Changes in bone mineral density in survivors of childhood acute lymphoblastic leukemia.

BACKGROUND: There is little information about factors modulating bone mineral density (BMD) in survivors of childhood acute lymphoblastic leukemia (ALL). PROCEDURE: We analyzed data from 57 survivors (26 male, 52 Caucasian) who underwent two serial quantitative computed tomography (QCT) studies of BMD. Using multiple linear regression, we evaluated the association of BMD change with demographic variables, treatment history, hormone therapy, exercise, and tobacco and alcohol use. RESULTS: The median age was 3.4 years (range, 0.9-17.4 years) at diagnosis of ALL; the median age at the first QCT (Study I) was 15.0 years (range, 10.6-31.0 years) and at the second QCT (Study II) was 18.2 years (range, 14.2-35.3 years). Mean height increased 4.7 cm and mean weight increased 8.8 kg between Studies I and II. While the mean BMD increased 9.33 mg/cc (P = 0.003), the BMD Z-score increased only slightly (0.21 SD, P = 0.035). Cortical bone density increased significantly (approximately 25.3 mg/cc; P = 0.001), but the ratio of trabecular to cortical BMD decreased significantly (P = 0.045). Factors independently associated with unfavorable BMD changes included older age at diagnosis (P = 0.001), female sex (P = 0.018), and nutritional supplementation (0.032). Alcohol (P = 0.009) was an unfavorable factor in a univariable analysis. CONCLUSIONS: Bone mineral accretion during adolescence is attenuated in childhood ALL survivors by a comparative deficit in trabecular versus cortical bone deposition. BMD is influenced favorably by exercise in early adolescence and unfavorably by the use of nutritional supplements and alcohol. These results provide new information about behavioral factors that affect bone accrual in survivors of childhood ALL and warrant definitive evaluation in a larger cohort.

Risk factors for the development of obesity in children surviving brain tumors.

Hypothalamic obesity, a syndrome of intractable weight gain due to hypothalamic damage, is an uncommon but devastating complication for children surviving brain tumors. We undertook a retrospective evaluation of the body mass index (BMI) curves for the St. Jude Children's Research Hospital brain tumor population diagnosed between 1965 and 1995 after completion of therapy to determine risk factors for the development of obesity. Inclusion criteria were: diagnosis less than 14 yr of age, no spinal cord involvement, ambulatory, no supraphysiologic hydrocortisone therapy (>12 mg/m(2) x d), treatment and follow-up at St. Jude Children's Research Hospital, and disease-free survival greater than 5 yr (n = 148). Risk factors examined were age at diagnosis, tumor location, histology, extent of surgery, hydrocephalus requiring ventriculoperitoneal shunting, initial high-dose glucocorticoids, cranial radiation therapy, radiation dosimetry to the hypothalamus, intrathecal chemotherapy, and presence of endocrinopathy. Analyses were performed both between groups within a risk factor and against BMI changes for age in normal children older than 5.5 yr (the age of adiposity rebound). Risk factors were: age at diagnosis (P = 0.04), radiation dosimetry to the hypothalamus (51-72 Gy, P = 0.002 even after hypothalamic and thalamic tumor exclusion), and presence of any endocrinopathy (P = 0.03). In addition, risk factors when compared with BMI slope for the general American pediatric population included: tumor location (hypothalamic, P = 0.001), tumor histology (craniopharyngioma, P = 0.009; pilocytic astrocytoma, P = 0.043; medulloblastoma, P = 0.039); and extent of surgery (biopsy, P = 0.03; subtotal resection, P = 0.018). These results verify hypothalamic damage, either due to tumor, surgery, or radiation, as the primary cause of obesity in survivors of childhood brain tumors. In particular, hypothalamic radiation doses of more than 51 Gy are permissive. These results reiterate the importance of the hypothalamus in energy balance, provide risk assessment criteria for preventative measures before the development of obesity in at-risk patients, and suggest therapeutic strategies to reduce the future development of obesity.

Radiation dose-volume effects on growth hormone secretion.

PURPOSE: Growth hormone (GH) deficiency is a known consequence of central nervous system irradiation. The relationship between the dose to the hypothalamus and the time to onset of clinically significant GH deficiency is unknown. Conformal radiotherapy (CRT) techniques allow for a more accurate determination of hypothalamic dosimetry. We correlated the dosimetry of the hypothalamus and the peak GH value after CRT in children with localized primary brain tumors. METHODS AND MATERIALS: The arginine tolerance/L-dopa test was performed before (baseline) and repeated 6 and 12 months after CRT in 25 children (median age 4.8 years) with ependymoma (n = 15) or low-grade (n = 8) or high-grade (n = 2) astrocytoma. None had evidence of GH deficiency (arginine tolerance/L-dopa peak GH level >10 ng/mL [10 microg/L]) at baseline. Peak GH levels were modeled as a function of time after CRT and volume of the hypothalamus receiving a dose within the specified intervals of 0-20 Gy, 20-40 Gy, and 40-60 Gy. The model was used to predict the change in the peak GH levels over time (0-12 months) and fit under the assumption that the integral effect of irradiation was a linear sum of the products of the volume receiving a particular dose and the impact of that dose. RESULTS: The peak GH level declined during the 0-12 months after CRT (p < 0.0001). GH deficiency was observed in 11 children at 6 months and a total of 20 children at 12 months. As expected, the effect of the dose interval 0-20 Gy was smaller than the 20-40-Gy dose interval; the largest effect was noted with the dose interval 40-60 Gy. The peak GH level may be predicted using the following estimating equation within the time limit of 0-12 months: GH(t)=Exp[ln(bGH)-(0.00058V(0-20 Gy)+0.00106V(20-40 Gy)+0.00156V(40-60 Gy))x t], where bGH is the baseline peak GH level, V(0-20 Gy), V(20-40 Gy), and V(40-60 Gy) is the percent-volume of the hypothalamus irradiated from 0 to 20 Gy, 20 to 40 Gy, and 40 to 60 Gy, respectively, and t is time after irradiation. When included in the model, the rate of decline in the peak GH response also was influenced by hydrocephalus and tumor location. CONCLUSION: The peak GH response within 12 months after CRT depends on hypothalamic dose-volume effects and may be predicted on the basis of a linear model that sums the effects of the entire distribution of dose. The modeled effects may be used to optimize radiotherapy and minimize and treat GH deficiency.