Deep learning segmentation of organs-at-risk with integration into clinical workflow for pediatric brain radiotherapy.

PURPOSE: Radiation therapy (RT) of pediatric brain cancer is known to be associated with long-term neurocognitive deficits. Although target and organs-at-risk (OARs) are contoured as part of treatment planning, other structures linked to cognitive functions are often not included. This paper introduces a novel automatic segmentation tool specifically designed for the unique challenges posed by pediatric patients undergoing brain RT, as well as its seamless integration into the existing clinical workflow. METHODS AND MATERIALS: Images of 47 pediatric brain cancer patients aged 1 to 20 years old and 33 two-year-old healthy infants were used to train a vision transformer, UNesT, for the segmentation of five brain OARs. The trained model was then incorporated to clinical workflow via DICOM connections between a treatment planning system (TPS) and a server hosting the trained model such that scans are sent from TPS to the server, automatically segmented, and sent back to TPS for treatment planning. RESULTS: The proposed automatic segmentation framework achieved a median dice similarity coefficient of 0.928 (frontal white matter), 0.908 (corpus callosum), 0.933 (hippocampi), 0.819 (temporal lobes), and 0.960 (brainstem) with a mean ± SD run time of 1.8 ± 0.67 s over 20 test cases. CONCLUSIONS: The pediatric brain segmentation tool showed promising performance on five OARs linked to neurocognitive functions and can easily be extended for additional structures. The proposed integration to the clinic enables easy access to the tool from clinical platforms and minimizes disruption to existing workflow while maximizing its benefits.

Dosimetric evaluation of cone-beam CT-based synthetic CTs in pediatric patients undergoing intensity-modulated proton therapy.

PURPOSE: To evaluate dosimetric changes detected using synthetic computed tomography (sCT) derived from online cone-beam CTs (CBCT) in pediatric patients treated using intensity-modulated proton therapy (IMPT). METHODS: Ten pediatric patients undergoing IMPT and aligned daily using proton gantry-mounted CBCT were identified for retrospective analysis with treated anatomical sites fully encompassed in the CBCT field of view. Dates were identified when the patient received both a CBCT and a quality assurance CT (qCT) for routine dosimetric evaluation. sCTs were generated based on a deformable registration between the initial plan CT (pCT) and CBCT. The clinical IMPT plans were re-computed on the same day qCT and sCT, and dosimetric changes due to tissue change or response from the initial plan were computed using each image. Linear regression analysis was performed to determine the correlation between dosimetric changes detected using the qCT and the sCT. Gamma analysis was also used to compare the dose distributions computed on the qCT and sCT. RESULTS: The correlation coefficients (p-values) between qCTs and sCTs for changes detected in target coverage, overall maximum dose, and organ at risk dose were 0.97 (< .001), 0.84 (.002) and 0.91 (< .001), respectively. Mean ± SD gamma pass rates of the sCT-based dose compared to the qCT-based dose at 3%/3 mm, 3%/2 mm, and 2%/2 mm criteria were 96.5%±4.5%, 93.2%±6.3%, and 91.3%±7.8%, respectively. Pass rates tended to be lower for targets near lung. CONCLUSION: While insufficient for re-planning, sCTs provide approximate dosimetry without administering additional imaging dose in pediatric patients undergoing IMPT. Dosimetric changes detected using sCTs are correlated with changes detected using clinically-standard qCTs; however, residual differences in dosimetry remain a limitation. Further improvements in sCT image quality may both improve online dosimetric evaluation and reduce imaging dose for pediatric patients by reducing the need for routine qCTs.

A multi-institutional phase 2 trial of stereotactic body radiotherapy in the treatment of bone metastases in pediatric and young adult patients with sarcoma.

BACKGROUND: Metastasectomy is standard of care for pediatric patients with metastatic sarcoma with limited disease. For patients with unresectable disease, stereotactic body radiotherapy (SBRT) may serve as an alternative. Herein, the authors report the results of a prospective, multi-institutional phase 2 trial of SBRT in children and young adults with metastatic sarcoma. METHODS: Patients aged >3 years and ≤40 years with unresected, osseous metastatic nonrhabdomyosarcoma sarcomas of soft tissue and bone were eligible. Patients received SBRT to a dose of 40 Gray (Gy) in 5 fractions. Local control (LC), progression-free survival (PFS), and overall survival (OS) were calculated using the Kaplan-Meier method. RESULTS: Fourteen patients with a median age of 17 years (range, 4-25 years) were treated to 37 distinct metastatic lesions. With a median follow-up of 6.8 months (30.5 months in surviving patients), the Kaplan-Meier patient-specific and lesion-specific LC rates at 6 months were 89% and 95%, respectively. The median PFS was 6 months and the median OS was 24 months. In a post hoc analysis, PFS (median, 9.3 months vs 3.7 months; log-rank P = .03) and OS (median not reached vs 12.7 months; log-rank P = .02) were improved when all known sites of metastatic disease were consolidated with SBRT compared with partial consolidation. SBRT was well tolerated, with 2 patients experiencing grade 3 toxicities. CONCLUSIONS: SBRT achieved high rates of LC in pediatric patients with inoperable metastatic nonrhabdomyosarcoma sarcomas of soft tissue and bone. These results suggest that the ability to achieve total consolidation of metastatic disease with SBRT is associated with improved PFS and OS.

Gliomas, germ cell tumors, and craniopharyngioma.

This report summarizes the current multimodality treatment approaches for children with low- and high-grade gliomas, germinoma, and nongerminomatous germ cell tumors, and craniopharyngiomas used in the Children's Oncology Group (COG) and the International Society of Pediatric Oncology (SIOP). Treatment recommendations are provided in the context of historical approaches regarding the roles of surgery, radiation, and chemotherapy. Future research strategies for these tumors in both COG and SIOP are also discussed.

Proton therapy for central nervous system tumors in children.

Proton therapy is a form of particle therapy with physical properties that provide a superior dose distribution compared to photons. The ability to spare healthy, developing tissues from low dose radiation with proton therapy is well known. The capability to decrease radiation exposure for children has been lauded as an important advance in pediatric cancer care, particularly for central nervous system (CNS) tumors. Favorable clinical outcomes have been reported and justify the increased cost and burden of this therapy. In this review, we summarize the current literature for proton therapy for pediatric CNS malignancies, with a focus on clinical outcomes to date.

Practice Patterns of Stereotactic Radiotherapy in Pediatrics: Results From an International Pediatric Research Consortium.

PURPOSE/OBJECTIVES: There is little consensus regarding the application of stereotactic radiotherapy (SRT) in pediatrics. We evaluated patterns of pediatric SRT practice through an international research consortium. MATERIALS AND METHODS: Eight international institutions with pediatric expertise completed a 124-item survey evaluating patterns of SRT use for patients 21 years old and younger. Frequencies of SRT use and median margins applied with and without SRT were evaluated. RESULTS: Across institutions, 75% reported utilizing SRT in pediatrics. SRT was used in 22% of brain, 18% of spine, 16% of other bone, 16% of head and neck, and <1% of abdomen/pelvis, lung, and liver cases across sites. Of the hypofractionated SRT cases, 42% were delivered with definitive intent. Median gross tumor volume to planning target volume margins for SRT versus non-SRT plans were 0.2 versus 1.4 cm for brain, 0.3 versus 1.5 cm for spine/other bone, 0.3 versus 2.0 cm for abdomen/pelvis, 0.7 versus 1.5 cm for head and neck, 0.5 versus 1.7 cm for lung, and 0.5 versus 2.0 cm for liver sites. CONCLUSIONS: SRT is commonly utilized in pediatrics across a range of treatment sites. Margins used for SRT were substantially smaller than for non-SRT planning, highlighting the utility of this approach in reducing treatment volumes.

Socioeconomic factors affect the selection of proton radiation therapy for children.

BACKGROUND: Proton radiotherapy remains a limited resource despite its clear potential for reducing radiation doses to normal tissues and late effects in children in comparison with photon therapy. This study examined the impact of race and socioeconomic factors on the use of proton therapy in children with solid malignancies. METHODS: This study evaluated 12,101 children (age ≤ 21 years) in the National Cancer Data Base who had been diagnosed with a solid malignancy between 2004 and 2013 and had received photon- or proton-based radiotherapy. Logistic regression analysis was used to evaluate patient, tumor, and socioeconomic variables affecting treatment with proton radiotherapy versus photon radiotherapy. RESULTS: Eight percent of the patients in the entire cohort received proton radiotherapy, and this proportion increased between 2004 (1.7%) and 2013 (17.5%). Proton therapy was more frequently used in younger patients (age ≤ 10 years; odds ratio [OR], 1.9; 95% confidence interval [CI], 1.6-2.2) and in patients with bone/joint primaries and ependymoma, medulloblastoma, and rhabdomyosarcoma histologies (P < .05). Patients with metastatic disease were less likely to receive proton therapy (OR, 0.4; 95% CI, 0.3-0.6). Patients with private/managed care were more likely than patients with Medicaid or no insurance to receive proton therapy (P < .0001). A higher median household income and educational attainment were also associated with increased proton use (P < .001). Patients treated with proton therapy versus photon therapy were more likely to travel more than 200 miles (13% vs 5%; P < .0001). CONCLUSIONS: Socioeconomic factors affect the use of proton radiotherapy in children. Whether this disparity is related to differences in the referral patterns, the knowledge of treatment modalities, or the ability to travel for therapy needs to be further clarified. Improving access to proton therapy in underserved pediatric populations is essential. Cancer 2017;123:4048-56. © 2017 American Cancer Society.

Practice patterns of palliative radiation therapy in pediatric oncology patients in an international pediatric research consortium.

BACKGROUND/OBJECTIVES: The practice of palliative radiation therapy (RT) is based on extrapolation from adult literature. We evaluated patterns of pediatric palliative RT to describe regimens used to identify opportunity for future pediatric-specific clinical trials. DESIGN/METHODS: Six international institutions with pediatric expertise completed a 122-item survey evaluating patterns of palliative RT for patients ≤21 years old from 2010 to 2015. Two institutions use proton RT. Palliative RT was defined as treatment with the goal of symptom control or prevention of immediate life-threatening progression. RESULTS: Of 3,225 pediatric patients, 365 (11%) were treated with palliative intent to a total of 427 disease sites. Anesthesia was required in 10% of patients. Treatment was delivered to metastatic disease in 54% of patients. Histologies included neuroblastoma (30%), osteosarcoma (18%), leukemia/lymphoma (12%), rhabdomyosarcoma (12%), medulloblastoma/ependymoma (12%), Ewing sarcoma (8%), and other (8%). Indications included pain (43%), intracranial symptoms (23%), respiratory compromise (14%), cord compression (8%), and abdominal distention (6%). Sites included nonspine bone (35%), brain (16% primary tumors, 6% metastases), abdomen/pelvis (15%), spine (12%), head/neck (9%), and lung/mediastinum (5%). Re-irradiation comprised 16% of cases. Techniques employed three-dimensional conformal RT (41%), intensity-modulated RT (23%), conventional RT (26%), stereotactic body RT (6%), protons (1%), electrons (1%), and other (2%). The most common physician-reported barrier to consideration of palliative RT was the concern about treatment toxicity (83%). CONCLUSION: There is significant diversity of practice in pediatric palliative RT. Combined with ongoing research characterizing treatment response and toxicity, these data will inform the design of forthcoming clinical trials to establish effective regimens and minimize treatment toxicity for this patient population.

Proton therapy for pediatric and adolescent esthesioneuroblastoma.

BACKGROUND: Esthesioneuroblastoma (EN) of the paranasal sinus comprises less than 3% of tumors of in pediatric and adolescent patients [1]. The collective adult literature indicates a critical role for radiotherapy in attaining cure [2], yet pediatric outcome data is limited. Radiation in pediatric patients with EN can cause significant morbidity due to the proximity of critical structures. Proton radiotherapy offers a potential dosimetric benefit that may improve long-term survival and toxicity outcomes in the pediatric population [3]. METHODS: We retrospectively identified eight patients treated for EN with proton radiotherapy from 2000-2013. Times to event clinical endpoints are summarized using the Kaplan-Meier methods and are from the date of radiotherapy completion. Toxicities are reviewed and graded according to CTCAE v. 4.0. RESULTS: Median follow up was 4.6 years for survivors (range 0.8-9.4 years). The 4 year overall survival was 87.5%. Four of eight patients (one elective) had comprehensive neck radiotherapy. No local or regional failures were observed. Two patients failed distantly with diffuse leptomeningeal disease and intraparenchymal brain metastases, at 0.6 and 1.3 months respectively. Four patients developed radiation related late toxicities including endocrine dysfunction, two cases of grade 2 retinopathy and one case of grade 3 optic neuropathy. CONCLUSIONS: In a limited cohort, proton radiotherapy appears to provide excellent locoregional disease control even in those patients with locally advanced disease and intracranial extension. Distant failure determined overall survival in our cohort. Toxicities were acceptable given disease location and extent.

The Prognostic Significance of Early Tumor Volume Change in Rhabdomyosarcoma.

Purpose: To describe early tumor volume change in patients with rhabdomyosarcoma (RMS) and investigate its association with overall survival (OS) and local failure. Methods and Materials: This retrospective study included patients who received diagnoses of group III/IV RMS with available computed tomography and/or magnetic resonance imaging scans at 2 time points: (1) pretherapy and (2) early therapy (acquired during weeks 8-12 of chemotherapy). Relative volumetric change (RVC) was calculated as the percentage of (early therapy - pretherapy volume) / (pretherapy volume). Cox regression was used to identify variables associated with OS. The Fine-Gray model was used to estimate local failure. Results: Eligible patients (n = 55) had the following characteristics: median age at diagnosis, 9.6 years and median follow-up, 30.4 months. Most tumors were alveolar (61.8%), followed by embryonal (34.6%) and spindle cell/sclerosing (4%). The median RVC was -86.4% with larger decreases observed in alveolar versus nonalveolar RMS (-89.4% vs -69.8%, P = .043). For embryonal and spindle cell/sclerosing RMS, all of which were FOXO1 fusion negative, RVC was independently associated with OS (hazard ratio for every 50% reduction in RVC [HRRVC], 0.5; 95% CI, 0.26-0.96; P = .037) and local failure (HRRVC, 0.57; 95% CI, 0.33-0.99; P = .049). The predominant pattern of failure in embryonal and spindle cell/sclerosing RMS was local, and most were group III. Conclusions: There was a greater reduction in tumor volume in alveolar versus nonalveolar RMS. Early tumor volume reduction was associated with OS and local failure in embryonal or spindle cell/sclerosing RMS, all of which were confirmed FOXO1 fusion negative and had higher incidence of local compared with distant failures.

Impact of Consolidative Radiation on Overall and Progression-Free Survival in Pediatric, Adolescent, and Young Adult Metastatic Bone and Soft Tissue Sarcoma.

PURPOSE: To determine the association between consolidative radiation (RT) and survival in children, adolescents, and young adults with metastatic sarcoma. METHODS AND MATERIALS: Eligibility criteria included patients aged ≤39 years with newly diagnosed metastatic bone or soft tissue sarcoma who completed local control of the primary tumor without disease progression. Consolidative RT was defined as RT to all known sites of metastatic disease. The Kaplan-Meier method was used to estimate overall survival (OS) and progression-free survival (PFS). The least absolute shrinkage and selection operator Cox provided adjusted estimates. To account for immortal time bias, consolidative RT was used as a time-varying covariate in a time dependent Cox model. Distant failure was estimated using the Fine-Gray model. RESULTS: Patients (n = 85) had a median age at diagnosis of 14.8 years. Most common histology was Ewing Sarcoma (45.9%) followed by rhabdomyosarcoma (40.0%). Receipt of consolidative RT was associated with Ewing Sarcoma (P < .001) and local control modality as those who underwent local control with surgery and RT compared with surgery alone were more likely to be treated with consolidative RT (P = .034). Consolidative RT was independently associated with improved OS (hazard ratio [HR], 0.41; 95% CI, 0.17-0.98; P = .045) and improved PFS (HR, 0.37; 95% CI, 0.16-0.88; P = .024) after adjusting for confounding variables and immortal time bias. Patients treated with consolidative RT also experienced a lower risk of distant failure (HR, 0.33; 95% CI, 0.17-0.64; P = .001). In an independent data set of patients with metachronous progression (n = 36), consolidative RT remained independently associated with improved OS. CONCLUSIONS: Consolidative RT was independently associated with improved OS and PFS and decreased risk of distant failure in child, adolescent, and young adult patients with metastatic sarcoma. Future work should evaluate biomarkers to optimize patient selection, timing, and dose for consolidative RT.

Metastatic site radiation therapy for Ewing sarcoma and rhabdomyosarcoma: Consensus guidelines from the National Pediatric Cancer Foundation.

BACKGROUND: Despite the urgent need for improved outcomes in patients with metastatic Ewing sarcoma (EWS) and rhabdomyosarcoma (RMS), it is unknown how to best approach metastatic site radiation therapy for these patients and whether such treatment provides a significant oncologic benefit that outweighs the toxicities. METHODS: We gathered a panel of pediatric radiation oncologists from academic hospitals to identify and discuss current controversies regarding the role of radiation in the management of metastatic EWS and RMS. The panel reviewed existing clinical data and ongoing trials to address five key questions: 1) the role of whole lung irradiation (WLI) in treating lung metastases 2) number of metastatic sites warranting radiotherapy and the radicality of such an approach; 3) radiation techniques, including stereotactic body radiation therapy (SBRT); 4) the timing of metastatic-site radiation therapy; and 5) the utility of metastatic site radiation therapy for relapsed metastatic disease. RESULTS: After a review of existing data, consensus recommendations were developed to support the decision-making process in metastatic-site irradiation with the goal of improving long-term disease control. Patients with pulmonary metastases should receive WLI. In patients with limited (<8 sites) metastatic disease, a comprehensive approach should be taken to treat all sites of metastatic disease diagnosed at presentation. SBRT should be considered as a preferred treatment technique. The timing of metastatic-site treatment should coincide with the end of systemic therapy. However, if there is a dosimetric advantage or improved compliance, concurrent treatment with the primary site may be preferred. CONCLUSIONS: A consensus guideline was established to address several critical questions regarding the role of radiation in the treatment of metastatic EWS and RMS. The study highlights the existing controversies, provides a structured approach, and underscores the need for future studies to further evaluate the therapeutic ratio of metastatic-site directed therapy.

Clinical Characterization of a Table Mounted Range Shifter Board for Synchrotron-Based Intensity Modulated Proton Therapy for Pediatric Craniospinal Irradiation.

Purpose: To report our design, manufacturing, commissioning and initial clinical experience with a table-mounted range shifter board (RSB) intended to replace the machine-mounted range shifter (MRS) in a synchrotron-based pencil beam scanning (PBS) system to reduce penumbra and normal tissue dose for image-guided pediatric craniospinal irradiation (CSI). Methods: A custom RSB was designed and manufactured from a 3.5 cm thick slab of polymethyl methacrylate (PMMA) to be placed directly under patients, on top of our existing couch top. The relative linear stopping power (RLSP) of the RSB was measured using a multi-layer ionization chamber, and output constancy was measured using an ion chamber. End-to-end tests were performed using the MRS and RSB approaches using an anthropomorphic phantom and radiochromic film measurements. Cone beam CT (CBCT) and 2D planar kV X-ray image quality were compared with and without the RSB present using image quality phantoms. CSI plans were produced using MRS and RSB approaches for two retrospective pediatric patients, and the resultant normal tissue doses were compared. Results: The RLSP of the RSB was found to be 1.163 and provided computed penumbra of 6.9 mm in the phantom compared to 11.8 mm using the MRS. Phantom measurements using the RSB demonstrated errors in output constancy, range, and penumbra of 0.3%, -0.8%, and 0.6 mm, respectively. The RSB reduced mean kidney and lung dose compared to the MRS by 57.7% and 46.3%, respectively. The RSB decreased mean CBCT image intensities by 86.8 HU but did not significantly impact CBCT or kV spatial resolution providing acceptable image quality for patient setup. Conclusions: A custom RSB for pediatric proton CSI was designed, manufactured, modeled in our TPS, and found to significantly reduce lateral proton beam penumbra compared to a standard MRS while maintaining CBCT and kV image-quality and is in routine use at our center.

Impact of socioeconomic status and chemotherapy on neurocognitive performance in children with brain tumors.

Background: Although the relationship between radiation and neurocognition has been extensively studied in the pediatric brain tumor population, it is increasingly recognized that neurocognitive impairment is multifactorial. Therefore, we quantified the effect of socioeconomic status (SES) and chemotherapy on neurocognitive impairment and decline post-treatment. Methods: Eligible patients included those diagnosed with a brain tumor at < 22 years of age with ≥1 neurocognitive assessment. Neurocognitive impairment was defined as performance 1.5 standard deviations below the normative mean using age-standardized measures of intellectual function. Neurocognitive decline was defined as a negative slope. Neurocognitive outcomes included Wechsler indices of Full-Scale Intelligence Quotient (IQ). Logistic regression identified variables associated with neurocognitive impairment. Longitudinal data was analyzed using linear mixed models. Results: Eligible patients (n = 152, median age at diagnosis = 9.6 years) had a mean neurocognitive follow-up of 50.2 months. After accounting for age and receipt of craniospinal irradiation, patients with public insurance had 8-fold increased odds of impaired IQ compared to private insurance (odds ratio [OR]: 7.59, P < .001). After accounting for age, change in IQ was associated with chemotherapy use (slope: -0.45 points/year with chemotherapy vs. 0.71 points/year without chemotherapy, P = .012). Conclusions: Public insurance, an indicator of low SES, was associated with post-treatment impairment in IQ, highlighting the need to incorporate SES measures into prospective studies. Chemotherapy was associated with change in IQ. Further work is needed to determine whether impairment associated with low SES is secondary to baseline differences in IQ prior to brain tumor diagnosis, brain tumor/therapy itself, or some combination thereof.

Comparing Ultra-hypofractionated Proton versus Photon Therapy in Extremity Soft Tissue Sarcoma.

Purpose: Recent single institution, phase II evidence has demonstrated the feasibility and efficacy of ultra-hypofractionated, preoperative photon therapy in 5 fractions for the treatment of soft tissue sarcoma (STS). Our purpose was to evaluate the dosimetric benefits of modern scanning beam proton therapy compared with conventional photon radiation therapy (RT) for the neoadjuvant treatment of adult extremity STS. Materials and Methods: Existing proton and photon plans for 11 adult patients with STS of the lower extremities previously treated preoperatively with neoadjuvant RT at our center were used to create proton therapy plans using Raystation Treatment Planning System v10.A. Volumes were delineated, and doses reported consistent with International Commission on Radiation Units and Measurements reports 50, 62, and 78. Target volumes were optimized such that 100% clinical target volume (CTV) was covered by 99% of the prescription dose. The prescribed dose was 30 Gy for PT and RT delivered in 5 fractions. For proton therapy, doses are reported in GyRBE = 1.1 Gy. The constraints for adjacent organs at risk (OARs) within 1 cm of the CTV were the following: femur V30Gy ≤ 50%, joint V30Gy < 50%, femoral head V30Gy ≤ 5 cm3, strip V12 ≤ 10%, and skin V12 < 50%. Target coverage goals, OAR constraints, and integral dose were compared by Student t test with P < .05 significance. Results: A minimum 99% CTV coverage was achieved for all plans. OAR dose constraints were achieved for all proton and photon plans; however, mean doses to the femur (10.7 ± 8.5 vs 16.1 ± 7.7 GyRBE), femoral head (2.0 ± 4.4 vs 3.6 ± 6.4 GyRBE), and proximal joint (1.8 ± 2.4 vs 3.5 ± 4.4 GyRBE) were all significantly lower with PT vs intensity-modulated radiation therapy (IMRT) (all P < .05). Integral dose was significantly reduced for proton vs photon plans. Conformity and heterogeneity indices were significantly better for proton therapy. Conclusion: Proton therapy maintained target coverage while significantly reducing integral and mean doses to the proximal organs at risk compared with RT. Further prospective investigation is warranted to validate these findings and potential benefit in the management of adult STS.

Predictors of Recurrence and Patterns of Initial Failure in Localized Ewing Sarcoma: A Contemporary 20-Year Experience.

BACKGROUND: The majority of patients with localized Ewing sarcoma will remain disease-free long term, but for those who suffer recurrence, successful treatment remains a challenge. Identification of clinicopathologic factors predictive of recurrence could suggest areas for treatment optimization. We sought to describe our experience regarding predictors of recurrence and patterns of first failure in patients receiving modern systemic therapy for nonmetastatic Ewing sarcoma. METHODS: The medical records of pediatric and adult patients treated for localized Ewing sarcoma between 1999 and 2019 at Johns Hopkins Hospital were retrospectively analyzed. Local control was surgery, radiotherapy, or both. Recurrence-free survival (RFS) was calculated using the Kaplan-Meier method. Univariable and multivariable Cox proportional-hazards modeling was performed to obtain hazard ratios (HR) for recurrence. RESULTS: In 94 patients with initially localized disease, there were 21 recurrences: 4 local, 14 distant, and 3 combined. 5-year and 10-year RFS were 75.6% and 70.5%, respectively. On multivariable analysis including age at diagnosis and tumor size, <95% tumor necrosis following neoadjuvant chemotherapy (NAC; HR 14.3, p = 0.028) and radiological tumor size change during NAC (HR 1.04 per 1% decrease in size change, p = 0.032) were independent predictors of recurrence. Among patients experiencing distant recurrence, pulmonary metastases were present in 82% and were the only identifiable site of disease in 53%. CONCLUSIONS: Poor pathologic or radiologic response to NAC is predictive of recurrence in patients with localized Ewing sarcoma. Suboptimal tumor size reduction following chemotherapy provides a means to risk-stratify patients who do not undergo definitive resection. Isolated pulmonary recurrence was a common event.

A Multi-institutional Comparative Analysis of Proton and Photon Therapy-Induced Hematologic Toxicity in Patients With Medulloblastoma.

PURPOSE: This multi-institutional retrospective study sought to examine the hematologic effects of craniospinal irradiation (CSI) in pediatric patients with medulloblastoma using proton or photon therapy. METHODS AND MATERIALS: Clinical and treatment characteristics were recorded for 97 pediatric patients with medulloblastoma who received CSI without concurrent chemotherapy or with concurrent single-agent vincristine from 2000 to 2017. Groups of 60 and 37 patients underwent treatment with proton-based and photon-based therapy, respectively. Overall survival was determined by Kaplan-Meier curves with log-rank test. Comparisons of blood counts at each timepoint were conducted using multiple t tests with Bonferroni corrections. Univariate and multivariate analyses of time to grade ≥3 hematologic toxicity were performed with Cox regression analyses. RESULTS: Median age of patients receiving proton and photon CSI was 7.5 years (range, 3.5-22.7 years) and 9.9 years (range, 3.6-19.5 years), respectively. Most patients had a diagnosis of standard risk medulloblastoma, with 86.7% and 89.2% for the proton and photon cohorts, respectively. Median total dose to involved field or whole posterior fossa was 54.0 Gy/Gy relative biological effectiveness (RBE) and median CSI dose was 23.4 Gy/Gy(RBE) (range, 18-36 Gy/Gy[RBE]) for both cohorts. Counts were significantly higher in the proton cohort compared with the photon cohort in weeks 3 to 6 of radiation therapy (RT). Although white blood cell counts did not differ between the 2 cohorts, patients receiving proton RT had significantly higher lymphocyte counts throughout the RT course. Similar results were observed when excluding patients who received vertebral body sparing proton RT or limiting to those receiving 23.4 Gy. Only photon therapy was associated with decreased time to grade ≥3 hematologic toxicity on univariate and multivariable analyses. No difference in overall survival was observed, and lymphopenia did not predict survival. CONCLUSIONS: Patients who receive CSI using proton therapy experience significantly decreased hematologic toxicity compared with those receiving photon therapy.

An open invitation to join the Pediatric Proton/Photon Consortium Registry to standardize data collection in pediatric radiation oncology.

OBJECTIVE: The Pediatric Proton/Photon Consortium Registry (PPCR) is a comprehensive data registry composed of pediatric patients treated with radiation. It was established to expedite outcomes-based research. The attributes which allow the PPCR to be a successful collaboration are reviewed. METHODS AND MATERIALS: Current eligibility criteria are radiotherapy patients < 22 years treated at one of the 15 US participating institutions. Detailed health and treatment data are collected about the disease presentation and treatment exposures, and annually thereafter, in REDCap (Research Electronic Data Capture). DICOM (Digital Imaging and Communications in Medicine) imaging and radiation plans are collected through MIM/MIMcloud. An optional patient-reported quality-of-life (PedsQL) study is administered at 10 sites. RESULTS: Accrual started October 2012 with 2,775 participants enrolled as of 25 July 2019. Most patients, 62.0%, were treated for central nervous system (CNS) tumors, the most common of which are medulloblastoma (n = 349), ependymoma (n = 309), and glial/astrocytoma tumors (n = 279). The most common non-CNS diagnoses are rhabdomyosarcoma (n = 284), Ewing's sarcoma (n = 153), and neuroblastoma (n = 130). While the majority of participants are US residents, 18.7% come from 36 other countries. Over 685 patients participate in the PedsQL study. CONCLUSIONS: The PPCR is a valuable research platform capable of answering countless research questions that will ultimately improve patient care. Centers outside of the USA are invited to participate directly or may engage with the PPCR to align data collection strategies to facilitate large-scale international research. ADVANCES IN KNOWLEDGE: For investigators looking to carry out research in a large pediatric oncology cohort or interested in registry work, this paper provides an updated overview of the PPCR.

Precision of 2 Low-dose Abdomen/Pelvis Cone Beam Computed Tomography Protocols for Alignment to Bone and Soft Tissue in Pediatric Patients Receiving Image Guided Radiation Therapy.

PURPOSE: To evaluate the precision of 2 low-dose cone (LD) beam computed tomography (CBCT) protocols to align to bone and soft tissue for pediatric patients receiving image guided radiation therapy (IGRT) to the abdomen and pelvis. METHODS AND MATERIALS: Image-quality evaluation was done for 858 CBCT scans from 46 pediatric patients treated with IGRT from January 2015 to December 2017. The evaluations guided the development of 2 significantly dose-reduced protocols, LD-CBCT1 and a further dose-reduced LD-CBCT2. Representative scans from LD-CBCT1 and LD-CBCT2 from 8 patients with at least 1 CBCT scan from both protocols were registered separately to a bone and soft-tissue landmark on the simulation computed tomography scan. Eighteen identical blinded random offsets were applied to each patient's LD-CBCT1 and LD-CBCT2 from a starting registration that was then realigned using rigid registration. The residual offset between the baseline registration and the final registration attempt was calculated and analyzed using a 1-sided, 1 sample t test to evaluate whether LD-CBCT1, delivering a higher dose, was superior to the lower-dose LD-CBCT2 for bone and soft-tissue alignment. RESULTS: In comparing 288 registrations with a bone landmark across 8 patients, no difference was found in the vector magnitude offsets using LD-CBCT 1 (mean [x¯], 0.73 mm; standard deviation [σ], 0.39 mm) and LD-CBCT2 (x¯, 0.74 mm; σ, 0.40 mm; P = .425). Comparing 216 registrations with a soft-tissue landmark across 6 patients, alignment using LD-CBCT2 (x¯, 1.55 mm; σ, 1.08 mm) resulted in larger differences in the vector magnitude of the offsets compared with LD-CBCT1 (x¯, 1.37 mm; σ, 0.74 mm; P = .049). CONCLUSIONS: Clinics treating pediatric patients should consider implementing a protocol mirroring LD-CBCT2 for abdomen and pelvis IGRT bone alignment. Further evaluation of the precision of LD-CBCTs for soft-tissue alignment is necessary.