A Prospective Study of Arterial Spin Labelling in Paediatric Posterior Fossa Tumour Survivors: A Correlation with Neurocognitive Impairment.

AIMS: Posterior fossa tumours (PFTs), which account for two-thirds of paediatric brain tumours, are successfully treated in about 70% of patients, but most survivors experience long-term cognitive impairment. We evaluated arterial spin labelling (ASL), a common, non-invasive magnetic resonance imaging (MRI) technique, as a biomarker of cognitive impairment in a paediatric PFT survivor population. MATERIALS AND METHODS: Sixty participants were prospectively analysed. PFT survivors were at least 5 years post-treatment and had been treated as appropriate for their age and type of tumour. Group 1 had received radiotherapy and Group 2 had not. Group 3 were healthy controls matched to Group 1 for age, sex and handedness. All participants underwent cognitive assessment and multimodal MRI, including an ASL perfusion sequence. We used semi-quantitative ASL methods to assess differences in mean perfusion in the thalamus, caudate, putamen and hippocampus. RESULTS: Statistically, no significant associations between cognitive data and radiation doses were identified. Compared with healthy controls, Group 1 patients had significantly lower overall mean perfusion values (20-30% lower, depending on the cerebral structure) and Group 2 had slightly lower mean perfusion values (5-10% lower). Perfusion values did not correlate with total prescribed irradiation doses nor with doses received by different cerebral structures. Episodic and semantic memory test scores were significantly lower in Group 1 and correlated with lower mean absolute perfusion values in the hippocampus (P < 0.04). CONCLUSIONS: These preliminary results indicate that radiotherapy affects the perfusion of specific cerebral structures and identify perfusion as a potential biomarker of hippocampus-dependent memory deficit.

The long-term impact of irradiation on functional connectivity in brain circuits involved in memory processes after pediatric posterior fossa tumor.

PURPOSE: Memory is one of the main specific cognitive domains impaired with attention and processing speed after a pediatric brain tumor. This work explored the long-term impact of radiotherapy in children with posterior fossa tumor (PFT) on brain connectivity in neural circuits involved in memory using resting-state functional magnetic resonance imaging (rs-fMRI). METHODS: A total of 20 irradiated and 15 non-irradiated PFT survivors, and 21 healthy controls, prospectively included in the IMPALA study (NCT04324450), performed memory tests assessing episodic, procedural, and working memories and were subjected to an rs-fMRI. We manually contoured main structures involved in memory to explore connectivity at rest in a seed-to-voxel analysis. The groups were compared and differences in connectivity were correlated with behavioral scores and irradiation doses. RESULTS: The performance of all mnesic tasks was lower in PFT survivors with a greater alteration in working and episodic memory in irradiated patients. Irradiated survivors had atypical connectivities in all memory circuits compared to controls and in cortico-caudate and cortico-cerebellar circuits compared to non-irradiated survivors. Non-irradiated survivors had only atypical connectivities in the cortico-cerebellar circuits compared to controls. In irradiated survivors, atypical connectivities in cortico-hippocampal circuits were linked with episodic memory scores and dose of irradiation to the left hippocampus and in cortico-striatal circuits with procedural memory scores and dose of irradiation to the striatum. CONCLUSION: The results of this study highlight that irradiation has a long-term impact on brain connectivity in brain circuits involved in memory after pediatric PFT with a specific radiation-dose effect in supratentorial structures.

Challenges in Treating Childhood Infratentorial Ependymoma: A Low- and Middle-Income Country Experience.

PURPOSE: Patients and physicians in low- and middle-income countries (LMICs) face challenges owing to limited expertise and suboptimal access to appropriate diagnostic and treatment modalities. We report our experience in treating posterior fossa ependymoma (PFE) at MAHAK, a charity organization in Iran whose radiation oncology department is the only one exclusively dedicated to childhood cancer in the whole country. METHODS AND MATERIALS: Pediatric patients with PFE referred to MAHAK between November 2008 and January 2016 were identified. Details on investigations and management done before referral were collected. Management at MAHAK and patient outcomes were analyzed. RESULTS: Of 80 patients diagnosed as having ependymoma, 54 with PFE were identified. Forty-three patients received adjuvant radiation therapy, and 11 were irradiated initially after recurrence. At a median follow-up of 5.1 years (range, 0.3-9.7 years), the latter group had the worst outcome, with a 5-year overall survival (OS) rate of 27% (95% CI, 7%-54%). Patients who started radiation therapy within 77 days after initial surgery had a better outcome compared with those who started later (5-year OS: 74% vs 32%; P = .05). Compliance with follow-up recommendations was poor. Only 22% of the patients had at least 2 IQ test assessments, and 50% showed some decline over time. Three cases of growth hormone deficiency were detected, but none of the patients received replacement therapy. CONCLUSIONS: Access to pediatric neurosurgery, anesthesia, and timely radiation therapy are among the most challenging obstacles to be overcome in LMICs. Our series confirmed that chemotherapy is not an appropriate option for delaying radiation therapy, especially in young children. The importance of long-term follow-up should be acknowledged by the parents and medical team.

Impact of a pediatric posterior fossa tumor and its treatments on motor procedural learning.

INTRODUCTION: Posterior fossa tumor (PFT) survivors have difficulty learning new skills. Procedural memory is a skill learning system that allows, through training, the automatization of procedures and progressive improvement of performance. It underlies most of the motor procedures in everyday life that we perform automatically, such as riding a bike or writing. Motor procedural memory is divided into two components: motor sequence learning involving mainly cortico-striatal networks, and motor adaptation involving mainly cortico-cerebellar networks. The aim of this work was to explore the impact of a tumor and its treatment during childhood on procedural learning hypothesizing that sequence learning would be impaired in PFT survivors who have been treated with radiotherapy, whereas motor adaptation would be impaired in all PFT survivors. METHOD: 22 irradiated survivors of PFT, 17 non-irradiated survivors and 21 healthy controls from the IMPALA study (NCT04324450) performed a motor sequence learning task and a motor adaptation task. Doses received by striatal and cerebellar structures were reported from the initial dosimetry plans. RESULTS: Sequence learning was preserved in both tumor groups, but at the individual level 7/22 irradiated, and 4/17 non-irradiated participants failed to learn the motor sequence. Motor adaptation was impaired in both tumor groups, predominantly in the irradiated group. CONCLUSION: This study sheds new light on the long-term impact of PFT treatments in childhood on a rarely-studied part of memory, which is perceptual-motor procedural learning. Our results suggest that the cerebellum and striatum could be considered as organs at risk with regard to procedural learning.

A review of long-term deficits in memory systems following radiotherapy for pediatric posterior fossa tumor.

INTRODUCTION: In recent years, progress in pediatric posterior fossa tumor (PFT) treatments has improved survival rates. However, the majority of survivors present neurocognitive sequelae that impact academic achievement. METHODS: This review examines the literature from 2000 to 2020 on long-term outcomes in different memory systems for survivors of pediatric PFT, considering the impact of radiotherapy which is a well-known prognostic factor for global neurocognitive function. RESULTS: Of the 43 articles selected, 31 explored working memory, 19 episodic memory, 9 semantic memory and 2 procedural memory. Irradiated survivors had scores of <-2 standard deviation (SD) (n = 4 studies/25) or between -2SD and -1SD (n = 7 studies/25) for working memory; <-1SD for anterograde memory (n = 11/13), with a progressive decline in these two memory systems; <-1SD (n = 4/7) in semantic memory, and a deficit in perceptual-motor procedural learning (n = 1/1). Reducing craniospinal irradiation dose, limiting tumor bed boosts, and using proton therapy seem to have had a beneficial effect with better preservation of the memory score and a reduction in the decline over time. Non-irradiated survivors had memory systems that were less affected, with preservation of anterograde memory and maintenance of long-term stability. CONCLUSION: Memory deficits are a core feature in survivors of pediatric PFT, especially when treatment requires radiotherapy. To limit these effects, dose constraints for specific brain areas involved in memory should be defined. During long-term follow-up, specific attention is essential to identify these deficits in order to limit their impact on the quality of life.

Postsurgical geometrical variations of tumor bed and brainstem during photon and proton therapy for pediatric tumors of the posterior fossa: dosimetric impact and predictive factors.

PURPOSE: Brainstem radionecrosis is an important issue during the irradiation of tumors of the posterior fossa. The aim of the present study is to analyze postsurgical geometrical variations of tumor bed (TB) and brainstem (BS) and their impact on dosimetry. METHODS: Retrospective collection of data from pediatric patients treated at a single institution. Availability of presurgical magnetic resonance imaging (MRI) was verified; availability of at least two postsurgical MRIs was considered a further inclusion criterion. The following metrics were analyzed: total volume, Dice similarity coefficient (DSC), and Haudsdorff distances (HD). RESULTS: Fourteen patients were available for the quantification of major postsurgical geometrical variations of TB. DSC, HD max, and HD average values were 0.47 (range: 0.08;0.76), 11.3 mm (7.7;24.5), and 2.6 mm (0.7;6.7) between the first and the second postoperative MRI, respectively. Postsurgical geometrical variations of the BS were also observed. Coverage to the TB was reduced in one patient (D95: -2.9 Gy), while D2 to the BS was increased for the majority of patients. Overall, predictive factors for significant geometrical changes were presurgical gross tumor volume (GTV) > 33 mL, hydrocephaly at diagnosis, Luschka foramen involvement, and younger age (≤ 8 years). CONCLUSION: Major volume changes were observed in this cohort, with some dosimetric impact. The use of a recent co-registration MRI is advised. The 2-3 mm HD average observed should be considered in the planning target volume/planning organ at risk volume (PTV/PRV) margin and/or robust optimization planning. Results from wider efforts are needed to verify our findings.

Cerebral Autoregulation and Neurovascular Coupling after Craniospinal Irradiation in Long-Term Survivors of Malignant Pediatric Brain Tumors of the Posterior Fossa.

INTRODUCTION: Long-term survivors of craniospinal irradiation have an increased risk for stroke which increases with radiation dose and follow-up time. Radiotherapy induces structural changes of the cerebral vasculature, affecting both, large, and small vessels. It is unknown how these structural changes affect functional mechanisms of cerebral blood flow regulation such as cerebral autoregulation and neurovascular coupling. METHODS: Using the transcranial Doppler, we compared dynamic cerebral autoregulation and neurovascular coupling of 12 patients after long-term survival of craniospinal irradiation due to a malignant pediatric brain tumor of the posterior fossa and 12 age- and sex-matched healthy patients. Mean arterial blood pressure and cerebral blood flow velocities in the middle and posterior cerebral artery were recorded at rest during normal breathing to assess cerebral autoregulation (transfer function parameters phase and gain, as well as the correlation coefficient indices Mx, Sx, and Dx), and during 10 cycles of a visual task to assess neurovascular coupling (parameters time delay, natural frequency, gain, attenuation, and rate time). RESULTS: Parameters of cerebral autoregulation showed a consistent trend toward reduced cerebral autoregulation in patients that did not reach statistical significance. Neurovascular coupling was not altered after craniospinal irradiation. CONCLUSION: In this pilot study, we demonstrated a trend toward reduced cerebral autoregulation, and no alteration of neurovascular coupling after irradiation in long-term survivors of malignant pediatric brain tumors of the posterior fossa.

Treatment patterns and outcomes for cerebellar glioblastoma in the concomitant chemoradiation era: A National Cancer database study.

Cerebellar glioblastoma (GB) is much rarer than its supratentorial counterpart, and potentially of different molecular origin. Prior database studies are of limited size and reported on patients who preceded the validation of temozolomide. Thus, we provide an updated population-based analysis of the treatment trends and outcomes since the standardization of GB adjuvant chemoradiation. Patients diagnosed with primary cerebellar and supratentorial GB were identified from the National Cancer Database spanning 2005-2015. Patients were characterized by demographics, extent of resection, and adjuvant chemotherapy or radiation status. Cohorts were primarily and secondarily assessed for overall survival by tumor site and treatment history, respectively. A total of 655 patients with cerebellar GB were identified (0.6%). Cerebellar GB patients, compared to supratentorial GB were more likely to undergo a biopsy or subtotal resection (13.4% vs 9.3% and 16.0% vs 13.4%, p-value < 0.001), and less likely to pursue adjuvant therapy (48.4% vs 52.7%, p-value < 0.001). Overall median survivals were 9.3 and 9.4 months, respectively. On multivariable analysis, gross total resection, radiation, and chemotherapy were found to be predictors of improved overall survival (HR 0.77, p = 0.038; HR 0.67, p < 0.001; and HR = 0.77, p = 0.030, respectively). While many management principles are currently shared between cerebellar and supratentorial GB, aggressive regimens appear less frequently prescribed. Survival continues to match supratentorial outcomes and may benefit from future, systemic guidance by distinguishing molecular features.

Estimating brain volume loss after radiation therapy in children treated for posterior fossa tumors (Corpus callosum and whole brain volume changes following radiotherapy in children).

BACKGROUND: More than half of pediatric tumors of central nervous system (CNS) primarily originate in the posterior fossa and are conventionally treated with radiation therapy (RT). OBJECTIVES: The objective of this study was to establish whether corpus callosum volumes (CCV) and whole brain volumes (WBV) are correlated and to determine the impact of whole-brain lowvs high-dose RT on brain parenchymal volume loss as assessed using each technique. MATERIAL AND METHODS: Of the 30 identified children (6-12 years) with newly diagnosed posterior fossa tumors treated with cranial RT, including focal and whole-brain RT, suitable imaging was obtained for 23. Radiotherapy regimens were the following: no whole-brain RT (Group 1, n = 7), low-dose whole-brain RT (<30 Gy, Group 2, n = 9) and high-dose whole-brain RT (>30 Gy, Group 3, n = 7) in addition to focal boost. Magnetic resonance images (MRIs) were analyzed at baseline and follow-up (median 14 months). The CCVs were manually segmented on midline sagittal slice (n = 23), while WBVs were segmented semi-automatically using Freesurfer (n = 15). This was done twice (6-month interval) for all baseline CCV measurements and 5 randomly selected WBV measurements to establish measurement reproducibility. Correlations between CCV and WBV were investigated and percentage of children demonstrating reduction in CCV or WBV noted. RESULTS: Correlation between baseline CCV and WBV was not significant (p = 0.37). Measurement reproducibility was from 6% to -9% for CCV and from 4.8% to -1.2% for WBV. Among the children studied, 30.4% (7/23) had >9% reduction in CCV at follow-up, while 33.3% (5/15) had >1.2% reduction in WBV. Five of 7 patients with CCV loss were not picked up by WBV measurements. Similarly, 3 of 5 patients with WBV loss were not picked up by CCV measurements. CONCLUSIONS: The CCV and the WBV are unrelated and may indicate different brain parenchymal losses following RT. Up to a third of posterior fossa tumors treated with RT have measurable CCV or WBV loss; incidence was equivalent in lowvs high-dose whole-brain RT.

Brainstem Injury in Pediatric Patients Receiving Posterior Fossa Photon Radiation.

PURPOSE: Brainstem necrosis is a rare, but dreaded complication of radiation therapy; however, data on the incidence of brainstem injury for tumors involving the posterior fossa in photon-treated patient cohorts are still needed. METHODS AND MATERIALS: Clinical characteristics and dosimetric parameters were recorded for 107 pediatric patients who received photon radiation for posterior fossa tumors without brainstem involvement from 2000 to 2016. Patients were excluded if they received a prescription dose <50.4 Gy, a brainstem maximum dose <50.4 Gy, or had fewer than 2 magnetic resonance imaging scans within 18 months after radiation. Post-radiation therapy magnetic resonance imaging findings were recorded, and brainstem toxicity was graded using National Cancer Institute Common Terminology Criteria for Adverse Events, version 5. RESULTS: The most common histologies were medulloblastoma (61.7%) and ependymoma (15.9%), and median age at diagnosis was 8.3 years (range, 0.8-20.7). Sixty-seven patients (62.6%) received craniospinal irradiation (median, 23.4 Gy; range, 18.0-39.6) as a component of their radiation therapy, and 39.3% and 40.2% of patients received an additional involved field or whole posterior fossa boost, respectively. Median prescribed dose was 55.8 Gy (range, 50.4-60.0). Median clinical and imaging follow-up were 4.7 years (range, 0.1-17.5) and 4.2 years (range, 0.1-17.3), respectively. No grade ≥2 toxicities were observed. The incidence of grade 1 brainstem necrosis was 1.9% (2 of 107). These patients were by definition asymptomatic and experienced resolution of imaging abnormality after 5.3 months and 2.1 years, respectively. CONCLUSIONS: Risk of brainstem necrosis was minimal in this multi-institutional study of pediatric patients treated with photon radiation therapy for tumors involving the posterior fossa with no cases of symptomatic brainstem injury, suggesting that brainstem injury risk is minimal in patients treated with photon therapy.

Radiation doses to brain substructures associated with cognition in radiotherapy of pediatric brain tumors.

Background: Several brain substructures associated with cognition (BSCs) are located close to typical pediatric brain tumors. Pediatric patients therefore have considerable risks of neurocognitive impairment after brain radiotherapy. In this study, we investigated the radiation doses received by BSCs for three common locations of pediatric brain tumor entities. Material and methods: For ten patients in each group [posterior fossa ependymoma (PFE), craniopharyngioma (CP), and hemispheric ependymoma (HE)], the cumulative fraction of BSCs volumes receiving various dose levels were analyzed. We subsequently explored the differences in dose pattern between the three groups and used available dose response models from the literature to estimate treatment-induced intelligence quotient (IQ) decline. Results: Doses to BSCs were found to differ considerably between the groups, depending on their position relative to the tumor. Large inter-patient variations were observed in the ipsilateral structures of the HE groups, and at low doses for all three groups. IQ decline estimates differed depending on the model applied, presenting larger variations in the HE group. Conclusion: While there were notable differences in the dose patterns between the groups, the extent of estimated IQ decline depended more on the model applied. This inter-model variability should be considered in dose-effect assessments on cognitive outcomes of pediatric patients.

The Effects of Radiation and Sex Differences on Adaptive Functioning in Adult Survivors of Pediatric Posterior Fossa Brain Tumors.

OBJECTIVE: Radiation therapy (RT) improves rates of survival of patients with childhood brain tumors but increases deficits in cognition and independent living skills. Previous literature has studied difficulties in basic cognitive processes, but few explore impairment in higher-order skills such as adaptive functioning. Some studies identify females as at risk for cognitive deficits due to RT, but few investigate sex differences in adaptive functioning. It was hypothesized that females would exhibit poorer long-term independent living skills and core cognitive skills relative to males following RT. METHODS: Forty-five adult survivors of posterior fossa childhood brain tumors (24 females) completed the Wechsler Abbreviated Scale of Intelligence (WASI-II), Wechsler Memory Scale, Third Edition (WMS-III) Digit Span Forward (DSF) and Backward (DSB), and Oral Symbol Digit Modalities Test (OSDMT). Informants completed the Scales of Independent Behavior-Revised (SIB-R). RESULTS: DSF and OSDMT were positively correlated with all five SIB-R domains, full-scale IQ (FSIQ) was positively correlated with four SIB-R domains, and DSB was positively correlated with three SIB-R domains. There was an interaction between sex and RT for OSDMT and community living skills with trend level interactions for personal living skills and broad independent living skills, where females without RT had higher scores than females with RT. CONCLUSIONS: Female survivors were more affected by RT than males across the community living skills domain of adaptive functioning as well as processing speed. Processing speed deficits may have a cascading impact on daily living skills. Future studies should investigate how clinical and biological factors may contribute to personalized treatment plans between sexes. (JINS, 2019, 25, 729-739).

Differential trajectories of neurocognitive functioning in females versus males following treatment for pediatric brain tumors.

BACKGROUND: Female and male trajectories of cerebellar and lobar brain structures are sexually dimorphic, making sex a potential candidate moderator of neurocognitive late effects from radiation treatment. We sought to evaluate longitudinal neurocognitive functioning in male versus female children treated for posterior fossa brain tumors. METHODS: Fifty-one female and 63 male survivors of posterior fossa tumors completed neuropsychological testing at 2 timepoints. We included patients treated with surgical resection, chemotherapy, and radiation therapy. Multilevel mixed modeling was used to predict IQ score as a function of patient sex following treatment (~2 or ~4 years post treatment). Effect sizes were used as a measure of clinical significance. RESULTS: Multilevel models resulted in a significant sex by time interaction (F = 6.69, P = 0.011). Females' cognitive scores were considerably higher compared with males at 4 years posttreatment. Females demonstrated an average improvement of 7.61 standard score IQ points compared with a decline of 2.97 points for males at 4 years follow-up. Effect sizes for female IQ compared with male IQ at 4 years posttreatment were between 0.8 and 0.9. CONCLUSION: Trajectories of neurocognitive functioning following posterior fossa tumor treatment differed between female and male children. Sexual dimorphism in radiation late effects may alter treatment decisions in children. Research into sex-specific neuroprotective mechanisms underlying neurocognitive development following pediatric brain tumor treatments is warranted.

Multifocal Infratentorial Pilocytic Astrocytoma in an Adult Patient.

BACKGROUND: Pilocytic astrocytoma is a benign glial tumor typically presenting in children. It is rare for adults to present with pilocytic astrocytoma and even less likely to manifest with multiple foci of lesions especially in nonoptic or hypothalamic locations. CASE DESCRIPTION: Our patient was a 37-year old man presenting with varied cranial neuropathies, cerebellar dysfunction, and long tract signs, with imaging demonstrating 3 discrete ill-defined contrast-enhancing lesions affecting the cerebellar peduncles, brainstem, and cervicomedullary junction. Neuronavigation-guided biopsy confirmed World Health Organization grade 1 pilocytic astrocytoma; the patient was treated with radiotherapy. CONCLUSIONS: To our knowledge, we believe this is the first reported case with multifocal infratentorial pilocytic astrocytoma on presentation in an adult patient in the absence of a prior history of associated risk factors such as neurofibromatosis 1 or chemoradiotherapeutic intervention.

Posterior fossa astroblastoma in a child: a case report and a review of the literature.

A 4-year-old girl presented to the hospital with a progressive headache, difficulty walking, and persistent daily vomiting for 3 weeks. Papilledema was observed on fundoscopic examination. A large left cerebellovermian tumor with "bubbly" appearance was discovered. Total removal of the tumor mass was performed, and a diagnosis of low-grade astroblastoma was made. Adjuvant radiotherapy was performed due to the risk of recurrence. The patient is disease-free and has been kept on close follow-up for 6 months. The occurrence of posterior fossa astroblastoma has been rarely reported in the literature. Thus, when a "bubby" appearance enhancing cystic solid tumor is located on the cerebellar hemisphere in a child, an astroblastoma should also be included in the differential diagnosis.

Single fraction stereotactic radiation therapy (stereotactic radiosurgery) is a feasible method for treating intracranial meningiomas in dogs.

The aim of this retrospective, pilot study was to evaluate stereotactic radiosurgery as a method for treating intracranial meningiomas in dogs. Included dogs had an imaging diagnosis of presumed intracranial meningioma, were treated using a standardized stereotactic radiosurgery protocol, and had a follow-up time of >6 months after stereotactic radiosurgery. A single fraction of 16 Gy stereotactic radiosurgery was delivered to the tumor, with an internal simultaneously integrated boost to a total dose of 20-24 Gy to the central portion of the tumor. Thirty-two dogs were sampled. One dog was euthanized in the periprocedural period, and 10 of the remaining 31 dogs (31%) experienced an acute adverse event (defined as declining neurologic function due to tumor progression or treatment-associated complication within the first 6 months after stereotactic radiosurgery), three of which were fatal. Too few subjects (n = 6) had cross-sectional imaging after stereotactic radiosurgery to determine an objective response rate; however, 17/30 (57%) dogs assessed for response had a perceived clinical benefit from treatment. The overall median survival time was 519 days (95% confidence interval: 330-708 days); 64% and 24% of dogs were alive at 1 and 2 years after stereotactic radiosurgery, respectively. Dogs with infratentorial tumor location and high gradient indices had shorter survival. There were no factors identified which were predictive of acute adverse event. Survival times reported herein are similar to what has previously been reported for other stereotactic and traditional fractionated radiotherapy protocols. Findings therefore supported the use of stereotactic radiosurgery as an alternative method for treating dogs with presumed intracranial meningiomas.

National Cancer Institute Workshop on Proton Therapy for Children: Considerations Regarding Brainstem Injury.

PURPOSE: Proton therapy can allow for superior avoidance of normal tissues. A widespread consensus has been reached that proton therapy should be used for patients with curable pediatric brain tumor to avoid critical central nervous system structures. Brainstem necrosis is a potentially devastating, but rare, complication of radiation. Recent reports of brainstem necrosis after proton therapy have raised concerns over the potential biological differences among radiation modalities. We have summarized findings from the National Cancer Institute Workshop on Proton Therapy for Children convened in May 2016 to examine brainstem injury. METHODS AND MATERIALS: Twenty-seven physicians, physicists, and researchers from 17 institutions with expertise met to discuss this issue. The definition of brainstem injury, imaging of this entity, clinical experience with photons and photons, and potential biological differences among these radiation modalities were thoroughly discussed and reviewed. The 3 largest US pediatric proton therapy centers collectively summarized the incidence of symptomatic brainstem injury and physics details (planning, dosimetry, delivery) for 671 children with focal posterior fossa tumors treated with protons from 2006 to 2016. RESULTS: The average rate of symptomatic brainstem toxicity from the 3 largest US pediatric proton centers was 2.38%. The actuarial rate of grade ≥2 brainstem toxicity was successfully reduced from 12.7% to 0% at 1 center after adopting modified radiation guidelines. Guidelines for treatment planning and current consensus brainstem constraints for proton therapy are presented. The current knowledge regarding linear energy transfer (LET) and its relationship to relative biological effectiveness (RBE) are defined. We review the current state of LET-based planning. CONCLUSIONS: Brainstem injury is a rare complication of radiation therapy for both photons and protons. Substantial dosimetric data have been collected for brainstem injury after proton therapy, and established guidelines to allow for safe delivery of proton radiation have been defined. Increased capability exists to incorporate LET optimization; however, further research is needed to fully explore the capabilities of LET- and RBE-based planning.

Brainstem Injury in Pediatric Patients With Posterior Fossa Tumors Treated With Proton Beam Therapy and Associated Dosimetric Factors.

PURPOSE: Proton radiation therapy is commonly used in young children with brain tumors for its potential to reduce late effects. However, some proton series report higher rates of brainstem injury (0%-16%) than most photon series (2.2%-8.6%). We report the incidence of brainstem injury and a risk factor analysis in pediatric patients with posterior fossa primary tumors treated with proton radiation therapy at our institution. METHODS AND MATERIALS: The study included 216 consecutive patients treated between 2000 and 2015. Dosimetry was available for all but 4 patients. Grade 2 to 5 late brainstem toxicity was assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. RESULTS: The histologies include medulloblastoma (n=154, 71.3%), ependymoma (n=56, 25.9%), and atypical teratoid rhabdoid tumor (n=6, 2.8%). The median age at irradiation was 6.6 years (range, 0.5-23.1 years); median dose, 54 gray relative biological effectiveness (Gy RBE) (range, 46.8-59.4 Gy RBE); and median follow-up period, 4.2 years (range, 0.1-15.3 years) among 198 survivors. Of the patients, 83.3% received chemotherapy; 70.4% achieved gross total resection. The crude rate of injury was 2.3% in all patients, 1.9% in those with medulloblastoma, 3.6% in those with ependymoma, and 0% in those with atypical teratoid rhabdoid tumor. The 5-year cumulative incidence of injury was 2.0% (95% confidence interval, 0.7%-4.8%). The median brainstem dose (minimum dose received by 50% of brainstem) in the whole cohort was 53.6 Gy RBE (range, 16.5-56.8 Gy RBE); maximum point dose within the brainstem (Dmax), 55.2 Gy RBE (range, 48.4-60.5 Gy RBE); and mean dose, 50.4 Gy RBE (range, 21.1-56.7 Gy RBE). In the 5 patients with injury, the median minimum dose received by 50% of the brainstem was 54.6 Gy RBE (range, 50.2-55.1 Gy RBE); Dmax, 56.2 Gy RBE (range, 55.0-57.1 Gy RBE); mean dose, 51.3 Gy RBE (range, 45.4-54.4 Gy RBE); and median volume of the brainstem receiving ≥55 Gy RBE (V55), 27.4% (range, 0%-59.4%). Of the 5 patients with injury, 4 had a brainstem Dmax in the highest quartile (≥55.8 Gy RBE, P = .016) and a V55 in the highest tertile (>6.0%) of the cohort distribution (P = .047). Of the 5 patients with injury, 3 were aged >6 years (age range, 4.1-22.8 years), and 4 of 5 patients received chemotherapy and achieved gross total resection. CONCLUSIONS: The incidence of injury in pediatric patients with posterior fossa tumors is consistent with previous reports in the photon setting. Our data suggest that when Dmax and V55 are kept <55.8 Gy RBE and ≤6.0%, respectively, the 5-year rate of radiation brainstem injury would be <2%.

Impact of radiation therapy and extent of resection for ependymoma in young children: A population-based study.

BACKGROUND: Young children with posterior fossa ependymoma (PF-EPN) have a worse prognosis than older children, and they have a unique molecular profile (PF-EPN-A subtype). Alternative treatment strategies are often used in these young patients, and their prognostic factors are less clear. METHODS: We characterized the prognostic factors and treatment outcomes of 482 patients between ages 0 and 3 years with the diagnosis of ependymoma identified from the Surveillance, Epidemiology, and End Results registry (1973-2013). RESULTS: Radiation therapy (RT) was delivered to 52.3% of patients, and gross total resection (GTR) was performed in 51.0% of patients. Overall survival (OS) at 10 years was 48.4% with median follow-up of 3.3 years. WHO grade was not predictive of OS. Extent of resection was significant for survival; the 10-year OS with GTR was 61.0%, and with subtotal resection (STR) and biopsy was 38.2% and 35.0%, respectively (P < 0.001). RT significantly benefitted OS for both grades II and III. The 10-year OS for grade II was 50.5% with RT and 43.4% without (P = 0.030); 10-year OS for grade III was 66.0% with RT and 40.0% without (P = 0.002). Multivariate analysis showed significantly improved OS with RT (hazard ratio [HR] 0.601, 95% CI: 0.439-0.820, P = 0.001) and GTR (HR 0.471, 95% CI: 0.328-0.677, P < 0.0001). CONCLUSIONS: Ependymoma outcomes in patients within 0-3 years of age significantly improved with RT and GTR. Histopathologic grading of ependymoma demonstrated no prognostic significance. Given the poor OS for this population and unique genetic profile, future prospective studies with molecular-based stratification should be performed to evaluate additional prognostic factors.