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Purpose: To evaluate the safety, maximum-tolerated dose, pharmacokinetics, and pharmacodynamics of vandetanib, an oral vascular endothelial growth factor receptor 2 (VEGFR2) and epidermal growth factor receptor inhibitor, administered once daily during and after radiotherapy in children with newly diagnosed diffuse intrinsic pontine glioma., Patients and Methods: Radiotherapy was administered as 1.8-Gy fractions (total cumulative dose of 54 Gy). Vandetanib was administered concurrently with radiotherapy for a maximum of 2 years. Dose-limiting toxicities (DLTs) were evaluated during the first 6 weeks of therapy. Pharmacokinetic studies were obtained for all patients. Plasma angiogenic factors and VEGFR2 phosphorylation in mononuclear cells were analyzed before and during therapy., Results: Twenty-one patients were administered 50 (n = 3), 65 (n = 3), 85 (n = 3), 110 (n = 6), and 145 mg/m(2) (n = 6) of vandetanib. Only one patient developed DLT (grade 3 diarrhea) at dosage level 5. An expanded cohort of patients were treated at dosage levels 4 (n = 10) and 5 (n = 4); two patients developed grade 4 hypertension and posterior reversible encephalopathy syndrome while also receiving high-dose dexamethasone. Despite significant interpatient variability, exposure to vandetanib increased with higher dosage levels. The bivariable analysis of vascular endothelial growth factor (VEGF) before and during therapy showed that patients with higher levels of VEGF before therapy had a longer progression-free survival (PFS; P = .022), whereas patients with increases in VEGF during treatment had a shorter PFS (P = .0015). VEGFR2 phosphorylation was inhibited on day 8 or 29 of therapy compared with baseline (P = .039)., Conclusion: The recommended phase II dose of vandetanib in children is 145 mg/m(2) per day. Close monitoring and management of hypertension is required, particularly for patients receiving corticosteroids.

The purpose was to quantify the setup margin for pediatric patients with neuro-blastoma using cone beam CT imaging (CBCT) and ultrasound localization. Ten patients, with a median age of 4.3 years (1.8 to 7.9) underwent daily pretreatment localization CBCT and every other day post-treatment CBCT to calculate interfractional and intrafraction movement. Localization was based on CBCT to treatment planning CT registration in the lumbar spine region. Each subject was treated in the supine position under IV general anesthesia using intensity-modulated radiation therapy. Patients were repositioned based on the daily pretreatment CBCT. Required setup margins based on inter- and intrafraction positioning errors were calculated based on weekly and daily imaging scenarios. Four patients had ultra-sound localization of the kidneys performed before the CBCT. Correlation between daily CBCT and ultrasound was investigated. A lateral, longitudinal and vertical setup margin of 5.4, 5.6, and 5.9 mm is required without daily CBCT. When daily CBCT was incorporated, the setup margin was reduced to 1.5, 2.1, and 1.7 mm. There was no correlation between the suggested ultrasound shifts and the shifts based on the CBCT. Daily localization based on CBCT of the lumbar spine can reduce the required setup margin for neuroblastoma patients, thereby reducing normal tissue exposure for this young patient population. The internal margin needs further investigation before PTV reduction can be made. Ultrasound localization was highly variable and not correlated to CBCT shifts.