Late Effects of Hypothalamic Radiation Exposure in Pediatric Brain Tumor Survivors

BACKGROUND: Brain tumors are the second most common childhood malignancy and overall survival rates exceed 70%. Pediatric brain tumor survivors treated with hypothalamic radiation are at increased risk for developing components of metabolic syndrome, characterized by central obesity and two of the following: elevated triglycerides, low HDL, elevated blood pressure, or fasting hyperglycemia. These patients may also be at risk for developing decreased bone density, which is associated with pathologic fractures. OBJECTIVE: Our aim is to compare the prevalence of metabolic syndrome or concomitant cardiometabolic risk, bone density, and body composition among pediatric brain tumor survivors treated with and without hypothalamic radiation. METHODS: This study evaluated 146 survivors of childhood brain tumors (70 radiated, 76 non-radiated) between 5-20 years old (mean: 12.3 years, SD: 4.1 years, average survival time: 6 years). Patients underwent fasting lab assays (lipid panel, insulin, glucose, leptin, and adiponectin), anthropometric measurements (height, weight, and waist circumference), and Dual-energy X-ray Absorptiometry (DXA) scan. Insulin resistance was identified using the homeostasis model assessment of insulin resistance (HOMA-IR). Metabolic syndrome was diagnosed according to the International Diabetes Foundation criteria in children 10 years and older; children between 5-10 years of age who met 3 of 5 risk factors were classified as having concomitant cardiometabolic risk. RESULTS: Metabolic syndrome or concomitant cardiometabolic risk was more common in patients who received hypothalamic-pituitary axis (HPA) radiation (7/38, 18.4%) than those who did not (4/76, 5.3%) (p = 0.04). Patients who received HPA radiation were more likely to have elevated triglyceride levels (p = 0.02), low HDL levels (p = 0.04), and lower IGF-1 z-scores (p < 0.001). On DXA scan, patients exposed to HPA radiation had lower Bone Mineral Content (BMC) and Bone Mineral Density (BMD) z-scores (-1.3 vs. -0.3, p = 0.003 and -1.4 vs. -0.2, p < 0.001 respectively) and lower Fat Free Mass Index z-scores (-1.4 vs. -0.1, p = 0.001) despite no significant difference in BMI (21.7 vs. 22.2, p = 0.7) or percent body fat (35.5% vs. 32.8%, p = 0.11). There was no significant difference in leptin/kg fat and adiponectin/kg fat between patients who received HPA radiation and those who did not (p = 0.55 and p = 0.98 respectively). Patients with elevated HOMA-IR had elevated leptin levels (p = 0.001), lower adiponectin levels (p = 0.04), and elevated leptin:adiponectin ratios (p = 0.001). CONCLUSION: These results suggest that exposure to hypothalamic radiation may have significant subclinical consequences that include components of metabolic syndrome, decreased bone density, and altered body composition. These results highlight the need for stringent follow-up surveillance of these patients and suggest that screening for dyslipidemia may be a sensitive way to detect patients at risk for developing metabolic syndrome.