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1.  Clinical controversies: Pediatric tumors 
Seminars in radiation oncology  2013;23(2):97-108.
Despite the claim in the published literature, the introduction of proton therapy for children is not analogous to the evolution of conformal photon irradiation relying on the understanding of the impact of altered dose distributions. The differences in radiobiological effect when comparing photons to protons means that we are comparing a known entity to an unknown entity: the dose-volume histogram for proton therapy might mean something substantially different than the dose-volume histogram for photon therapy. The multifaceted difference between the two modalities supports the argument for careful evaluation, follow-up and clinical trials with adverse event monitoring when using proton therapy in children. We review the current data on the outcome of proton therapy in a range of pediatric tumours and compare them to the often excellent results of photon therapy in the setting of multidisciplinary management of childhood cancer.
It is hoped that the apparent dosimetric advantage of proton therapy over photons will lead to improved indications for therapy, disease control and functional outcomes. While physical dose distribution is of clear importance, the multimodality management of children by an expert pediatric oncology team and the availability of ancillary measures that improve the quality of treatment delivery may be more important than the actual beam. In addition, current estimates of the benefit of proton therapy over photon therapy based on toxicity reduction will only be realized when survivorship has been achieved. Once substantive data proton therapy data become available, it will be necessary to demonstrate benefit in clinically relevant outcome measures in comparison to best existing photon outcome data. Such an effort will require improved funding and appreciation for late effects research. Only real clinical outcome data combined with better understanding of the radiobiological differences between protons and photons will help us to further reduce side effects in children and exploit the full curative potential of this relatively new modality.
PMCID: PMC3595134  PMID: 23473686
2.  Evaluation of children with craniopharyngioma using carbon-11 methionine PET prior to proton therapy 
Neuro-Oncology  2013;15(4):506-510.
Fluorine-18 (18F) fluorodeoxyglucose (FDG) positron emission tomography (PET) is limited in its evaluation of brain tumors due to the high basal activity of the cerebral cortex and white matter. Carbon-11 methionine (11C MET) has little uptake under normal conditions. We prospectively investigated the uptake of 18F FDG and 11C MET PET in patients with craniopharyngioma prior to proton therapy.
Ten patients newly diagnosed with craniopharyngioma underwent PET imaging using 18F FDG and 11C MET. PET and MRI studies were registered to help identify tumor volume. Measurements of maximum standardized uptake value (SUVmax) were taken of the tumor and compared with noninvolved left frontal background white matter using a paired t-test. Uptake was graded using a 4-point scale.
Median patient age was 9 years (range 5–19). Seven patients were diagnosed by pathology, 1 by cyst fluid aspiration, and 2 by neuroimaging. Median FDG SUVmax for tumor and background were 2.65 and 3.2, respectively. Median MET SUVmax for tumor and background were 2.2 and 1, respectively. There was a significant difference between MET tumor SUVmax and MET background SUVmax (P = .0001). The difference between FDG tumor SUVmax and FDG background SUVmax was not significant (P = .3672).
11C MET PET uptake is significantly greater within the tumor compared with noninvolved background white matter, making it more useful than FDG PET in identifying active tumor in patients with craniopharyngioma. Future work will focus on using 11C MET PET to discriminate between active and inactive tumor after irradiation.
PMCID: PMC3607263  PMID: 23408862
craniopharyngioma; fluorodeoxyglucose; FDG; methionine; positron emission tomography; proton therapy
3.  The Utility of Parent Report in the Assessment of Working Memory among Childhood Brain Tumor Survivors 
Childhood brain tumor survivors are at increased risk for neurocognitive impairments, including working memory (WM) problems. WM is typically assessed using performance measures. Little is known about the value of parent ratings for identifying WM difficulties, the relationship between rater and performance measures, or predictors of parent-reported WM problems in this population. Accordingly, the current study examined the utility of parent report in detecting WM difficulties among childhood brain tumor survivors treated with conformal radiation therapy (n=50) relative to siblings (n=40) and solid tumor survivors not receiving CNS-directed therapy (n=40). Parents completed the Behavior Rating Inventory of Executive Function (BRIEF). Participants were administered WM measures (digit span, self-ordered search tasks). Findings revealed parents rated brain tumor survivors as having significantly more WM problems (p<.01) compared to controls. However, the BRIEF-WM scale demonstrated poor sensitivity and specificity for detecting performance-based problems. Significant, albeit modest, correlations were found between the BRIEF-WM scale and performance measures (r=−.24 −.22; p<.05) for the combined group. Age at testing, socioeconomic status, and IQ were significant predictors of parent reported WM problems. Rater and performance measures offer complimentary yet different information in assessing WM, which reiterates the importance of utilizing both within the context of clinical assessment.
PMCID: PMC3630283  PMID: 23351399
cancer; cognitive late effects; pediatrics; BRIEF; rater-based measures; executive functions
4.  Longitudinal Investigation of Adaptive Functioning following Conformal Irradiation for Pediatric Craniopharyngioma and Low-Grade Glioma 
Children treated for brain tumors with conformal radiation therapy experience preserved cognitive outcomes. Early evidence suggests that adaptive functions or independent living skills may be spared. This longitudinal investigation prospectively examined intellectual and adaptive functioning during the first 5 years following irradiation for childhood craniopharyngioma and low-grade glioma (LGG). The effect of visual impairment on adaptive outcomes was investigated.
Methods and Materials
Children with craniopharyngioma (n=62) and LGG (n=77) were treated using conformal or intensity-modulated radiation therapy. The median age was 8.05 years (3.21 years –17.64 years) and 8.09 years (2.20 years–19.27 years), respectively. Serial cognitive evaluations including measures of intelligence quotient (IQ) and the Vineland Adaptive Behavior Scales (VABS) were conducted at pre-irradiation baseline, 6 months after treatment, and annually through 5 years. A total of 588 evaluations were completed during the follow-up period.
Baseline assessment revealed no deficits in IQ and VABS indices for children with craniopharyngioma, with significant (p < .05) longitudinal decline in VABS Communication and Socialization indices. Clinical factors associated with more rapid decline included females and pre-irradiation chemotherapy (interferon). The only change in VABS Daily Living Skills correlated with IQ change (r = .34; p = .01) in children with craniopharyngioma. Children with LGG performed below population norms (p < .05) at baseline on VABS Communication, Daily Living Indices, and the Adaptive Behavior Composite, with significant (p < .05) longitudinal decline limited to VABS Communication. Older age at irradiation was a protective factor against longitudinal decline. Severe visual impairment did not independently correlate with poorer adaptive outcomes for either tumor group.
There was relative sparing of post-irradiation functional outcomes over time in this sample. Baseline differences in functional abilities prior to the initiation of irradiation suggested that other factors influence functional outcomes above and beyond the effects of irradiation.
PMCID: PMC3685870  PMID: 23245284
Conformal radiation; craniopharyngioma; low-grade glioma; adaptive functioning; neurocognitive outcomes
To estimate the rate of disease control after conformal radiation therapy using reduced clinical target volume (CTV) margins and determine factors that predict for tumor progression.
Eighty-eight children (median age 8.5 years, range 3.2–17.6 years) received conformal or intensity-modulated radiation therapy between 1998 and 2009. This included those prospectively treated from 1998 to 2003 using a 10 mm CTV, defined as the margin surrounding the solid and cystic tumor targeted to receive the prescription dose of 54 Gy. The CTV margin was subsequently reduced after 2003 yielding two groups of patients: those treated with a CTV margin greater than 5 mm (n=26) and those treated with a CTV margin less than or equal to 5 mm (n=62). Disease progression was estimated on the basis of additional variables including sex, race, extent of resection, tumor interventions, target volume margins, and the frequency of weekly surveillance MR imaging during radiation therapy. The median follow-up was 5 years.
There was no difference comparing progression-free survival based on CTV margin (>5mm vs. ≤ 5mm) at 5 years, 88.1 + 6.3% vs. 96.2 + 4.4% (P=0.6386). There was no difference based on the planning target volume (PTV) margin (or combined CTV+PTV). The PTV was systematically reduced from 5 to 3mm during the time period of the study. Factors predictive of superior progression-free survival included Caucasian race (P=0.0175), absent CSF shunting requirement (P=0.0066), and the number of surveillance imaging studies during treatment (P=0.0216). Patients whose treatment protocol included a higher number of weekly surveillance MR imaging evaluations had a lower rate of tumor progression.
These results suggest that targeted volume reductions for radiation therapy using smaller margins are feasible and safe but require careful monitoring. We are currently investigating the differences in outcome based on host factors to explain the results.
PMCID: PMC3594571  PMID: 23245282
Radiotherapy; Pediatrics; Brain Tumor; Craniopharyngioma; Adaptive Therapy
6.  Supratentorial Ependymoma: Disease Control, Complications and Functional Outcomes after Irradiation 
Ependymoma is less commonly found in the supratentorial brain and has known clinical and molecular features that are unique. Our single institution series provides valuable information about disease control for supratentorial ependymoma and the complications of supratentorial irradiation in children.
Methods and Materials
A total of 50 children with newly diagnosed supratentorial ependymoma were treated with adjuvant radiation therapy (RT); 36 were using conformal methods after 1996. The median age at RT was 6.5 years (range, 1–18.9). The entire group was characterized according to sex (girls = 27), race (Caucasian = 43), extent of resection (gross-total = 46), and tumor grade (anaplastic = 28). The conformal RT group was prospectively evaluated for neurological, endocrine and cognitive effects.
With a median follow-up of 9.1 years from the start of RT for survivors (range 0.2–23.2), the 10-year progression-free and overall survival were 73% + 7% and 76% + 6%, respectively. None of the evaluated factors was prognostic for disease control. Local and distant failures were evenly divided among the 16 patients who experienced progression. Eleven patients died from disease and one from CNS necrosis. Seizure disorders were present in 17 patients and 4 were considered to be clinically disabled. Clinically significant cognitive effects were limited to children with difficult to control seizures. Average values for IQ and academic achievement (reading, spelling, and math) were within the range of normal through 10 years of follow-up. Central hypothyroidism was the most commonly treated endocrinopathy.
RT may be administered with acceptable risks for complications in children with supratentorial ependymoma. These results suggest that outcomes for these children are improving and that complications may be limited by use of focal irradiation methods.
PMCID: PMC3705553  PMID: 23245280
PT promises to reduce side effects in children with brain tumors by sparing normal tissue when compared to 3-dimensional conformal or intensity-modulated radiation therapy. Information is lacking about the combined effects of PT and chemotherapy in young children. We describe imaging changes in eight very young children with localized brain tumors who received PT after chemotherapy. Mostly transient signal abnormalities and enhancement in brain parenchyma were observed by serial MR imaging that were consistent with radiation-induced effects on normal appearing tissue. Correlation with PT planning data revealed that the areas of imaging abnormality were located within or adjacent to the volume that received the highest radiation dose. Radiologists should be aware of these findings in children who receive PT after chemotherapy. In this report we describe the time course of these PT-related imaging findings and correlate with treatment and clinical outcomes.
PMCID: PMC3573244  PMID: 22821924
8.  Topotecan and vincristine combination is effective against advanced bilateral intraocular retinoblastoma and has manageable toxicity 
Cancer  2012;118(22):5663-5670.
New, effective chemotherapeutic agents are needed for intraocular retinoblastoma.
Our institutional clinical trial sought to estimate the rate of response to 2 courses of vincristine and topotecan (VT) window therapy in patients with bilateral retinoblastoma and advanced disease (Reese-Ellsworth Group IV or V) in at least one eye. The topotecan dose started at 3 mg/m2/day for 5 days, and was adjusted to target a systemic exposure of 140 ± 20 ng/ml*hr. The vincristine dose was 0.05 mg/kg for patients < 12 months of age and 1.5 mg/m2 for those > 12 months of age at diagnosis.
From February 2005 to June 2010, 27 patients received VT window therapy. Median age at enrollment was 8.1 months (range, 0.7–22.1 months). Twenty-four patients (88.9%) responded to window therapy (95% CI, 71.3%–96.9%). Hematologic toxicity comprised grade 4 neutropenia (n=27), grade 3 anemia (n=19), and grade 3/4 thrombocytopenia (n=16). Thirteen patients had grade 3 non-hematologic toxicity. G-CSF support was added after 10 patients had been treated and significantly reduced the duration of grade 4 neutropenia (median, 7 vs. 24 days; P <0.001). Pharmacokinetic studies showed rapid changes in topotecan clearance rates during the first year of life.
The combination of topotecan and vincristine is effective for the treatment of advanced intraocular retinoblastoma. G-CSF treatment alleviates the duration of grade 4 neutropenia. Appropriate topotecan starting doses for patients 0–3, 3–6, 6–9, 9–12, and >12 months of age are specified.
PMCID: PMC3413782  PMID: 22516936
Retinoblastoma; topotecan; pharmakokinetic; first year of life; toxicity
9.  Predicting the Probability of Abnormal Stimulated Growth Hormone Response in Children After Radiotherapy for Brain Tumors 
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.
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%.
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.
PMCID: PMC3554243  PMID: 22483696
Pediatric brain tumor; Radiotherapy; Growth hormone; Insulin-like growth factor; Stimulation test
10.  Learning and Memory Following Conformal Radiation Therapy for Pediatric Craniopharyngioma and Low-Grade Glioma 
The primary objective of this study was to examine whether children with low-grade glioma (LGG) or craniopharyngioma had impaired learning and memory after conformal radiation therapy (CRT). A secondary objective was to determine whether children who received chemotherapy before CRT, a treatment often used to delay radiation therapy in younger children with LGG, received any protective benefit with respect to learning.
Methods and Materials
Learning and memory in 57 children with LGG and 44 children with craniopharyngioma were assessed with the California Verbal Learning Test–Children’s Version and the Visual-Auditory Learning tests. Learning measures were administered before CRT, 6 months later, and then yearly for a total of 5 years.
No decline in learning scores after CRT was observed when patients were grouped by diagnosis. For children with LGG, chemotherapy before CRT did not provide a protective effect on learning. Multiple regression analyses, which accounted for age and tumor volume and location, found that children treated with chemotherapy before CRT were at greater risk of decline on learning measures than those treated with CRT alone. Variables predictive of learning and memory decline included hydrocephalus, shunt insertion, younger age at time of treatment, female gender, and pre-CRT chemotherapy.
This study did not reveal any impairment or decline in learning after CRT in over-all aggregate learning scores. However, several important variables were found to have a significant effect on neurocognitive outcome. Specifically, chemotherapy before CRT was predictive of worse outcome on verbal learning in LGG patients. In addition, hydrocephalus and shunt insertion in craniopharyngioma were found to be predictive of worse neurocognitive outcome, suggesting a more aggressive natural history for those patients.
PMCID: PMC3534785  PMID: 22867897
11.  Dosimetric Impact of Intrafractional Patient Motion in Pediatric Brain Tumor Patients 
The purpose of this study was to determine the dosimetric consequences of intrafractional patient motion on the clinical target volume (CTV), spinal cord, and optic nerves for non-sedated pediatric brain tumor patients. The patients were immobilized for treatment using a customized thermoplastic full-face mask and bite-block attached to an array of reflectors. The array was optically tracked by infra-red cameras at a frequency of 10 Hz. Patients were localized based on skin/mask marks and weekly films were taken to ensure proper setup. Before each noncoplanar field was delivered, the deviation from baseline of the array was recorded. The systematic error (SE) and random error (RE) were calculated. Direct simulation of the intrafractional motion was used to quantify the dosimetric changes to the targets and critical structures. Nine patients utilizing the optical tracking system were evaluated. The patient cohort had a mean of 31 ± 1.5 treatment fractions; motion data were acquired for a mean of 26 ± 6.2 fractions. The mean age was 15.6 ± 4.1 years. The SE and RE were 0.4 and 1.1 mm in the posterior-anterior, 0.5 and 1.0 mm in left-right, and 0.6 and 1.3 mm in superior-inferior directions, respectively. The dosimetric effects of the motion on the CTV were negligible; however, the dose to the critical structures was increased. Patient motion during treatment does affect the dose to critical structures, therefore, planning risk volumes are needed to properly assess the dose to normal tissues. Because the motion did not affect the dose to the CTV, the 3-mm PTV margin used is sufficient to account for intrafractional motion, given the patient is properly localized at the start of treatment.
PMCID: PMC3800030  PMID: 19931014
Pediatric brain tumor; intra-fraction motion; target localization
12.  Induction Chemotherapy and Conformal Radiation Therapy for Very Young Children With Nonmetastatic Medulloblastoma: Children's Oncology Group Study P9934 
Journal of Clinical Oncology  2012;30(26):3181-3186.
P9934 was a prospective trial of systemic chemotherapy, second surgery, and conformal radiation therapy (CRT) limited to the posterior fossa and primary site for children between 8 months and 3 years old with nonmetastatic medulloblastoma. The study was open from June 2000 until June 2006.
Patients and Methods
After initial surgery, children received four cycles of induction chemotherapy, followed by age- and response-adjusted CRT to the posterior fossa (18 or 23.4 Gy) and tumor bed (cumulative 50.4 or 54 Gy) and maintenance chemotherapy. Neurodevelopmental outcomes were evaluated and event-free survival (EFS) results were directly compared with a previous study of multiagent chemotherapy without irradiation (Pediatric Oncology Group [POG] trial 9233).
Seventy-four patients met eligibility requirements. The 4-year EFS and overall survival probabilities were 50% ± 6% and 69% ± 5.5%, respectively, which compared favorably to the results from POG 9233. Analysis showed that the desmoplastic/nodular subtype was a favorable factor in predicting survival. Our 4-year EFS rate was 58% ± 8% for patients with desmoplasia. Whereas seven of 10 patients who had disease progression before CRT had primary-site failure, 15 of 19 patients who progressed after CRT had distant-site failure. Neurodevelopmental assessments did not show a decline in cognitive or motor function after protocol-directed chemotherapy and CRT.
The addition of CRT to postoperative chemotherapy in young children with nonmetastatic medulloblastoma increased event-free survival compared with the use of postoperative chemotherapy alone. Future studies will use histopathologic typing (desmoplastic/nodular versus nondesmoplastic/nodular) to stratify patients for therapy by risk of relapse.
PMCID: PMC3434977  PMID: 22851568
13.  Pilot Study of Systemic and Intrathecal Mafosfamide followed by Conformal Radiation for Infants with Intracranial Central Nervous System Tumors: A Pediatric Brain Tumor Consortium Study (PBTC-001) 
Journal of neuro-oncology  2012;109(3):565-571.
A pilot study to investigate the feasibility of the addition of intrathecal (IT) mafosfamide to a regimen of concomitant multi-agent systemic chemotherapy followed by conformal radiation therapy (RT) for children <3 years with newly diagnosed embryonal CNS tumors was performed.
Patients and Methods
Ninety-three newly diagnosed infants and children (<3 years) with embryonal CNS tumors were enrolled. Twenty weeks of systemic multi-agent chemotherapy commenced within 35 days of surgery. Patients without CSF flow obstruction (n=71) received IT mafosfamide (14 mg) with chemotherapy. Localized (M0) patients with SD or better subsequently received RT followed by 20 additional weeks of chemotherapy. Second look surgery was encouraged prior to RT if there was an incomplete surgical resection at diagnosis.
71 evaluable patients with normal CSF flow received IT Mafosfamide with systemic chemotherapy; patients with M+ disease were removed from protocol therapy at 20 weeks and those with PD at the time of progression. One and 5-year progression free survival (PFS) and overall survival (OS) for the cohort of 71 evaluable patients were 52±6.5% and 33±13%, and 67±6.2% and 51±11%, respectively. The 1-year Progression Free Survival (PFS) for M0 patients with medulloblastoma (MB, n=20), supratentorial primitive neuroectodermal tumor (PNET, n=9), and atypical teratoid rhabdoid tumor (ATRT, n=12) was 80±7%, 67±15% and 27±13% and 5-year PFS was 65± 19%, 37±29%, and 0±0%, respectively.
The addition of IT mafosfamide to systemic chemotherapy in infants with embryonal CNS tumors was feasible. The PFS for M0 patients appears comparable to or better than most prior historical comparisons and was excellent for those receiving conformal radiotherapy.
PMCID: PMC3529096  PMID: 22790443
mafosfamide; intrathecal; infant brain tumor; embryonal CNS tumor; conformal radiation therapy
14.  A 5-Year Investigation of Children’s Adaptive Functioning Following Conformal Radiation Therapy for Localized Ependymoma 
Conformal and intensity modulated radiation therapies have the potential to preserve cognitive outcomes in children with ependymoma; however, functional behavior remains uninvestigated. This longitudinal investigation prospectively examined intelligence quotient (IQ) and adaptive functioning during the first 5 years after irradiation in children diagnosed with ependymoma.
Methods and Materials
The study cohort consisted of 123 children with intracranial ependymoma. Mean age at irradiation was 4.60 years (95% confidence interval [CI], 3.85–5.35). Serial neurocognitive evaluations, including an age-appropriate IQ measure and the Vineland Adaptive Behavior Scales (VABS), were completed before irradiation, 6 months after treatment, and annually for 5 years. A total of 579 neurocognitive evaluations were included in these analyses.
Baseline IQ and VABS were below normative means (P<.05), although within the average range. Linear mixed models revealed stable IQ and VABS across the follow-up period, except for the VABS Communication Index, which declined significantly (P=.015). Annual change in IQ (−.04 points) did not correlate with annual change in VABS (−.90 to +.44 points). Clinical factors associated with poorer baseline performance (P<.05) included preirradiation chemotherapy, cerebrospinal fluid shunt placement, number and extent of surgical resections, and younger age at treatment. No clinical factors significantly affected the rate of change in scores.
Conformal and intensity modulated radiation therapies provided relative sparing of functional outcomes including IQ and adaptive behaviors, even in very young children. Communication skills remained vulnerable and should be the target of preventive and rehabilitative interventions.
PMCID: PMC3534783  PMID: 22541967
15.  Visual Outcomes in Pediatric Optic Pathway Glioma After Conformal Radiation Therapy 
To assess visual outcome prospectively after conformal radiation therapy (CRT) in children with optic pathway glioma.
Methods and Materials
We used CRT to treat optic pathway glioma in 20 children (median age 9.3 years) between July 1997 and January 2002. We assessed changes in visual acuity using the logarithm of the minimal angle of resolution after CRT (54 Gy) with a median follow-up of 24 months. We included in the study children who underwent chemotherapy (8 patients) or resection (9 patients) before CRT.
Surgery played a major role in determining baseline (pre-CRT) visual acuity (better eye: P=.0431; worse eye: P=.0032). The visual acuity in the worse eye was diminished at baseline (borderline significant) with administration of chemotherapy before CRT (P=.0726) and progression of disease prior to receiving CRT (P=.0220). In the worse eye, improvement in visual acuity was observed in patients who did not receive chemotherapy before CRT (P=.0289).
Children with optic pathway glioma initially treated with chemotherapy prior to receiving radiation therapy have decreased visual acuity compared with those who receive primary radiation therapy. Limited surgery before radiation therapy may have a role in preserving visual acuity.
PMCID: PMC3554252  PMID: 22607912
Vision; Pediatrics; Glioma; Radiotherapy
16.  Antioxidant enzyme polymorphisms and neuropsychological outcomes in medulloblastoma survivors: a report from the Childhood Cancer Survivor Study 
Neuro-Oncology  2012;14(8):1018-1025.
Psychological or neurocognitive impairment is often seen in medulloblastoma survivors after craniospinal radiation; however, significant variability in outcomes exists. This study investigated the role of antioxidant enzyme polymorphisms in moderating this outcome and hypothesized that patients who had polymorphisms associated with lower antioxidant enzyme function would have a higher occurrence of impairment. From the Childhood Cancer Survivor Study (CCSS) cohort, 109 medulloblastoma survivors and 143 siblings were identified who completed the CCSS Neurocognitive Questionnaire (NCQ) and the Brief Symptom Inventory-18 (BSI-18) and who provided buccal DNA samples. Real-time polymerase chain reaction (PCR) allelic discrimination was used for SOD2 (rs4880), GPX1 (rs1050450), and GSTP1 (rs1695 and rs1138272) genotyping and PCR for GSTM1 and GSTT1 gene deletions. Outcomes on NCQ and BSI-18 subscale scores were examined in association with genotypes and clinical factors, including age at diagnosis, sex, and radiation dose, using univariate and multivariate analysis of variance. Patients <7 years of age at diagnosis displayed more problems with task efficiency (P < .001) and fewer problems with somatic complaints (P = .004) than did patients ≥7 years of age. Female patients reported more organization problems than did male patients (P = .02). Patients with homozygous GSTM1 gene deletion reported higher anxiety (mean null genotype = 47.3 ± 9.2, non-null = 43.9 ± 7.8; P = .04), more depression (null = 51.0 ± 9.8, non-null = 47.0 ± 9.4; P = .03), and more global distress (null = 50.2 ± 9.7, non-null = 45.2 ± 9.9; P = .01). All associations for the GSTM1 polymorphism remained statistically significant in a multivariate model controlling for age, sex, and radiation dose. Homozygous GSTM1 gene deletion was consistently associated with greater psychological distress in medulloblastoma survivors across multiple domains, suggesting that this genotype may predispose patients for increased emotional late effects.
PMCID: PMC3408256  PMID: 22661588
Childhood Cancer Survivor Study; glutathione S-transferase polymorphisms; medulloblastoma; neuropsychological impairment; radiation therapy
Necrosis of the CNS is a known complication of craniospinal irradiation (CSI) in children with medulloblastoma and similar tumors. We reviewed the incidence of necrosis in our prospective treatment series.
Between 1996 and 2009, 236 children with medulloblastoma (n = 185) or other CNS embryonal tumors (n=51) received post-operative CSI followed by dose-intense cyclophosphamide, vincristine, and cisplatin. Average-risk cases (n = 148) received 23.4 Gy CSI, 36 Gy posterior fossa, and 55.8 Gy primary; after 2003, the treatment was 23.4 Gy CSI and 55.8 Gy primary. All high-risk cases (n = 88) received 36–39.6 Gy CSI and 55.8 Gy primary. The primary site clinical target volume margin was 2-cm (pre-2003) or 1-cm (post-2003). With competing risk of death by any cause, we determined the cumulative incidence of necrosis.
With a median follow-up of 52 months (range, 4–163 months), eight cases of necrosis were documented. One death was attributed. The median time to the imaging evidence was 4.8 months and symptoms 6.0 months. The cumulative incidence at 5 years was 3.7% ± 1.3% (n = 236) for the entire cohort, and 4.4% ± 1.5% (n = 196) for infratentorial tumor location. The mean relative volume of infratentorial brain receiving high-dose irradiation was significantly greater for patients with necrosis compared to those without: ≥ 50 Gy (92.12% ± 4.58 vs. 72.89% ± 1.96, p = 0.0337), ≥ 52 Gy (88.95% ± 5.50 vs. 69.16% ± 1.97, p = 0.0275), and ≥ 54 Gy (82.28% ± 7.06 vs. 63.37% ± 1.96, p = 0.0488).
Necrosis in patients with CNS embryonal tumors is uncommon. When competing risks are considered, the incidence is 3.7% at 5 years. The volume of infratentorial brain receiving greater than 50, 52, and 54 Gy is predictive for necrosis.
PMCID: PMC3529413  PMID: 22768993
necrosis; medulloblastoma; craniospinal irradiation; pediatrics
18.  Distinct disease-risk groups in pediatric supratentorial and posterior fossa ependymomas 
Acta neuropathologica  2012;124(2):247-257.
No reliable classification exists for the therapeutic stratification of children with ependymoma, such that disease-risk might be identified and patients treated to ensure a combination of maximal cure rates and minimal adverse therapeutic effects. This study examined associations between clinicopathological and cytogenetic variables and outcome in a trial cohort of children with ependymoma, with the aim of defining a practical scheme for grading this heterogeneous tumor.
Intracranial ependymomas (n=146) from children treated on the RT1 trial at St. Jude Children’s Research Hospital were evaluated for the status of multiple pathological features. Interphase FISH (iFISH) defined the status of chromosomes 1q, 6q (LATS1), and 9p21 (CDKN2A). Data relating to these variables were compared with survival data in order to model disease-risk groups.
Extent of surgical resection was a significant determinant of outcome. Tumor cell density and mitotic count were associated with outcome among children with posterior fossa ependymomas (n=119). Among pathologic factors, only brain invasion was associated with outcome in children with supratentorial ependymomas (n=27). Gain of 1q was independently associated with outcome and in combination with clinicopathological variables defined a three-tier system of disease-risk for posterior fossa tumors.
Among children developing posterior fossa ependymomas treated with maximal surgical resection and conformal radiotherapy, key clinicopathological variables and chromosome 1q status can be used to define tiers of disease-risk. In contrast, risk factors for pediatric supratentorial tumors are limited to subtotal resection and brain invasion.
PMCID: PMC3554251  PMID: 22526017
19.  Factors Associated with Neurological Recovery of Brainstem Function Following Postoperative Conformal Radiation Therapy for Infratentorial Ependymoma 
To identify risk factors associated with incomplete neurological recovery in pediatric patients with infratentorial ependymoma treated with postoperative conformal radiation therapy (CRT).
The study included 68 patients (median age ± standard deviation of 2.6 ± 3.8 years) who were followed for 5 years after receiving CRT (54–59.4 Gy) and were assessed for function of cranial nerves V to VII and IX to XII, motor weakness, and dysmetria. The mean (± standard deviation) brainstem dose was 5,487 (±464) cGy. Patients were divided into four groups representing those with normal baseline and follow-up, those with abnormal baseline and full recovery, those with abnormal baseline and partial or no recovery, and those with progressive deficits at 12 (n = 62 patients), 24 (n = 57 patients), and 60 (n = 50 patients) months. Grouping was correlated with clinical and treatment factors.
Risk factors (overall risk [OR], p value) associated with incomplete recovery included gender (male vs. female, OR = 3.97, p = 0.036) and gross tumor volume (GTV) (OR/ml = 1.23, p = 0.005) at 12 months, the number of resections (>1 vs. 1; OR = 23.7, p = 0.003) and patient age (OR/year = 0.77, p = 0.029) at 24 months, and cerebrospinal fluid (CSF) shunting (Yes vs. No; OR = 21.9, p = 0.001) and GTV volume (OR/ml = 1.18, p = 0.008) at 60 months. An increase in GTV correlated with an increase in the number of resections (p = 0.001) and CSF shunting (p = 0.035); the number of resections correlated with CSF shunting (p < 0.0001), and male patients were more likely to undergo multiple tumor resections (p = 0.003). Age correlated with brainstem volume (p < 0.0001). There were no differences in outcome based on the absolute or relative volume of the brainstem that received more than 54 Gy.
Incomplete recovery of brainstem function after CRT for infratentorial ependymoma is related to surgical morbidity and the volume and the extent of tumor.
PMCID: PMC3730270  PMID: 19464817
Ependymoma; Brainstem; Radiotherapy; Pediatrics; Tolerance
20.  Treatment Outcomes in Black and White Children With Cancer: Results From the SEER Database and St Jude Children's Research Hospital, 1992 Through 2007 
Journal of Clinical Oncology  2012;30(16):2005-2012.
Treatment outcome for black patients with cancer has been significantly worse than for their white counterparts. We determined whether recent improved treatment had narrowed the gap in outcome between black and white pediatric patients.
Patients and Methods
In a parallel comparison, we analyzed survival by disease category between black and white patients with childhood cancer registered in one of the 17 cancer registries of the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) program or treated at St Jude Children's Research Hospital, which provides comprehensive treatment to all patients regardless of their ability to pay, from 1992 to 2000 and from 2001 to 2007.
Analysis of the SEER data indicated that in both study periods, black patients had significantly poorer rates of survival than did white patients, with the exception of a few types of cancer. Despite significantly improved treatment outcomes for patients who were treated from 2001 to 2007, the racial difference in survival has actually widened for acute myeloid leukemia and neuroblastoma. By contrast, in the cohorts treated at St Jude Children's Research Hospital, there were no significant differences in survival between black and white patients in either study period, regardless of the cancer type. Importantly, the outcome of treatment for acute lymphoblastic leukemia, acute myeloid leukemia, and retinoblastoma has improved in parallel for both races during the most recent study period.
With equal access to comprehensive treatment, black and white children with cancer can achieve the same high cure rates.
PMCID: PMC3383176  PMID: 22547602
21.  Working Memory Performance among Childhood Brain Tumor Survivors 
While longitudinal studies of children treated for brain tumors have consistently revealed declines on measures of intellectual functioning, greater specification of cognitive changes following treatment is imperative for isolating vulnerable neural systems and developing targeted interventions. Accordingly, this cross-sectional study evaluated the performance of childhood brain tumor survivors (n= 50) treated with conformal radiation therapy, solid tumor survivors (n= 40) who had not received CNS-directed therapy, and healthy sibling controls (n= 40) on measures of working memory [Digit Span and computerized self-ordered search (SOS) tasks]. Findings revealed childhood brain tumor survivors were impaired on both traditional [Digit Span Backward- F(2, 127)= 5.98, p< .01] and experimental [SOS-Verbal- F(2, 124)= 4.18, p< .05; SOS-Object- F(2, 126)= 5.29, p< .01] measures of working memory, and performance on working memory measures correlated with intellectual functioning (Digit Span Backward- r= .45, p< .0001; SOS- r= −.32 − −.26, p< .01). Comparison of performance on working memory tasks to recognition memory tasks (computerized delayed match-to-sample) offered some support for greater working memory impairment. This pattern of findings is consistent with vulnerability in functional networks that include prefrontal brain regions and has implications for the clinical management of children with brain tumors.
PMCID: PMC3461093  PMID: 22691544
cancer; radiation therapy; cognitive late effects; prefrontal cortex; pediatric; neurodevelopment
22.  Excessive Daytime Sleepiness and Sleep-Disordered Breathing Disturbances in Survivors of Childhood Central Nervous System Tumors 
Pediatric blood & cancer  2011;58(5):746-751.
Improvements in treatment and management for pediatric central nervous system (CNS) tumors have increased survival rates, allowing clinicians to focus on long-term sequelae, including sleep disorders. The objective of this study was to describe a series of CNS tumor survivors who had sleep evaluations that included polysomnography with attention to sleep disorder in relation to the tumor site.
We report on 31 patients who had retrievable reports including an overnight polysomnography (PSG); 17 also underwent multiple sleep latency tests (MSLT) to characterize their sleepiness.
Mean age at tumor diagnosis was 7.4 years, mean age at sleep referral 14.3 years, and a mean time between tumor diagnosis and sleep referral of 6.9 years. The most common tumor location was the suprasellar region, the most common reason for sleep referral was excessive daytime sleepiness (EDS), and the most common sleep diagnosis was obstructive sleep apnea (n = 14) followed by central sleep apnea (n=4), hypersomnia due to medical condition (n= 4) and narcolepsy (n=3). Twenty-six of the 31 subjects were obese/overweight, and among those with the concurrent complaint of EDS, the mean sleep latency on MSLT was 3.16 minutes, consistent with excessive sleepiness.
Suprasellar region tumor survivors who are obese or overweight are more likely to have complaints of EDS and are at greater risk of sleep-disordered breathing. Sleep-related symptoms may not be recognized and referral initiated until years after CNS diagnosis. A periodic and thorough sleep history should be taken when caring for CNS tumor survivors.
PMCID: PMC3519925  PMID: 22009579
children; adolescents; sleep; CNS tumors
23.  Role of Adaptive Radiation Therapy for Pediatric Patients with Diffuse Pontine Glioma 
We investigate the role of adaptive radiation therapy in pediatric patients with diffuse pontine glioma and the impact of steroid-related weight gain on treatment parameters utilizing cone-beam CT.
Methods and Materials
Fifteen patients with diffuse pontine glioma were treated with three-dimensional conformal radiation therapy and enrolled on a daily localization protocol. The median age was 6 years (range: 2–13 years). Patient charts were examined to obtain the prescribed daily dose of dexamethasone and weight. The original treatment plan was recalculated based on the data obtained from the daily cone-beam CT. The change in target and critical structure doses were calculated using gEUD. Correlations between prescribed dexamethasone, weight gain, skin to source distance (SSD) changes, and dosimetric changes were investigated.
11 of the 15 patients gained weight during radiation therapy, with an average gain of 2.2 kg (8.0%). The mean gEUD decreased was 0.57 Gy (range: 0.24–1.4 Gy) for the PTV and the mean gEUD increase for critical structures was 1.14%. No strong correlations between prescribed dexamethasone doses, weight gain, and dosimetric changes were found. Change in SSD vs. dose to PTV was correlated (R2=0.51).
Weight gain and changes to the external surface are apparent in these patients; however, the dosimetric changes to the target and critical structures were small and in most cases did not warrant an adaptive plan. The potential exist for a decrease in target dose in these patients; therefore, they should be monitored to assess for re-planning when necessary.
PMCID: PMC3619395  PMID: 21587190
Pontine Glioma; Adaptive Radiation Therapy
24.  A Prospective Study of Conformal Radiation Therapy for Pediatric Ependymoma 
The lancet oncology  2009;10(3):258-266.
Successful therapy for ependymoma includes aggressive surgical intervention and radiation therapy administered using methods which minimize the risk of side effects. We extended this treatment approach to include children under the age of 3 years.
Between July 1997 and 2007, 153 pediatric patients (median age 2·9 years, range 0·9–22·9 years) with localized ependymoma received conformal radiation therapy after definitive surgery. Doses of 59·4 (n=131) or 54·0 Gy (n=22) were prescribed to a 10mm clinical target volume margin surrounding the post-operative residual tumor and/or tumor bed. The patients had the following characteristics: anaplastic ependymoma (n=85), infratentorial location (n=122), prior chemotherapy (n=35) and extent of resection (gross-total=125, near-total=17, subtotal=11). Disease control, patterns of failure and complications were recorded for patients followed through 10 years.
With a median follow-up of 5·3 years (range 0·4 to 10·4 years), death was recorded in 23 patients and tumor progression in 36, including local (n=14), distant (n=15) and combined failure (n=7). Tumor grade predicted overall (OS) and event-free (EFS) survival and distant failure. Extent of resection predicted OS, EFS and local failure. Race predicted OS. The 7 year local control, event-free and overall survival were 83·7% (95% CI: 73·9–93·5%), 69·1% (95% CI: 56·9–81·3%) and 81·0% (95% CI: 71·0–91·0%), respectively. The cumulative incidence of local and distance failure were 16·3% (95% CI: 9·6–23·0%) and 11·48% (95% CI: 5·9–17·1%), respectively. Considering only those patients treated with immediate post-operative CRT (without delay or chemotherapy) the 7 year OS, EFS and CI of local and distant failure were 85·0% (95% CI: 74·2–95·8%), 76·9% (95% CI: 63·4–90·4%), 12·59% (95% CI: 5·1–20·1%)and 8·56% (95% CI: 2·8–14·3%), respectively. The incidence of secondary malignant brain tumor at 7 years was 2·3% (95% CI: 0–5·6%) and brainstem necrosis 1·6% (95% CI: 0–4·0%).
This study provides new disease control benchmarks and a unifying approach for the treatment of ependymoma that should include surgery with the aim of gross-total resection and conformal, high-dose, post-operative irradiation even for the youngest children. Future trials might consider treatment stratification based on gender and age as female patients are more likely to be long-term survivors and younger patients have higher rates of failure.
PMCID: PMC3615425  PMID: 19274783
To characterize therapy-induced changes in normal-appearing brainstems of childhood brain tumor patients by serial diffusion tensor imaging (DTI).
Methods and Materials
We analyzed 109 DTI studies from 20 brain tumor patients, aged 4-23 years, with normal-appearing brainstems included in the treatment fields. Those with medulloblastomas, supratentorial primitive neuroectodermal tumors and atypical teratoid rhabdoid tumors (n=10) received postoperative craniospinal irradiation (23.4-39.6 Gy) and a cumulative dose of 55.8 Gy to the primary site, followed by 4 cycles of high-dose chemotherapy. Patients with high-grade gliomas (n=10) received erlotinib during and after irradiation (54-59.4 Gy). Parametric maps of fractional anisotropy (FA) and apparent diffusion coefficient (ADC) were computed and spatially registered to three-dimensional radiation dose data. Volumes of interest included corticospinal tracts, medial lemnisci, and the pons. Serving as an age-related benchmark for comparison, 37 DTI studies from 20 healthy volunteers, aged 6-25 years, were included in the analysis.
The median DTI follow-up was 3.5 years (range, 1.6-5.0 years). The median mean dose to the pons was 56 Gy (range, 7-59 Gy). Three patterns were seen in longitudinal FA and ADC changes: (1) a stable or normal developing time trend, (2) initial deviation from normal with subsequent recovery, and (3) progressive deviation without evidence of complete recovery. The maximal decline in FA often occurred 1.5 to 3.5 years after the start of radiation therapy. A full recovery time trend could be observed within 4 years. Patients with incomplete recovery often had a larger decline in FA within the first year. Radiation dose alone did not predict long-term recovery patterns.
Variation existed among individual patients after therapy in longitudinal evolution of brainstem white matter injury and recovery. Early response in brainstem anisotropy may serve as an indicator of the recovery time trend over 5 years following radiation therapy.
PMCID: PMC3181276  PMID: 21664060
Diffusion tensor imaging; Brainstem; Radiation therapy

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