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.
Pediatric brain tumor; intra-fraction motion; target localization
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.
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.
mafosfamide; intrathecal; infant brain tumor; embryonal CNS tumor; conformal radiation therapy
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.
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.
Vision; Pediatrics; Glioma; Radiotherapy
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.
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.
METHODS AND MATERIALS
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.
necrosis; medulloblastoma; craniospinal irradiation; pediatrics
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.
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.
Ependymoma; Brainstem; Radiotherapy; Pediatrics; Tolerance
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.
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.
cancer; radiation therapy; cognitive late effects; prefrontal cortex; pediatric; neurodevelopment
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.
children; adolescents; sleep; CNS tumors
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.
Pontine Glioma; Adaptive Radiation Therapy
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.
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.
Diffusion tensor imaging; Brainstem; Radiation therapy
Carboplatin-induced ototoxicity remains poorly defined but is of potential great consequence in children with retinoblastoma. We retrospectively assessed the incidence of ototoxicity and its risk factors in children with retinoblastoma who were treated with carboplatin.
Patients and Methods
We reviewed the audiologic test results of 60 patients with retinoblastoma who received front-line treatment with systemic carboplatin and vincristine according to the St Jude RET-3 protocol (n = 23) or best clinical management (n = 37). Ototoxicity was evaluated by three different grading systems.
Twelve patients (20%) developed ototoxicity at some time after treatment initiation; however, ototoxicity resolved in two patients, and thus,10 patients (17%) had sustained hearing loss as documented at their most recent audiologic evaluation. Nine of these 10 patients had grade 3 or 4 ototoxicity, and nine patients were less than 6 months of age at the start of chemotherapy. Age at the start of chemotherapy was the only risk factor identified as a significant predictor of sustained hearing loss. Younger age was associated with an increased incidence of hearing loss. The different ototoxicity grading systems showed good overall agreement in the identification of patients with ototoxicity. Agreement was greatest between the Brock and Children's Cancer Group systems.
We found that young patients with retinoblastoma who were treated with systemic carboplatin had a higher incidence of ototoxicity than previously reported. Younger patients (< 6 months of age at the start of treatment) were more likely to have ototoxicity than were older patients. Children treated with carboplatin should routinely undergo thorough, long-term audiologic monitoring.
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.
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 progression before 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.
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.
Atypical teratoid rhabdoid tumor; Local failure; Radiation therapy; Therapeutic sequencing; Pattern of failure
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 (CT) simulation and 4-dimensional CT (4DCT) acquisition (slice thickness, 3 mm). Kidneys and diaphragms were contoured during 8 phases of respiration to estimate center of mass motion. We quantified center of kidney mass mobility vectors in 3 dimensions: anterior-posterior (A-P), medial-lateral (M-L), and superior-inferior (S-I).
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 to 9 mm in the M-L direction, 4 to 11 mm in the A-P direction, and 12 to 25 mm in the S-I dimension for both kidneys. In children older than 9 years, the same confidence interval reveals a widening range of motion that was 5 to 16 mm in the M-L direction, 6 to 17 mm in the A-P direction, and 21 to 52 mm in the S-I direction. Although not statistically significant, renal motion correlated with diaphragm motion in older patients. The correlation between diaphragm motion and BMI was borderline (r = 0.52, p = 0.0816) in younger patients.
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.
pediatric; kidney; organ motion; abdominal tumors; 4D computed tomography
Damage to normal tissue is a limiting factor in clinical radiotherapy (RT). We tested the hypothesis that the presence of tumor alters the response of normal tissues to irradiation using a rat in situ brain tumor model.
Methods and Materials
Intravital microscopy was used with a rat cranial window to assess the in situ effect of rat C6 glioma on peritumoral tissue with and without RT. The RT regimen included 40 Gy at 8 Gy/day starting Day 5 after tumor implant. Endpoints included blood–brain barrier permeability, clearance index, leukocyte-endothelial interactions and staining for vascular endothelial growth factor (VEGF) glial fibrillary acidic protein, and apoptosis. To characterize the system response to RT, animal survival and tumor surface area and volume were measured. Sham experiments were performed on similar animals implanted with basement membrane matrix absent of tumor cells.
The presence of tumor alone increases permeability but has little effect on leukocyte–endothelial interactions and astrogliosis. Radiation alone increases tissue permeability, leukocyte-endothelial interactions, and astrogliosis. The highest levels of permeability and cell adhesion were seen in the model that combined tumor and irradiation; however, the presence of tumor appeared to reduce the volume of rolling leukocytes. Unirradiated tumor and peritumoral tissue had poor clearance. Irradiated tumor and peritumoral tissue had a similar clearance index to irradiated and unirradiated sham-implanted animals. Radiation reduces the presence of VEGF in peritumoral normal tissues but did not affect the amount of apoptosis in the normal tissue. Apoptosis was identified in the tumor tissue with and without radiation.
We developed a novel approach to demonstrate that the presence of the tumor in a rat intracranial model alters the response of normal tissues to irradiation.
Peritumoral; Radiation; Blood–brain barrier; Glioma; Astrogliosis
To quantify the rotational offsets and estimate the dose effect of rotation on the target volume and normal tissues in children with brain tumor.
Twenty-one pediatric patients with brain tumors were included in this study. Cone-beam CT was performed before each treatment and at the end of every other treatment. Translational offsets were corrected before the treatment. An offline analysis was performed to quantify rotational errors. The treatment plans were altered and recalculated to simulate a rotation of 2° and 4°, and the dose changes were quantified.
1016 CBCT datasets were analyzed for this report. The mean of the rotations were not meaningfully different from zero. 18.1% of the fractions had rotations with a magnitude ≥2°, 5.0% had rotations ≥3° and 0.9% had rotations ≥4°. For the 2° rotational simulation, the gEUD values of the PTV and critical structures changed by less than 2%. For the 4° simulation, parallel type normal structures had minor changes (<2%), but serial type normal structures and the PTV had changes of 10% and 5%, respectively.
The majority of rotational errors observed were less than 1°. A rotational error of 2° produced negligible changes in the gEUD to critical structures or target volumes. Rotational errors ≥4° produced undesirable results, therefore, at a minimum, errors >2° should be corrected.
Pediatric; Brain tumor; Rotation errors; Set-up errors; CBCT
Craniopharyngioma is a pediatric brain tumor whose volume is prone to change during radiation therapy. We compared photon- and proton-based irradiation methods to determine the effect of tumor volume change on target coverage and normal tissue irradiation in these patients.
Methods and Materials
For this retrospective study, we acquired imaging and treatment-planning data from 14 children with craniopharyngioma (mean age, 5.1 years) irradiated with photons (54 Gy) and monitored by weekly magnetic resonance imaging (MRI) examinations during radiation therapy. Photon intensity-modulated radiation therapy (IMRT), double-scatter proton (DSP) therapy, and intensity-modulated proton therapy (IMPT) plans were created for each patient based on his or her pre-irradiation MRI. Target volumes were contoured on each weekly MRI scan for adaptive modeling. The measured differences in conformity index (CI) and normal tissue doses, including functional sub-volumes of the brain, were compared across the planning methods, as was target coverage based on changes in target volumes during treatment.
CI and normal tissue dose values of IMPT plans were significantly better than those of the IMRT and DSP plans (p < 0.01). Although IMRT plans had a higher CI and lower optic nerve doses (p < 0.01) than did DSP plans, DSP plans had lower cochlear, optic chiasm, brain, and scanned body doses (p < 0.01). The mean planning target volume (PTV) at baseline was 54.8 cm3, and the mean increase in PTV was 11.3% over the course of treatment. The dose to 95% of the PTV was correlated with a change in the PTV; the R2 values for all models, 0.73 (IMRT), 0.38 (DSP), and 0.62 (IMPT), were significant (p < 0.01).
Compared with photon IMRT, proton therapy has the potential to significantly reduce whole-brain and -body irradiation in pediatric patients with craniopharyngioma. IMPT is the most conformal method and spares the most normal tissue; however, it is highly sensitive to target volume changes, whereas the DSP method is not.
Craniopharyngioma; Proton; IMPT; Adaptive planning
Dysembryoplastic neuroepithelial tumors (DNETs) are benign glioneuronal tumors that occur in children. These tumors are characterized by seizures, lack of neurologic deficits, and a seemingly benign course after resection.
We conducted a retrospective review of data relating to 11 children diagnosed with DNET between January 1988 and December 2007 at St. Jude Children's Research Hospital. This report documents the clinical features, neurocognitive function, and treatment outcomes in our institutional series.
Our patient cohort included 8 boys and 3 girls (median age at diagnosis, 10 years); all patients presented with seizures: 4 complex partial, 3 generalized tonic clonic, 2 absence, 1 partial simple, and 1 not classified. Of the 11 patients, 1 died of cardiac fibrosis, and tumors recurred or progressed in 4 (36%). Seizure control was achieved in all patients but 1. Of the 9 patients who completed neuropsychologic testing, only 3 (23%) functioned at or above the expected level of same-age peers.
The high recurrence and progression rates of DNETs and the high rate of abnormal neurocognitive test results in this study highlight the need for regular follow-up and appropriate academic counseling of children with these tumors.
Dysembryoplastic neuroepithelial tumors (DNETs); pediatric; recurrence; neuropsychologic outcome
We have reviewed the published data regarding radiotherapy (RT)-induced brain injury. Radiation necrosis appears a median of 1–2 years after RT; however, cognitive decline develops over many years. The incidence and severity is dose and volume dependent and can also be increased by chemotherapy, age, diabetes, and spatial factors. For fractionated RT with a fraction size of <2.5 Gy, an incidence of radiation necrosis of 5% and 10% is predicted to occur at a biologically effective dose of 120 Gy (range, 100–140) and 150 Gy (range, 140–170), respectively. For twice-daily fractionation, a steep increase in toxicity appears to occur when the biologically effective dose is >80 Gy. For large fraction sizes (≥2.5 Gy), the incidence and severity of toxicity is unpredictable. For single fraction radiosurgery, a clear correlation has been demonstrated between the target size and the risk of adverse events. Substantial variation among different centers’ reported outcomes have prevented us from making toxicity–risk predictions. Cognitive dysfunction in children is largely seen for whole brain doses of ≥18 Gy. No substantial evidence has shown that RT induces irreversible cognitive decline in adults within 4 years of RT.
Radiotherapy; stereotactic radiosurgery; brain; tolerance; side effects
To determine the time course and clinical significance of cytokines and peptide growth factors in pediatric patients with ependymoma treated with postoperative radiotherapy (RT).
Methods and Materials
We measured 15 cytokines and growth factors (fibroblast growth factor, epidermal growth factor, vascular endothelial growth factor [VEGF], interleukin [IL]-1β, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, interferon-γ, tumor necrosis factor-α, granulocyte-macrophage colony-stimulating factor, monocyte chemoattractant protein-1, and macrophage inflammatory protein-α) from 30 patients before RT and 2 and 24 h, weekly for 6 weeks, and at 3, 6, 9, and 12 months after the initiation of RT. Two longitudinal models for the trend of log-transformed measurements were fitted, one during treatment and one through 12 months.
During RT, log IL-8 declined at a rate of −0.10389/wk (p = 0.0068). The rate of decline was greater (p = 0.028) for patients with an infratentorial tumor location. The decline in IL-8 after RT was significant when stratified by infratentorial tumor location (p = 0.0345) and more than one surgical procedure (p = 0.0272). During RT, the decline in log VEGF was significant when stratified by the presence of a ventriculoperitoneal shunt. After RT, the log VEGF declined significantly at a rate of −0.06207/mo. The decline was significant for males (p = 0.0222), supratentorial tumors (p = 0.0158), one surgical procedure (p = 0.0222), no ventriculoperitoneal shunt (p = 0.0005), and the absence of treatment failure (p = 0.0028).
The pro-inflammatory cytokine IL-8 declined significantly during RT and the decline differed according to tumor location. The angiogenesis factor VEGF declined significantly during the 12 months after RT. The decline was greater in males, those without a ventriculoperitoneal shunt, and in those with favorable disease factors, including one surgical procedure, supratentorial tumor location, and tumor control.
Radiotherapy; Pediatrics; Ependymoma; Cytokines; Central nervous system tumors
To estimate radiation therapy planning margins based on inter- and intrafractional uncertainty for pediatric brain and head and neck tumor patients at different imaging frequencies.
Pediatric patients with brain (n = 83) and head and neck (n = 17) tumors (median age = 7.2 years) were enrolled on an internal review board–approved localization protocol and stratified according to treatment position and use of anesthesia. Megavoltage cone-beam CT (CBCT) was performed before each treatment and after every other treatment. The pretreatment offsets were used to calculate the interfractional setup uncertainty (SU), and posttreatment offsets were used to calculate the intrafractional residual uncertainty (RU). The SU and RU are the patient-related components of the setup margin (SM), which is part of the planning target volume (PTV). SU data was used to simulate four intervention strategies using different imaging frequencies and thresholds.
The SM based on all patients treated on this study was 2.1 mm (SU = 0.9 mm, RU = 1.9 mm) and varied according to treatment position (supine = 1.8 mm, prone = 2.6 mm) and use of anesthesia (with = 1.7 mm, without = 2.5 mm) because of differences in the RU. The average SU for a 2-mm threshold based on no imaging, once per week imaging, initial five images, and daily imaging was 3.6, 2.1, 2.2, and 0.9 mm, respectively.
On the basis of this study, the SM component of the PTV may be reduced to 2 mm for daily CBCT compared with 3.5 mm for weekly CBCT. Considering patients who undergo daily pretreatment CBCT, the SM is larger for those treated in the prone position or smaller for those treated under anesthesia because of differences in the RU.
Pediatric brain tumor; Patient motion; CBCT; Target localization; Margins