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Purpose Primary mediastinal B cell lymphoma (PMBCL) is a highly curable subtype of non-Hodgkin lymphoma that is diagnosed predominantly in adolescents and young adults. Consequently, long-term treatment-related morbidity is critical to consider when devising treatment strategies that include different chemoimmunotherapy strategies with or without radiation therapy. Furthermore, adaptive approaches using the end-of-chemotherapy (EOC) positron emission tomography (PET)/computed tomography (CT) scanning may help to determine which patients may benefit from additional therapies. We aimed to develop evidence-based guidelines for treating these patients. Methods and Materials We conducted a systematic review in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guideline using the PubMed database. The ARS expert committee, composed of radiation oncologists, hematologists, and pediatric oncologists, developed consensus guidelines using the modified Delphi framework. Results Nine studies met the full criteria for inclusion based on reporting outcomes on patients with primary mediastinal B cell lymphoma with EOC PET/CT response scored with the 5-point Deauville scale. These studies formed the evidence for these guidelines in managing patients with PMBCL according to the EOC PET response, including after a 5-point Deauville scale of 1 to 3, 4, or 5, and for patients with relapsed and refractory disease. The expert group also developed guidance on radiation simulation, treatment planning, and plan evaluation based on expert opinion. Conclusions Various treatment approaches exist in the management of PMBCL, including different chemoimmunotherapy regimens, the use of consolidative radiation therapy, and adaptive approaches based on EOC PET/CT response. These guidelines can be used by practitioners to provide appropriate treatment according to different disease scenarios.

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.

Brainstem necrosis is a rare, but dreaded complication of radiation therapy; however, data on the incidence of brainstem injury for tumors involving the posterior fossa in photon-treated patient cohorts are still needed.Clinical characteristics and dosimetric parameters were recorded for 107 pediatric patients who received photon radiation for posterior fossa tumors without brainstem involvement from 2000 to 2016. Patients were excluded if they received a prescription dose50.4 Gy, a brainstem maximum dose50.4 Gy, or had fewer than 2 magnetic resonance imaging scans within 18 months after radiation. Post-radiation therapy magnetic resonance imaging findings were recorded, and brainstem toxicity was graded using National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.The most common histologies were medulloblastoma (61.7%) and ependymoma (15.9%), and median age at diagnosis was 8.3 years (range, 0.8-20.7). Sixty-seven patients (62.6%) received craniospinal irradiation (median, 23.4 Gy; range, 18.0-39.6) as a component of their radiation therapy, and 39.3% and 40.2% of patients received an additional involved field or whole posterior fossa boost, respectively. Median prescribed dose was 55.8 Gy (range, 50.4-60.0). Median clinical and imaging follow-up were 4.7 years (range, 0.1-17.5) and 4.2 years (range, 0.1-17.3), respectively. No grade ≥2 toxicities were observed. The incidence of grade 1 brainstem necrosis was 1.9% (2 of 107). These patients were by definition asymptomatic and experienced resolution of imaging abnormality after 5.3 months and 2.1 years, respectively.Risk of brainstem necrosis was minimal in this multi-institutional study of pediatric patients treated with photon radiation therapy for tumors involving the posterior fossa with no cases of symptomatic brainstem injury, suggesting that brainstem injury risk is minimal in patients treated with photon therapy.

Radiation therapy (RT) for the management of lymphoma has evolved over the past few decades. Large, extended, or involved fields have been replaced by smaller involved sites or nodal volumes. Currently, customized plans are created for each individual patient, and these plans encompass only the areas involved by disease. A critical factor that has enabled this shift in practice is the evolving use of imaging studies. Imaging plays a key role in patient selection and RT planning and delivery. The objective of this manuscript is to provide guidelines for best practice of use of imaging in pretreatment evaluation, treatment choice, RT target volume definition, and RT treatment verification and delivery.

Radiation therapy (RT) provides an effective and often rapid means to alleviate symptomatic progression in pediatric patients with advanced or metastatic cancer. As part of a comprehensive, multimodality approach to pediatric palliative care, RT can be a useful tool to manage pain, spinal cord compression, dyspnea, neurologic compromise, bleeding, and bowel or urinary obstruction. Whether such symptoms present earlier in the disease course or in children and adolescents approaching the end of life, they can significantly impact the quality of life of patients and caregivers. Control of symptoms is therefore an important aspect in maximizing end of life care. Outcomes for palliative RT in both children and adults are favorable. While RT has been widely adopted as a component of palliative oncologic care for many adult malignancies, it remains infrequently utilized in pediatric patients despite the relative radiosensitivity of many pediatric tumors. Potential barriers to palliative radiation for pediatric patients include insufficient understanding by care providers regarding the utility of RT for a given symptom, lack of comfort in discussing a transition away from definitive management, concern over radiation-related side effects, and hesitancy toward radiation treatment on the part of parents and caregivers. Delivery of palliative RT can also be impeded by logistical obstacles including lack of on-site radiation facilities, unavailability of radiation oncologists comfortable with pediatric treatments, and the potential need for specialized medical care such as pediatric anesthesia. The aim of this review is to foster a more complete understanding of the benefits and limitations of palliative RT in the pediatric oncology setting, including common symptoms experienced by children and adolescents with cancer that may be indications for the integration of RT into palliative care paradigms, as well as the expected efficacy of treatment. We describe the logistics, delivery, common doses for palliative radiation regimens, and management of potential side effects. While palliative RT is generally well tolerated in the pediatric population, we also discuss potential side effects of RT to various body sites and approaches for prevention or mitigation.

Ongoing rapid advances in molecular diagnostics, precision imaging, and development of targeted therapies have resulted in a constantly evolving landscape for treatment of pediatric cancers. Radiotherapy remains a critical element of the therapeutic toolbox, and its role in the era of precision medicine continues to adapt and undergo re-evaluation. Here, we review emerging strategies for combining radiotherapy with novel targeted systemic therapies (for example, for pediatric gliomas or soft tissue sarcomas), modifying use or intensity of radiotherapy when appropriateviamolecular diagnostics that allow better characterization and individualization of each patient’s treatments (for example, de-intensification of radiotherapy in WNT subgroup medulloblastoma), as well as exploring more effective targeted systemic therapies that may allow omission or delay of radiotherapy. Many of these strategies are still under investigation but highlight the importance of continued pre-clinical and clinical studies evaluating the role of radiotherapy in this era of precision oncology.

Non-rhabdomyosarcoma soft-tissue sarcomas (NRSTS) comprise 4% of childhood cancers and consist of numerous histologic subtypes. Prognostic factors associated with poor outcome include high histologic grade, large tumor size, presence of metastases, and unresectability. Complete surgical resection is critical for the best oncologic outcomes and is prioritized in treatment algorithms. The use of radiation therapy (RT) and chemotherapy is based upon factors such as resectability, histologic grade, tumor size, and stage. North American and European trials are defining a risk-based approach to NRSTS to limit treatment-related toxicity and to maximize therapeutic efficacy. In this paper, we summarize the current roles of surgery, RT, and chemotherapy in NRSTS and describe ongoing research that is advancing the care of NRSTS patients.

PURPOSE/OBJECTIVE(S) To evaluate the relationship between total body irradiation (TBI) and other factors in the development of idiopathic pneumonia syndrome (IPS) in pediatric patients undergoing allogeneic hematopoietic cell transplantation (HCT) for acute leukemia. MATERIALS/METHODS Between 2006-2019, 121 pediatric patients with acute leukemia (84 lymphoblastic, 37 myeloid), ranging in age from 1 to 21 years (median 12), underwent allogeneic HCT at a single institution with matched sibling (n = 33), single unrelated cord blood (sUCB; n = 57), or double unrelated cord blood (dUCB; n = 31) donor. Pretransplantation conditioning included cyclophosphamide (100-120 mg/kg) with (n = 89) or without fludarabine (75 mg/m2) (n = 32). TBI was delivered in 8 b.i.d. fractions of 1.65 Gy over 4 days via opposed lateral beams of 6, 18, or 25 MV prescribed to midplane at umbilicus, with the patient in a semi-recumbent position, and without lung shielding. Aluminum lung compensator was utilized if predicted mid-lung point dose was ≥3% higher than prescription dose (n = 28). Dose rate was specified at 9-20 cGy/min and depended on linear accelerator availability. Patients were stratified by receipt of high-dose-rate (HDR; > 15 cGy/min; 36%) or low-dose-rate (LDR; ≤15 cGy/min; 64%) delivery. IPS was defined as pulmonary injury based on clinical symptoms, radiographic evidence, or pulmonary function testing within 100 days of HCT in the absence of concurrent infection. The association between treatment factors and IPS was examined. RESULTS Overall, IPS developed in 22 (18%) patients from day 6 to 83 (median 20) after HCT. On univariate analysis, factors associated with IPS included donor type (matched sibling 12%, sUCB 12%, dUCB 35%, P < 0.01), HDR TBI (35% vs 9% for LDR, P < 0.01), and lower beam energy (35% for 6 MV and 15% for 18/25 MV, P = 0.04). The finding of beam energy significance is likely the result of the 6 MV cohort having a greater dose rate (median 16 cGy/min) than the 18/25 MV cohort (11 cGy/min). On competing risk regression analysis, the pre-specified factors of dose rate, beam energy, lung compensator, age, HCT comorbidity index, and donor type were included in the model. All factors except age (hazard ratio [HR] 1.09, P = 0.20) and lung compensator (HR 1.8, P = 0.17) showed an independent statistically significant association with IPS. Kaplan-Meier estimated 1-year survival was 73% for the entire cohort. Time-dependent effect of IPS did not show an association with overall survival (HR 1.2, P = 0.76). CONCLUSION TBI dose rate is an important variable in the risk of pulmonary toxicity in children treated with allogeneic HCT. TBI dose rates ≤15 cGy/min reduced the risk of posttransplantation IPS and should be strongly considered as an easily implemented parameter in pre-transplantation TBI-based conditioning.

We present the case of a 79-year-old male, who was initially treated for mucosa-associated lymphoid tissue lymphoma (MALT lymphoma) of the right eyelid, and later for disease relapse in the stomach. During follow up, he was noted to have developed left arm nodules just medial to the proximal biceps muscle, which were found to be multiply enlarged lymph nodes on subsequent ultrasound imaging. Excisional biopsy of these nodes revealed MALT lymphoma. He was initially referred for consideration of radiation, but a restaging F-18 fluorodeoxyglucose positron emission tomography integrated with computed tomography (F-18 FDG PET/CT) further identified a focus of suspicious uptake in left calf, which was later also biopsy proven to be MALT lymphoma. His disease was upstaged as the result of this later finding, and the overall recommendation for treatment changed to favor systemic treatment with Rituximab.

PurposeThe ARST0332 trial for pediatric and young adults with nonrhabdomyosarcoma soft tissue sarcoma (NRSTS) used risk-based treatment including primary resection with lower-than-standard radiation doses to optimize local control (LC) while minimizing long-term toxicity in those requiring radiation therapy (RT). RT for high-grade NRSTS was based on extent of resection (R0: negative margins, R1: microscopic margins, R2/U: gross disease/unresectable); those with >5 cm tumors received chemotherapy (CT; ifosfamide/doxorubicin). This analysis evaluates LC for patients assigned to RT and prognostic factors associated with local recurrence (LR).Methods and materialsPatients aged 5 cm tumor (arm C); or neoadjuvant RT (45 Gy)/CT plus delayed surgery, CT, and postoperative boost to 10.8 Gy R0

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

This guideline for nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) by the American Radium Society was developed by a multidisciplinary expert panel of medical, pediatric, and radiation oncologists convened to formulate guidelines for evaluation and treatment. The guideline development was based on an in-depth literature review and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of the recommendations by the panel. Given the scarcity of compelling data for strong recommendations for a rare lymphoma that has been shown to be more indolent than classical Hodgkin lymphoma, in instances where evidence is not available or equivocal, expert opinion guided the recommendations. Four clinical variants exemplify common scenarios and represent the consensus recommendations for patients with nodular lymphocyte Hodgkin lymphoma. A summary of the available published literature is also presented.

BackgroundOutcomes for children and adults with advanced soft tissue sarcoma are poor with traditional therapy. We investigated whether the addition of pazopanib to preoperative chemoradiotherapy would improve pathological near complete response rate compared with chemoradiotherapy alone.MethodsIn this joint Children's Oncology Group and NRG Oncology multicentre, randomised, open-label, phase 2 trial, we enrolled eligible adults (aged ≥18 years) and children (aged between 2 and 16 years) performance status score of at least 70. Patients received ifosfamide (2·5 g/m2 per dose intravenously on days 1-3 with mesna) and doxorubicin (37·5 mg/m2 per dose intravenously on days 1-2) with 45 Gy preoperative radiotherapy, followed by surgical resection at week 13. Patients were randomly assigned (1:1) using a web-based system, in an unmasked manner, to receive oral pazopanib (if patients

Purpose The purpose of this study was to characterize and evaluate the clinical significance of volume changes of soft tissue sarcomas during radiation therapy (RT), prior to definitive surgical resection. Materials and methods Patients with extremity or pelvis soft tissue sarcomas treated at our institution from 2013 to 2016 with RT prior to resection were identified retrospectively. Tumor volumes were measured using cone-beam computed tomography obtained daily during RT. Linear regression evaluated the linearity of volume changes. Kruskal-Wallis tests, Mann-Whitney U tests, and linear regression evaluated predictors of volume change. Logistic and Cox regression evaluated volume change as a predictor of resection margin status, histologic treatment response, and tumor recurrence. Results Thirty-three patients were evaluated. Twenty-nine tumors were high grade. Prior to RT, median tumor volume was 189 mL (range, 7.2 to 4,885 mL). Sixteen tumors demonstrated significant linear volume changes during RT. Of these, 5 tumors increased and 11 decreased in volume. Myxoid liposarcoma (n = 5, 15%) predicted decreasing tumor volume (p = 0.0002). Sequential chemoradiation (n = 4, 12%) predicted increasing tumor volume (p = 0.008) and corresponded to longer times from diagnosis to RT (p = 0.01). Resection margins were positive in three cases. Five patients experienced local recurrence, and 7 experienced distant recurrence, at median 8.9 and 6.9 months post-resection, respectively. Volume changes did not predict resection margin status, local recurrence, or distant recurrence. Conclusion Volume changes of pelvis and extremity soft tissue sarcomas followed linear trends during RT. Volume changes reflected histologic subtype and treatment characteristics but did not predict margin status or recurrence after resection.

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.

PURPOSE For pediatric patients with large, high-grade, extremity nonrhabdomyosarcoma soft-tissue sarcomas, preoperative radiation therapy (RT) provides the opportunity for smaller radiation fields and tumor shrinkage resulting in less extensive surgery. The potential disadvantage is an increased risk of wound complications after surgery compared with rates after postoperative chemoradiation. We assessed the impact of preoperative RT technique on target coverage in relationship to dose to skin and adjacent joints to determine whether acute wound complications and late musculoskeletal injury might be influenced by treatment technique. METHODS AND MATERIALS Of 550 eligible patients

Local ablative treatment to oligometastatic patients can result in long-term disease-free survival in some cancer patients. The importance of this treatment paradigm in prostate cancer is a rapidly evolving field. Herein, we report on the safety and preliminary clinical outcomes of a modern cohort of oligometastatic prostate cancer (OPC) patients treated with consolidative stereotactic ablative radiation (SABR). Records of men with OPC who underwent consolidative SABR at our institution were reviewed. SABR was delivered in 1–5 fractions of 5–18 Gray. Kaplan–Meier estimates of local progression-free survival (LPFS), biochemical progression-free survival (bPFS; PSA nadir + 2), distant progression-free survival (DPFS), and time-to-next intervention (TTNI) were calculated. In total, 66 OPC patients were identified with consolidative SABR delivered to 134 metastases: 89 bone, 40 nodal, and 5 viscera. The majority of men (49/66) had hormone-sensitive prostate cancer (HSPC). Crude grade 1 and 2 acute toxicities were 36% and 11%, respectively, with no ≥ grade 3 toxicity. At 1 year, LPFS was 92% and bPFS and DPFS were 69%. Of the 18 men with HSPC who had deferred hormone therapy , 11 (56%) remain disease free following SABR (1-year ADT-FS was 78%). In 17 castration-resistant men, 11 had > 50% prostate-specific antigen (PSA) declines with 1-year TTNI of 30%. Consolidative SABR in OPC is feasible and well tolerated. The heterogeneity and small size of our series limit extrapolation of clinically meaningful outcomes following consolidative SABR in OPC, but our preliminary data suggest that this approach warrants continued prospective study.

Purpose Our aim was to review the advances in radiation therapy for the management of pediatric cancers made by the Children's Oncology Group (COG) radiation oncology discipline since its inception in 2000. Methods and Materials The various radiation oncology disease site leaders reviewed the contributions and advances in pediatric oncology made through the work of the COG. They have presented outcomes of relevant studies and summarized current treatment policies developed by consensus from experts in the field. Results The indications and techniques for pediatric radiation therapy have evolved considerably over the years for virtually all pediatric tumor types, resulting in improved cure rates together with the potential for decreased treatment-related morbidity and mortality. Conclusions The COG radiation oncology discipline has made significant contributions toward the treatment of childhood cancer. Our discipline is committed to continuing research to refine and modernize the use of radiation therapy in current and future protocols with the goal of further improving the cure rates and quality of life of children with cancer.

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

Purpose/Objective(s) Post-transplant lymphoproliferative disease (PTLD) is a rare disease complicating solid organ transplantation (SOT) and hematopoietic cell transplantation (HCT). Management of PTLD includes immunosuppression reduction, systemic therapy, surgery and radiation therapy (RT). Data regarding the efficacy and outcomes of radiation therapy in treatment of PTLD is limited. Here, we report our institution's experience with the treatment of PTLD including RT outcomes. Materials/Methods We retrospectively reviewed patients with biopsy proven PTLD who were treated at our institution. After obtaining Institutional Review Board approval, patient demographics, disease characteristics, treatment modalities and follow-up data were recorded. Disease response before and after RT use was assessed per response evaluation criteria in solid tumors (RECIST) 1.1 including complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD). Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan Meier method. Cox Proportional Hazards models were utilized to determine variables associated with OS. Results We identified and reviewed medical records of 48 patients with PTLD. Median follow up was 38 months. The median age was 58 (range:10-81). The majority were white (79%) and male (56%). 50% of the cohort were SOT recipients, 44% were HCT recipients and 6% underwent combined transplants. The most common site of PTLD was CNS (29%). Monomorphic PTLD was the most common histological type with EBV positivity in 75% of patients. Median time from SOT-to-PTLD was 77 months (range:5-322) and HCT-to-PTLD was 5 months (range: 2-46). Systemic therapy was the most commonly used modality in 92% of patients. The most commonly used regimen was Rituximab monotherapy. Surgery was employed in 10% of patients. RT was utilized after induction therapy in 37.5%. The most common treated site was the brain (61%). Overall response of the entire cohort was 87% (58% CR and 29% PR), 6% achieved SD and 7% had PD. Among the RT cohort, 55% achieved CR, 33% achieved PR and 12% had SD. Local control rate was 100%. Of 21 patients who did not respond completely to induction therapy, 6 patients with initial PR achieved CR, 1 patient with initial SD achieved CR, 1 patient with initial PD achieved CR, and 2 patients with initial PD achieved PR and SD, respectively, after RT receipt. The median RT dose was 3,600 cGy (range: 2400-4600). 3- and 5-year PFS were 90% and 85%, respectively, while 3- and 5-year OS were 70% and 55%, respectively. Cox hazards modeling confirmed that HCT receipt was associated with better OS on multivariate analysis (HR 0.26, 95% CI 0.008- 0.671, P = 0.007). Conclusion RT provides excellent local control and improves overall disease response of PTLD. Further optimization and standardization of combined modality paradigms are needed to improve clinical outcomes of this rare entity.

Purpose Reirradiation has been proposed as an effective modality for recurrent central nervous system (CNS) malignancies in adults. We evaluated the toxicity and outcomes of CNS reirradiation in pediatric patients. Methods and Materials The data from pediatric patients Results Sixty-seven pediatric patients underwent CNS reirradiation. The primary diagnoses included medulloblastoma/primitive neuroectodermal tumor (n=20; 30%), ependymoma (n=19; 28%), germ cell tumor (n=8; 12%), high-grade glioma (n=9; 13%), low-grade glioma (n=5; 7%), and other (n=6; 9%). The median age at the first course of RT was 8.5 years (range 0.5-19.5) and was 12.3 years (range 3.3-30.2) at reirradiation. The median interval between RT courses was 2.0 years (range 0.3-16.5). The median radiation dose and fractionation in equivalent 2-Gy fractions was 63.7 Gy (range 27.6-74.8) for initial RT and 53.1 Gy (range 18.6-70.1) for repeat RT. The relapse location was infield in 52 patients (78%) and surrounding the initial RT field in 15 patients (22%). Thirty-seven patients (58%) underwent gross or subtotal resection at recurrence. The techniques used for reirradiation were intensity modulated RT (n=46), 3-dimensional conformal RT (n=9), stereotactic radiosurgery (n=4; 12-13 Gy × 1 or 5 Gy × 5), protons (n=4), combined modality (n=3), 2-dimensional RT (n=1), and brachytherapy (n=1). Radiation necrosis was detected in 2 patients after the first RT course and 1 additional patient after reirradiation. Six patients (9%) developed secondary neoplasms after initial RT (1 hematologic, 5 intracranial). One patient developed a secondary neoplasm identified shortly after repeat RT. The median overall survival after completion of repeat RT was 12.8 months for the entire cohort and 20.5 and 8.4 months for patients with recurrent ependymoma and medulloblastoma after reirradiation, respectively. Conclusions CNS reirradiation in pediatric patients could be a reasonable treatment option, with moderate survival noted after repeat RT. However, prospective data characterizing the rates of local control and toxicity are needed.

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.

Objectives High-grade soft-tissue sarcoma (STS) has a poor prognosis. The goal of this study was to review treatment outcomes of patients with high-grade STS treated with interdigitated neoadjuvant chemotherapy (CT) and radiation at our institution. Materials and methods Patients with high-grade STS (1997 to 2010) were planned for treatment with 3 cycles of neoadjuvant CT, interdigitated preoperative radiation therapy (44 Gy administered in split courses with a potential 16 Gy postoperative boost), and 3 cycles of postoperative CT. Cancer control outcomes at 3 years were analyzed. Results Sixteen patients with high-grade STS were evaluated. Median age was 53 years, the median longest tumor diameter was 14.6 cm, and median follow-up was 33 months. All 16 patients received 2 or 3 cycles of neoadjuvant CT and all patients completed neoadjuvant RT. The estimated 3-year rate for local control was 100%, disease-free survival 62.5%, and overall survival 73.4%. Conclusions Patients with high-grade STS treated with interdigitated neoadjuvant CT and radiation before surgical resection had excellent rates of local control, along with disease-free survival and overall survival similar to previously published reports. This combined-modality approach continues to have a role in the treatment of patients with high-grade STS.

PURPOSE Pediatric Spinal cord ependymoma (SCE) is rare, and the management is often heterogeneous across centers. We evaluated the impact of clinical, pathologic, and treatment-related factors on outcomes in a multi-institutional, international cohort. METHODS SCE patients age RESULTS 125 patients were identified, 18 (14.4%) with metastases. Initial surgery was GTR, and STR in 44, 56% of patients respectively. Histology was grade 1, 2, and 3 in 55, 17.7 and 23.2% respectively. 55 patients with initial GTR were observed (52.7%) or irradiated (43.6%); 60 patients had STR and were observed (40%) or irradiated (60%). The 7-year event-free (EFS) and overall survival (OS) was 60% (95% CI 51.5–71.4) and 79% (95% CI 71.1–87.8) respectively. STR and metastasis increased the hazard for death [HR 1.87, 95% CI 1.02–3.57, p=0.05 (vs. GTR)] and [HR 2.28, 95% CI 1.1–5.2, p=0.048 (vs. localized)] respectively. Across 43 failures, local failure predominated (48.8%). Distant and combined failure occurred in 30.2 and 13.9% respectively. Adjuvant RT offered a 20% absolute improvement (vs. observation) in EFS at 5 years regardless of extent of resection. RPA identified thoracic (vs. non-thoracic), grade (1 & 3 vs. 2), STR (vs. GTR) and metastases as determinants of inferior EFS. CONCLUSIONS Tumor and treatment-related factors are predictive of EFS. OS is favorable despite diverse schema and frequent distant failures.

Retroperitoneal sarcomas are rare tumors that can be locally aggressive with high rates of recurrence. Given that data on survival in patients with retroperitoneal sarcomas are conflicting, we sought to use a nationwide cancer database to identify factors associated with survival in patients with retroperitoneal sarcomas.The Surveillance, Epidemiology, and End Results database was utilized to identify patients with retroperitoneal sarcomas from 2002 to 2012. Univariable and multivariable survival analysis was performed using a generalized gamma parametric survival function.A total of 2,920 patients were included; overall 5- and 10-year survivals were 58.4% and 45.3%, respectively. On multivariable survival analysis, age, histologic type, grade, size, local extension, lymph node, and distant metastasis were associated with decreased survival (all P .05). Patients undergoing operative resection survived 2.5 times longer (95% confidence interval: 2.0-3.0, P .001) and those receiving radiation therapy 1.3 times longer (95% confidence interval: 1.1-1.6, P = .001), respectively.During the past decade, retroperitoneal sarcoma patients treated with radiation demonstrate longer survival compared with patients who did not receive radiation. Further study is needed to fully elucidate the mechanisms that underlie the radiation-related survival benefit observed in this study.

Patients requiring desensitization prior to renal transplantation are at risk for developing severe antibody-mediated rejection (AMR) refractory to treatment with plasmapheresis and intravenous immunoglobulin (PP/IVIg). We have previously reported success at graft salvage, long-term graft survival and protection against transplant glomerulopathy with the use of eculizumab and splenectomy in addition to PP/IVIg. Splenectomy may be an important component of this combination therapy and is itself associated with a marked reduction in donor-specific antibody (DSA) production. However, splenectomy represents a major operation, and some patients with severe AMR have comorbid conditions that substantially increase their risk of complications during and after surgery. In an effort to spare recipients the morbidity of a second operation, we used splenic irradiation in lieu of splenectomy in two incompatible live donor kidney transplant recipients with severe AMR in addition to PP/IVIg, rituximab and eculizumab. This novel approach to the treatment of severe AMR was associated with allograft salvage, excellent graft function and no short- or medium-term adverse effects of the radiation therapy. One-year surveillance biopsies did not show transplant glomerulopathy (tg) on light microscopy, but microcirculation inflammation and tg were present on electron microscopy.

BACKGROUND Cranial radiation therapy (RT) is an important component in the treatment of pediatric brain tumors. However, it can result in long-term effects on the developing brain. This prospective study assessed the effects of cranial RT on cerebral, frontal lobe, and temporal lobe volumes and their correlation with higher cognitive functioning. METHODS Ten pediatric patients with primary brain tumors treated with cranial RT and 14 age- and sex-matched healthy children serving as controls were evaluated. Quantitative magnetic resonance imaging and neuropsychological assessments (language, memory, auditory and visual processing, and vocabulary) were performed at the baseline and 6, 15, and 27 months after RT. The effects of age, the time since RT, and the cerebral RT dose on brain volumes and neuropsychological performance were analyzed with linear mixed effects model analyses. RESULTS Cerebral volume increased significantly with age in both groups (P = .01); this increase in volume was more pronounced in younger children. Vocabulary performance was found to be significantly associated with a greater cerebral volume (P = .05) and a lower RT dose (P = .003). No relation was observed between the RT dose and the cerebral volume. There was no difference in the corresponding neuropsychological tests between the 2 groups. CONCLUSIONS This prospective study found significant relations among the RT dose, cerebral volumes, and rate of vocabulary development among children receiving RT. The results of this study provide further support for clinical trials aimed at reducing cranial RT doses in the pediatric population. Cancer 2016. © 2016 American Cancer Society.

The treatment of pediatric intracranial low-grade gliomas (LGG) generally begins with maximal safe resection. Radiation therapy (RT) and chemotherapy are typically reserved for patients with incomplete resection and/or disease progression. We report long-term treatment outcomes and toxicities in a cohort of pediatric patients with LGG after RT. Thirty-four patients

Background Retroperitoneal sarcomas are connective tissue tumors arising in the retroperitoneum. Surgical resection is the mainstay of treatment. Debate has arisen over extent of resection, changes in histological classification/grading, and interest in incorporating radiotherapy. Therefore, we reviewed our institution's experience to evaluate prognostic factors. Methods Retrospective chart review of all primary RPS patients at Johns Hopkins Hospital from 1994 to 2010. Histologic diagnosis and grading were re-evaluated with current criteria. Prognostic factors for survival, and recurrence were assessed. Results One hundred thirty-one primary RPS patients met inclusion criteria. Median survival for patients who undergo en-bloc resection to negative margins (R0/R1) is 81.7 months. Surgical margins and grade were the most important factors for survival along with age, gender, presence of metastases and resection of ≥5 organs. Five-year survival for R0/R1 resection was 60%, similar to compartmental resection. Radiotherapy significantly decreased local recurrence (P = 0.026) on multivariate analysis. Grade in leiomyosarcomas and dedifferentiation in liposarcomas dictated patterns of local versus distal recurrence. Conclusions En bloc surgical resection to R0/R1 margins remains the cornerstone of therapy and provides comparable outcomes to compartmental resections. Grade remains important for prognosis, and histology dictates recurrence patterns. Radiotherapy appears promising for local control and warrants further investigation. J. Surg. Oncol. 2016;114:56–64. © 2016 Wiley Periodicals, Inc.

Importance Standard chemotherapy for first relapse of B-cell acute lymphoblastic leukemia (B-ALL) in children, adolescents, and young adults is associated with high rates of severe toxicities, subsequent relapse, and death, especially for patients with early relapse (high risk) or late relapse with residual disease after reinduction chemotherapy (intermediate risk). Blinatumomab, a bispecific CD3 to CD19 T cell-engaging antibody construct, is efficacious in relapsed/refractory B-ALL and has a favorable toxicity profile. Objective To determine whether substituting blinatumomab for intensive chemotherapy in consolidation therapy would improve survival in children, adolescents, and young adults with high- and intermediate-risk first relapse of B-ALL. Design, setting, and participants This trial was a randomized phase 3 clinical trial conducted by the Children's Oncology Group at 155 hospitals in the US, Canada, Australia, and New Zealand with enrollment from December 2014 to September 2019 and follow-up until September 30, 2020. Eligible patients included those aged 1 to 30 years with B-ALL first relapse, excluding those with Down syndrome, Philadelphia chromosome-positive ALL, prior hematopoietic stem cell transplant, or prior blinatumomab treatment (n = 669). Interventions All patients received a 4-week reinduction chemotherapy course, followed by randomized assignment to receive 2 cycles of blinatumomab (n = 105) or 2 cycles of multiagent chemotherapy (n = 103), each followed by transplant. Main outcome and measures The primary end point was disease-free survival and the secondary end point was overall survival, both from the time of randomization. The threshold for statistical significance was set at a 1-sided P Results Among 208 randomized patients (median age, 9 years; 97 [47%] females), 118 (57%) completed the randomized therapy. Randomization was terminated at the recommendation of the data and safety monitoring committee without meeting stopping rules for efficacy or futility; at that point, 80 of 131 planned events occurred. With 2.9 years of median follow-up, 2-year disease-free survival was 54.4% for the blinatumomab group vs 39.0% for the chemotherapy group (hazard ratio for disease progression or mortality, 0.70 [95% CI, 0.47-1.03]); 1-sided P = .03). Two-year overall survival was 71.3% for the blinatumomab group vs 58.4% for the chemotherapy group (hazard ratio for mortality, 0.62 [95% CI, 0.39-0.98]; 1-sided P = .02). Rates of notable serious adverse events included infection (15%), febrile neutropenia (5%), sepsis (2%), and mucositis (1%) for the blinatumomab group and infection (65%), febrile neutropenia (58%), sepsis (27%), and mucositis (28%) for the chemotherapy group. Conclusions and relevance Among children, adolescents, and young adults with high- and intermediate-risk first relapse of B-ALL, postreinduction treatment with blinatumomab compared with chemotherapy, followed by transplant, did not result in a statistically significant difference in disease-free survival. However, study interpretation is limited by early termination with possible underpowering for the primary end point. Trial registration ClinicalTrials.gov Identifier: NCT02101853.

Radiation therapy (RT) for non-Hodgkin lymphoma (NHL) of the head and neck (HN) has historically been delivered by involved field radiation therapy (IFRT) using conventional delivery techniques. Mo...

Background We sought to assess patterns of failure in pediatric patients with intracranial germ cell tumors (GCT) treated with intensity-modulated radiation therapy with dose painting (DP-IMRT). Procedure Between July 2007 and October 2013, 11 patients with localized GCT—five germinomas and six nongerminoma GCT (NGGCT)—received definitive treatment with DP-IMRT. Three representative patients were selected for replanning with (i) whole ventricular irradiation (WVI) with opposed lateral beams plus IMRT to the primary tumor and (ii) sequential IMRT. These plans were compared to the patients’ original DP-IMRT plans for dosimetric analyses. Results Four patients with germinoma received radiation therapy alone: 45 Gy in 1.8 Gy fractions to the primary tumor and 25 Gy in 1.0 Gy fractions to whole ventricles using a dose-painting plan. One patient with germinoma received a reduced dose of 30.6 Gy to the primary tumor after neoadjuvant chemotherapy. Patients with NGGCT (n = 6) underwent multimodality treatment including chemotherapy (n = 6) and surgery (n = 3). These patients received 54 Gy to the primary tumor and 32.4–36 Gy to the whole ventricles. Dosimetric analyses showed DP-IMRT delivered decreased mean dose to whole brain, temporal lobes, hippocampi, cochleae, and optic nerves. With median follow-up of 4 years, 3-year failure-free survival was 100% for patients with germinoma and 67% for patients with NGGCT. One patient with a pineal NGGCT experienced a local recurrence within the high dose–volume while another experienced an isolated biochemical failure. Conclusions DP-IMRT is dosimetrically superior to standard IMRT techniques for sparing of normal tissues. Disease control in this small series appears at least comparable to published results.

We describe the case of a 14-year-old boy who presented with a large, 17.6-cm retroperitoneal mass, along with multiple metastases, and was diagnosed with desmoplastic small round cell tumor. After initial chemotherapy, he underwent gross total resection with a positive margin. On postoperative radiation planning computed tomography, a 6.8-cm heterogeneous mass was noted in the surgical bed. Given the tumor's aggressive nature and positive surgical margins, there was real concern for recurrent disease. Further evaluation with magnetic resonance imaging elucidated that the mass consisted of simple fluid and fat, without contrast enhancement, suggesting a postoperative fluid collection. He was able to continue with adjuvant treatment as planned. This case example illustrates that even large postoperative heterogeneous masses may still be related to postoperative fluid collection in patients with aggressive tumor. However, it is important to rule out recurrent disease before starting adjuvant therapy given improved outcomes with gross total resection in desmoplastic small round cell tumor.

The optimal approach to managing incident learning system (ILS) reports remains unclear. Here, we describe our experience with prospective coding of events reported to the ILS with comparisons of risk scores on the basis of event type and process map location.Reported events were coded by type, origin, and method of discovery. Events were given a risk priority number (RPN) and near-miss risk index (NMRI) score. We compared workflow versus near-miss events with respect to origin and detection in the process map and by risk scores. A χDuring 2016, 1351 events were reported. Of these events, 1300 (96.2%) were workflow and 51 (3.8%) near-miss events. Workflow events were more likely to both originate (1041 of 1300 events; 81.2%) compared with near-miss events (31 of 51 events; 62.7%; P = .005) and be detected in pre-treatment (997 of 1300 events; 76.7%) compared with near-miss events (24 of 51 events; 47%; P.001). Average occurrence (scale: 1-10) was 6.14 for workflow versus 3.33 for near-miss events (P.001), average severity was 2.94 versus 7.35 (P.001), and average detectability was 1.33 versus 4.67 (P.001). Mean overall RPN was 22.4 for workflow versus 108.4 for near-miss events (P = .07) and mean NMRI was 1.16 versus 3.19, respectively. Events that originated and were detected in treatment delivery had the greatest mean overall RPN (38.2 and 32.1, respectively) and NMRI scores (1.62 and 1.6, respectively).Our experience demonstrates that workflow event reports are far more common than near-misses and that near-miss events are more likely to both originate and be discovered in later treatment phases. The frequency of workflow reports highlights the imperative need for safety and operational teams to work collaboratively to maximize the benefit of ILS. We suggest a potential utility of the RPN system to guide mitigation strategies for future near-miss events.

Patients with connective tissue disorders are clinically challenging for radiation oncologists as these patients may be at increased risk for radiation-related skin toxicity. A clinical dilemma presents itself in a patient with lupus who presents with confluent skin lesions from mycosis fungoides requiring radiotherapy. In this report, we discuss an innovative technique used to develop an immobilization device that also effectively functioned as a uniform bolus with distinct dosimetric advantages to the use of a facial moulage.

Background Mantle cell lymphoma (MCL) rarely presents as early-stage disease, but clinical observations suggest that patients who present with early-stage disease may have better outcomes than those with advanced-stage disease. Patients and methods In this 13-institution study, we examined outcomes among 179 patients with early-stage (stage I or II) MCL in an attempt to identify prognostic factors that influence treatment selection and outcome. Variables examined included clinical characteristics, treatment modality, response to therapy, sites of failure, and survival. Results Patients were predominantly male (78%) with head and neck being the most common presenting sites (75%). Most failures occurred outside the original disease site (79%). Although the administration of radiation therapy, either alone or with chemotherapy, reduced the risk of local failure, it did not translate into an improved freedom from progression or overall survival (OS). The treatment outcomes were independent of treatment modality. The 10-year OS for patients treated with chemotherapy alone, chemo-radiation therapy and radiation therapy alone were 69%, 62%, and 74% (P = 0.79), and the 10-year freedom from progression were 46%, 43%, and 31% (P = 0.64), respectively. Conclusion Given the excellent OS rates regardless of initial therapy in patients with early-stage MCL, de-intensified therapy to limit treatment-related toxicity is a reasonable approach.

Background: High dose-rate Intra-Operative Radiation Therapy (HD-IORT) is used to provide effective local control for patients with high-risk locally advanced or recurrent tumors. However, the utility of HD-IORT for patients with bladder cancer has not been studied. Objective: To characterize our institutional experience with HD-IORT in patients with cancer requiring genitourinary surgery, in an effort to identify patients with bladder cancer that may benefit from HD-IORT. Methods: We performed a retrospective review of all patients who have undergone HD-IORT during genitourinary surgery at our institution. Patients were stratified by surgical margin status, and primary outcomes assessed were overall survival, recurrence free survival and 90-day complications. Patients undergoing cystectomy and HD-IORT with sarcomatoid urothelial cancer were compared to a similar cohort undergoing cystectomy alone. A sample case of one such patient is discussed in detail. Results: 84 patients at our institution have undergone HD-IORT with genitourinary surgery. Positive surgical margin status was the greatest predictor of both OS (HR = 3.42) and RFS (HR = 2.61). The overall 90-day complication rate was 61%, with wound infections (43%) and GI complications (21%) being most common. 4 of these patients had sarcomatoid urothelial histology, and all are still alive with >2 yrs follow up. This compares to a 52% 1 yr survival in our sarcomatoid urothelial cohort (25 pts) that did not undergo HD-IORT. Conclusions: Our institutional experience with HD-IORT has been promising, particularly among patients with locally advanced disease and sarcomatoid histology. We are currently enrolling patients in a multi-institutional registry to assess the utility of HD-IORT in high risk bladder cancer.

11002 Background: Pazopanib is a multi-targeted tyrosine kinase inhibitor with activity in advanced soft tissue sarcoma. ARST1321 is a phase II study designed to compare the near complete pathologic response rate (≥ 90% necrosis) of preoperative chemoradiation +/- pazopanib in children and adults with intermediate/high risk chemotherapy-sensitive NRSTS. Methods: ARST1321 is a jointly designed COG and NRG Oncology study opened to enrollment in July 2014. Eligible adult (≥18 years) and pediatric ( < 18 years) patients with unresected, newly diagnosed truncal/extremity NRSTS were enrolled into the Chemotherapy Cohort ( > 5 cm, grade 2/3, protocol-designated chemotherapy-sensitive histology). Following a dose-finding phase, patients were randomized to receive (Regimen A) or not receive (Regimen B) pazopanib ( < 18 years: 350 mg/m2/day; ≥ 18 years: 600 mg/day) in combination with ifosfamide (7.5 gm/m2/cycle) and doxorubicin (75 mg/m2/cycle) + 45 Gy preoperative RT followed by primary resection at week 13, then adjuvant chemotherapy. Results: As of June 30, 2018, 81 eligible patients were enrolled and randomized. Week 13 response is available for 42 patients (60% of expected information). The rate of ≥ 90% pathologic necrosis was 58.3% for Regimen A and 22.2% for Regimen B. Based on the significance level of 0.081 (for the second efficacy analysis with overall one-sided significance level of 0.20, power of 0.80, and O’Brien-Fleming-type cumulative error spending function), the 83.8% confidence interval for the difference was between 16.5% and 55.8%. At this predetermined interim analysis, the efficacy bound was crossed indicating that Regimen A is more efficacious than Regimen B. Given these findings, enrollment was stopped. Grade 3/4 toxicities were 73.8% for Regimen A and 29% for Regimen B with neutropenia, thrombocytopenia and febrile neutropenia being the most common toxicities. Conclusions: The rate of near complete pathologic response was significantly greater with the addition of pazopanib to preoperative chemoradiation in children and adults with intermediate/high risk NRSTS. The comparison of survival outcomes requires longer follow-up. Clinical trial information: NCT02180867.

11070 Background: Pazopanib is a tyrosine kinase inhibitor approved globally for advanced soft tissue sarcomas. The dose finding phase of this cooperative group trial assessed the dose limiting toxicities (DLT) and the maximally tolerated dose (MTD) of adding pazopanib to neoadjuvant chemoradiation or radiation therapy in children and adults with unresected intermediate/high-risk trunk and extremity non-rhabdomyosarcoma soft tissue sarcomas (NRSTS). Methods: ARST1321, a jointly designed intergroup study lead by Children's Oncology Group and NRG Oncology opened for enrollment in July 2014. Eligible adult and pediatric patients with newly diagnosed, unresected trunk/extremity NRSTS with plans for primary tumor resection were enrolled into either the Chemotherapy Cohort (those with chemosensitive NRSTS > 5 cm, grade 3, including all synovial sarcoma) or the Non-Chemotherapy Cohort (those with chemotherapy insensitive NRSTS of any size, grade 2/3, or any chemosensitive NRSTS for whom no chemotherapy was planned per discretion of patients and treatment teams). In the Chemotherapy Cohort, pazopanib was given with ifosfamide (7.5 grams/m2) and doxorubicin (75 mg/m2) plus 45 Gy preoperative RT starting after cycle 2. Primary tumor was resected at week 13, followed by chemotherapy and pazopanib to week 25. In the Non-Chemotherapy Cohort, pazopanib was given with 50 Gy preoperative RT, primary tumor was resected at week 10, and pazopanib continued to week 25. Feasibility was assessed through week 6 of therapy to determine pazopanib dose escalation/de-escalation based on DLT, total doses of pazopanib, and overall adverse event profile. Results: In the Chemotherapy Cohort, MTD was reached at Dose Level 1 (350 mg/m2 peds; 600 mg adults) with two DLTs (1 grade 3 ALT rise, 1 intolerability to therapy) in 10 patients. In the Non-Chemotherapy Cohort, 11 patients enrolled at Dose Level 1 (350 mg/m2 peds; 600 mg adults) without any observed DLTs and all received ≥75% of prescribed total pazopanib dose; MTD was reached at Dose Level 2 (450 mg/m2 peds; 800 mg adults) with 2 DLTs in ten patients enrolled (1 grade 3 dermatitis and 1 intolerability to therapy) and 9/10 receiving ≥75% of full dose. Conclusions: Pazopanib in combination with chemoradiation or radiation therapy alone was found to be safe in children and adults with NRSTS. Following this finding, ARST1321 opened in both arms using the newly determined pazopanib MTDs. Clinical trial information: NCT02180867.

Pediatric Hodgkin lymphoma is a highly curable malignancy and potential long-term effects of therapy need to be considered in optimizing clinical care. An expert panel was convened to reach consensus on the most appropriate approach to evaluation and treatment of pediatric Hodgkin lymphoma. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed every 2 years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer reviewed journals and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances where evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment. Four clinical variants were developed to assess common clinical scenarios and render recommendations for evaluation and treatment approaches to pediatric Hodgkin lymphoma. We provide a summary of the literature as well as numerical ratings with commentary. By combining available data in published literature and expert medical opinion, we present a consensus to the approach for management of pediatric Hodgkin lymphoma. Pediatr Blood Cancer 2014;61:1305–1312. © 2014 American College of Radiology.

We present an unusual case of a germinoma of the pineal region arising adjacent to an epidermoid cyst in a 16-year-old male. Initial imaging findings were classic for epidermoid cyst. The patient underwent two partial resections at an outside institution, each specimen demonstrating pure epidermoid cyst. Follow-up imaging over a period of 24 months showed an area of progressive contrast enhancement adjacent to the initial lesion, suggesting the development of a neoplasm. Given the area of contrast enhancement in addition to worsening headaches and visual changes, he underwent a third and final resection at our institution. Pathology revealed a mixed germ cell tumor with prominent germinoma component in addition to a well-differentiated epidermoid cyst. Details of his imaging and pathologic findings are presented, and possible explanations for these findings are explored, the most likely of which is lack of complete resection at the onset failed to identify the whole of the neoplasm. We conclude that pediatric epidermoid cysts of the pineal region should always receive close follow-up, particularly when total resection is not performed.

Purpose Systems to ensure patient safety are of critical importance. The electronic incident reporting systems (IRS) of 2 large academic radiation oncology departments were evaluated for events that may be suitable for submission to a national reporting system (NRS). Methods and Materials All events recorded in the combined IRS were evaluated from 2007 through 2010. Incidents were graded for potential severity using the validated French Nuclear Safety Authority (ASN) 5-point scale. These incidents were categorized into 7 groups: ( 1 ) human error, ( 2 ) software error, ( 3 ) hardware error, ( 4 ) error in communication between 2 humans, ( 5 ) error at the human-software interface, ( 6 ) error at the software-hardware interface, and ( 7 ) error at the human-hardware interface. Results Between the 2 systems, 4407 incidents were reported. Of these events, 1507 (34%) were considered to have the potential for clinical consequences. Of these 1507 events, 149 (10%) were rated as having a potential severity of ≥2. Of these 149 events, the committee determined that 79 (53%) of these events would be submittable to a NRS of which the majority was related to human error or to the human-software interface. Conclusions A significant number of incidents were identified in this analysis. The majority of events in this study were related to human error and to the human-software interface, further supporting the need for a NRS to facilitate field-wide learning and system improvement.

Background. Neurocognitive toxicity from radiation therapy (RT) for brain tumors may be related to damage to neural progenitor cells that reside in the subventricular zone and hippocampus. This prospective study examines the relationship between RT dose to neural progenitor cell niches, temporal lobes, and cerebrum and neurocognitive dysfunction following cranial irradiation. Methods. Standardized assessments of motor speed/ dexterity, verbal memory, visual perception, vocabulary, and visuospatial working memory were conducted in 19 pediatric patients receiving cranial RT and 55 controls at baseline and 6, 15, and 27 months following completion of RT. Prescription doses ranged from 12 Gy to 59.4 Gy. Linear mixed effects regression model analyses were used to examine the relationships among neuropsychological performance, age, and radiation dose to the subventricular zone, hippocampus, temporal lobes, and cerebrum. Results. Performance on all neuropsychological tests, except vocabulary, was significantly reduced in patients relative to controls, particularly among younger

Rhabdomyosarcoma is the most common soft tissue sarcoma of childhood. Improvements in the clinical outcomes of rhabdomyosarcoma have been secondary to the intensification and refinement of treatment investigated by the Intergroup Rhabdomyosarcoma Study Group. Advances in diagnostic imaging techniques have led to improvements in staging and contribute to precision in radiation field design. Radiation treatment has been integrated into the primary treatment of most patients with rhabdomyosarcoma. Each treatment site has special considerations with regards to prognosis, outcomes and potential morbidities that affect the choice of local therapy. Advanced radiotherapy techniques using conformal treatment with intensity-modulated radiotherapy and proton therapy are particularly advantageous for the treatment of sites close to critical structures, such as the head and neck and genitourinary system. Active investigation is underway to develop strategies to reduce the radiation dose and volume in an effort to minimise late toxicity and improve the therapeutic ratio.

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.