Response to GH Treatment After Radiation Therapy Depends on Location of Irradiation

OBJECTIVES: Cancer survivors with GH deficiency (GHD) receive GH therapy (GHT) after 1+ year observation to ensure stable tumor status/resolution. HYPOTHESIS: Radiation therapy (RT) to brain, spine, or extremities alters growth response to GHT. AIM: Identify differences in growth response to GHT according to type/location of RT. METHODS: The Pfizer International Growth Database was searched for cancer survivors on GHT for ≥5 years. Patient data, grouped by tumor type, were analyzed for therapy (surgery, chemotherapy, RT of the focal central nervous system, cranial, craniospinal, or total body irradiation [TBI] as part of bone marrow transplantation), sex, peak stimulated GH, age at GHT start, and duration from RT to GHT start. Kruskal-Wallis test and quantile regression modeling were performed. RESULTS: Of 1149 GHD survivors on GHT for ≥5 years (male 733; median age 8.4 years; GH peak 2.8 ng/mL), 431 had craniopharyngioma (251, cranial RT), 224 medulloblastoma (craniospinal RT), 134 leukemia (72 TBI), and 360 other tumors. Median age differed by tumor group (P < 0.001). Five-year delta height SD score (SDS) (5-year ∆HtSDS; median [10th-90th percentile]) was greatest for craniopharyngioma, 1.6 (0.3-3.0); for medulloblastoma, 5-year ∆HtSDS 0.9 (0.0-1.9); for leukemia 5-year ∆HtSDS, after TBI (0.3, 0-0.7) versus without RT (0.5, 0-0.9), direct comparison P < 0.001. Adverse events included 40 treatment-related, but none unexpected. CONCLUSIONS: TBI for leukemia had significant impact on growth response to GHT. Medulloblastoma survivors had intermediate GHT response, whereas craniopharyngioma cranial RT did not alter GHT response. Both craniospinal and epiphyseal irradiation negatively affect growth response to GH therapy compared with only cranial RT or no RT

A Genome-Wide Pharmacogenetic Study of Growth Hormone Responsiveness

Individual patients vary in their response to growth hormone (GH). No large-scale genome-wide studies have looked for genetic predictors of GH responsiveness. To identify genetic variants associated with GH responsiveness. Genome-wide association study (GWAS). Cohorts from multiple academic centers and a clinical trial. A total of 614 individuals from 5 short stature cohorts receiving GH: 297 with idiopathic short stature, 276 with isolated GH deficiency, and 65 born small for gestational age. Association of more than 2 million variants was tested. Primary analysis: individual single nucleotide polymorphism (SNP) association with first-year change in height standard deviation scores. Secondary analyses: SNP associations in clinical subgroups adjusted for clinical variables; association of polygenic score calculated from 697 genome-wide significant height SNPs with GH responsiveness. No common variant associations reached genome-wide significance in the primary analysis. The strongest suggestive signals were found near the B4GALT4 and TBCE genes. After meta-analysis including replication data, signals at several loci reached or retained genome-wide significance in secondary analyses, including variants near ST3GAL6. There was no significant association with variants previously reported to be associated with GH response nor with a polygenic predicted height score. We performed the largest GWAS of GH responsiveness to date. We identified 2 loci with a suggestive effect on GH responsiveness in our primary analysis and several genome-wide significant associations in secondary analyses that require further replication. Our results are consistent with a polygenic component to GH responsiveness, likely distinct from the genetic regulators of adult height

The prevalence of the metabolic syndrome and associated cardiovascular complications in adult-onset GHD during GH replacement: a KIMS analysis

Background: Adult-onset growth hormone deficiency (AO-GHD) is associated with an increased prevalence of the metabolic syndrome (MetS). Aim: To determine the effect of GH replacement on the prevalence of MetS in AO-GHD and to study the impact of MetS on the incidence of cardiovascular events during GH replacement. Patients and methods: 1449 AO-GHD patients (males 48.9%; mean age 48.9 ± 12.8 year) were retrieved from KIMS (Pfizer International Metabolic Database). The prevalence of MetS (using International Diabetes Federation criteria) and its components were calculated at baseline and after one year of GH replacement. The relative risk to develop cardiovascular events according to the presence of MetS at baseline was assessed in another group of 3282 patients after prolonged GH replacement. Results: The prevalence of MetS was 46.9% at baseline and 48.2% after one year of GH replacement (P = NS). The percentage of patients with abnormal waist circumference decreased significantly (80.3 vs 77.4%; P < 0.001), but impaired glucose metabolism (17.1 vs 23.3%; P < 0.001) increased and HDL cholesterol (48.2 vs 50.9%; P = 0.011) decreased. Switch from MetS to NoMS (18.5%) and from NoMS to MetS (18.8%) occurred. All patients showed a significant and comparable amelioration of quality of life. During seven years of GH replacement patients with MetS had a 66% higher risk (P = 0.0016) to develop a new coronary disease compared to NoMS. Conclusion: MetS prevalence remains unchanged in AO-GHD during one year of GH replacement whereas its components are differentially affected. Besides GH replacement, consequent pharmacotherapy of all risk factors and endorsement of lifestyle intervention appears to be of uttermost importance together with early GHD diagnosis to prevent cardiovascular disease during prolonged treatment

Radiotherapy, especially at young age, increases the risk for de novo brain tumors in patients treated for pituitary/sellar lesions

Context: De novo brain tumors developing after treatment of pituitary/sellar lesions have been reported, but it is unknown whether this is linked to any of the treatment modalities. Objective: To study the occurrence of malignant brain tumors and meningiomas in a large cohort of patients treated for pituitary/sellar lesions, with special emphasis on the role of radiotherapy (RT). Patients and Methods: Patients (n = 8917) who were hypopituitary due to pituitary adenomas, craniopharyngiomas, and other sellar tumors followed in KIMS (Pfizer International Metabolic Database) from 1994 to 2012 were included. Treatment consisted of surgery and/or medical therapy in 4927 patients, RT alone, or with surgery in 3236 patients; data were missing in 754. Incidence rate ratios (RRs) were analyzed through Poisson regression methods with internal comparisons. Results: During 53,786 patient-years, 17 cases of malignant brain tumors (13 exposed to RT) and 27 meningiomas (22 exposed to RT) were reported. RR for RT vs no RT was 3.34 [95% confidence interval (CI), 1.06 to 10.6] for malignant brain tumors, and 4.06 (95% CI, 1.51 to 10.9) for meningiomas. The risk of developing a malignant brain tumor increased by 2.4-fold (P = 0.005) and meningioma by 1.6-fold with every 10 years of younger age at RT (P = 0.05). Incidence rates were similar in patients treated with conventional RT compared with stereotactic RT. Conclusion: RT of pituitary tumors is associated with increased risk of developing malignant brain tumors and meningiomas, especially when given at younger ages. In balancing risks and benefits of RT, our findings emphasize that special consideration should be given to the age of the patient

New Neoplasm During GH Replacement in Adults With Pituitary Deficiency Following Malignancy: A KIMS Analysis.

CONTEXT: Data on the association between growth hormone (GH) replacement in patients with GH deficiency (GHD) after malignancies and new neoplasms show conflicting results. OBJECTIVE: To clarify the incidence of new malignant neoplasm in childhood-onset (CO) and adult-onset (AO) adult cancer survivors (CSs). DESIGN: Retrospective comparison of CO-CS and AO-CS with CO idiopathic GHD (IGHD) and AO nonfunctioning pituitary adenoma (NFPA) patients and with the general population [standardized incidence ratio (SIR)]. SETTING: Data from the Pfizer International Metabolic Database study (KIMS). PATIENTS: CO-CS [n = 349; 50.4% females; mean baseline (MBL) IGF-I standard deviation score (SDS), -2.4], IGHD (n = 619; 35.7% females; MBL IGF-I SDS, -3.4), AO-CS (n = 174; 42.5% females; MBL IGF-I SDS, -1.4), and NFPA (n = 2449; 38.1% females; MBL IGF-I SDS, -1.0). MAIN OUTCOME MEASURES: SIRs of malignant neoplasms. RESULTS: After a median follow-up of 5.9 years (2192 patient-years), 15 CO-CS (4.3%) had developed 16 new neoplasms. The SIR was 10.4 [95% confidence interval (CI), 5.9 to 16.9] and 6.5 (95% CI, 3.0 to 12.4) after exclusion of seven patients with skin cancers. In IGHD, three malignant neoplasms (0.5%) were observed after a median follow-up of 5.4 years (3908 patient-years; SIR, 0.47; 95% CI, 0.09 to 1.37). New malignant neoplasms occurred in three AO-CS (1.7%; SIR, 1.1; 95% CI, 0.2 to 3.2) and 146 NFPA patients (153 cases, 6.0%; SIR, 1.1; 95% CI, 0.9 to 1.2) after a median follow-up of 4.9 (1024 patient-years) and 5.6 years (15,215 patient-years). CONCLUSIONS: The risk of second malignant neoplasms was increased in CO-CS but not in AO-CS, which illustrates the need to closely follow patients on GH replacement because of a prior malignancy

Improvements in body composition after 4 years of growth hormone treatment in adult-onset hypopituitarism compared to age-matched controls

BACKGROUND/AIMS: It is unknown whether long-term growth hormone replacement therapy (GHRT) affects body composition in an age- or sex dependent manner. We aimed to study the effects of 4 years of GHRT on body composition in a large cohort of patients with hypopituitarism compared to a reference population matched by age and sex. METHODS: A total of 964 GH deficient adults from KIMS (Pfizer International Metabolic Database) with adult-onset hypopituitarism, adequately replaced with all pituitary hormones except for GH at baseline were included. A random sample of the general population (2301 subjects) from a similar time period was used as reference. Patients and controls were grouped by sex in 5 age cohorts of 10 years. Main outcome measures were changes in BMI and waist circumference after 4 years of GHRT. RESULTS: In younger patients (28-47 years), four years of GHRT resulted in a BMI increase similar to that observed in the reference population, but older patients (48-67 years) had significantly less BMI increase than age-matched healthy controls. Significant differences were seen in waist circumference in patients of all age cohorts who showed virtually no change after 4 years of GHRT compared to approximately 4 cm of increase in the reference population. CONCLUSION: Four years of GHRT resulted in improvements in BMI and waist circumference in patients with adult-onset hypopituitarism compared to age-matched controls observed during the same follow-up time. Despite these beneficial effects on body composition, BMI and waist circumference remained higher in patients on GHRT compared to healthy controls.