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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.

OBJECTIVE The internal high-dose volume varies widely for a given prescribed dose during stereotactic radiosurgery (SRS) to treat brain metastases (BMs). This may be altered during treatment planning, and the authors have previously shown that this improves local control (LC) for non–small cell lung cancer BMs without increasing toxicity. Here, they seek to identify potentially actionable dosimetric predictors of LC after SRS for melanoma BM. METHODS The records of patients with unresected melanoma BM treated with single-fraction Gamma Knife RS between 2006 and 2017 were reviewed. LC was assessed on a per-lesion basis, defined as stability or a decrease in lesion size. Outcome-oriented approaches were utilized to determine optimal dichotomization for dosimetric variables relative to LC. Univariable and multivariable Cox regression analysis was implemented to evaluate the impact of collected parameters on LC. RESULTS Two hundred eighty-seven melanoma BMs in 79 patients were identified. The median age was 56 years (range 31–86 years). The median follow-up was 7.6 months (range 0.5–81.6 months), and the median survival was 9.3 months (range 1.3–81.6 months). Lesions were optimally stratified by volume receiving at least 30 Gy (V30) greater than or equal to versus less than 25%. V30 was ≥ and < 25% in 147 and 140 lesions, respectively. For all patients, 1-year LC was 83% versus 66% for V30 ≥ and < 25%, respectively (p = 0.001). Stratifying by volume, lesions 2 cm or less (n = 215) had 1-year LC of 82% versus 70% (p = 0.013) for V30 ≥ and < 25%, respectively. Lesions > 2 to 3 cm (n = 32) had 1-year LC of 100% versus 43% (p = 0.214) for V30 ≥ and < 25%, respectively. V30 was still predictive of LC even after controlling for the use of immunotherapy and targeted therapy. Radionecrosis occurred in 2.8% of lesions and was not significantly associated with V30. CONCLUSIONS For a given prescription dose, an increased internal high-dose volume, as indicated by measures such as V30 ≥ 25%, is associated with improved LC but not increased toxicity in single-fraction SRS for melanoma BM. Internal dose escalation is an independent predictor of improved LC even in patients receiving immunotherapy and/or targeted therapy. This represents a dosimetric parameter that is actionable at the time of treatment planning and warrants further evaluation.

ImportanceEarly reports suggest adverse events following proton therapy (PT) for childhood cancer are more prevalent given the increased number of PT centers and use in clinical trials.ObjectiveTo assess treatment-failure and toxicity events following Pencil Beam Scanning (PBS)-PT in children.Design, Setting, and ParticipantsThe single-institution Phase IV surveillance trial screened 856 children, of which 528 were eligible for PBS-PT, and 500 enrolled in SJPROTON1 from 2017–2020. The median follow-up was 2.1 years (range 1.1-4.4). PBS-RT attributable toxicities were systematically identified, and graded at baseline to four years following PBS-PT.InterventionsAll patients underwent PBS-PT or combined photon/PBS-PT.Main Outcomes and MeasuresThe primary objective was the CI of ≥grade 3 non-hematologic, PBS-PT attributable Common Terminology Criteria for Adverse Events (CTCAE) v 4.0. Additional outcomes included PBS-PT attributable hospitalization, toxicity related procedures, and treatment-related mortality. Pre-specified toxicities including necrosis, vasculopathy, neurologic deficits, and fracture/osteoradionecrosis were further characterized (any grade) as a secondary objective. Medical record review augmented in-person visits for failure and adverse event reporting. Competing risk regression was used to evaluate predictors of ≥grade 3 PBS-PT attributable toxicity.ResultsAt two years, the event-free survival was 73.2% (95% CI, 68.9%-77.8%). Distant and local failure predominated with a 2-year cumulative incidence (CI) of 16.5% (95% CI 13.1-20.4) and 6.8% (95% CI 4.6-9.5) respectively. The CI of ≥ grade 3 toxicity events at four years was 24.5%; including necrosis (3.7%), permanent neurologic deficit (2.9%), and fracture/osteoradionecrosis (0.79%). The rates of hospitalization and procedures due to PBS-PT– attributable toxicity was 3.9% and 7.6%, respectively. Predictors of an increased event-specific hazard for any ≥ grade 3 toxicity included baseline total toxicity burden (TTB) (HR 1.043, 95% CI 1.012-1.07, p=0.007), use of mixed photon/PBS-PT (HR 2.62, 95% CI 1.51-4.54, p=0.006) in the CNS population, and treatment of the pelvic body site (HR 4.25, 95% CI 1.08-16.72, p=0.038), and TTB (HR 1.1, 95% CI 1.04-1.16, p=0.002) in the non-CNS population, respectively.Conclusions and RelevanceChildren treated with PBS-PT experience a low incidence of toxicity, but subsets may be at increased risk, and experience toxicity that requires additional procedures or hospitalization.Key PointsQuestionWhat is the efficacy and safety profile of Pencil Beam Scanning Proton therapy (PBS-PT) in children?FindingsIn this single institution phase IV trial, the rate of local failure and clinically significant ≥grade 3 PBS-RT attributable toxicity were low, but a subset of patients may be at increased risk for hospitalization and procedures related to managing PBS-RT attributable adverse events.MeaningPBS-RT has an acceptable therapeutic ratio in children but the risk of adverse events requiring hospitalization or subsequent procedures may be increased in select populations.

Purpose To determine whether self-attention cycle-generative adversarial networks (cycle-GANs), a novel deep-learning method, can generate accurate synthetic computed tomography (sCT) to facilitate adaptive proton therapy in children with brain tumors. Materials and Methods Both CT and T1-weighted magnetic resonance imaging (MRI) of 125 children (ages 1-20 years) with brain tumors were included in the training dataset. A model introducing a self-attention mechanism into the conventional cycle-GAN was created to enhance tissue interfaces and reduce noise. The test dataset consisted of 7 patients (ages 2-14 years) who underwent adaptive planning because of changes in anatomy discovered on MRI during proton therapy. The MRI during proton therapy-based sCT was compared with replanning CT (ground truth). Results The Hounsfield unit-mean absolute error was significantly reduced with self-attention cycle-GAN, as compared with conventional cycle-GAN (65.3 ± 13.9 versus 88.9 ± 19.3, P Conclusion The novel cycle-GAN model with self-attention outperforms conventional cycle-GAN for children with brain tumors. Encouraging dosimetric results suggest that sCT generation can be used to identify patients who would benefit from adaptive replanning.

OBJECTIVE Indications for adjuvant radiation in pediatric salivary gland carcinoma rely on high-risk criteria extrapolated from adult data. We sought to determine whether adult-derived high-risk criteria were prognostic in children aged ≤21 years or young adults aged 22 to 39 years. STUDY DESIGN Cross-sectional analysis of a hospital-based national registry. SETTING Patients were identified from the National Cancer Database between 2004 and 2015. METHODS High-risk criteria were defined as adenoid cystic histology, intermediate/high grade, T3/T4, positive margins, and/or lymph node involvement. Exact matching was used to adjust for differences in baseline characteristics between pediatric and young adult patients. RESULTS We identified 215 pediatric patients aged ≤21 years, 317 patients aged 22 to 30 years, and 466 patients aged 31 to 39 years. Within the pediatric cohort, there was no significant difference in overall survival (OS) between low- and high-risk groups (5-year OS, 100% vs 98.5%; P = .29). In contrast, within the young adult cohorts, there was a significant difference in OS between low- and high-risk groups in patients aged 22 to 30 years (5-year OS, 100% vs 96.1%; P = .01) and 31 to 39 years (5-year OS, 100% vs 88.5%; P

Purpose Whole lung irradiation (WLI) is indicated for certain pediatric patients with lung metastases. This study investigated whether WLI delivered as intensity-modulated proton therapy (IMPT) could significantly spare the heart and breasts when compared with conventional WLI delivered with anteroposterior/posteroanterior photon fields and with intensity-modulated photon therapy (IMRT) WLI. Materials and Methods Conventional, IMRT, and IMPT plans were generated for 5 patients (aged 5-22 years). The prescription dose was 16.5 GyRBE in 1.5-GyRBE fractions. Conventional plans used 6-MV photons prescribed to the midline and a field-in-field technique to cover the planning target volume (the internal target volume [ITV] + 1 cm). IMRT plans used 6-MV photons with a 7-beam arrangement with dose prescribed to the planning target volume. IMPT plans used scenario-based optimization with 5% range uncertainty and 5-mm positional uncertainty to cover the ITV robustly. Monte Carlo dose calculation was used for all IMPT plans. Doses were compared with paired Student t test. Results The ITV Dmean was similar for the IMPT, conventional, and IMRT plans, but the IMPT plans had a lower Dmin and a higher Dmax at tissue interfaces than conventional plans (Dmean ratio: 0.96, P > .05; Dmin ratio: 0.9, P Conclusions IMPT resulted in comparable ITV coverage and lower mean doses to the heart and breasts when compared with other techniques. Whole lung irradiation delivered as IMPT warrants prospective evaluation in pediatric patients.

Background Unresectable hypothalamic/optic pathway pilocytic astrocytoma (PA) often progresses despite multiple therapies. Identifying clinical and molecular characteristics of progressive tumors may aid in prognostication and treatment. Methods We collected 72 unresectable, non-neurofibromatosis type 1-associated hypothalamic/optic pathway PA to identify clinical and biologic factors associated with tumor progression. Tumors that progressed after therapy, metastasized, or resulted in death were categorized into Cohort B; those that did not meet these criteria were categorized into Cohort A. DNA methylation and transcriptome analyses were performed on treatment-naïve tumors, and the findings were validated by immunohistochemistry (IHC). Results The median follow-up of the entire cohort was 12.3 years. Cohort B was associated with male sex (M:F = 2.6:1), younger age at diagnosis (median 3.2 years vs 6.7 years, P = .005), and high incidence of KIAA1549-BRAF fusion (81.5% vs 38.5%, P = .0032). Cohort B demonstrated decreased CpG methylation and increased RNA expression in mitochondrial genes and genes downstream of E2F and NKX2.3. Transcriptome analysis identified transcription factor TBX3 and protein kinase PIM1 as common downstream targets of E2F and NKX2.3. IHC confirmed increased expression of TBX3 and PIM1 in Cohort B tumors. Gene enrichment analysis identified enrichment of MYC targets and MAPK, PI3K/AKT/mTOR, and p53 pathways, as well as pathways related to mitochondrial function. Conclusions We identified risk factors associated with progressive PA. Our results support the model in which the p53-PIM1-MYC axis and TBX3 act alongside MAPK and PI3K/AKT/mTOR pathways to promote tumor progression, highlighting potential new targets for combination therapy and refining disease prognostication.

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).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.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.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.

To generate synthetic relative proton stopping power (sRPSP) images from magnetic resonance imaging (MRI) sequence(s) and develop an online quality assurance (QA) tool for sRPSP to facilitate safe integration of magnetic resonance (MR)-only proton planning into clinical practice.Planning computed tomography (CT) and MR images of 195 pediatric brain tumor patients were utilized (training: 150, testing: 45). Seventeen consistent-cycle generative adversarial network (ccGAN) models were trained separately using paired CT-converted RPSP and MRI datasets to transform a subject's MRI into sRPSP. T1-weighted (T1W), T2-weighted (T2W), and FLAIR MRI were permutated to form 17 combinations, with or without preprocessing, for determining the optimal training sequence(s). For evaluation, sRPSP images were converted to synthetic CT (sCT) and compared to the real CT in terms of mean absolute error (MAE) in Hounsfield units (HU). For QA, sCT was deformed and compared to a reference template built from training dataset to produce a flag map, highlighting pixels that deviate by100 HU and fall outside the mean ± standard deviation reference intensity. The gamma intensity analysis (10%/3 mm) of the deformed sCT against the QA template on the intensity difference was investigated as a surrogate of sCT accuracy.The sRPSP images generated from a single T1W or T2W sequence outperformed that generated from multi-MRI sequences in terms of MAE (all p 0.05). Preprocessing with N4 bias and histogram matching reduced MAE of T2W MRI-based sCT (54 ± 21 HU vs. 42 ± 13 HU, p = 0.002). The gamma intensity analysis of sCT against the QA template was highly correlated with the MAE of sCT against the real CT in the testing cohort (r = -0.89 for T1W sCT; r = -0.93 for T2W sCT).Accurate sRPSP images can be generated from T1W/T2W MRI for proton planning. A QA tool highlights regions of inaccuracy, flagging problematic cases unsuitable for clinical use.

Unresectable hypothalamic/optic pathway pilocytic astrocytoma (PA) can be challenging to manage due to repeated progressions despite multiple lines of therapy. To identify clinical and biologic factors associated with tumor progression, we retrospectively identified 72 unresectable non-NF1-associated hypothalamic/optic pathway PA. Tumors were classified as high-risk (50%) if they progressed after three or more lines of chemotherapy/targeted therapy, progressed after radiation, developed metastatic disease, or died of disease. DNA methylation profiling and transcriptome analysis (RNA sequencing) were performed on treatment-naïve tumors with available tissue (n=40), and the findings were validated by immunohistochemistry (IHC) on additional tumor tissue. The median follow-up of the entire cohort was 12.3 years. High-risk tumors were associated with male sex (M:F = 2.6:1), younger age at diagnosis (median 3.2 years vs. 6.7 years, P = 0.005), and high incidence of KIAA1549-BRAF fusion (81.5% vs. 38.5%, P = 0.0032). High-risk tumors demonstrated decreased CpG methylation and increased RNA expression in many mitochondrial genes and genes downstream of E2F and NKX2.3 transcription factors. Transcriptome analysis identified transcription factor TBX3 and proto-oncogene serine/threonine protein kinase PIM1 as common downstream targets of both E2F and NKX2.3 and potential drivers of tumor progression. IHC confirmed increased expression of TBX3 and PIM1 in high-risk tumors. PIM1 is known to increase the stability and transcriptional activity of MYC, and gene enrichment analysis identified enrichment of MYC targets. Signaling pathways known to be implicated in PA, such as MAPK and PI3K/AKT/mTOR, were also enriched, in addition to pathways related to mitochondrial biogenesis and oxidative phosphorylation. Our results support the model in which the p53-PIM1-MYC axis and TBX3 act alongside MAPK and PI3K/AKT/mTOR pathways to promote tumor progression, highlighting potential new targets for combination therapy and refining disease prognosis.

PURPOSE To characterize the association between neurocognitive outcomes (memory and processing speed) and radiation (RT) dose to the hippocampus, corpus callosum (CC), and frontal white matter (WM) in children with medulloblastoma treated on a prospective study, SJMB03. PATIENTS AND METHODS Patients age 3-21 years with medulloblastoma were treated at a single institution on a phase III study. The craniospinal RT dose was 23.4 Gy for average-risk patients and 36-39.6 Gy for high-risk patients. The boost dose was 55.8 Gy to the tumor bed. Patients underwent cognitive testing at baseline and once yearly for 5 years. Performance on tests of memory (associative memory and working memory) and processing speed (composite processing speed and perceptual speed) was analyzed. Mixed-effects models were used to estimate longitudinal trends in neurocognitive outcomes. Reliable change index and logistic regression were used to define clinically meaningful neurocognitive decline and identify variables associated with decline. RESULTS One hundred and twenty-four patients were eligible for inclusion, with a median neurocognitive follow-up of 5 years. Mean right and left hippocampal doses were significantly associated with decline in associative memory in patients without posterior fossa syndrome (all P < .05). Mean CC and frontal WM doses were significantly associated with decline in both measures of processing speed (all P < .05). Median brain substructure dose–volume histograms were shifted to the right for patients with a decline in associative memory or processing speed. The odds of decline in associative memory and composite processing speed increased by 23%-26% and by 10%-15% for every 1-Gy increase in mean hippocampal dose and mean CC or frontal WM dose, respectively. CONCLUSION Increasing RT dose to the CC or frontal WM and hippocampus is associated with worse performance on tests of processing speed and associative memory, respectively. Brain substructure–informed RT planning may mitigate neurocognitive impairment.

Background Management of unresectable pediatric low-grade glioma and glioneuronal tumor (LGG/LGGNT) is controversial. There are no validated prognostic features to guide use of radiation therapy (RT). Our study aimed to identify negative prognostic features in patients treated with RT using clinicopathologic and molecular data and validate these findings in an external dataset. Methods Children with non-metastatic, biopsy-proven unresectable LGG/LGGNT treated with RT at a single institution between 1997 and 2017 were identified. Recursive partitioning analysis (RPA) was used to stratify patients into low- and high-risk prognostic groups based on overall survival (OS). CNS9702 data were used for validation. Results One hundred and fifty patients met inclusion criteria. Median follow-up was 11.4 years. RPA yielded low- and high-risk groups with 10-year OS of 95.6% versus 76.4% (95% CI: 88.7%–98.4% vs 59.3%–87.1%, P = 0.003), respectively. These risk groups were validated using CNS9702 dataset (n = 48) (4-year OS: low-risk vs high-risk: 100% vs 64%, P < 0.001). High-risk tumors included diffuse astrocytoma or location within thalamus/midbrain. Low-risk tumors included pilocytic astrocytoma/ganglioglioma located outside of the thalamus/midbrain. In the subgroup with known BRAF status (n = 49), risk stratification remained prognostic independently of BRAF alteration (V600E or fusion). Within the high-risk group, delayed RT, defined as RT after at least one line of chemotherapy, was associated with a further decrement in overall survival (P = 0.021). Conclusion A high-risk subgroup of patients, defined by diffuse astrocytoma histology or midbrain/thalamus tumor location, have suboptimal long-term survival and might benefit from timely use of RT. These results require validation.

PURPOSE: Most pediatric spinal tumors are low-grade gliomas (LGGs). Characterization of these tumors has been difficult given their heterogeneity and rare incidence. The objective was to characterize such tumors diagnosed at our institution. METHODS: Spinal tumors diagnosed in our pediatric patients between 1984 and 2014 were reviewed retrospectively. Demographics, presentation, pathology, imaging, management, and sequelae were examined. RESULTS: Forty patients had spinal LGG tumors, 24 (62%) of which were pilocytic astrocytomas. The most common initial presentations were pain (n=15), partial extremity paralysis (n=13), and ataxia (n=11), with the diagnosis frequently delayed by months (median=5.9 months, range=4 days-6.2 years). Twenty-nine patients had some tumor resection, and 8 required adjuvant therapy with chemotherapy (n=4) or radiation (n=4) post-resection. Ten other patients received only biopsy for histologic diagnosis, who were treated with chemotherapy (n=4) or radiation (n=5) post biopsy. Tumor progression was noted in 16 patients (2 after gross-total resection; 10, partial resection; and 4, biopsy). During the evaluation period, 3 patients died secondary to tumor progression. BRAF status could have shortened progression-free survival: patients with BRAFV600E mutations (n=3) all experienced progression within 10 months. Long-term sequelae of the disease/treatment were mostly residual neurologic deficits (paresthesia, paralysis), chemotherapy-induced hearing loss, and scoliosis. CONCLUSIONS: Spinal LGG is a rare entity with significant long-term effects. Although surgery is the most common initial treatment option, more in-depth analysis of molecular biomarkers may improve stratification and prognostication.

Background Hippocampal avoidance has been suggested as a strategy to reduce short-term memory decline in adults receiving whole-brain radiation therapy (RT). The purpose of this study was to determine whether the hippocampal dose in children and adolescents undergoing RT for low-grade glioma was associated with memory, as measured by verbal recall. Methods Eighty patients aged at least 6 years but less than 21 years with low-grade glioma were treated with RT to 54 Gy on a phase II protocol. Patients underwent age-appropriate cognitive testing at baseline, 6 months posttreatment, yearly through 5 years posttreatment, year 7 or 8, and year 10 posttreatment. Random coefficient models were used to estimate the longitudinal trends in cognitive assessment scores. Results Median neurocognitive follow-up was 9.8 years. There was a significant decline in short-delay recall (slope = −0.01 standard deviation [SD]/year, P < 0.001), total recall (slope = −0.09 SD/y, P = 0.005), and long-delay recall (slope = −0.01 SD/y, P = 0.002). On multivariate regression, after accounting for hydrocephalus, decline in short-delay recall was associated with the volume of right (slope = −0.001 SD/y, P = 0.019) or left hippocampus (slope = −0.001 SD/y, P = 0.025) receiving 40 Gy (V40 Gy). On univariate regression, decline in total recall was only associated with right hippocampal dosimetry (V40 Gy slope = −0.002, P = 0.025). In children Conclusion In this 10-year longitudinal study, greater hippocampal dose was associated with a greater decline in delayed recall. Such findings might be informative for radiation therapy planning, warranting prospective evaluation.

Choriocarcinoma syndrome is an uncommon, potentially fatal complication of germ cell tumors (GCTs) in adults, but it is not well documented in children. Pediatric central nervous system (CNS) GCTs comprise a rare group of malignancies not usually associated with extra-CNS metastatic disease. Here, we report the case of a pediatric patient with a suprasellar mixed GCT and pulmonary metastases who presented with intratumoral hemorrhage and stroke. Choriocarcinoma syndrome developed soon after initiating chemotherapy. The primary tumor and pulmonary metastases were successfully treated using a multidisciplinary approach, including neurovascular intervention, chemotherapy, and craniospinal irradiation.

Purpose/Objective(s) An interim analysis of a Phase IV clinical trial was performed to estimate the incidence of CNS radiation necrosis (CNS-RN) and identify predictive parameters. Materials/Methods At the time of analysis, the trial had accrued 366 patients with CNS and base of skull tumors treated with pencil beam scanning proton therapy (PBS-PT). Patients with a prior history of radiation therapy (n = 32), treatments with no reported dose to the brain (n = 4), or incomplete dosimetry (n = 39) were excluded. Cox proportional hazards models were used to evaluate the impact of interventions on time to resolution. Events were graded according to CTCAE v4 guidelines. Eloquent cortex was defined as a brain region which, when damaged, lead to severe focal neurologic deficits. Brain and brainstem dose volume histograms were pooled to create complication incidence maps for grade 1+ radiation necrosis. The total probability that the true rate of necrosis exceeded 5% in the brainstem and 10% in the brain was estimated at all dose-volume combinations. Intersections at volumes of 0.1cc and 1cc were assessed at probabilities of 10% and 50%. Results Twenty-three (n = 23) CNS-RN events, corresponding to 15 grade 1 and 8 grade 3 events, were observed in 291 patients resulting in a 2-year CI in grade 3 necrosis of 6.02% +/- 0.013 (s.e). CNS-RN (any grade) was more common in astrocytic-oligodendroglial, embryonal, and ependymal tumors. PBS-PT attribution was likely or plausible in all but 2 events. Although CNS-RN could not be attributed solely to end-of-range effects, 11 (48%) cases occurred in the region of the cervico-medullary junction. Complete resolution of CNS necrosis occurred in all 8 grade 3 patients and in 12 of 15 (80%) grade 1 events. Grade 3 or more severe events were treated with bevacizumab, corticosteroids, or hyperbaric oxygen therapy. Symptomatic resolution was comparable between treatments although bevacizumab showed an advantage for radiographic resolution (HR 4.3, 95% CI 1.6-11). Factors predictive of symptom resolution were eloquence of the region of necrosis (HR 0.15, 95% CI 0.035-0.67, P = 0.0003) and any chemotherapy exposure (HR 0.16, 95% CI 0.03-0.88, P = 0.034). The probability of true necrosis rate exceeding 5% in brainstem increased from less than 10% to greater than 50% at 58.5CGE to a volume of 0.1cc and 57.7CGE to a volume of 1cc. The probability that the true necrosis rate exceeded 10% in the brain increased from less than 10% to greater than 50% at a dose of 63.1CGE to a volume of 0.1cc. At a volume of 1cc, sparsity of data limited analysis to the less than 50% to greater than 50% probability level, which occurred at 60.5CGE. Conclusion Incidence of radiation necrosis was consistent with photon historical data. These data will aid the development of PBS-PT delivery guidelines aimed at minimizing CNS necrosis risk for children requiring RT which involves or approximates the CNS.

Proton therapy planning requires Hounsfield unit (HU) data from CT images to calculate dose and, in the case of pelvic sarcomas, accurate registration of the CT to MRI to delineate tumor. MR-only proton therapy planning would eliminate the uncertainty associated with CT/MR image registration and the need for CT, reducing exposure to radiation and anesthesia in children. We determined whether MR-only proton therapy planning is feasible by introducing a transfer learning-based cycleGAN (TL-cycleGAN) method to convert pelvic MRI to synthetic CT (sCT) for dose calculation and to specifically address the challenge of a small training dataset, commonly associated with pediatric studies. The TLcycleGAN was designed to transfer knowledge gained from converting a large number (n=125) of pediatric brain MRI studies to sCT and finetune the well-trained model on pelvic data. Sixteen patients (aged 1.1–21.3 years, 7 females) who received proton therapy to the pelvis were randomly divided into training (n=11) and testing (n=5) groups. sCT generated from T1- T2-weighted fat suppression MR images was compared to the real CT in terms of peak signal-tonoise ratio (PSNR), structural similarity (SSIM) index, mean error (ME), and mean absolute error (MAE) in HU. The mean ± standard deviation of PSNR, SSIM, ME and MAE were 30.6±3.0, 0.93±0.04 -3.4±10.2 HU, and 52.4±17.6 HU, respectively, for T1W MRI; 29.2±1.5, 0.93±0.02, -6.6±24.8 HU, and 85.4±18.8 HU, respectively, for T2W MRI. Transfer learning facilitates MR-only pediatric pelvic proton therapy planning by generating highly accurate sCT for a small training dataset and a large variation.

Background: Early reports suggest adverse events following proton therapy (PT) for childhood cancer are more prevalent. We evaluated treatment-failure and toxicity following Pencil Beam Scanning (PBS)-PT in children. Methods: The single-institution Phase IV trial screened 856 children, of which 528 were eligible for PBS-PT, and 500 enrolled in SJPROTON1 from 2017–2020. The median follow-up was 2.1 years (range 1.1-4.4). The primary objective was the cumulative incidence (CI) of ≥grade 3 non-hematologic, PBS-PT attributable toxicity by CTCAE v4.0. Additional outcomes included PBS-PT toxicity attributable hospitalization, procedures, and treatment-related mortality. Toxicities including necrosis, vasculopathy, neurologic deficits, and fracture/osteoradionecrosis were further characterized (any grade). Competing risk regression was used to evaluate predictors of ≥grade 3 PBS-PT attributable toxicity. Findings: At two years, the event-free survival was 73.2% (95% CI, 68.9%-77.8%). Distant and local failure predominated with a 2-year CI of 16.5% (95% CI 13.1-20.4) and 6.8% (95% CI 4.6-9.5) respectively. The 4 year CI of ≥grade 3 toxicity was 24.5%; including necrosis (3.7%), neurologic deficit (2.9%), and fracture/osteoradionecrosis (0.79%). The rates of PBS-PT-toxicity attributable hospitalization and procedures were 3.9% and 7.6%. Predictors of any ≥grade 3 toxicity included baseline total toxicity burden (TTB) (HR 1.043, 95% CI 1.012-1.07, p=0.007), and mixed photon/PBS-PT (HR 2.62, 95% CI 1.51-4.54, p=0.006) in CNS patients, and pelvic radiotherapy (HR 4.25, 95% CI 1.08-16.72, p=0.038), and TTB (HR 1.1, 95% CI 1.04-1.16, p=0.002) in non-CNS patients. Interpretation: PBS-PT yields a low incidence of toxicity, but subsets are at increased risk, and may require additional procedures or hospitalization. Funding: This work was supported by ALSAC and Cancer Center Core Grant CA21765. Declaration of Interest: None to declare. Ethical Approval: The SJPROTON1 trial was reviewed and approved by the Institutional Review Board at St. Jude. Informed consent was obtained from the parent, caregiver, or patient, with assent from the patient, as appropriate.

To train a deep neural network for correcting abdominal and pelvic cone-beam computed tomography (CBCT) of children and young adults in the presence of diverse patient size, anatomic extent, and scan parameters.Pretreatment CBCT and planning/repeat CT image pairs from 64 children and young adults treated with proton therapy (aged 1-23 years) were analyzed. To evaluate the impact of anatomic extent in CBCT and data size in the training data, we compared the performance of three cycle-consistent generative adversarial network models that were separately trained by three datasets comprising abdominal (n = 21), pelvic (n = 29), and combined abdominal-pelvic image pairs (n = 50), respectively. The maximum body width of each patient was normalized to a fixed width before training and model application to reduce the impact of variations in body size. The corrected CBCT images by the three models were comparatively evaluated against the repeat CT closest in time to the CBCT (median gap, 0 days; range, 0-6 days) in HU accuracy, estimated dose distribution, and proton range.The network model trained by the combined dataset significantly outperformed the abdomen and pelvis models in mean absolute HU error of the corrected CBCT from 14 testing patients (47 ± 7 HU versus 51 ± 8 HU; paired Wilcoxon signed-rank test, P 0.01). The larger error (60 ± 7 HU) without the body-size normalization confirmed the efficacy of the preprocessing. The model trained with the combined dataset resulted in gamma passing rates of 98.5 ± 1.9% (2%/2 mm criterion) and the range (80% distal fall-off) differences from the reference within ±3 mm for 91.2 ± 11.5% beamlets.Combining data from adjacent anatomic sites and normalizing age-dependent body sizes in children and young adults were beneficial in training a neural network to accurately estimate proton dose from CBCT despite limited training data size and anatomic diversities.

Background Low-grade gliomas (LGGs) and low-grade glioneuronal tumors (LGGNTs) diagnosed during the first year of life carry unique clinical characteristics and challenges in management. However, data on the treatment burden, outcomes, and morbidities are lacking. Methods A retrospective study of LGGs and LGGNTs diagnosed in patients younger than 12 months at St. Jude Children's Research Hospital (1986-2015) was conducted. Results For the 51 patients (including 31 males), the mean age at diagnosis was 6.47 months (range, 0.17-11.76 months), and the mean follow-up period was 11.8 years (range, 0.21-29.19 years). Tumor locations were hypothalamic/optic pathway (61%), hemispheric (12%), brainstem (12%), cerebellar (8%), and spinal (8%). There were 41 patients with histological diagnoses: 28 had World Health Organization grade 1 tumors, 6 had grade 2 tumors, and 7 had an LGG/LGGNT not definitively graded. Forty-one patients required an active intervention at diagnosis. Throughout their treatment course, 41 patients eventually underwent tumor-directed surgeries (median, 2 surgeries; range, 1-6), 39 received chemotherapy (median, 2 regimens; range, 1-13), and 21 received radiotherapy. Forty patients experienced disease progression (median, 2 progressions; range, 1-18). Ten patients died of progression (n = 5), malignant transformation (n = 2), a second cancer (n = 2), or a shunt infection (n = 1). The 10-year overall survival, progression-free survival, and radiation-free survival rates were 85% ± 5.3%, 16.9% ± 5.3%, and 51.2% ± 7.5%, respectively. Forty-nine patients experienced health deficits (eg, endocrinopathies, obesity, seizures, visual/hearing impairments, neurocognitive impairments, and cerebrovascular disease). Predictors of progression and toxicities were defined. Conclusions Infantile LGG/LGGNT is a chronic, progressive disease universally associated with long-term morbidities and requires multidisciplinary intervention.

PURPOSE: Low-grade gliomas (LGG) are a heterogeneous group of brain tumors, which are often assumed to have a benign course. Yet, children diagnosed and treated for LGG in infancy are at increased risk for neurodevelopmental disruption. We sought to investigate neuropsychological outcomes of infants diagnosed with LGG. METHODS: Between 1986 and 2013, 51 patients were diagnosed with LGG before 12 months of age and managed at St. Jude Children’s Research Hospital. Twenty-five of the 51 patients received a cognitive assessment (68% male; 6.8 ± 3.3 months at diagnosis; 10.5 ± 4.8 years at latest assessment). Approximately half the patients received radiation therapy (n = 12; aged 4.0 ± 3.0 years at radiation therapy), with a median of 2 chemotherapy regimens (range = 0 – 5) and 1 tumor directed surgery (range = 0 – 5). RESULTS: The analyses revealed performance below age expectations on measures of IQ, memory, reading, mathematics, and fine motor functioning as well as parent-report of attention, executive, and adaptive functioning. Following correction for multiple comparisons, a greater number of chemotherapy regimens was associated with lower scores on measures of IQ and mathematics. More tumor directed surgeries and presence of visual field loss were associated with poorer dominant hand fine motor control. Radiation therapy exposure was not associated with decline in neuropsychological performance. CONCLUSIONS: Children diagnosed with LGG in infancy experience substantial neuropsychological deficits. Treatment factors, including number of chemotherapy regimens and tumor directed surgeries, may increase risk for neurodevelopmental disruption and need to be considered in treatment planning.

Purpose To analyze the incidence of and risk factors for clinically significant radiation necrosis (cRN) in adult cranial oligodendrogliomas and astrocytomas treated with proton or photon therapy. Methods and Materials Between 2007 and 2015, 160 patients with grade 2 or 3 oligodendrogliomas (with 1p/19q codeletion, n = 53) or astrocytomas (without 1p/19q codeletion, n = 107) were treated with proton (n = 37) or photon (n = 123) therapy. Clinically significant radiation necrosis (RN) was defined as symptomatic RN or asymptomatic RN that resulted in surgery or bevacizumab administration. The cumulative incidence was calculated using competing risks. Risk factors were identified using Cox proportional hazards. Results After a median follow-up period of 28.5 months, cRN developed in 18 patients (proton, 6; photon, 12). The 2-year cumulative incidence of cRN for proton and photon therapy was 18.7% (95% confidence interval [CI], 7.5%-33.8%) and 9.7% (95% CI, 5.1%-16%), respectively (P = .16). On multivariate analysis, risk factors for cRN included oligodendroglioma (hazard ratio [HR], 3.57; 95% CI, 1.38-9.25; P = .009) and higher prescription dose (in gray relative biological equivalents [GyRBE]) (HR, 1.30; 95% CI, 1.05-1.61; P = .015). The 2-year cumulative incidence of cRN in oligodendrogliomas and astrocytomas was 24.2% and 6.2%, respectively (P = .01). The relative volume (percentage) of brain receiving 60 GyRBE was a significant dosimetric predictor of cRN in oligodendrogliomas (HR, 1.11; 95% CI, 1.03-1.20; P = .005). Conclusions The study showed that 1p/19q codeleted oligodendroglioma was a significant risk factor associated with cRN and the relative volume (percentage) of brain receiving 60 GyRBE was an important dosimetric predictor of cRN for oligodendroglioma patients. There is insufficient evidence at this time to conclude a significant difference in the incidence of cRN between proton and photon therapy.

PURPOSE/OBJECTIVE(S) To characterize the association between neurocognitive outcomes and radiation dose to the corpus callosum and the hippocampus in children with medulloblastoma treated on a phase III study. MATERIALS/METHODS Patients aged 3 to 21 years with medulloblastoma were treated at a single institution on a phase III risk-adapted study. Craniospinal radiation dose was 23.4 Gy for average-risk patients (M0 and GTR/NTR) and 36-39.6 Gy for high-risk patients (M+ or STR). All patients were treated with photons and received 55.8 Gy to the tumor bed using a 1cm clinical target volume margin. Metastasis > 0.5 cm received 50.4-54 Gy. Patients underwent age-appropriate cognitive testing at baseline (prior to completion of radiation) and yearly for 5 years. Neurocognitive scores were reported as standard deviations (SD) derived from age-standardized normative samples. Mixed effects models were used to estimate the longitudinal trends in neurocognitive scores. Reliable change index was used to identify patients whose scores declined significantly from baseline to last follow-up. Logistic regression was used to identify variables associated with a significant decline in neurocognitive outcomes. RESULTS One hundred and twenty-four patients were eligible for analysis. The median neurocognitive follow-up was 59.4 months. Decline in processing speed was associated with mean dose to the corpus callosum genu (slope: -.166 points/year/Gy, P < .001), body (slope: -.176 points/year/Gy, P < .001) and splenium (slope: -.115 points/year/Gy, P < .001), after adjusting for age and sex. Of the 90 patients with baseline processing speed scores, 21 (19%) demonstrated significant decline at last follow up. Patients with a mean corpus callosum genu and body dose of ≥40 Gy were at a four to seven-fold increased odds of experiencing significant decline compared to those with a mean dose of < 40 Gy (genu: OR: 7.47, 95% CI: 2.64 - 21.12, P < .001; body: OR: 4.47, 95% CI: 1.65 - 12.11, P = .003). Decline in associative memory was associated with mean right hippocampal dose (slope: -.11 points/year/Gy, P = .013) and left hippocampal dose (slope: -.109 points/year/Gy, P = .019), after adjusting for age and sex. Of 98 patients with baseline memory scores, 11 (11%) demonstrated significant decline at last follow up. Patients with a mean hippocampal dose of ≥50 Gy were at a five to seven-fold increased odds of experiencing significant decline compared to those with mean dose < 50 Gy (right hippocampus: Odds Ratio [OR]: 7.21, 95% Confidence Interval [CI]: 1.98 - 27.46, P = .004; left hippocampus: OR: 5.17, 95% CI: 1.38 - 19.36, P = .015). CONCLUSION For children with medulloblastoma, increasing radiation dose to the corpus callosum and hippocampus is associated with decreased performance on tests of processing speed and memory, respectively. During radiation plan optimization, careful consideration should be given to minimizing dose to these structures while achieving appropriate tumor bed coverage.

BACKGROUND: The objective of this study was to evaluate the contribution of radiation dose to different intracranial structures on changes in intellectual function for children with brain tumors. METHODS: We evaluated children with brain tumors treated in 2005–2017 who had longitudinal neuropsychological assessments and available photon dosimetric data (if radiation therapy [RT] given). Full Scale Intelligence Quotient (FSIQ) and index scores were evaluated (perceptual reasoning index [PRI], processing speed index [PSI], verbal comprehension index [VCI], and working memory index [WMI]). Multivariable linear mixed effects models were used to model endpoints, with age at RT and dose to different brain regions as fixed effects and patient-specific random intercepts. P-values (P*) were adjusted for multiple comparisons. RESULTS: Sixty-nine patients were included, 56 of whom received RT. Median neuropsychological follow-up was 3.2 years. Right temporal lobe mean dose was strongly associated with decline in FSIQ (P* = 0.005); with each gray increase in mean dose, there was a decrease of 0.052 FSIQ points per year. Dose to 50% (D50) of the supratentorial brain was associated with decline in PSI (P* = 0.006) and WMI (P* = 0.001). Right and left hippocampus D50 were individually strongly associated with declines in VCI (P* = 0.009 for each). Presence of a ventriculoperitoneal shunt decreased FSIQ by 10 points. CONCLUSIONS: We reported associations between dosimetry to specific brain regions and intellectual outcomes, with suggested avoidance structures during RT planning. These models can help clinicians anticipate changes in neurocognition post-RT and guide selection of an optimal RT plan.

Children with sporadic optic pathway glioma (OPG) commonly experience a decline in visual acuity (VA). This study aimed to quantify long-term VA outcomes after definitive radiation therapy (RT). From 1997 to 2017, 41 patients underwent RT for OPG and had baseline VA testing. All patients underwent serial VA testing every 3–6 months during the first 5 years and annually thereafter. The cumulative incidence of VA decline or improvement (per eye) was estimated using death as a competing risk. Mean follow-up was 5 years. Most tumors (93%) involved the postchiasmatic optic tracts and/or hypothalamus. Of the tumors tested for BRAF alterations (n = 15), 67% had a BRAF fusion. Median time to VA decline was 20 months in the eye with worse vision and 22 months in the better eye. For the worse eye, the 5-year cumulative incidences of VA decline and improvement were 17.9% [95% confidence interval (CI) 7–32.8%] and 13.5% (95% CI 4.7–26.7%), respectively. For the better eye, the 5-year cumulative incidences of VA decline and improvement were 11.5% (95% CI 3.5–30.7%) and 10.6% (95% CI 2.6–25.2%), respectively. Visual outcomes did not correlate with radiographic evidence of tumor progression. The 5-year cumulative incidence of VA decline was low. VA decline is most likely to occur within the first 2 years after RT and is not associated with radiographic progression of disease, highlighting the need for frequent ophthalmologic exams during this period.

Purpose To use magnetic resonance image guided radiation therapy (MR-IGRT) for accelerated partial-breast irradiation (APBI) to ( 1 ) determine intrafractional motion of the breast surgical cavity; and ( 2 ) assess delivered dose versus planned dose. Methods and Materials Thirty women with breast cancer (stages 0-I) who underwent breast-conserving surgery were enrolled in a prospective registry evaluating APBI using a 0.35-T MR-IGRT system. Clinical target volume was defined as the surgical cavity plus a 1-cm margin (excluding chest wall, pectoral muscles, and 5 mm from skin). No additional margin was added for the planning target volume (PTV). A volumetric MR image was acquired before each fraction, and patients were set up to the surgical cavity as visualized on MR imaging. To determine the delivered dose for each fraction, the electron density map and contours from the computed tomography simulation were transferred to the pretreatment MR image via rigid registration. Intrafractional motion of the surgical cavity was determined by applying a tracking algorithm to the cavity contour as visualized on cine MR. Results Median PTV volume was reduced by 52% when using no PTV margin compared with a 1-cm PTV margin used conventionally. The mean (± standard deviation) difference between planned and delivered dose to the PTV (V95) was 0.6% ± 0.1%. The mean cavity displacement in the anterior–posterior and superior–inferior directions was 0.6 ± 0.4 mm and 0.6 ± 0.3 mm, respectively. The mean margin required for at least 90% of the cavity to be contained by the margin for 90% of the time was 0.7 mm (5th-95th percentile: 0-2.7 mm). Conclusion Minimal intrafractional motion was observed, and the mean difference between planned and delivered dose was less than 1%. Assessment of efficacy and cosmesis of this MR-guided APBI approach is under way.

With modern therapy, overall survival (OS) for children with acute lymphoblastic leukemia approaches 90%. However, inferior outcomes for minority children have been reported. Data on the effects of ethnicity/race as it relates to socioeconomic status are limited. Using state cancer registry data from Texas and Florida, we evaluated the impact of neighborhood-level poverty rate and race/ethnicity on OS for 4719 children with acute lymphoblastic leukemia. On multivariable analysis, patients residing in neighborhoods with the highest poverty rate had a 1.8-fold increase in mortality compared with patients residing in neighborhoods with the lowest poverty rate (hazard ratio [HR], 1.8; 95% confidence interval [CI], 1.41-2.30). Hispanic and non-Hispanic black patients also had increased risk of mortality compared with non-Hispanic white patients (Hispanic: HR, 1.18; 95% CI, 1.01-1.39; non-Hispanic black: HR, 1.31; 95% CI, 1.03-1.66). On subgroup analysis, there was a 21.7% difference in 5-year OS when comparing non-Hispanic white children living in the lowest poverty neighborhoods (5-year OS, 91.2%; 95% CI, 88.6-93.2) to non-Hispanic black children living in the highest poverty neighborhoods (5-year OS, 69.5%; 95% CI, 61.5-76.1). To address such disparities in survival, further work is needed to identify barriers to cancer care in this pediatric population.

Most pediatric spinal tumors are low-grade gliomas (LGGs). Characterization of these tumors has been difficult given their heterogeneity and rare incidence. Spinal tumors diagnosed in pediatric patients at our institution between 1984 and 2014 were reviewed retrospectively. Demographics, clinical presentation, pathology, imaging, management, and late effects were examined. Of the 730 patients with LGG, forty patients (5.5%) had spinal tumors, twenty-four (60%) of which were pilocytic astrocytomas. The most common initial presentations were pain (n=15), partial extremity paralysis (n=13), and ataxia (n=11), with the diagnosis frequently delayed by months and sometimes years (range

Aim To describe the clinical implementation and optimization of magnetic resonance imaging (MRI) systems installed in a radiation oncology department for dedicated use in radiotherapy (RT) simulation and treatment planning for pediatric patients. Methods Two wide-bore MRI systems were installed and commissioned in 2016. Patient setups, coil placements, and scan protocols were developed to image various anatomic sites in children. Patients with brain tumors were routinely imaged using a pair of flexible loop coils and a posterior receiver coil integrated into the patient couch. The integrated posterior coil and the flexible anterior torso coil supported by the coil bridge were used together when imaging the abdomen, pelvis, or spine. A three-dimensional acquisition was most often performed, given the benefit of high-resolution multiplanar reformation as well as elimination of B0-related distortions in the slice selection direction. Results We performed 542 MRI studies (265 for planning and 277 for monitoring on-treatment tumor changes) on pediatric patients in the first year after system installation. Multisequence images of pediatric RT patients with ependymoma, medulloblastoma, craniopharyngioma, rhabdomyosarcoma, or Ewing sarcoma were shown to illustrate the image quality obtainable with optimized planning sequences. Conclusions Magnetic resonance imaging (MRI) of pediatric patients in their treatment positions with setup devices in place can be performed with coil arrangements that include flexible coils. The resulting image quality is suitable for treatment planning and on-treatment monitoring. We provide optimized site-specific sequence parameters to support the continued improvement of MRI for pediatric RT planning.

Purpose To assess the use of brachytherapy (BT) with or without external beam radiation (EBRT) in inoperable stage I endometrial adenocarcinoma in the United States and to determine the effect of BT on overall survival (OS) and cause-specific survival (CSS). Methods and Materials Data between 1998 and 2011 from the National Cancer Institute's Surveillance, Epidemiology and End Results database were analyzed. Coarsened exact matching was used to adjust for differences in age and grade between patients who received BT and those who did not. Prognostic factors affecting OS and CSS were evaluated using the Kaplan-Meier product-limit method and a Cox proportional hazards regression model. Results A total of 460 patients with inoperable stage I endometrial adenocarcinoma treated with radiation therapy were identified. Radiation consisted of either EBRT (n=260) or BT with or without EBRT (n=200). The only factor associated with BT use was younger patient age (median age, 72 vs 76 years, P =.001). Patients who received BT had a higher 3-year OS (60% vs 47%, P P =.032) compared with those who did not. On multivariate analysis, BT use was independently associated with an improved OS (hazard ratio [HR] 0.67, 95% confidence interval [CI] 0.52-0.87) and CSS (HR 0.61, 95% CI 0.39-0.93). When patients were matched on age, BT use remained significant on multivariate analysis for OS (HR 0.65, 95% CI 0.48-0.87) and CSS (HR 0.52, 95% CI 0.31-0.84). When matched on age and grade, BT remained independently associated with improved OS and CSS (OS HR 0.62, 95% CI 0.46-0.83; CSS HR 0.57, 95% CI 0.34-0.92). Conclusion Brachytherapy is independently associated with improved OS and CSS. It should be considered as part of the treatment regimen for stage I inoperable endometrial cancer patients undergoing radiation.