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
To investigate the relationship between jaw function, patient and treatment variables, and radiation dosimetry of the mandibular muscles and joints in children and young adults receiving radiation for soft tissue and bone sarcomas.
Methods and Materials
Twenty-four pediatric and young adult patients with head and neck sarcomas were treated on an IRB-approved prospective study of focal radiation therapy for local tumor control. Serial jaw depression measurements were related to radiation dosimetry delivered to the medial and lateral pterygoid muscles, masseter muscles, and temporomandibular joints to generate mathematical models of jaw function.
Baseline jaw depression was only influenced by the degree of surgical resection. In the first 12 weeks from initiation of radiation, surgical procedures greater than a biopsy, administration of cyclophosphamide containing chemotherapy regimes, and large gross tumor volumes adversely affected jaw depression. Increasing dose to the pterygoid and masseter muscles above 40 Gy predicted loss of jaw function over the full course of follow-up.
Clinical and treatment factors are related to initial and subsequent jaw dysfunction. Understanding these complex interactions and the affect of specific radiation doses may help reduce the risk for jaw dysfunction in future children and young adults undergoing radiation therapy for the management of soft tissue and bone sarcomas.
Jaw Depression; Radiation; Dosimetry; Pediatric Sarcomas; Pterygoid Muscle
The clinical difference between brain tumors in adults and children is striking. Compared with adults, pediatric tumor types (mostly glial and neuronal) are more sensitive to adjuvant irradiation and chemotherapy. Pediatric tumors more often require craniospinal irradiation based on their propensity to disseminate within the neuraxis. The spectrum of side effects is broader in the child based on age and extent of treatment: radiation therapy brings increased risk of severe long-term sequelae affecting neurologic, endocrine, and cognitive function. In this review of glioma, ependymoma and medulloblastoma, we highlight the differences between adults and children including the higher incidence of spinal cord ependymoma and supratentorial high-grade glioma in the adult and a higher incidence of medulloblastoma in the child. With the exception of completely resected low-grade glioma, radiation therapy remains a standard of care for most patients. In some settings, the radiation oncologist should suggest further surgery or additional adjuvant therapy in an effort to optimize local tumor control. An effort is underway to better characterize adult and pediatric brain tumors biologically with an emphasis on improving our understanding of tumor genesis, malignant transformation, and some of the similarities and differences between tumor types and their response to conventional therapy.
Growth hormone deficiency (GHD) after radiation therapy negatively affects growth and development and quality of life in children with brain tumors.
Patients and Materials
Between 1997 and 2008, 192 pediatric patients with localized primary brain tumors (ependymoma, n = 88; low-grade glioma, n = 51; craniopharyngioma, n = 28; high-grade glioma, n = 23; and other tumor types, n = 2) underwent provocative testing of GH secretion by using the secretogogues arginine and l-dopa before and after (6, 12, 36, and 60 months) conformal radiation therapy (CRT). A total of 664 arginine/l-dopa test procedures were performed.
Baseline testing revealed preirradiation GHD in 22.9% of tested patients. On the basis of data from 118 patients, peak GH was modeled as an exponential function of time after CRT and mean radiation dose to the hypothalamus. The average patient was predicted to develop GHD with the following combinations of the time after CRT and mean dose to the hypothalamus: 12 months and more than 60 Gy; 36 months and 25 to 30 Gy; and 60 months and 15 to 20 Gy. A cumulative dose of 16.1 Gy to the hypothalamus would be considered the mean radiation dose required to achieve a 50% risk of GHD at 5 years (TD50/5).
GH secretion after CRT can be predicted on the basis of dose and time after irradiation in pediatric patients with localized brain tumors. These findings provide an objective radiation dose constraint for the hypothalamus.
Long-term morbidity for children with low-grade glioma (LGG) requires exposure-specific characterization. Overall survival (OS) and progression-free survival (PFS) were estimated for 361 children diagnosed with LGG between 1985 and 2007 at a single institution. Five-year survivors (n = 240) received risk-based clinical assessment. Cumulative incidence of late effects 15 years from diagnosis were estimated. Risk factors for adverse health were identified using Fine and Gray's approach to Cox's proportional hazards model, accounting for death as a competing risk. OS at 15 years was 86% (95% confidence interval [CI] 82%–90%), and PFS was 55% (95% CI 51%–58%). Among the 240 5-year survivors, the 5-, 10-, and 15-year cumulative incidence of adverse outcomes included blindness: 10%, 13%, and 18%, respectively; hearing loss: 8%, 14%, and 22%; obesity/overweight: 18%, 35%, and 53%; hyperinsulinism: 1%, 5%, and 24%; growth hormone deficiency: 13%, 27%, and 29%;thyroid hormone deficiency: 16%, 28%, and 33%; and adrenocorticotropic hormone (ACTH) deficiency: 12%, 22%, and 26%. Multivariable models demonstrated radiation therapy to be a significant independent predictor of hearing loss, growth hormone deficiency, abnormal thyroid function, and ACTH deficiency. Diencephalic location was a statistically significant independent risk factor for blindness, growth hormone deficiency, abnormal thyroid function, and ACTH deficiency. Among the 182 5-year survivors assessed for intellectual function, 34% had an intelligence quotient (IQ) below average (<85), associated with younger age at diagnosis, epilepsy, and shunt placement. Survivors of childhood LGG experience substantial long-term adverse effects that continue to increase well beyond the 5-year survival time point.
cancer; glioma; pediatric; survivor
To evaluate the safety, maximum-tolerated dose, pharmacokinetics, and pharmacodynamics of vandetanib, an oral vascular endothelial growth factor receptor 2 (VEGFR2) and epidermal growth factor receptor inhibitor, administered once daily during and after radiotherapy in children with newly diagnosed diffuse intrinsic pontine glioma.
Patients and Methods
Radiotherapy was administered as 1.8-Gy fractions (total cumulative dose of 54 Gy). Vandetanib was administered concurrently with radiotherapy for a maximum of 2 years. Dose-limiting toxicities (DLTs) were evaluated during the first 6 weeks of therapy. Pharmacokinetic studies were obtained for all patients. Plasma angiogenic factors and VEGFR2 phosphorylation in mononuclear cells were analyzed before and during therapy.
Twenty-one patients were administered 50 (n = 3), 65 (n = 3), 85 (n = 3), 110 (n = 6), and 145 mg/m2 (n = 6) of vandetanib. Only one patient developed DLT (grade 3 diarrhea) at dosage level 5. An expanded cohort of patients were treated at dosage levels 4 (n = 10) and 5 (n = 4); two patients developed grade 4 hypertension and posterior reversible encephalopathy syndrome while also receiving high-dose dexamethasone. Despite significant interpatient variability, exposure to vandetanib increased with higher dosage levels. The bivariable analysis of vascular endothelial growth factor (VEGF) before and during therapy showed that patients with higher levels of VEGF before therapy had a longer progression-free survival (PFS; P = .022), whereas patients with increases in VEGF during treatment had a shorter PFS (P = .0015). VEGFR2 phosphorylation was inhibited on day 8 or 29 of therapy compared with baseline (P = .039).
The recommended phase II dose of vandetanib in children is 145 mg/m2 per day. Close monitoring and management of hypertension is required, particularly for patients receiving corticosteroids.
Childhood cancer survivors exposed to CNS irradiation are at increased risk for neurocognitive deficits; however, limited data exist linking outcomes with region-specific exposure to CNS irradiation. We report associations between region-specific radiation dose and self-reported neurocognitive and health-related quality of life (HRQOL) outcomes in 818 adult survivors of childhood central nervous system (CNS) malignancies from the Childhood Cancer Survivor Study. Survivors were compared with a sibling group and national normative samples to calculate standardized scores. Cumulative radiation dose was calculated for 4 specific brain regions. Logistic regression was used to estimate the association between radiation dose to specific brain regions and outcome measures of functional impairment adjusted for clinical and demographic factors, including sex and age at diagnosis. High radiation dose levels to temporal regions were associated with a higher risk for memory impairment (radiation doses ≥30 to <50 Gy: OR, 1.95; 95% CI, 1.01–3.78; dose ≥50 Gy: OR, 2.34; 95% CI, 1.25–4.39) compared with those with no radiation exposure. No such association was seen with radiation exposure to other regions. Exposure to temporal regions was associated with more social and general health problems, whereas exposure to frontal regions was associated with general health problems and physical performance limitations. Adult survivors of childhood CNS malignancies report higher rates of neuropsychological and HRQOL outcomes, which vary as a function of dose to specific neuroanatomical regions. Survivors with a history of radiation exposure to temporal brain regions are at increased risk for impairment in memory and social functioning.
CNS malignancies; Childhood Cancer Survivor Study (CCSS); health-related quality of life; neuropsychological functioning; radiation therapy
The primary objective of this study was to determine if children with localized ependymoma experience a decline in verbal or visual-auditory learning after conformal radiation therapy (CRT). The secondary objective was to investigate the impact of age and select clinical factors on learning before and after treatment.
Methods and Materials
Learning in a sample of 71 patients with localized ependymoma was assessed with the California Verbal Learning Test (CVLT-C) and the Visual-Auditory Learning Test (VAL). Learning measures were administered before CRT, at six months and then yearly for a total of five years.
There was no significant decline on measures of verbal or visual-auditory learning after CRT; however, younger age, more surgeries and CSF shunting did predict lower scores at baseline. There were significant longitudinal effects (improved learning scores after treatment) among older children on the CVLT-C and children that did not receive pre-CRT chemotherapy on the VAL.
There was no evidence of global decline in learning after CRT in children with localized ependymoma. Several important implications from the findings include: 1) identification of and differentiation among variables with transient versus long-term effects on learning; 2) demonstration that children treated with chemotherapy prior to CRT had greater risk of adverse visual-auditory learning performance, and; 3) establishment of baseline and serial assessment as critical in ascertaining necessary sensitivity and specificity for the detection of modest effects.
ependymoma; brain tumor; radiotherapy; memory; pediatrics
Children treated for childhood malignancies may be at risk for early or delayed onset hearing loss that can impact learning, communication, school performance, social interaction, and overall quality of life (QOL). Survivors at particular risk include those treated with platinum compounds (cis-and/or carboplatin) for neuroblastoma, hepatoblastoma, osteosarcoma, or germ cell tumors and/or those treated with radiation impacting the ear at doses greater than 30 Gray (Gy) for pediatric head and neck tumors. The aims of the Auditory/Hearing Late Effects Task Force of Children’s Oncology Group in this report were: 1) to review ototoxicity resulting from childhood cancer therapy including platinum compounds (cisplatin and carboplatin) and radiation; 2) to describe briefly cochlear pathophysiology and genetics of cisplatin-related hearing loss; 3) to explain the impact of hearing loss resulting from chemotherapy and radiation; and 4) to offer recommendations regarding evaluation and management of pediatric patients at risk for treatment-related hearing loss. A questionnaire is included as a tool to assist pediatricians in assessment.
Ototoxicity; Carboplatin; Cisplatin; Radiation; Hearing loss
Ionizing radiation, an important component of glioma therapy, is critically dependent on tumor oxygenation. However, gliomas are notable for areas of necrosis and hypoxia, which foster radioresistance. We hypothesized that pharmacologic manipulation of the typically dysfunctional tumor vasculature would improve intratumoral oxygenation and, therefore, the anti-glioma efficacy of ionizing radiation.
Methods and Materials
Orthotopic U87 xenografts were treated with either continuous interferon-beta (IFN-β) or bevacizumab, alone, or in combination with cranial irradiation (RT). Tumor growth was assessed by quantitative bioluminescence imaging; tumor vasculature, with immunohistochemical staining; and tumor oxygenation, with hypoxyprobe staining.
Both IFN-β and bevaziumab profoundly affected the tumor vasculature, albeit with different cellular phenotypes. IFN-β caused a doubling in the percent area of perivascular cell staining while bevacizumab caused a rapid decrease in the percent area of endothelial cell staining. However, both agents increased intratumoral oxygenation, although with bevacizumab the effect was transient, being lost by five days. Administration of IFN-β or bevacizumab prior to RT was significantly more effective than any of the three modalities as monotherapy or when RT was administered concomitantly with IFN-β or bevacizumab, or five days after bevacizumab.
Bevacizumab and continuous delivery of IFN-β each induced significant changes in glioma vascular physiology, improving intratumoral oxygenation and enhancing the anti-tumor activity of ionizing radiation. Further investigation into the use and timing of these and other agents that modify vascular phenotype, in combination with radiation, is warranted in order to optimize cytotoxic activity.
Vascular normalization; oxygenation; bevacizumab; interferon-beta; ionizing radiation; glioma
There is renewed attention in primary site irradiation and local control for patients with high-risk neuroblastoma (NB). We conducted a retrospective review to identify factors that might predict for loco-regional tumor control and its impact on overall survival.
Methods and Materials
Between July 2000 through August 2006, 44 pediatric patients with NB received radiation therapy (RT) with curative intent using CT-based treatment planning. The median age was 3.4 years and the median cumulative dose was 23.4 Gy. Overall survival and loco-regional tumor control were measured from the start of RT to the date of death or event as determined by CT/MRI/MIBG. The influence of age at irradiation, gender, race, cumulative radiation dose, INSS stage, treatment protocol and resection status was determined with respect to loco-regional tumor control.
With a median follow-up of 34 months ± 21 months, loco-regional tumor progression was observed in 11 (25%) and was evenly divided between primary site and adjacent nodal/visceral site failure. The influence of loco-regional control reached borderline statistical significance (p=0.06). Age (p=0.5), dose (p=0.6), resection status (p=0.7) and INSS stage (P=0.08) did not influence overall survival.
Overall survival in high-risk neuroblastoma is influenced by loco-regional tumor control. Despite CT-based planning, progression in adjacent nodal/visceral sites appears to be common; this requires further investigation regarding target volume definitions, dose and the effects of systemic therapy.
pediatric; neuroblastoma; radiation; loco-regional failure; overall survival
To demonstrate the safety and efficacy of limited margin radiotherapy in the local control of pediatric and young adult patients with high grade non-rhabdomyosarcoma soft tissue sarcoma (NRSTS).
Methods and Materials
Pediatric patients with high-grade NRSTS requiring radiation were treated on an IRB approved prospective institutional study of conformal / intensity modulated / interstitial brachytherapy using a 2 cm anatomically constrained margin.
Thirty-two patients (median age 15.3 years, range 2–22 years) received adjuvant (27 patients) or definitive (5 patients) irradiation. With a median follow-up of 32 months, the 3-year cumulative incidence of local failure was 3.7% for patients irradiated after surgical resection. In total four patients experienced local failure; the mean dose to the volume of recurrence was ≥ 97% of the prescribed dose.
Delivery of limited margin radiotherapy using external beam or brachytherapy provides a high rate of local tumor control without marginal failure. Further follow-up is required to determine if normal tissue effects are minimized using this approach.
Soft-tissue sarcoma; Conformal; IMRT; Margin; Radiation
Understanding the biology that underlies histologically similar but molecularly distinct subgroups of cancer has proven difficult since their defining genetic alterations are often numerous, and the cellular origins of most cancers remain unknown1–3. We sought to decipher this heterogeneity by integrating matched genetic alterations and candidate cells of origin to generate accurate disease models. First, we identified subgroups of human ependymoma, a form of neural tumor that arises throughout the central nervous system (CNS). Subgroup specific alterations included amplifications and homozygous deletions of genes not yet implicated in ependymoma. To select cellular compartments most likely to give rise to subgroups of ependymoma, we matched the transcriptomes of human tumors to those of mouse neural stem cells (NSCs), isolated from different regions of the CNS at different developmental stages, with an intact or deleted Ink4a/Arf locus. The transcriptome of human cerebral ependymomas with amplified EPHB2 and deleted INK4A/ARF matched only that of embryonic cerebral Ink4a/Arf−/− NSCs. Remarkably, activation of Ephb2 signaling in these, but not other NSCs, generated the first mouse model of ependymoma, which is highly penetrant and accurately models the histology and transcriptome of one subgroup of human cerebral tumor. Further comparative analysis of matched mouse and human tumors revealed selective deregulation in the expression and copy number of genes that control synaptogenesis, pinpointing disruption of this pathway as a critical event in the production of this ependymoma subgroup. Our data demonstrate the power of cross-species genomics to meticulously match subgroup specific driver mutations with cellular compartments to model and interrogate cancer subgroups.
Infratentorial ependymoma is a common central nervous system tumor of childhood and in patients > 1 year of age is treated with maximally feasible surgical resection and radiotherapy. Because of this tumor typically arises within the 4th ventricle and can invade the brainstem, patients are at risk for significant neurological impairment.
To characterize the incidence, evolution, and persistence of neurologic impairment in children with infratentorial ependymoma following maximal safe surgery and conformal or intensity-modulated radiation therapy (CRT/IMRT).
Patients and Methods
After surgical resection, 96 children with non-metastatic infratentorial ependymoma were enrolled on a phase II study of image-guided radiation therapy and were prospectively followed with interval comprehensive neurological examinations. Late adverse neurological severity was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 3.0.
The most common deficits detected at baseline examination were limb dysmetria, cranial nerve VI/VII palsy, limb paresis, dysphagia, and truncal ataxia/hypotonia. When present, gait dysfunction and dysphagia were often severe. Oculomotor dysfunction, facial paresis, dysphagia, and gait impairment improved over time. With the exception of hearing loss, in the survivor cohort, very few severe late effects (CTCAE Grade 3/4/5) were present at 60 month survival.
In general, neurological deficits were maximal in the post-operative period and either remained stable or improved during radiation and the post-treatment evaluation period. With the exception of hearing, the majority of chronic residual neurological deficits in this at-risk population are mild and only minimally intrude upon daily life.
ependymoma; children; conformal radiation; neurological impairment
We conducted a prospective trial to evaluate late effects in pediatric patients with low-grade glioma (LGG) treated with conformal radiation therapy (CRT).
Patients and Methods
Between August 1997 and August 2006, 78 pediatric patients with LGG (mean age, 9.7 years; standard deviation, ±4.4 years) received 54 Gy of CRT with a 10-mm clinical target volume margin. Tumor locations were diencephalon (n = 58), cerebral hemisphere (n = 3), and cerebellum (n = 17). Baseline and serial evaluations were performed to identify deficits in cognition, endocrine function, and hearing. Deficits were correlated with clinical factors and radiation dose within specific normal tissue volumes.
Cognitive effects of CRT through 5 years after CRT correlated with patient age, neurofibromatosis type 1 status, tumor location and volume, extent of resection, and radiation dose. The effect of age exceeded that of radiation dose; patients younger than 5 years experienced the greatest decline in cognition. Before CRT, growth hormone (GH) secretion abnormality was diagnosed in 24% of tested patients, and 12% had precocious puberty. The 10-year cumulative incidence of GH replacement was 48.9%; of thyroid hormone replacement, 64.0%; of glucocorticoid replacement, 19.2%; and of gonadotropin-releasing hormone analog therapy, 34.2%. The mean ± standard errors of the cumulative incidence of hearing loss at 10 years did not exceed 5.7% ± 3.3% at any frequency.
To our knowledge, this is the largest series of prospectively followed children with LGG to undergo irradiation. Adverse effects are limited and predictable for most patients; however, this study provides additional evidence that CRT should be delayed for young patients and identifies the potential benefits of reducing radiation dose to normal brain.
The use of radiotherapy in pediatric low-grade glioma (LGG) is controversial, especially for young patients. We conducted a phase II trial of conformal radiation therapy (CRT) to estimate disease control by using a 10-mm clinical target volume (CTV) margin.
Materials and Methods
Between August 1997 and August 2006, 78 pediatric patients with LGG and a median age of 8.9 years (range, 2.2 to 19.8 years) received 54 Gy CRT by using a 10-mm CTV and by targeting with systematic magnetic resonance imaging (MRI) registration. Tumor locations were diencephalon (n = 58), cerebral hemisphere (n = 3), and cerebellum (n = 17). Sixty-seven patients had documented or presumed WHO grade 1 tumors, 25 patients had prior chemotherapy, and 13 patients had neurofibromatosis type 1.
During a median follow-up of 89 months, 13 patients experienced disease progression. One patient experienced marginal treatment failure, eight experienced local failures, and four experienced metastatic failure. The mean and standard error 5- and 10-year event-free (87.4% ± 4.4% and 74.3% ± 15.4%, respectively) and overall (98.5% ± 1.6% and 95.9% ± 5.8%, respectively) survival rates were determined. The mean and standard error cumulative incidences of local failure at 5 and 10 years were 8.7% ± 3.5% and 16.4% ± 5.4%, respectively. The mean and standard error cumulative incidence of vasculopathy was 4.79% ± 2.73% at 6 years, and it was higher for those younger than 5 years of age (P = .0105) at the time of CRT.
This large, prospective series of irradiated children with LGG demonstrates that CRT with a 10-mm CTV does not compromise disease control. The results suggest that CRT should be delayed in young patients to reduce the risk of vasculopathy.
Publications relating brainstem radiation toxicity to quantitative dose and dose–volume measures derived from three-dimensional treatment planning were reviewed. Despite the clinical importance of brainstem toxicity, most studies reporting brainstem effects after irradiation have fewer than 100 patients. There is limited evidence relating toxicity to small volumes receiving doses above 60–64 Gy using conventional fractionation and no definitive criteria regarding more subtle dose–volume effects or effects after hypofractionated treatment. On the basis of the available data, the entire brainstem may be treated to 54 Gy using conventional fractionation using photons with limited risk of severe or permanent neurological effects. Smaller volumes of the brainstem (1–10 mL) may be irradiated to maximum doses of 59 Gy for dose fractions ≤2 Gy; however, the risk appears to increase markedly at doses >64 Gy.
Brainstem; Radiation; Tolerance; NTCP
Although radiation therapy is a primary treatment for craniopharyngioma, it can exacerbate existing problems related to the tumor and pre-irradiation management. Survival is often marked by neurologic deficits, panhypopituitarism, diabetes insipidus, cognitive deficiencies and behavioral and social problems.
The Achenbach Child Behavior Checklist (CBCL) was used to evaluate behavioral and social problems during the first five years of follow-up in 27 patients with craniopharyngioma treated with conformal radiation therapy.
All group averages for the CBCL scales were within the age-typical range at pre-irradiation baseline. Extent of surgical resection was implicated in baseline differences for the Internalizing, Externalizing, Behavior Problem and Social scores. Significant longitudinal changes were found in Internalizing, Externalizing, Behavior Problem and School scores that correlated with tumor and treatment related factors.
The most common variables implicated in post-irradiation behavioral and social problems were CSF shunting, presence of an Ommaya reservoir, diabetes insipidus, and low pre-irradiation growth hormone levels.
Craniopharyngioma; Brain Tumor; Child Behavior Checklist; Pediatric
Retinoblastoma is curable when diagnosed early and treated appropriately; however, the prognosis is dismal when the basic elements in diagnosis and treatment are lacking. In developing countries, poor education, lower socioeconomic conditions, and inefficient health care systems result in delayed diagnosis and suboptimal care. Furthermore, the complexity of multidisciplinary care required is seldom possible. While ocular salvage is a priority in the Western world, death from retinoblastoma is still a major problem in developing countries. To bring the two ends of this spectrum together and provide a forum for discussion, the One World, One Vision symposium was organized, where clinicians and researchers from various cultural, geographic, and socioeconomic backgrounds converged to discuss their experiences. Strategies for early diagnosis in developing countries were discussed. Elements in the development of retinoblastoma centers in developing countries were discussed, and examples of successful programs were highlighted. An important component in this process is twinning between centers in developing countries and mentor institutions in high-income countries. Global initiatives by nongovernmental organizations such as the International Network for Cancer Treatment and Research, Orbis International, and the International Agency for Prevention of Blindness were presented. Treatment of retinoblastoma in developing countries remains a challenge. However, it is possible to coordinate efforts at multiple levels, including public administrations and nonprofit organizations, to improve the diagnosis and treatment of retinoblastoma and to improve the outcome for these children.