SIR (95% CI) Sex        Male 18 83.7 (52.7, 132.8)a 18 464.9 (292.9, 737.8)a 0 0.0 (0.0, 20.5)  Female 20 69.2 (44.7, 107.3)a 19 467.6 (298.3, 733.1)a 1 4.0 (0.6, 28.6) Country of residence        Belgium 0 0.0 (0.0, 92.2) 0 0.0 (0.0, 368.9) 0 0.0 (0.0, 92.2)  Netherlands 9 84.4 (43.9, 162.2)a 9 503.4 (261.9, 967.5)a 0 0.0 (0.0, 41.0)  Sweden 7 40.5 (19.3, 85.0)a 7 385.6 (183.8, 808.8)a 0 0.0 (0.0, 24.6)  Switzerland 0 0.0 (0.0, 368.9) 0 0.0 (0.0, 6148.1) 0 0.0 (0.0, 368.9)  United Kingdom 22 126.8 (83.5, 192.6)a 21 593.5 (387.0, 910.3)a 1 7.2 (1.0, 51.4) Diagnosis leading to GH treatment        CNS tumor 29 533.7 (370.9, 768.0)a 29 533.7 (370.9, 768.0)a — —  Hematological malignancy 7 319.2 (152.2, 669.5)a 7 319.2 (152.2, 669.5)a — —  Non-CNS solid tumor 1 324.1 (45.6, 2300.6)b 1 324.1 (45.6, 2300.6)b — —  Turner syndrome 1 9.2 (1.3, 65.0)c — — 1 9.2 (1.3, 65.0)c  Isolated growth failure 0 0.0 (0.0, 19.4) — — 0 0.0 (0.0, 19.4)  Other noncancer 0 0.0 (0.0, 30.7) — — 0 0.0 (0.0, 30.7) Total 38 75.4 (54.9, 103.6)a 37 466.3 (337.8, 643.5)a 1 2.4 (0.3, 16.7)  a P < 0.001. b P < 0.01. c P < 0.05. View Large We had information that 1178 of the patients had received cranio(-spinal) radiotherapy (all but 13 for cancer) and 3055 had not received cranio(-spinal) radiotherapy, and for 6170, this was not known. Thirty of the 38 meningiomas occurred in the cancer patients known to have received cranio(-spinal) radiotherapy (Table 3). The relative risk of meningioma for cancer patients treated with radiotherapy was over 600 (Table 3). The SIR was not related to age at first GH treatment, time since starting treatment, or attained age. There were also no significant trends in risk with mean daily GH dose, duration of treatment, or cumulative dose of GH. Of the remaining meningioma cases, seven occurred in patients with unknown radiotherapy status [SIR = 277.5 (95% CI: 132.3 to 582.1)]; all were in Sweden, for which the databases used for this study did not include data on radiotherapy to allow them to be included in risk analyses, but on separate inquiry, four had received prior radiotherapy, and for three, no information on this was available. One meningioma occurred among patients without radiotherapy (a patient with Turner syndrome), for whom risk was not significantly raised. Table 3. Risk of Meningioma in Patients Whose Initial Diagnosis Was Cancer and Were Treated by Radiotherapy, by Age and GH Treatment Variables  n SIR (95% CI) Age started GH treatment, y    0–4 1 1401.5 (197.4, 9949.0)a  5–9 9 782.4 (407.1, 1503.7)b  10–14 19 644.7 (411.2, 1010.7)b  15-19 1 258.1 (36.4, 1832.1)a  P trend  0.21 Time since started GH treatment, y    0–4 2 338.0 (84.5, 1351.4)b  5–9 2 197.5 (49.4, 789.5)b  10–14 14 1130.7 (669.7, 1909.2)b  15–19 10 857.0 (461.1, 1592.8)b  ≥20 2 365.8 (91.5, 1462.5)b  P trend  0.26 Attained age, y    0–9 0 0.0 (0.0, 12,296.3)  10–19 6 487.2 (218.9, 1084.3)b  20–29 21 863.5 (563.0, 1324.4)b  ≥30 3 346.7 (111.8, 1074.8)b  P trend  0.95 Duration of GH treatment, y    <3 8 547.5 (273.8, 1094.7)b  3–5 11 587.3 (325.3, 1060.5)b  ≥6 11 998.9 (553.2, 1803.8)b  P trend  0.19 Mean GH dose, µg/kg/d    <20 7 635.1 (302.8, 1332.2)b  20–29 17 805.4 (500.7, 1295.6)b  30–39 3 425.1 (137.1, 1318.1)b  ≥40 1 1297.5 (182.8, 9210.9)a  P trend  0.92 Cumulative GH dose, mg/kg    <25 8 511.9 (256.0, 1023.7)b  25–49 10 601.3 (323.6, 1117.6)b  50–99 11 1286.0 (712.2, 2322.1)b  ≥100 0 0.0 (0.0, 4098.8)  P trend  0.13 Total 30 658.4 (460.4, 941.7)b   n SIR (95% CI) Age started GH treatment, y    0–4 1 1401.5 (197.4, 9949.0)a  5–9 9 782.4 (407.1, 1503.7)b  10–14 19 644.7 (411.2, 1010.7)b  15-19 1 258.1 (36.4, 1832.1)a  P trend  0.21 Time since started GH treatment, y    0–4 2 338.0 (84.5, 1351.4)b  5–9 2 197.5 (49.4, 789.5)b  10–14 14 1130.7 (669.7, 1909.2)b  15–19 10 857.0 (461.1, 1592.8)b  ≥20 2 365.8 (91.5, 1462.5)b  P trend  0.26 Attained age, y    0–9 0 0.0 (0.0, 12,296.3)  10–19 6 487.2 (218.9, 1084.3)b  20–29 21 863.5 (563.0, 1324.4)b  ≥30 3 346.7 (111.8, 1074.8)b  P trend  0.95 Duration of GH treatment, y    <3 8 547.5 (273.8, 1094.7)b  3–5 11 587.3 (325.3, 1060.5)b  ≥6 11 998.9 (553.2, 1803.8)b  P trend  0.19 Mean GH dose, µg/kg/d    <20 7 635.1 (302.8, 1332.2)b  20–29 17 805.4 (500.7, 1295.6)b  30–39 3 425.1 (137.1, 1318.1)b  ≥40 1 1297.5 (182.8, 9210.9)a  P trend  0.92 Cumulative GH dose, mg/kg    <25 8 511.9 (256.0, 1023.7)b  25–49 10 601.3 (323.6, 1117.6)b  50–99 11 1286.0 (712.2, 2322.1)b  ≥100 0 0.0 (0.0, 4098.8)  P trend  0.13 Total 30 658.4 (460.4, 941.7)b  a P < 0.01. b P < 0.001. c P < 0.05. View Large Table 3. Risk of Meningioma in Patients Whose Initial Diagnosis Was Cancer and Were Treated by Radiotherapy, by Age and GH Treatment Variables  n SIR (95% CI) Age started GH treatment, y    0–4 1 1401.5 (197.4, 9949.0)a  5–9 9 782.4 (407.1, 1503.7)b  10–14 19 644.7 (411.2, 1010.7)b  15-19 1 258.1 (36.4, 1832.1)a  P trend  0.21 Time since started GH treatment, y    0–4 2 338.0 (84.5, 1351.4)b  5–9 2 197.5 (49.4, 789.5)b  10–14 14 1130.7 (669.7, 1909.2)b  15–19 10 857.0 (461.1, 1592.8)b  ≥20 2 365.8 (91.5, 1462.5)b  P trend  0.26 Attained age, y    0–9 0 0.0 (0.0, 12,296.3)  10–19 6 487.2 (218.9, 1084.3)b  20–29 21 863.5 (563.0, 1324.4)b  ≥30 3 346.7 (111.8, 1074.8)b  P trend  0.95 Duration of GH treatment, y    <3 8 547.5 (273.8, 1094.7)b  3–5 11 587.3 (325.3, 1060.5)b  ≥6 11 998.9 (553.2, 1803.8)b  P trend  0.19 Mean GH dose, µg/kg/d    <20 7 635.1 (302.8, 1332.2)b  20–29 17 805.4 (500.7, 1295.6)b  30–39 3 425.1 (137.1, 1318.1)b  ≥40 1 1297.5 (182.8, 9210.9)a  P trend  0.92 Cumulative GH dose, mg/kg    <25 8 511.9 (256.0, 1023.7)b  25–49 10 601.3 (323.6, 1117.6)b  50–99 11 1286.0 (712.2, 2322.1)b  ≥100 0 0.0 (0.0, 4098.8)  P trend  0.13 Total 30 658.4 (460.4, 941.7)b   n SIR (95% CI) Age started GH treatment, y    0–4 1 1401.5 (197.4, 9949.0)a  5–9 9 782.4 (407.1, 1503.7)b  10–14 19 644.7 (411.2, 1010.7)b  15-19 1 258.1 (36.4, 1832.1)a  P trend  0.21 Time since started GH treatment, y    0–4 2 338.0 (84.5, 1351.4)b  5–9 2 197.5 (49.4, 789.5)b  10–14 14 1130.7 (669.7, 1909.2)b  15–19 10 857.0 (461.1, 1592.8)b  ≥20 2 365.8 (91.5, 1462.5)b  P trend  0.26 Attained age, y    0–9 0 0.0 (0.0, 12,296.3)  10–19 6 487.2 (218.9, 1084.3)b  20–29 21 863.5 (563.0, 1324.4)b  ≥30 3 346.7 (111.8, 1074.8)b  P trend  0.95 Duration of GH treatment, y    <3 8 547.5 (273.8, 1094.7)b  3–5 11 587.3 (325.3, 1060.5)b  ≥6 11 998.9 (553.2, 1803.8)b  P trend  0.19 Mean GH dose, µg/kg/d    <20 7 635.1 (302.8, 1332.2)b  20–29 17 805.4 (500.7, 1295.6)b  30–39 3 425.1 (137.1, 1318.1)b  ≥40 1 1297.5 (182.8, 9210.9)a  P trend  0.92 Cumulative GH dose, mg/kg    <25 8 511.9 (256.0, 1023.7)b  25–49 10 601.3 (323.6, 1117.6)b  50–99 11 1286.0 (712.2, 2322.1)b  ≥100 0 0.0 (0.0, 4098.8)  P trend  0.13 Total 30 658.4 (460.4, 941.7)b  a P < 0.01. b P < 0.001. c P < 0.05. View Large Of the 22 meningiomas diagnosed in patients in the United Kingdom, we were able to obtain information on the events leading to diagnosis for 14; of these, nine were diagnosed after symptomatic presentations and five at routine follow-up. Discussion Our analysis of over 10,000 patients treated with GH in childhood showed meningioma risk over 70-fold, highly significantly, raised in this cohort compared with general population expectations. This was a consequence of a risk six times greater than this in the subset of patients who had received GH after treatment of cancer, and within these, greater risk again in the patients who had received cranio(-spinal) radiotherapy. Although we do not have data on radiotherapy dose, incidence of GH deficiency after cranial radiotherapy is dose and time dependent (12–14), and most of the cancer patients had brain tumors, which are usually treated with 40 to 50 Gy (12), so we would expect that radiotherapy doses in the cohort will generally have been ≥40 Gy. The relative risks in our cohort for meningioma are far larger than for any other tumor after GH treatment (9). Because ionizing radiation exposure is a well-established cause of meningioma (15, 16), including after radiation therapy of childhood cancers (17, 18), the extraordinarily large risk in our GH-treated cohort does not in itself incriminate GH. Comparisons of follow-up of GH-treated and untreated cancer patients in the United States and United Kingdom (5, 6) have given some evidence of raised risk of meningioma associated with GH, although a later analysis from the US cohort (7) did not find raised risk. Our study had the weakness that we were not able to compare risks in our GH cohort directly with untreated patients, because we did not have data on such patients. On the other hand, our study had the strength that we were able to, unlike previous studies, analyze risks in relation to dose and duration of GH treatment—critical variables in assessing whether there is an etiological relationship (19). These GH variables were not significantly related to meningioma risk and furthermore there was no significant raised risk of meningioma in the 8573 noncancer patients in our cohort who received GH therapy. Thus our data, based on different variables and a far larger cohort than previously, do not support the hypothesis that GH treatment influences meningioma risk. We were not able to collect IGF-1 data for the cohort, but future research would be improved by investigating, if practical, whether IGF-1 levels during GH treatment relate to subsequent meningioma risk. We were also not able to analyze meningioma risks in relation to extent of, or treatment of, other pituitary deficiencies, but these seem unlikely to explain the meningioma risk in these patients because the majority of cases did not have a record of other pituitary deficiencies and only 13 had a record of treatment of such deficiencies. The main reason for the raised meningioma risk in the cohort is likely to be ionizing radiation exposure. Previous cohort studies of meningioma risk after radiation exposure have found excess relative risks per Gy ranging from 0.64 to 5.1, with a summary excess relative risk across studies of 1.81 (16). Our relative risks are of the same order as those for ≥40 Gy exposures to the meninges in a large UK childhood cancer cohort (17), but several times larger than those found in a similar US cohort (18). Meningioma is a tumor for which there is known to be a high prevalence of subclinical disease: on brain MRI in the general population, 0.5% of individuals aged 45 to 59 (the youngest ages studied) had incidental findings of meningioma (20). There is therefore considerable scope for intensive medical contacts and cerebral imaging (especially MRI) consequent on underlying cerebral malignancies and GH treatment in our cohort to lead to diagnosis of asymptomatic meningiomas that would not otherwise have been detected, or at least not at that time. Such a “screening” effect, if there is one, might be expected to operate particularly around (or indeed before) the time of first treatment with GH, when prevalent asymptomatic meningiomas incident over many years previously might come to light, and to diminish subsequently, when only newly incident cases would be available for detection. Our data, however, did not show diminishing risks with longer time since first treatment. Furthermore, among the UK cases for whom we could identify the pathway to diagnosis, most of the tumors were investigated because of symptoms (although we cannot tell, of course, whether these symptoms would not have been presented, or not have been investigated further, if the patient had not had a previous cerebral tumor and GH treatment). A subtler screening effect might have occurred if improvements in imaging technology over time had caused detection of some meningiomas in the cohort in recent years that were already present but undetected at the time of earlier, lower sensitivity imaging (6). This could have led to artifactual raised risks throughout follow-up; we do not have data to measure the extent, if any, of such an effect. In conclusion, our data add to evidence of the very high relative risks of meningioma in patients treated in childhood with r-hGH after cranial radiotherapy for malignancy. Clinically it is important to be aware of this risk when following up such patients. Our data and the previous literature on radiation effects indicate that the raised risk is mainly due to radiotherapy, although it may also to some extent reflect detection of asymptomatic meningiomas as a consequence of intensive medical surveillance and cerebral imaging in these patients. Our data also suggest, however, that GH treatment has not augmented further the radiotherapy-related risk. Abbreviations: Abbreviations:   CNS central nervous system   r-hGH recombinant GH   SAGhE Safety and Appropriateness of Growth Hormone Treatments in Europe   SIR standardized incidence ratio Acknowledgments We gratefully acknowledge the assistance in all countries of the GH patients and their families. We also thank: in Belgium, Colienne de la Barre, Christine Derycke, and Siska Verlinde for collecting and verifying data, the members of the Belgian Society for Pediatric Endocrinology and Diabetology, Lisbeth van Eycken and the persons of the Belgian Cancer Registry, the persons of the National Population Registry, the Federal and Regional Death Registries for their essential contribution of sharing their data with us, and Marc Maes; in France, Caroline Arnaud-Sarthou, Vean-Eng Ly, Florentia Kaguelidou, and Fabienne Landier for their invaluable contributions, members of the French SAGhE study steering committee, Michel Andrejak (Centre Hospitalier Universitaire d’Amiens), Juliette Bloch (Institut de Veille Sanitaire), Anne Castot (Agence Française de Sécurité Sanitaire des Produits de Santé), Jean-Louis Chaussain (Académie de Médecine), Dominique Costagliola (INSERM), Nathalie Hoog-Labouret (Institut National du Cancer), Carmen Kreft-Jaïs (Agence Française de Sécurité Sanitaire des Produits de Santé), Anne Périllat (Direction Générale de la Santé), Béatrice Porokhov (Agence Française de Sécurité Sanitaire des Produits de Santé), Catherine Rey-Quinio (Agence Française de Sécurité Sanitaire des Produits de Santé), all the physicians involved in the follow-up of patients and in the review process at Association France Hypophyse, and, in particular, those who contributed to the collection of data for the study; in Germany, the physicians and nurses caring for the GH patients and their families, and Mandy Vogel; in Italy, Flavia Pricci, Cristina Fazzini, Pietro Panei, Giuseppe Scirè, Gian Luigi Spadoni, Franco Cavallo, Patrizia Matarazzo, Gianluca Aimaretti, and Laura Perrone; in the Netherlands, Sandra de Zeeuw for verifying data, members of the Dutch Growth Hormone Advisory Board of the Dutch Society for Paediatrics and all pediatric endocrinologists of the Advisory Group Growth Hormone involved in GH treatment of children, the registration teams of the Comprehensive Cancer Centre of the Netherlands and Comprehensive Cancer Centre South for the collection of data for the Netherlands Cancer Registry, and the scientific staff of the Comprehensive Cancer Centre of the Netherlands; in Sweden, the statistician team led by Nils-Gunnar Pehrsson, the Board of the National Growth Hormone Registry, Kerstin Albertsson-Wikland, Stefan A. Aronson, Peter Bang, Jovanna Dahlgren, Maria Elfving, Jan Gustafsson, Lars Hagenäs, Anders Häger, Sten A. Ivarsson, Berit Kriström, Claude Marcus, Christian Moell, Karl Olof Nilsson, Svante Norgren, Martin Ritzen, Johan Svensson, Torsten Tuvemo, Ulf Westgren, Otto Westphal, Jan Åman, and all pediatric endocrinologists and pediatricians involved in the GH treatment of children for their assistance in collecting and verifying data; in Switzerland, Rahel Kuonen, Urs Eiholzer, Juerg Girard, Sylvia Gschwendt, Michael Hauschild, Marco Janner, Beatrice Kuhlmann, Dagmar l’Allemand, Udo Meinhardt, Primus-Eugen Mullis, Franziska Phan-Hug, Eugen Schoenle, Michael Steigert, Urs Zumsteg, and Rolf Zurbruegg; and in the United Kingdom, the members of the British Society for Paediatric Endocrinology and Diabetes in the 21 historic UK Growth Centres for tracking down and contacting former and current patients, in particular, Justin Davies, Jo Blair, Fiona Ryan, Liz Crowne, Savitha Shenoy, Carlo Acerini, Jeremy Kirk, Tim Cheetham, Leo Dunkel, Tabitha Randell, Sabah Alvi, Neil Wright, Justin Warner, Amalia Mayo, Guftar Shaikh, Louise Bath, the Medicines for Children Research Network and the Scottish Medicines for Children Network who supported the network of research nurses, the former Pfizer UK International Growth Database team for assistance in making electronic database records of treated patients available to the local investigators at each of the UK Growth Centres, and Sharon Squires. Financial Support: This work was supported by funding in all countries from the European Union (HEALTH-F2-2009-223497; to J.-C.C.). In addition, there was funding, in Belgium, from the Belgian Study Group for Paediatric Endocrinology; in France, the Agence Française de Sécurité Sanitaire des Produits de Santé (the French drug safety agency; to J.-C.C.), Direction Générale de la Santé (French Ministry of Health; to J.-C.C.), and the Institut National du Cancer (to J.-C.C.); in Sweden, from the Swedish Research Council (to L.S.), Regional University Hospital Grants (to L.S.), the Swedish Cancer Society (to L.S.), and the Swedish Childhood Cancer Foundation (to L.S.); in Switzerland, from the Swiss Cancer League (KLS-02586-02-2010 and KLS-2948-02-2012; to C.E.K.), Pfizer AG (to C.E.K.), Novo Nordisk Pharma AG (to C.E.K.), and Sandoz Pharmaceuticals AG (to C.E.K.); and in the United Kingdom, University College London and the UK Child Growth Foundation (to G.B.). Disclosure Summary: P.C. is a consultant for MerckSerono. L.S. is a member of the NordiNet International Study Committee (Novo Nordisk) and recipient of investigator-initiated independent research awards from MerckSerono (Grant for Growth Innovation award), NovoNordisk, and Pfizer and lecture honoraria from Ferring, Novo Nordisk, Pfizer, and Merck Serono. J.-C.C. is an investigator in clinical trials using GH sponsored by Pfizer and Lilly and in post-marketing studies using several brands of GH and received support for travel to international meetings from several GH manufacturers. S.C. has received lecture fees from Ipsen, Merck-Serono, Novo Nordisk, and Pfizer, research grants from Merck Serono, Eli Lilly, and Pfizer, and support for travel to international meetings from several GH manufacturers and is a member of the PRISM advisory board (Ipsen). W.K. is a member of the Novo Nordisk Advisory Board on GH treatment and has received lecture and consultancy honoraria from Pfizer, Ipsen, and Sandoz. A.C.S.H.-K. is a member of the Pfizer International Growth Database Steering Committee and Novo Nordisk Advisory Board on GH treatment and a recipient of investigator-initiated independent research grants from Novo Nordisk and Pfizer and has received lecture fees from Novo Nordisk, Sandoz, and Pfizer. The remaining authors have nothing to disclose. References 1. Clayton PE , Banerjee I , Murray PG , Renehan AG . Growth hormone, the insulin-like growth factor axis, insulin and cancer risk . Nat Rev Endocrinol  . 2011 ; 7 ( 1 ): 11 – 24 . Google Scholar Crossref Search ADS PubMed   2. Swerdlow AJ . Does growth hormone therapy increase the risk of cancer ? Nat Clin Pract Endocrinol Metab  . 2006 ; 2 ( 10 ): 530 – 531 . Google Scholar Crossref Search ADS PubMed   3. Friend KE , Radinsky R , McCutcheon IE . 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Swerdlow, Anthony J, Cooke, Rosie, Beckers, Dominique, Butler, Gary, Carel, Jean-Claude, Cianfarani, Stefano, Clayton, Peter, Coste, Joël, Deodati, Annalisa, Ecosse, Emmanuel, Hokken-Koelega, Anita C S, Khan, Aysha J, Kiess, Wieland, Kuehni, Claudia E, Flück, Christa E, Pfaffle, Roland, Sävendahl, Lars, Sommer, Grit, Thomas, Muriel, Tidblad, Anders, Tollerfield, Sally, Zandwijken, Gladys R J. Risk of Meningioma in European Patients Treated With Growth Hormone in Childhood: Results From the SAGhE Cohort, The Journal of Clinical Endocrinology & Metabolism, 2019, 658-664, DOI: 10.1210/jc.2018-01133