The Pediatric Proton and Photon Therapy Comparison Cohort: Study Design for a Multicenter Retrospective Cohort to Investigate Subsequent Cancers After Pediatric Radiation Therapy.

Purpose: The physical properties of protons lower doses to surrounding normal tissues compared with photons, potentially reducing acute and long-term adverse effects, including subsequent cancers. The magnitude of benefit is uncertain, however, and currently based largely on modeling studies. Despite the paucity of directly comparative data, the number of proton centers and patients are expanding exponentially. Direct studies of the potential risks and benefits are needed in children, who have the highest risk of radiation-related subsequent cancers. The Pediatric Proton and Photon Therapy Comparison Cohort aims to meet this need. Methods and Materials: We are developing a record-linkage cohort of 10,000 proton and 10,000 photon therapy patients treated from 2007 to 2022 in the United States and Canada for pediatric central nervous system tumors, sarcomas, Hodgkin lymphoma, or neuroblastoma, the pediatric tumors most frequently treated with protons. Exposure assessment will be based on state-of-the-art dosimetry facilitated by collection of electronic radiation records for all eligible patients. Subsequent cancers and mortality will be ascertained by linkage to state and provincial cancer registries in the United States and Canada, respectively. The primary analysis will examine subsequent cancer risk after proton therapy compared with photon therapy, adjusting for potential confounders and accounting for competing risks. Results: For the primary aim comparing overall subsequent cancer rates between proton and photon therapy, we estimated that with 10,000 patients in each treatment group there would be 80% power to detect a relative risk of 0.8 assuming a cumulative incidence of subsequent cancers of 2.5% by 15 years after diagnosis. To date, 9 institutions have joined the cohort and initiated data collection; additional centers will be added in the coming year(s). Conclusions: Our findings will affect clinical practice for pediatric patients with cancer by providing the first large-scale systematic comparison of the risk of subsequent cancers from proton compared with photon therapy.

Modeling the Risk of Hearing Loss From Radiation Therapy in Childhood Cancer Survivors: A PENTEC Comprehensive Review.

PURPOSE: The Pediatric Normal Tissue Effects in the Clinic (PENTEC) hearing loss (HL) task force reviewed investigations on cochlear radiation dose-response relationships and risk factors for developing HL. Evidence-based dose-response data are quantified to guide treatment planning. METHODS AND MATERIALS: A systematic review of the literature was performed to correlate HL with cochlear dosimetry. HL was considered present if a threshold exceeded 20 dB at any frequency. Radiation dose, ototoxic chemotherapy exposure, hearing profile including frequency spectra, interval to HL, and age at radiation therapy (RT) were analyzed. RESULTS: Literature was systematically reviewed from 1970 to 2021. This resulted in 739 abstracts; 19 met inclusion for meta-analysis, and 4 included data amenable to statistical modeling. These 4 studies included 457 cochleas at risk in patients treated with RT without chemotherapy, and 398 cochlea treated with chemotherapy. The incidence and severity of cochlear HL from RT exposure alone is related to dose and age. Risk of HL was <5% in cochlea receiving a mean dose ≤35 Gy but increased to 30% at 50 Gy. HL risk ranged from 25% to 40% in children under the age of 5 years at diagnosis, declining to 10% in older children for any radiation dose. Probability of similar severe HL occurred at doses 18.3 Gy higher for children <3 versus >3 years of age. High-frequency HL was most common, with average onset occurring 3.6 years (range, 0.4-13.2 years) after RT. Exposure to platinum-based chemotherapies added to the rates of HL at a given cochlear dose level, with 300 mg/m2 shifting the dose response by 7 Gy. CONCLUSIONS: In children treated with RT alone, risk of HL was low for cochlear dose <35 Gy and rose when dose exceeded 35 Gy without clear RT dose dependence. High-frequency HL was most prevalent, but all frequencies were affected. Children younger than 5 years were at highest risk of developing HL, although independent effects of dose and age were not fully elucidated. Future reports with more granular data are needed to better delineate time to onset of HL and the effects of chemoradiotherapy.

Multi-institutional Characterization of Outcomes for Pediatric and Young Adult Patients With High-Risk Myxopapillary Ependymoma After Radiation Therapy.

PURPOSE: Myxopapillary ependymoma (MPE) is a rare, typically slow-growing subtype of spinal ependymomas. There are no standard guidelines for radiotherapy and long-term outcomes after radiation, particularly patterns of relapse, for pediatric and young adult (YA) patients with MPE remain under-characterized. METHODS AND MATERIALS: This is an Institutional Review Board-approved multi-institutional retrospective cohort study of 60 pediatric and YA patients diagnosed with MPE and received radiotherapy between 2000-2020. Clinical and treatment characteristics, and long-term outcomes were recorded. Site(s) of progression was compared to radiation fields. Survival outcomes were analyzed using Kaplan-Meier method. Cumulative incidence of local in-field progression (CILP) after initial radiotherapy was analyzed using Gray's method with out-of-field-only progression as a competing risk. Univariate analyses were performed using Cox proportional hazard's model. RESULTS: The median age at radiation was 14.8 years (range: 7.1-26.5). At time of radiotherapy, 45 (75.0%) and 35 (58.3%) patients had gross residual and multifocal disease, respectively. Forty-eight (80.0%), seven (11.7%) and five (8.3%) patients received involved field radiotherapy, craniospinal irradiation, and whole spine radiation, respectively. Median follow-up from end of radiotherapy was 6.2 years (range: 0.6-21.0). Five-year overall survival, progression-free survival, and CILP were 100%, 60.8% and 4.1%, respectively. Both local recurrences were at sites of gross residual disease. Of the eighteen out-of-field first recurrences after radiotherapy, all were superior to the initial treatment field and nine had intracranial relapse. On univariate analyses, distant-only recurrence before radiation (HR: 4.00, 95% CI: 1.54-10.43, p = 0.005) was significantly associated with shorter time to progression. CONCLUSIONS: While the risk of recurrence within the radiation field is low, pediatric and YA patients with high-risk MPE remain at risk for recurrences in the spine above the radiation field and intracranially after radiotherapy. Future prospective studies are needed to investigate the appropriate radiation field and dose based on the extent of metastases.

Minimum data elements for the Australian Particle Therapy Clinical Quality Registry.

INTRODUCTION: Construction of the first Australian particle therapy (PT) centre is underway. Establishment of a national registry, to be known as the Australian Particle Therapy Clinical Quality Registry (ASPIRE), has been identified as a mandatory requirement for PT treatment to be reimbursed by the Australian Medicare Benefits Schedule. This study aimed to determine a consensus set of Minimum Data Elements (MDEs) for ASPIRE. METHODS: A modified Delphi and expert consensus process was completed. Stage 1 compiled currently operational English-language international PT registries. Stage 2 listed the MDEs included in each of these four registries. Those included in three or four registries were automatically included as a potential MDE for ASPIRE. Stage 3 interrogated the remaining data items, and involved three rounds - an online survey to a panel of experts, followed by a live poll session of PT-interested participants, and finally a virtual discussion forum of the original expert panel. RESULTS: One hundred and twenty-three different MDEs were identified across the four international registries. The multi-staged Delphi and expert consensus process resulted in a total of 27 essential MDEs for ASPIRE; 14 patient factors, four tumour factors and nine treatment factors. CONCLUSIONS: The MDEs provide the core mandatory data items for the national PT registry. Registry data collection for PT is paramount in the ongoing global effort to accumulate more robust clinical evidence regarding PT patient and tumour outcomes, quantifying the magnitude of clinical benefit and justifying the relatively higher costs of PT investment.

Radiotherapy-Induced Neurocognitive Impairment Is Driven by Heightened Apoptotic Priming in Early Life and Prevented by Blocking BAX.

Although external beam radiotherapy (xRT) is commonly used to treat central nervous system (CNS) tumors in patients of all ages, young children treated with xRT frequently experience life-altering and dose-limiting neurocognitive impairment (NI) while adults do not. The lack of understanding of mechanisms responsible for these differences has impeded the development of neuroprotective treatments. Using a newly developed mouse model of xRT-induced NI, we found that neurocognitive function is impaired by ionizing radiation in a dose- and age-dependent manner, with the youngest animals being most affected. Histologic analysis revealed xRT-driven neuronal degeneration and cell death in neurogenic brain regions in young animals but not adults. BH3 profiling showed that neural stem and progenitor cells, neurons, and astrocytes in young mice are highly primed for apoptosis, rendering them hypersensitive to genotoxic damage. Analysis of single-cell RNA sequencing data revealed that neural cell vulnerability stems from heightened expression of proapoptotic genes including BAX, which is associated with developmental and mitogenic signaling by MYC. xRT induced apoptosis in primed neural cells by triggering a p53- and PUMA-initiated, proapoptotic feedback loop requiring cleavage of BID and culminating in BAX oligomerization and caspase activation. Notably, loss of BAX protected against apoptosis induced by proapoptotic signaling in vitro and prevented xRT-induced apoptosis in neural cells in vivo as well as neurocognitive sequelae. On the basis of these findings, preventing xRT-induced apoptosis specifically in immature neural cells by blocking BAX, BIM, or BID via direct or upstream mechanisms is expected to ameliorate NI in pediatric patients with CNS tumor. SIGNIFICANCE: Age- and differentiation-dependent apoptotic priming plays a pivotal role in driving radiotherapy-induced neurocognitive impairment and can be targeted for neuroprotection in pediatric patients.

Radiotherapy for Atypical Teratoid/Rhabdoid Tumor (ATRT) on the Pediatric Proton/Photon Consortium Registry (PPCR).

PURPOSE: Atypical teratoid/rhabdoid tumors (ATRT) of the central nervous system (CNS) are rare tumors with a poor prognosis and variable use of either focal or craniospinal (CSI) radiotherapy (RT). Outcomes on the prospective Pediatric Proton/Photon Consortium Registry (PPCR) were evaluated according to RT delivered. METHODS: Pediatric patients receiving RT were prospectively enrolled on PPCR to collect initial patient, disease, and treatment factors as well as provide follow-up for patient outcomes. All ATRT patients with evaluable data were included. Kaplan-Meier analyses with log-rank p-values and cox proportional hazards regression were performed. RESULTS: The PPCR ATRT cohort includes 68 evaluable ATRT patients (median age 2.6 years, range 0.71-15.40) from 2012 to 2021. Median follow-up was 40.8 months (range 3.4-107.7). Treatment included surgery (65% initial gross total resection or GTR), chemotherapy (60% with myeloablative therapy including stem cell rescue) and RT. For patients with M0 stage (n = 60), 50 (83%) had focal RT and 10 (17%) had CSI. Among patients with M + stage (n = 8), 3 had focal RT and 5 had CSI. Four-year overall survival (OS, n = 68) was 56% with no differences observed between M0 and M + stage patients (p = 0.848). Local Control (LC) at 4 years did not show a difference for lower primary dose (50-53.9 Gy) compared to ≥ 54 Gy (73.3% vs 74.7%, p = 0.83). For patients with M0 disease, four-year OS for focal RT was 54.6% and for CSI was 60% (Hazard Ratio 1.04, p = 0.95. Four-year event free survival (EFS) among M0 patients for focal RT was 45.6% and for CSI was 60% (Hazard Ratio 0.71, p = 0.519). For all patients, the 4-year OS comparing focal RT with CSI was 54.4% vs 60% respectively (p = 0.944), and the 4-year EFS for focal RT or CSI was 42.8% vs 51.4% respectively (p = 0.610). CONCLUSION: The PPCR ATRT cohort found no differences in outcomes according to receipt of either higher primary dose or larger RT field (CSI). However, most patients were M0 and received focal RT. A lower primary dose (50.4 Gy), regardless of patient age, is appealing for further study as part of multi-modality therapy.

Patterns of failure in pediatric medulloblastoma and implications for hippocampal sparing.

BACKGROUND: Hippocampal avoidance (HA) has been shown to preserve cognitive function in adult patients with cancer treated with whole-brain radiation therapy for brain metastases. However, the feasibility of HA in pediatric patients with brain tumors has not been explored because of concerns of increased risk of relapse in the peri-hippocampal region. Our aim was to determine patterns of recurrence and incidence of peri-hippocampal relapse in pediatric patients with medulloblastoma (MB). METHODS AND MATERIALS: We identified pediatric patients with MB treated with protons between 2002 and 2016 and who had recurrent disease. To estimate the risk of peri-hippocampal recurrence, three hippocampal zones (HZs) were delineated corresponding to ≤5 mm (HZ-1), 6 to 10 mm (HZ-2), and >10 mm (HZ-3) distance of the recurrence from the contoured hippocampi. To determine the feasibility of HA, three standard-risk patients with MB were planned using either volumetric-modulated arc therapy (VMAT) or intensity-modulated proton therapy (IMPT) plans. RESULTS: Thirty-eight patients developed a recurrence at a median of 1.6 years. Of the 25 patients who had magnetic resonance imaging of the recurrence, no patients failed within the hippocampus and only two patients failed within HZ-1. The crude incidence of peri-hippocampal failure was 8%. Both HA-VMAT and HA-IMPT plans were associated with significantly reduced mean dose to the hippocampi (p < .05). HA-VMAT and HA-IMPT plans were associated with decreased percentage of the third and lateral ventricles receiving the prescription craniospinal dose of 23.4 Gy. CONCLUSIONS: Peri-hippocampal failures are uncommon in pediatric patients with MB. Hippocampal avoidance should be evaluated in a prospective cohort of pediatric patients with MB. PLAIN LANGUAGE SUMMARY: In this study, the patterns of disease recurrence in patients with a pediatric brain tumor known as medulloblastoma treated with proton radiotherapy were examined. The majority of failures occur outside of an important structure related to memory formation called the hippocampus. Hippocampal sparing radiation plans using proton radiotherapy were generated and showed that dose to the hippocampus was able to be significantly reduced. The study provides the rationale to explore hippocampal sparing in pediatric medulloblastoma in a prospective clinical trial.

Effects of Proton Craniospinal Radiation on Vertebral Body Growth Retardation in Children.

PURPOSE: It is of great interest to physicians and patients/patients' families to be able to predict the amount of growth decrement after craniospinal irradiation (CSI). Little data exist on the effect of proton CSI. Our aim was to determine the effect of proton CSI on vertebral body (VB) growth retardation, and to identify factors associated with growth delay. METHODS AND MATERIALS: We performed a retrospective outcome data analysis of 80 patients <16 years old with central nervous system tumors who received proton radiation therapy (PRT) at the Massachusetts General Hospital between 2002 and 2010 with available spinal magnetic resonance imaging. Forty-eight patients received CSI, and 32 patients with brain tumors who received focal cranial irradiation served as controls. VB height was measured midline using sagittal T1-weighted contrast or noncontrast enhanced magnetic resonance imaging of the spine. Measurements were repeated at multiple levels (C3, C3-C4, T4, T4-T5, C3-T6, T4-T7, L3, L1-L5) on available scans for the duration of follow-up. Data were fitted using a mixed-effects multivariable regression model, including follow-up time, CSI dose, age at CSI, and pretreatment VB percentile as parameters. RESULTS: Median follow-up was 69.6 months for patients treated with proton CSI and 52.9 months for the control group. There was a significant association of CSI dose, follow-up time, age at treatment, and pretreatment VB percentile with VB growth retardation. Growth retardation was shown to be independent of gender or growth hormone deficiency. CONCLUSIONS: Although the current practice of PRT CSI delivery allows for sparing of the organs anterior to the spine, the vertebral column receives radiation therapy because of its close proximity to the targeted spinal canal. In growing children, the whole VB has generally been included so that growth impairment is even across the VB. We present a quantitative model predicting the growth retardation of patients treated with PRT CSI based on age at treatment, CSI dose, follow-up time, and pretreatment growth percentile.

Delphi Panel Consensus Recommendations for Screening and Managing Childhood Cancer Survivors at Risk for Cardiomyopathy.

Background: Cardiomyopathy is a leading cause of late morbidity and mortality in childhood cancer survivors (CCS). Evidence-based guidelines recommend risk-stratified screening for cardiomyopathy, but the management approach for abnormalities detected when screening asymptomatic young adult CCS is poorly defined. Objectives: The aims of this study were to build upon existing guidelines by describing the expert consensus-based cardiomyopathy screening practices, management approach, and clinical rationale for the management of young adult CCS with screening-detected abnormalities and to identify areas of controversy in practice. Methods: A multispecialty Delphi panel of 40 physicians with expertise in cancer survivorship completed 3 iterative rounds of semi-open-ended questionnaires regarding their approaches to the management of asymptomatic young adult CCS at risk for cardiomyopathy (screening practices, referrals, cardiac testing, laboratory studies, medications). Consensus was defined as ≥90% panelist agreement with recommendation. Results: The response rate was 100% for all 3 rounds. Panelists reached consensus on the timing and frequency of echocardiographic screening for anthracycline-associated cardiomyopathy, monitoring during pregnancy, laboratory testing for modifiable cardiac risk factors, and referral to cardiology for ejection fraction ≤50% or preserved ejection fraction with diastolic dysfunction. Controversial areas (<75% agreement) included chest radiation dose threshold to merit screening, indications for advanced cardiac imaging and cardiac serum biomarkers for follow-up of abnormal echocardiographic findings, and medical management of asymptomatic left ventricular systolic dysfunction. Conclusions: Expert practice is largely consistent with existing risk-based screening guidelines. Some recommendations for managing abnormalities detected on screening echocardiography remain controversial. The rationale offered by experts for divergent approaches may help guide clinical decisions in the absence of guidelines specific to young adult CCS.

Management of childhood cancer survivors at risk for thyroid function abnormalities: A Delphi study.

BACKGROUND: Thyroid function abnormalities can occur after treatment for childhood cancer. Evidence for the management of thyroid dysfunction among asymptomatic childhood cancer survivors (CCS) is lacking. We used a Delphi consensus methodology to expand guidelines for screening asymptomatic CCS at risk for thyroid dysfunction and explore recommendations for the clinical management of abnormal results. PROCEDURE: A Delphi panel of 40 expert physicians representing oncology, endocrinology, and primary care participated in three rounds of anonymous, iterative questionnaires formatted as clinical scenarios. Consensus is defined as ≥ 90% of panelists agree with recommendation and disagreement as < 70% agree. RESULTS: Panelists reached consensus that CCS treated with radiation including neck, total body, whole brain, brain including the hypothalamic-pituitary axis (HPA), and therapeutic meta-iodobenzylguanidine (MIBG) should have annual, lifelong screening using serum thyroid-stimulating hormone (TSH) and free T4 starting within one year off-treatment (98%). Panelists disagreed on continuing to screen CCS for thyroid dysfunction after immunotherapy associated with acute thyroid injury (31%-50%). There was also disagreement on indications for brain (17%-43%) or thyroid (50%-65%) imaging, laboratory tests to assess the HPA (29%-75%), and TSH threshold to initiate treatment of subclinical hypothyroidism. Lack of evidence was the most frequent rationale panelists offered for not recommending additional testing or medications. Panelists' recommendations did not vary by geography, specialty, or survivorship clinical experience. CONCLUSIONS: Consensus was reached on most recommendations for screening and management of cancer treatment-related thyroid dysfunction. Screening after completion of thyroid-toxic immunotherapy, indications for imaging, and treatment of subclinical hypothyroidism are areas of disagreement for further investigation.

Long-term outcomes and late toxicity of adult medulloblastoma treated with combined modality therapy: A contemporary single-institution experience.

BACKGROUND: Medulloblastoma (MB) is a rare central nervous system malignancy of adults, with limited contemporary studies to define treatment guidelines and expected late toxicity. METHODS: A single-center, retrospective study was conducted of patients age ≥18 years from 1997-2019 with MB and who were treated with postoperative radiotherapy. Late toxicity was defined as a minimum of 18 months from diagnosis. Overall survival (OS) and progression-free survival (PFS) were characterized using Kaplan-Meier and Cox regression analyses. RESULTS: Fifty-nine patients met criteria, with median age of 25 years (range 18-62 y) and median follow-up of 6.5 years (range 0.7-23.1 y). At diagnosis, 68% were standard-risk, 88% Chang M0, and 22% with anaplastic histology. Gross total resection was achieved in 75%; median craniospinal irradiation dose was 30.6 Gy (relative biological effectiveness [RBE]), median total dose was 54.0 Gy (RBE), 80% received proton radiotherapy; 81% received chemotherapy. 5 year PFS and OS were 86.5% and 95.8%, respectively; 10 year PFS and OS were 83.9% and 90.7%, respectively. Anaplastic histology was associated with worse PFS (P = .04). Among eight recurrences, 25% presented after 5 years. Most common grade ≥2 late toxicities were anxiety/depressive symptoms (30%), motor dysfunction (25%), and ototoxicity (22%). Higher posterior fossa radiation dose was associated with increased risk of late toxicity, including worse cognitive dysfunction (P = .05). CONCLUSIONS: Adults with MB have favorable survival outcomes, but late failures and toxicity are not uncommon. Better understanding of prognostic factors, possibly from molecular subtyping, may help to define more personalized treatments for patients with high risk of recurrence and long-term treatment sequelae.

Radiation Necrosis with Proton Therapy in a Patient with Aarskog-Scott Syndrome and Medulloblastoma.

PURPOSE: Medulloblastoma is known to be associated with multiple cancer-predisposition syndromes. In this article, we explore a possible association among a patient's Aarskog-Scott syndrome, development of medulloblastoma, and subsequent brainstem radiation necrosis. CASE PRESENTATION: A 5-year-old male with Aarskog-Scott syndrome initially presented to his pediatrician with morning emesis, gait instability, and truncal weakness. He was ultimately found to have a posterior fossa tumor with pathology consistent with group 3 medulloblastoma. After receiving a gross total resection and standard proton beam radiation therapy with concurrent vincristine, he was noted to develop brainstem radiation necrosis, for which he underwent therapy with high-dose dexamethasone, bevacizumab, and hyperbaric oxygen therapy with radiographic improvement and clinical stabilization. CONCLUSION: Based on several possible pathologic correlates in the FDG1 pathway, there exists a potential association between this patient's Aarskog-Scott syndrome and medulloblastoma, which needs to be investigated further. In patients with underlying, rare genetic syndromes, further caution should be taken when evaluating chemotherapy and radiation dosimetry planning.

Bicentric Treatment Outcomes After Proton Therapy for Nonmyxopapillary High-Grade Spinal Cord Ependymoma in Children.

PURPOSE: Few studies report outcomes in children treated with radiation for nonmyxopapillary ependymoma of the spinal cord, and little evidence exists to inform decisions regarding target volume and prescription dose. Moreover, virtually no mature outcome data exist on proton therapy for this tumor. We describe our combined institutional experience treating pediatric classical/anaplastic ependymoma of the spinal cord with proton therapy. METHODS AND MATERIALS: Between 2008 and 2019, 14 pediatric patients with nonmetastatic nonmyxopapillary grade II (n = 6) and grade III (n = 8) spinal ependymoma received proton therapy. The median age at radiation was 14 years (range, 1.5-18 years). Five tumors arose within the cervical cord, 3 within the thoracic cord, and 6 within the lumbosacral cord. Before radiation therapy, 3 patients underwent subtotal resection, and 11 underwent gross-total or near total resection. Two patients received chemotherapy. For radiation, the clinical target volume received 50.4 Gy (n = 8), 52.2 (n = 1), or 54 Gy (n = 5), with the latter receiving a boost to the gross tumor volume after the initial 50.4 Gy, modified to respect spinal cord tolerance. RESULTS: With a median follow-up of 6.3 years (range, 1.5-14.8 years), no tumors progressed. Although most patients experienced neurologic sequela after surgery, only 1 developed additional neurologic deficits after radiation: An 18-year-old male who received 54 Gy after gross total resection of a lumbosacral tumor developed grade 2 erectile dysfunction. There were 2 cases of musculoskeletal toxicity attributable to surgery and radiation. At analysis, no patient had developed cardiac, pulmonary, or other visceral organ complications or a second malignancy. CONCLUSION: Radiation to a total dose of 50 to 54 Gy can be safely delivered and plays a beneficial role in the multidisciplinary management of children with nonmyxopapillary spinal cord ependymoma. Proton therapy may reduce late radiation effects and is not associated with unexpected spinal cord toxicity.

Decade-long disease, secondary malignancy, and brainstem injury outcomes in pediatric and young adult medulloblastoma patients treated with proton radiotherapy.

BACKGROUND: Survivors of pediatric medulloblastoma experience long-term morbidity associated with the toxic effects of postoperative radiotherapy (RT). Proton RT limits radiation dose to normal tissues thereby reducing side effects of treatment while maintaining high cure rates. However, long-term data on disease outcomes and long-term effects of proton RT remain limited. METHODS: One hundred seventy-eight pediatric medulloblastoma patients treated with proton RT between 2002 and 2016 at the Massachusetts General Hospital comprise the cohort of patients who were treated with surgery, radiation therapy, and chemotherapy. We evaluated event-free survival (EFS), overall survival (OS), and local control using the Kaplan-Meier method. The cumulative incidence of brainstem injury and secondary malignancies was assessed. RESULTS: Median follow-up was 9.3 years. One hundred fifty-nine patients (89.3%) underwent a gross total resection (GTR). The 10-year OS for the entire cohort, standard-risk (SR), and intermediate/high-risk (IR/HR) patients was 79.3%, 86.9%, and 68.9%, respectively. The 10-year EFS for the entire cohort, SR, and IR/HR cohorts was 73.8%, 79.5%, and 66.2%. The 10-year EFS and OS for patients with GTR/NTR were 75.3% and 81.0% vs 57.7% and 61.0% for subtotal resection (STR). On univariate analysis, IR/HR status was associated with inferior EFS, while both anaplastic histology and IR/HR status were associated with worse OS. The 10-year cumulative incidence of secondary tumors and brainstem injury was 5.6% and 2.1%, respectively. CONCLUSIONS: In this cohort study of pediatric medulloblastoma, proton RT was effective, and disease outcomes were comparable to historically treated photon cohorts. The incidence of secondary malignancies and brainstem injury was low in this cohort with mature follow-up.

Factors Associated With Acute Toxicity in Pediatric Patients Treated With Proton Radiation Therapy: A Report From the Pediatric Proton Consortium Registry.

PURPOSE: Limited prospective information regarding acute toxicity in pediatric patients receiving proton therapy (PT) exists. In this study, Pediatric Proton Consortium Registry (PPCR) data was analyzed for factors associated with development of acute toxicity in children receiving passively scattered or pencil beam scanning PT. METHODS AND MATERIALS: Pediatric patients treated with PT and enrolled on the PPCR from 2016 to 2017 at 7 institutions were included. Data were entered on presence versus absence of acute general, cardiac, endocrine, eye, gastrointestinal, genitourinary, hematologic, mouth, musculoskeletal, neurologic, psychological, respiratory, and skin toxicities before (baseline) and at the end of PT (acute). Associations between patient and treatment variables with development of acute toxicity were assessed with multivariable modeling. RESULTS: Of 422 patients included, PT technique was passively scattered in 241 (57%), pencil beam scanning in 180 (43%), and missing in 1 (<1%) patient. Median age was 9.9 years. Daily anesthesia for treatment was used in 169 (40%). Treatments were categorized as craniospinal irradiation (CSI; n = 100, 24%), focal central nervous system PT (n = 157, 38%), or body PT (n = 158, 38%). Passively scattered PT was associated with increased risk of hematologic toxicity compared with pencil beam scanning PT (odds ratio [OR]: 3.03; 95% confidence interval [CI], 1.38-6.70; P = .006). There were no other differences toxicities between PT techniques. Uninsured patients had increased risk of GI (OR: 2.71; 95% CI, 1.12-6.58; P = .027) and hematologic toxicity (OR: 10.67; 95% CI, 2.68-42.46; P <.001). Patients receiving concurrent chemotherapy were more likely to experience skin (OR: 2.45; 95% CI, 1.23-4.88; P = .011), hematologic (OR: 2.87; 95% CI, 1.31-6.25; P = .008), GI (OR: 2.37; 95% CI, 1.33-4.21; P = .003), and mouth toxicities (OR: 2.03; 95% CI, 1.10-3.73; P = .024). Patients receiving 49 to 55 Gy were more likely to experience skin (OR: 2.18; 95% CI, 1.06-4.44; P = .033) toxicity than those receiving <49 Gy. CONCLUSIONS: The PPCR registry highlights broad differences in acute toxicity rates in children receiving PT, and identifies opportunities for improvements in prevention, monitoring, and treatment of toxicities.

Intellectual functioning among case-matched cohorts of children treated with proton or photon radiation for standard-risk medulloblastoma.

BACKGROUND: Proton therapy may reduce cognitive deficits after radiotherapy among brain tumor survivors, although current data are limited to retrospective comparisons between historical cohorts. The authors compared intelligence quotient scores within a case-matched cohort of children with medulloblastoma treated with proton radiation (PRT) or photon radiation (XRT) over the same time period. METHODS: Among 88 consecutive patients with standard-risk medulloblastoma treated with PRT or XRT at 2 institutions from 2000 to 2009, 50 were matched 1:1 (25 with PRT and 25 with XRT) according to age, gender, date of diagnosis, histology, radiation boost, and craniospinal irradiation dose. One-way analyses of variance were performed to compare the Full-Scale Intelligence Quotient (FSIQ) and associated index scores between the 2 cohorts. RESULTS: Neurocognitive data were available for 37 survivors (17 with PRT and 20 with XRT) from the matched cohort. The mean age was 8.5 years (SD, 4.14 years). The median follow-up was 5.3 years (range, 1.0-11.4 years) and 4.6 years (range, 1.1-11.2 years) for the PRT and XRT cohorts, respectively (P = .193). Patients treated with PRT had significantly higher mean FSIQ (99.6 vs 86.2; P = .021), verbal (105.2 vs 88.6; P = .010), and nonverbal scores (103.1 vs 88.9; P = .011) than the XRT-treated cohort. Differences in processing speed (82.9 vs 77.2; P = .331) and working memory (97.0 vs 92.7; P = .388) were not statistically significant. CONCLUSIONS: Radiotherapy-associated cognitive effects appear to be more attenuated after proton therapy. Comprehensive prospective studies are needed to appropriately evaluate the neurocognitive advantages of proton therapy.

Excellent Outcome for Pediatric Patients With High-Risk Hodgkin Lymphoma Treated With Brentuximab Vedotin and Risk-Adapted Residual Node Radiation.

PURPOSE: Brentuximab vedotin, an effective anti-CD30 antibody-drug conjugate approved for use in adults with classical Hodgkin lymphoma (HL), was introduced in this frontline trial to reduce prescribed radiation in children and adolescents with classical HL. METHODS: Open-label, single-arm, multicenter trial for patients (age ≤ 18 years) with stage IIB, IIIB, or IV classical HL was conducted. Brentuximab vedotin replaced each vincristine in the OEPA/COPDac (vincristine, etoposide, prednisone, and doxorubicin/cyclophosphamide, vincristine, prednisone, and dacarbazine) regimen according to GPOH-HD2002 treatment group 3 (TG3); two cycles of AEPA and four cycles of CAPDac. Residual node radiotherapy (25.5 Gy) was given at the end of all chemotherapy only to nodal sites that did not achieve a complete response (CR) at the early response assessment (ERA) after two cycles of therapy. Primary objectives were to evaluate the safety and efficacy (complete remission at ERA) of this combination and the 3-year event-free (EFS) and overall survival (OS). The trials are registered at ClinicalTrials.gov (identifier: NCT01920932). RESULTS: Of the 77 patients enrolled in the study, 27 (35%) achieved complete remission at ERA and were spared radiation. Patients who were irradiated received radiation to individual residual nodal tissue. At a median follow-up of 3.4 years, the 3-year EFS was 97.4% (SE 2.3%) and the OS was 98.7% (SE 1.6%). One irradiated patient experienced disease progression at the end of therapy and now remains disease free more than 6 years following salvage therapy, and one unexpected death occurred. Only 4% of patients experienced grade 3 neuropathy. CONCLUSION: The integration of brentuximab vedotin in the frontline treatment of pediatric high-risk HL is highly tolerable, facilitated significant reduction in radiation exposure, and yielded excellent outcomes.

Clinical outcomes of pediatric patients with autism spectrum disorder and other neurodevelopmental disorders and intracranial germ cell tumors.

INTRODUCTION: Intracranial germ cell tumors (IGCTs) are rare tumors of the central nervous system with peak incidence around puberty. Given the developmental origins of IGCTs, we investigated the prevalence of neurodevelopmental disorders (NDDs) in patients with IGCTs and characterized outcomes for patients with NDD and IGCTs. METHODS: A retrospective review of medical records was conducted for 111 patients diagnosed with IGCTs between 1998 and 2018 and evaluated at the Massachusetts General Hospital. Kaplan-Meier method and log-rank test was used for survival analyses. Cox regression analyses were performed for parameters associated with progression-free survival (PFS). RESULTS: Median age at IGCT diagnosis was 12.8 years (range: 4.3-21.7) and median follow-up was 6.5 years (range: 0.2-20.5). Eighteen patients were diagnosed with NDDs prior to IGCT diagnosis, including five patients with autism spectrum disorder (ASD). Of the 67 patients with pure germinomas, four (6.0 %) had prior ASD diagnoses. Patients with NDD had significantly inferior PFS in the nongerminomatous germ cell tumor (NGGCT) cohort. On univariate and multivariable analyses, craniospinal irradiation (CSI) was significantly associated with improved PFS in the NGGCT cohort. CONCLUSIONS: Our study found an ASD prevalence in the pure germinoma cohort more than threefold greater than the national prevalence, suggesting an association between ASD and pure germinomas. Furthermore, patients with NDD and NGGCT had worse PFS, possibly due to fewer patients with NDD receiving CSI. Future prospective studies with larger cohorts are needed to examine associations between NDDs and IGCTs, and further characterize outcomes for patients with NDDs and IGCTs.