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Title: Predicting the Probability of Abnormal Stimulated Growth Hormone Response in Children After Radiotherapy for Brain Tumors

Abstract

Purpose: To develop a mathematical model utilizing more readily available measures than stimulation tests that identifies brain tumor survivors with high likelihood of abnormal growth hormone secretion after radiotherapy (RT), to avoid late recognition and a consequent delay in growth hormone replacement therapy. Methods and Materials: We analyzed 191 prospectively collected post-RT evaluations of peak growth hormone level (arginine tolerance/levodopa stimulation test), serum insulin-like growth factor 1 (IGF-1), IGF-binding protein 3, height, weight, growth velocity, and body mass index in 106 children and adolescents treated for ependymoma (n = 72), low-grade glioma (n = 28) or craniopharyngioma (n = 6), who had normal growth hormone levels before RT. Normal level in this study was defined as the peak growth hormone response to the stimulation test {>=}7 ng/mL. Results: Independent predictor variables identified by multivariate logistic regression with high statistical significance (p < 0.0001) included IGF-1 z score, weight z score, and hypothalamic dose. The developed predictive model demonstrated a strong discriminatory power with an area under the receiver operating characteristic curve of 0.883. At a potential cutoff point of probability of 0.3 the sensitivity was 80% and specificity 78%. Conclusions: Without unpleasant and expensive frequent stimulation tests, our model providesmore » a quantitative approach to closely follow the growth hormone secretory capacity of brain tumor survivors. It allows identification of high-risk children for subsequent confirmatory tests and in-depth workup for diagnosis of growth hormone deficiency.« less

Authors:
 [1];  [2];  [3]; ;  [1]
  1. Department of Radiological Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee (United States)
  2. Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, Tennessee (United States)
  3. Division of Endocrinology, Department of Pediatric Medicine, St. Jude Children's Research Hospital, Memphis, Tennessee (United States)
Publication Date:
OSTI Identifier:
22149642
Resource Type:
Journal Article
Resource Relation:
Journal Name: International Journal of Radiation Oncology, Biology and Physics; Journal Volume: 84; Journal Issue: 4; Other Information: Copyright (c) 2012 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
62 RADIOLOGY AND NUCLEAR MEDICINE; ARGININE; BRAIN; CHILDREN; DIAGNOSIS; EVALUATION; GLIOMAS; GROWTH FACTORS; HEALTH HAZARDS; INSULIN; MATHEMATICAL MODELS; MULTIVARIATE ANALYSIS; PEDIATRICS; PROBABILITY; RADIATION DOSES; RADIOTHERAPY; SECRETION; SENSITIVITY; SPECIFICITY; STH; STIMULATION

Citation Formats

Hua Chiaho, E-mail: Chia-Ho.Hua@stjude.org, Wu Shengjie, Chemaitilly, Wassim, Lukose, Renin C., and Merchant, Thomas E. Predicting the Probability of Abnormal Stimulated Growth Hormone Response in Children After Radiotherapy for Brain Tumors. United States: N. p., 2012. Web. doi:10.1016/J.IJROBP.2012.01.049.
Hua Chiaho, E-mail: Chia-Ho.Hua@stjude.org, Wu Shengjie, Chemaitilly, Wassim, Lukose, Renin C., & Merchant, Thomas E. Predicting the Probability of Abnormal Stimulated Growth Hormone Response in Children After Radiotherapy for Brain Tumors. United States. doi:10.1016/J.IJROBP.2012.01.049.
Hua Chiaho, E-mail: Chia-Ho.Hua@stjude.org, Wu Shengjie, Chemaitilly, Wassim, Lukose, Renin C., and Merchant, Thomas E. 2012. "Predicting the Probability of Abnormal Stimulated Growth Hormone Response in Children After Radiotherapy for Brain Tumors". United States. doi:10.1016/J.IJROBP.2012.01.049.
@article{osti_22149642,
title = {Predicting the Probability of Abnormal Stimulated Growth Hormone Response in Children After Radiotherapy for Brain Tumors},
author = {Hua Chiaho, E-mail: Chia-Ho.Hua@stjude.org and Wu Shengjie and Chemaitilly, Wassim and Lukose, Renin C. and Merchant, Thomas E.},
abstractNote = {Purpose: To develop a mathematical model utilizing more readily available measures than stimulation tests that identifies brain tumor survivors with high likelihood of abnormal growth hormone secretion after radiotherapy (RT), to avoid late recognition and a consequent delay in growth hormone replacement therapy. Methods and Materials: We analyzed 191 prospectively collected post-RT evaluations of peak growth hormone level (arginine tolerance/levodopa stimulation test), serum insulin-like growth factor 1 (IGF-1), IGF-binding protein 3, height, weight, growth velocity, and body mass index in 106 children and adolescents treated for ependymoma (n = 72), low-grade glioma (n = 28) or craniopharyngioma (n = 6), who had normal growth hormone levels before RT. Normal level in this study was defined as the peak growth hormone response to the stimulation test {>=}7 ng/mL. Results: Independent predictor variables identified by multivariate logistic regression with high statistical significance (p < 0.0001) included IGF-1 z score, weight z score, and hypothalamic dose. The developed predictive model demonstrated a strong discriminatory power with an area under the receiver operating characteristic curve of 0.883. At a potential cutoff point of probability of 0.3 the sensitivity was 80% and specificity 78%. Conclusions: Without unpleasant and expensive frequent stimulation tests, our model provides a quantitative approach to closely follow the growth hormone secretory capacity of brain tumor survivors. It allows identification of high-risk children for subsequent confirmatory tests and in-depth workup for diagnosis of growth hormone deficiency.},
doi = {10.1016/J.IJROBP.2012.01.049},
journal = {International Journal of Radiation Oncology, Biology and Physics},
number = 4,
volume = 84,
place = {United States},
year = 2012,
month =
}
  • The growth hormone (GH) responses to (A) GRF 1-44, 1 microgram/kg i.v., (B) L-dopa and either arginine, insulin, or glucagon, and (C) exercise were evaluated in 10 children (3 girls, 7 boys; ages 10 years to 15 years, 8 months), 2-10.75 years following cranial irradiation for medulloblastoma (8 patients), pineoblastoma (1 patient), and a fourth ventricular ependymoma (1 patient). Nine of the 10 children had abnormal growth rates. All children were euthyroid at the time of the study. The mean 0-60-min peak GH response to GRF (10.06 +/- 2.6 ng/ml) in the patients was less than the mean peak GHmore » response (29 +/- 2.3 ng/ml) in the control children (n = 7). In 6 patients (5 with poor growth rates), a decreased GH response was noted to GRF and all other tests. Of the remaining patients, all with poor growth rates, two patients demonstrated an adequate response to GRF and pharmacologic testing; one patient had a normal GH response to GRF with a low GH response to pharmacologic testing; and one patient had a low response to GRF, despite a normal response to both exercise and pharmacologic testing. The decrease in mean peak GH response to GRF in the patient population confirms that radiation to the hypothalamic-pituitary region produces abnormalities in growth hormone release. Furthermore, in these patients, discordant GH responses to GRF and pharmacologic or physiologic tests can be observed. The abnormality in growth hormone release may result from a hypothalamic dysfunction in GRF release and/or damage to GH secretory pituicytes.« less
  • Ninety-one children younger than age five years have been treated with radiotherapy for primary intracranial tumors. Patients with cerebellar astrocytomas and optic chiasm gliomas did relatively well, whereas brain stem tumors, extensive posterior fossa tumors and cerebral gliomas had a poor prognosis. Medulloblastomas, ependymomas, and midbrain tumors were of intermediate prognosis. There was no definite correlation between age at diagnosis and survival, although patients over 24 months of age seemed to do sightly better. Tumor doses of at least 4000 rad seem necessary for any likelihood of control. Of 63 children diagnosed over five years ago, 27(43%) survived at leastmore » five years. The majority of long-term survivors are leading normal lives, although many have mild impairments.« less
  • Purpose: To describe the preliminary results after intraoperative radiotherapy (IORT) with the photon radiosurgery system in children with recurrent brain tumors treated at the first dose level (10 Gy) of a Phase I protocol. Methods and Materials: A Phase I IORT dose escalation protocol was initiated at Children's Memorial Hospital to determine the maximal tolerated IORT dose in children with recurrent brain tumors. Results: Fourteen children have received IORT thus far. Eight had been previously irradiated. Thirteen children had ependymoma. The median follow-up was 16 months. Three patients (21%) developed radiation necrosis on follow-up MRI scans 6 to 12 monthsmore » after IORT. They had not been previously irradiated and had received 10 Gy to a depth of 5 mm. One required surgery and the other two had resolution of their lesions without treatment. All 3 patients were asymptomatic at the last follow-up. No other late toxicity was observed at the last follow-up visit. Eight patients (57%) had tumor control within the surgical bed after IORT. Conclusion: Our findings have demonstrated the safety and feasibility of IORT to a dose of 10 Gy to 2 mm in children with previously irradiated brain tumors. IORT to a dose of 10 Gy at 5 mm was associated with a greater complication rate.« less
  • Purpose: To present prospective neuropsychological data at baseline and follow-up in children and young adults with benign and low-grade gliomas treated with focal stereotactic conformal radiotherapy (SCRT). Methods and Materials: A total of 22 patients (age 4-25 years) with residual/progressive benign and low-grade brain tumors considered suitable for SCRT underwent detailed and in-depth neuropsychological and cognitive testing at baseline before SCRT. The test battery included measurement of age-adjusted intelligence quotients (IQs) and cognitive parameters of visual, spatial, visuomotor, and attention concentrations. Anxiety was measured using the State-Trait Anxiety Inventory for Children and Hamilton Anxiety Rating Scale for patients >16 yearsmore » old. Patients were treated with high-precision conformal radiotherapy under stereotactic guidance to a dose of 54 Gy in 30 fractions. All neuropsychological assessments were repeated at 6 and 24 months after SCRT completion and compared with the baseline values. Results: The baseline mean full-scale IQ before starting RT for patients <16 years was 82 (range, 33-105). For those >16 years, the corresponding value was 72 (range, 64-129). Of 20 evaluable patients, 14 (70%) had less than average IQs at baseline, even before starting radiotherapy. The verbal IQ, performance IQ, and full-scale IQ, as well as other cognitive scores, did not change significantly at the 6- and 24-month follow-up assessments for all patients. The memory quotient in older children and young adults was maintained at 6 and 24 months after SCRT, with a mean value of 93 and 100, respectively, compared with a mean baseline value of 81 before RT. The mean anxiety score in children measured by the C1 and C2 components of the State-Trait Anxiety Inventory for Children (STAIC) was 48 and 40, respectively, which improved significantly to mean values of 30 and 26, respectively, at the 24-month follow-up assessment (p = 0.005). The mean depression score in patients >16 years old was 23 at baseline and had improved to 17 and 14 at the 6-month and 24-month follow-up assessments, respectively. Conclusion: Our data demonstrated neuropsychological impairment in a cohort of young patients with benign and low-grade tumors even before starting radiotherapy. SCRT, however, did not result in any additional worsening. These encouraging results need to be validated in a study with a larger number of patients and longer follow-up.« less
  • To evaluate the effects of two different doses of cranial irradiation on growth and growth hormone (GH) release, we studied 61 children with acute lymphocytic leukemia who had survived at least five years in continuous complete remission. Forty-three children received 24 Gy (group 1) and 18 children received 18 Gy (group 2). Height was evaluated at diagnosis, at the end of treatment, and 6, 12, and 24 months later. Growth hormone release was evaluated by arginine and levodopa tests after the end of treatment. After diagnosis, the height SD score decreased significantly in both groups; two years after the endmore » of treatment, only group 1 showed an SD score for height that was still significantly lower than at diagnosis. Group 1 showed impaired GH responses to the tests and, compared with controls, group 1 in fact included a percentage of subjects with a normal response to levodopa (ie, greater than 8 micrograms/L) that was significantly lower (56.4% vs 83.3%) and a percentage of nonresponders to both tests that was significantly higher (21.6% vs 0%). These data indicate that only patients treated with lower cranial irradiation dosage (18 Gy) had complete growth recovery and normal GH responses to pharmacologic tests.« less