Cognitive outcomes among survivors of focal low-grade brainstem tumors diagnosed in childhood.

Pediatric focal low-grade brainstem tumors are associated with excellent prognosis. Surgical resection and conformal radiation therapy are front-line treatment options; radiation therapy (RT) serves as an excellent treatment for disease progression. Given high survival rates and limited research regarding functional outcomes, the current study examined neurocognitive outcomes in a group of low-grade brainstem glioma survivors. Forty-three survivors of focal low-grade brainstem gliomas underwent neurocognitive assessment (58 % male; median = 6.9 years at diagnosis; median = 14.9 years at latest assessment). Treatment included combinations of surgery, chemotherapy, and RT with 70 % ultimately receiving RT. Neurocognitive outcomes were evaluated through retrospective chart review. Intellectual and academic performance were significantly different from normative expectations (full scale IQ = 86.5 ± 16.8; reading comprehension = 91.3 ± 16.4; math reasoning = 88.2 ± 18.9; reference group = 100 ± 15). Further, the percentage performing below average exceeded the expected 16 % in the normative sample (full scale IQ = 43 %; reading comprehension = 37 %; math reasoning = 50 %). Mean parent ratings did not reflect concerns regarding internalizing and externalizing behaviors or executive functioning (internalizing = 54.9 ± 12.7; externalizing = 51.6 ± 14.6, global executive composite = 57.1 ± 16.0; reference group = 50 ± 10); however, the proportion with clinically elevated scores was higher than the expected 16 % (internalizing = 42 %; externalizing = 26 %; global executive composite = 38 %). Mean performance fell below average for visual-motor coordination (81.8 ± 13.2) and parent ratings of adaptive functioning (73.4 ± 24.2), with 65 and 62 % falling outside the average range, respectively. There were no significant differences between those receiving and not receiving RT. Multiple cognitive domains were significantly different from normative expectations. Despite focal disease and treatment targeting subcortical brain regions, neurocognitive risks exist that may impact treatment planning and caregiver education.

Whole-Body Pediatric Neuroblastoma Imaging: 123I-mIBG and Beyond.

Pediatric cancer imaging stands to benefit from higher tumor detection sensitivity without ionizing radiation exposure. A prospective protocol compared diagnostic I-metaiodobenzylguanidine (I-mIBG) with whole-body diffusion-weighted MRI (DWI) to validate adjunctive methods of identifying small-volume oligometastatic neuroblastoma tumor deposits. Dual-modality imaging (I-mIBG and DWI) was obtained within a 3- and 25-day window at baseline and again at one year in the first enrolled patient. MRI was able to define the full extent of metastatic disease foci with improved resolution. These findings may provide critical information for definitive locoregional surgery and radiotherapy for high-risk neuroblastoma treatment.

Phase II Trial of Erlotinib during and after Radiotherapy in Children with Newly Diagnosed High-Grade Gliomas.

BACKGROUND: Epidermal growth factor receptor is overexpressed in most pediatric high-grade gliomas (HGG). Since erlotinib had shown activity in adults with HGG, we conducted a phase II trial of erlotinib and local radiotherapy (RT) in children with newly diagnosed HGG. METHODS: Following maximum surgical resection, patients between 3 and 21 years with non-metastatic HGG received local RT at 59.4 Gy (54 Gy for spinal tumors and those with ≥70% brain involvement). Erlotinib started on day 1 of RT (120 mg/m(2) per day) and continued for 2 years unless there was tumor progression or intolerable toxicities. The 2-year progression-free survival (PFS) was estimated for patients with intracranial anaplastic astrocytoma (AA) and glioblastoma (GBM). RESULTS: Median age at diagnosis for 41 patients with intracranial tumors (21 with GBM and 20 with AA) was 10.9 years (range, 3.3-19 years). The 2-year PFS for patients with AA and GBM was 15 ± 7 and 19 ± 8%, respectively. Only five patients remained alive without tumor progression. Twenty-six patients had at least one grade 3 or 4 toxicity irrespective of association with erlotinib; only four required dose modifications. The main toxicities were gastrointestinal (n = 11), dermatologic (n = 5), and metabolic (n = 4). One patient with gliomatosis cerebri who required prolonged corticosteroids died of septic shock associated with pancreatitis. CONCLUSION: Although therapy with erlotinib was mostly well-tolerated, it did not change the poor outcome of our patients. Our results showed that erlotinib is not a promising medication in the treatment of children with intracranial AA and GBM.

Effect of time from diagnosis to start of radiotherapy on children with diffuse intrinsic pontine glioma.

BACKGROUND: Children with diffuse intrinsic pontine glioma (DIPG) continue to have poor outcomes, and radiotherapy (RT) is the only temporarily effective treatment. In this retrospective analysis, we studied the effect of time from diagnosis to start of RT on event-free survival (EFS) and overall survival (OS) in children with DIPG. METHODS: Records of children (n = 95) with DIPG treated with RT at a single institution between April 1999 and September 2009 were analyzed. RT was delivered at doses of 54.0-55.8 Gy at 1.8 Gy per fraction, and children were followed prospectively. The effect of gender, race, interruption during treatment course, age at diagnosis, duration of symptoms prior to diagnosis, use of protocol-based chemotherapy, and time from diagnosis to initiation of RT on EFS and OS was assessed by the Cox proportional hazards model. RESULTS: Time as a continuous variable from diagnosis to start of RT did not affect outcome. Time dichotomized to ≤14 days significantly affected OS (hazard ratio [HR] = 1.70, P = 0.014) and race other than white or black affected EFS (HR = 2.32, P = 0.017). The 95 patients had a 6-month EFS and OS of 60 ± 5% and 94.7 ± 2.3%, respectively, and a 12-month EFS and OS of 11.6 ± 3.1% and 49.5 ± 5%, respectively. CONCLUSIONS: Time as a continuous variable did not affect OS or EFS in our cohort; however, children treated within 2 weeks of diagnosis had poor outcomes. Although rapid initiation of RT is desirable, our findings do not support intensive efforts aimed at shortening delays from diagnosis to start of RT.

Clinico-radiologic characteristics of long-term survivors of diffuse intrinsic pontine glioma.

Diffuse intrinsic pontine glioma (DIPG) is the deadliest central nervous system tumor in children. The survival of affected children has remained poor despite treatment with radiation therapy (RT) with or without chemotherapy. We reviewed the medical records of all surviving patients with DIPG treated at our institution between October 1, 1992 and May 31, 2011. Blinded central radiologic review of the magnetic resonance imaging at diagnosis of all surviving patients and 15 controls with DIPG was performed. All surviving patients underwent neurocognitive assessment during follow-up. Five (2.6 %) of 191 patients treated during the study period were surviving at a median of 9.3 years from their diagnosis (range 5.3-13.2 years). Two patients were younger than 3 years, one lacked signs of pontine cranial nerve involvement, and three had longer duration of symptoms at diagnosis. One patient had a radiologically atypical tumor and one had a tumor originating in the medulla. All five patients received RT. Chemotherapy was variable among these patients. Neurocognitive assessments were obtained after a median interval of 7.1 years. Three of four patients who underwent a detailed evaluation showed cognitive function in the borderline or mental retardation range. Two patients experienced disease progression at 8.8 and 13 years after diagnosis. A minority of children with DIPG experienced long-term survival with currently available therapies. These patients remained at high risk for tumor progression even after long follow-ups. Four of our long-term survivors had clinical and radiologic characteristics at diagnosis associated with improved outcome.

Phase I trial, pharmacokinetics, and pharmacodynamics of vandetanib and dasatinib in children with newly diagnosed diffuse intrinsic pontine glioma.

PURPOSE: Testing of promising drug combinations is crucial in the treatment of diffuse intrinsic pontine glioma (DIPG). As the VEGF and platelet-derived growth factor (PDGF) pathways are critical in gliomas, we evaluated the safety, maximum tolerated dose (MTD), pharmacokinetics, and pharmacodynamics of vandetanib, a VEGFR-2 inhibitor, combined with dasatinib, a potent PDGFR inhibitor, during and after radiotherapy in children with newly diagnosed DIPG. EXPERIMENTAL DESIGN: Dasatinib was started concurrently with radiotherapy. Vandetanib was started 8 days later. We tested increasing doses of vandetanib (65 and 85 mg/m(2) once daily) and dasatinib (65 and 85 mg/m(2) twice daily). Dose-limiting toxicities were evaluated during the first 6 weeks of therapy. Plasma pharmacokinetics was obtained on days 8 and 42 ± 3 in all patients and concomitantly with cerebrospinal fluid (CSF) when possible. Inhibition of targets of dasatinib in peripheral blood mononuclear cells (PBMC) was evaluated. RESULTS: Twenty-five patients were treated. Treatment was well tolerated. The median duration of treatment was 184 days. Diarrhea was the most significant toxicity. Three patients experienced substantial myelosuppression. The steady-state plasma pharmacokinetics of vandetanib was comparable with previous studies. Although the plasma exposure to dasatinib decreased from days 8 to 42, it remained similar to adult studies. CSF to plasma exposure of vandetanib and dasatinib were approximately 2% in 2 patients. Phosphorylated 70S6K decreased during therapy in PBMCs. CONCLUSIONS: The MTD of vandetanib and dasatinib in combination was 65 mg/m(2) for each drug. Other studies are underway to test dasatinib and other PDGFR inhibitors alone or in combination for this deadly cancer.

Management and outcome of focal low-grade brainstem tumors in pediatric patients: the St. Jude experience.

OBJECT: Whereas diffuse intrinsic pontine gliomas generally have a short symptom duration and more cranial nerve involvement, focal brainstem gliomas are commonly low grade, with fewer cranial neuropathies. Although these phenotypic distinctions are not absolute predictors of outcome, they do demonstrate correlation in most cases. Because there is a limited literature on focal brainstem gliomas in pediatric patients, the objective of this paper was to report the management and outcome of these tumors. METHODS: The authors reviewed the records of all children diagnosed with radiographically confirmed low-grade focal brainstem gliomas from 1986 to 2010. Each patient underwent biopsy or resection for tissue diagnosis. Event-free survival (EFS) and overall survival were evaluated. Univariate analysis was conducted to identify demographic and treatment variables that may affect EFS. RESULTS: Fifty-two patients (20 girls, 32 boys) with follow-up data were identified. Median follow-up was 10.0 years, and the median age at diagnosis was 6.5 years (range 1-17 years). The tumor locations were midbrain (n = 22, 42%), pons (n = 15, 29%), and medulla (n = 15, 29%). Surgical extirpation was the primary treatment in 25 patients (48%). The 5- and 10-year EFS and overall survival were 59%/98% and 52%/90%, respectively. An event or treatment failure occurred in 24 patients (46%), including 5 deaths. Median time to treatment failure was 3.4 years. Disease progression in the other 19 patients transpired within 25.1 months of diagnosis. Thirteen of these patients received radiation, including 11 within 2 months of primary treatment failure. Although children with intrinsic tumors had slightly better EFS at 5 years compared with those with exophytic tumors (p = 0.054), this difference was not significant at 10 years (p = 0.147). No other variables were predictive of EFS. CONCLUSIONS: Surgery suffices in many children with low-grade focal brainstem gliomas. Radiation treatment is often reserved for disease progression but offers comparable disease control following biopsy. In the authors' experience, combining an assessment of clinical course, imaging, and tumor biopsy yields a reasonable model for managing children with focal brainstem tumors.

Intensity modulated radiation therapy provides excellent local control in high-risk abdominal neuroblastoma.

BACKGROUND: Locoregional failure is a significant concern in patients with high-risk abdominal neuroblastoma (NB) receiving radiotherapy. Locoregional control outcomes were studied in children with NB receiving intensity modulated radiotherapy (IMRT). PROCEDURE: Twenty children (11 females, 9 males) with NB (median age at diagnosis 3.4 years) receiving IMRT were analyzed for locoregional failure, outcomes, and toxicities. IMRT doses were 23.4 Gy (n = 12), 30 Gy (n = 1), 30.6 Gy (n = 5), and 36.0 Gy (n = 2) based on extent of resection. Five patients had tumors with MYCN amplification, and 19 had metastatic disease. All patients were treated consistently using reproducible immobilization techniques; physiological motion was assessed by 4D-CT, and target localization by cone-beam computed tomography. ICRU 62 volumetric conventions were employed based on institutional data for pediatric target volume and organ motion. RESULTS: No patient developed primary site infield or locoregional failure at a median follow-up of 2.2 years. Distant failure (median time to distant failure 1.6 years) occurred in the brain, lungs, or skeletal sites in eight patients, five of whom died. The 2-year event-free survival was 58.5 ± 13.3% and cumulative incidence of local and distant failures was 0% and 41.5 ± 11.9%, respectively. Asymptomatic loose stool during RT occurred in nearly all patients, but required no intervention. CONCLUSIONS: IMRT is feasible, safe in the short term, and yields excellent locoregional control. Despite subtotal resection in some cases, locoregional control appeared to be increased by conformal radiotherapy with ICRU 62-compliant volumes. Dose escalation beyond 30.6 Gy may be unnecessary with improved target volume coverage.

Methods for image guided and intensity modulated radiation therapy in high-risk abdominal neuroblastoma.

PURPOSE: Our purpose was to determine methods for image guided intensity modulated radiation therapy (IMRT) in pediatric abdominal high-risk neuroblastoma and to quantify the degree of normal tissue dose reduction by using volumes compliant with International Commission on Radiation Units and Measurements (ICRU) Report 62. METHODS AND MATERIALS: Eight consecutive children with high-risk abdominal neuroblastoma (median age, 2.5 years; range, 20 months-5 years) were treated with IMRT using volumes accounting for physiologic motion (IMRT_phys) and daily pretreatment cone beam computed tomographic localization. Comparative IMRT planning using conventional volumes (IMRT_std) provided quantification for dose reduction to normal tissues. RESULTS: The IMRT_phys plan reduced the mean planning target volume from 668.8 ± 200.6 cc to 393.0 ± 132.5 cc (P < .001) and reduced mean body V50 from 1774.4 ± 383.9 cc to 1385.7 ± 365.7 cc (P < .001). The IMRT_phys plan reduced the percent mean dose to the ipsilateral kidney from 70.1% ± 4.3% to 66.0% ± 5.2% (P =.002); that to the contralateral kidney was reduced from 56.3% ± 7.0% to 40.7% ± 9.5% (P < .001), and that to the liver was reduced from 57.8% ± 16.0% to 22.1% ± 6.8% (P = .001). CONCLUSIONS: For IMRT planning, ICRU 62-compliant volume definition with image guidance in the pediatric abdomen enables volumetric reduction of the planning target volume and reduces normal tissue dose. These methods provide a framework for more conformal treatment planning in the pediatric abdomen.

Sequencing of local therapy affects the pattern of treatment failure and survival in children with atypical teratoid rhabdoid tumors of the central nervous system.

PURPOSE: To assess the pattern of treatment failure associated with current therapeutic paradigms for childhood atypical teratoid rhabdoid tumors (AT/RT). METHODS AND MATERIALS: Pediatric patients with AT/RT of the central nervous system treated at our institution between 1987 and 2007 were retrospectively evaluated. Overall survival (OS), progression-free survival, and cumulative incidence of local failure were correlated with age, sex, tumor location, extent of disease, and extent of surgical resection. Radiotherapy (RT) sequencing, chemotherapy, dose, timing, and volume administered after resection were also evaluated. RESULTS: Thirty-one patients at a median age of 2.3 years at diagnosis (range, 0.45-16.87 years) were enrolled into protocols that included risk- and age-stratified RT. Craniospinal irradiation with focal tumor bed boost (median dose, 54 Gy) was administered to 18 patients. Gross total resection was achieved in 16. Ten patients presented with metastases at diagnosis. RT was delayed more than 3 months in 20 patients and between 1 and 3 months in 4; 7 patients received immediate postoperative irradiation preceding high-dose alkylator-based chemotherapy. At a median follow-up of 48 months, the cumulative incidence of local treatment failure was 37.5% ± 9%; progression-free survival was 33.2% ± 10%; and OS was 53.5% ± 10%. Children receiving delayed RT (≥1 month postoperatively) were more likely to experience local failure (hazard ratio [HR] 1.23, p = 0.007); the development of distant metastases before RT increased the risk of progression (HR 3.49, p = 0.006); and any evidence of disease progressionbefore RT decreased OS (HR 20.78, p = 0.004). Disease progression occurred in 52% (11/21) of children with initially localized tumors who underwent gross total resection, and the progression rate increased proportionally with increasing delay from surgery to RT. CONCLUSIONS: Delayed RT is associated with a higher rate of local and metastatic disease progression in children with AT/RT. Current treatment regimens for pediatric patients with AT/RT are distinctly age stratified; novel protocols investigating RT volumes and sequencing are needed.

Novel assessment of renal motion in children as measured via four-dimensional computed tomography.

OBJECTIVES: Abdominal intensity-modulated radiation therapy and proton therapy require quantification of target and organ motion to optimize localization and treatment. Although addressed in adults, there is no available literature on this issue in pediatric patients. We assessed physiologic renal motion in pediatric patients. METHODS AND MATERIALS: Twenty free-breathing pediatric patients at a median age of 8 years (range, 2-18 years) with intra-abdominal tumors underwent computed tomography simulation and four-dimensional computed tomography acquisition (slice thickness, 3 mm). Kidneys and diaphragms were contoured during eight phases of respiration to estimate center-of-mass motion. We quantified center of kidney mass mobility vectors in three dimensions: anteroposterior (AP), mediolateral (ML), and superoinferior (SI). RESULTS: Kidney motion decreases linearly with decreasing age and height. The 95% confidence interval for the averaged minima and maxima of renal motion in children younger than 9 years was 5-9 mm in the ML direction, 4-11 mm in the AP direction, and 12-25 mm in the SI dimension for both kidneys. In children older than 9 years, the same confidence interval reveals a widening range of motion that was 5-16 mm in the ML direction, 6-17 mm in the AP direction, and 21-52 mm in the SI direction. Although not statistically significant, renal motion correlated with diaphragm motion in older patients. The correlation between diaphragm motion and body mass index was borderline (r = 0.52, p = 0.0816) in younger patients. CONCLUSIONS: Renal motion is age and height dependent. Measuring diaphragmatic motion alone does not reliably quantify pediatric renal motion. Renal motion in young children ranges from 5 to 25 mm in orientation-specific directions. The vectors of motion range from 5 to 52 mm in older children. These preliminary data represent novel analyses of pediatric intra-abdominal organ motion.

Enhancement of cell recognition in vitro by dual-ligand cancer targeting gold nanoparticles.

A dual-ligand gold nanoparticle (DLGNP) was designed and synthesized to explore the therapeutic benefits of multivalent interactions between gold nanoparticles (GNPs) and cancer cells. DLGNP was tested on human epidermal cancer cells (KB), which had high expression of folate receptor. The cellular uptake of DLGNP was increased by 3.9 and 12.7 folds compared with GNP-folate or GNP-glucose. The enhanced cell recognition was due to multivalent interactions between both ligands on GNPs and cancer cells as shown by the ligand competition experiments. Furthermore, the multivalent interactions increased contrast between cells with high and low expression of folate receptors. The enhanced cell recognition enabled DLGNP to kill KB cells under X-ray irradiation at a dose that was safe to folate receptor low-expression (such as normal) cells. Thus DLGNP has the potential to be a cancer-specific nano-theranostic agent.

Daily image-guided localization for neuroblastoma.

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.

Phase I study of vandetanib during and after radiotherapy in children with diffuse intrinsic pontine glioma.

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.

Radiation therapy as part of local control of metastatic neuroblastoma: the St Jude Children's Research Hospital experience.

PURPOSE: The purpose of the study was to compare outcomes of pediatric patients with high-risk metastatic neuroblastoma who received radiotherapy (RT) with those of patients who did not. PATIENTS AND METHODS: We reviewed the records of 63 patients with newly diagnosed metastatic neuroblastoma treated at our institution (1989-2001) to investigate their characteristics at presentation, dose and field of RT, treatment response, and failure patterns. RESULTS: Seventeen patients received RT, and 46 did not. In the RT group, a greater percentage of patients had residual disease before consolidation than did those in the no-RT group (88.2% vs 69.6%, P = .008). Gross total resection was achieved less often in the RT group (65% vs 89%, P = .055), but the 5-year cumulative incidences of local failure were similar (35.3% +/- 12.4% vs 32.6% +/- 7.1%). Although there was no difference in 5-year event-free survival, overall survival was better in the no-RT group (47.8% +/- 7.2% vs 23.5% +/- 9.2%, P = .026). CONCLUSION: The addition of RT to the therapy of a group of patients with more residual locoregional disease appeared to improve the local failure rate to approximately that of patients with less residual disease. Radiotherapy may provide even greater benefit to those with less residual disease before consolidation.

Irradiation of pediatric high-grade spinal cord tumors.

PURPOSE: To report the outcome using radiation therapy (RT) for pediatric patients with high-grade spinal cord tumors. METHODS AND MATERIALS: A retrospective chart review was conducted that included 17 children with high-grade spinal cord tumors treated with RT at St. Jude Children's Research Hospital between 1981 and 2007. Three patients had gross total resection, 11 had subtotal resection, and 3 underwent biopsy. The tumor diagnosis was glioblastoma multiforme (n = 7), anaplastic astrocytoma (n = 8), or anaplastic oligodendroglioma (n = 2). Seven patients received craniospinal irradiation (34.2-48.6 Gy). The median dose to the primary site was 52.2 Gy (range, 38-66 Gy). RESULTS: The median progression-free and overall survivals were 10.8 and 13.8 months, respectively. Local tumor progression at 12 months (79% vs. 30%, p = 0.02) and median survival (13.1 vs. 27.2 months, p = 0.09) were worse for patients with glioblastoma multiforme compared with anaplastic astrocytoma or oligodendroglioma. The median overall survival was shorter for patients when failure included neuraxis dissemination (n = 8) compared with local failure alone (n = 5), 9.6 vs. 13.8 months, p = 0.08. Three long-term survivors with World Health Organization Grade III tumors were alive with follow-up, ranging from 88-239 months. CONCLUSIONS: High-grade spinal cord primary tumors in children have a poor prognosis. The propensity for neuraxis metastases as a component of progression after RT suggests the need for more aggressive therapy.

Locoregional tumor progression after radiation therapy influences overall survival in pediatric patients with neuroblastoma.

PURPOSE: There is renewed attention to primary site irradiation and local control for patients with high-risk neuroblastoma (NB). We conducted a retrospective review to identify factors that might predict for locoregional tumor control and its impact on overall survival. METHODS AND MATERIALS: Between July 2000 through August 2006, a total of 44 pediatric patients with NB received radiation therapy (RT) with curative intent using computed tomography (CT)-based treatment planning. The median age was 3.4 years and the median cumulative dose was 23.4 Gy. Overall survival and locoregional tumor control were measured from the start of RT to the date of death or event as determined by CT/magnetic resonance imaging/meta-iodobenzylguanidine. The influence of age at irradiation, gender, race, cumulative radiation dose, International Neuroblastoma Staging System stage, treatment protocol and resection status was determined with respect to locoregional tumor control. RESULTS: With a median follow-up of 34 months +/- 21 months, locoregional tumor progression was observed in 11 (25%) and was evenly divided between primary site and adjacent nodal/visceral site failure. The influence of locoregional control reached borderline statistical significance (p = 0.06). Age (p = 0.5), dose (p = 0.6), resection status (p = 0.7), and International Neuroblastoma Staging System stage (p = 0.08) did not influence overall survival. CONCLUSIONS: Overall survival in high-risk neuroblastoma is influenced by locoregional tumor control. Despite CT-based planning, progression in adjacent nodal/visceral sites appears to be common; this requires further investigation regarding target volume definitions, dose, and the effects of systemic therapy.