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Although primary tumor control rates after surgery and/or radiation therapy (RT) are generally high in patients with Ewing sarcoma (EWS), those with unresectable tumors have failure rates approaching 30% and experience poorer outcomes. Additionally, although metastatic site irradiation is associated with improved survival, dose, and volume effects influence the long‐term toxicity risk. Consequently, it is important to identify novel systemic agents to enhance the therapeutic ratio of RT. Given the reported DNA damage response deficits in EWS, we hypothesized that PARP inhibitors (PARPis) would preferentially potentiate radiation relative to standard‐of‐care (SOC) chemotherapeutics. We investigated primary and recurrent SOC drugs and PARPis with varied trapping potential in combination with radiation in EWS cell lines. At physiologically relevant concentrations, the strong PARP trapper talazoparib (TAL) potentiated radiation to a greater extent than did SOC or other PARPis, although the magnitude of the effect was modest. The radiosensitizing effect of TAL was mediated through the induction of DNA double‐strand breaks, rather than through the catalytic inhibition of PARP1. Drug + RT combinations were further tested in vivo by using orthotopic xenograft models of EWS treated with image‐guided fractionated radiation. The addition of RT to the combination of TAL plus irinotecan (IRN), a recently evaluated clinical regimen for relapsed pediatric solid tumors, significantly prolonged survival and reduced tumor burden in all EWS‐treated mice. This triplet therapy (TAL + IRN + RT) was feasible and yielded responses in several patients with EWS and may represent a useful salvage strategy in recurrent or progressive disease. The addition of RT to the combination of TAL plus irinotecan (IRN), a recently evaluated clinical regimen for relapsed pediatric solid tumors, significantly prolonged survival and reduced tumor burden in EWS mouse models. This triplet therapy (TAL + IRN + RT) was feasible and yielded responses in several patients with EWS and may represent a useful salvage strategy in recurrent or progressive disease.

Purpose This study aimed to compare the histological response, a surrogate preoperative treatment efficacy marker, of patients treated with preoperative chemotherapy with or without preoperative radiotherapy. Moreover, local recurrence in both groups was investigated. Methods Surgical specimens from 210 patients with Ewing sarcoma were assessed between 2003 and 2020 to evaluate their histological response to preoperative treatment; 181 patients received preoperative chemotherapy, while 29 received both preoperative chemotherapy and radiotherapy. The histological response rate in the surgical section was assessed based on tumour necrosis and reparative fibrous tissue. Results The median histological response rates were 100% (interquartile range = 83–100%) for the preoperative chemotherapy and radiotherapy group and 90% (interquartile range = 60–100%) for the preoperative chemotherapy group ( P  = 0.004). Multivariate logistic regression analysis indicated that the administration of the preoperative radiotherapy (Odds ratio = 3.36 [95% confidence interval, CI 1.32–8.54]; P  = 0.011) and small tumour volume (< 200 mL) were associated with the achievement of > 95% histological response (Odds ratio = 0.52 [95% CI 0.27–0.99]; P  = 0.047). Local recurrence occurred in 9.9% (18/181) of patients who received preoperative chemotherapy and in 2.4% (1/29) of patients who received both preoperative chemotherapy and radiotherapy ( P  = 0.258). Conclusion Preoperative radiotherapy might enhance histological response, potentially reducing local recurrence. Therefore, it should be considered for patients with Ewing sarcoma who are at high risk of local recurrence or may have inadequate surgical margins.

We examined the role of total body magnetic resonance imaging (TB-MRI)-governed involved compartment irradiation (ICI) and high-dose chemotherapy (HDC), followed by stem cell rescue (SCR) in patients with high-risk Ewing tumors (ETs) with multiple primary bone metastases (high-risk ET-MBM). Eleven patients with high-risk ET-MBM receiving initial assessment of involved bones by TB-MRI were registered from 1995 to 2000 (group A). In all, 6 patients out of 11 had additional lung disease at initial diagnosis; all had multifocal bone disease with more than three bones involved. After systemic induction with etoposide, vincristine, adriamycin (doxorubicin), ifosfamide, and actinomycin D (EVAIA) or VAIA chemotherapy, ICI of all sites positive by TB-MRI was administered, followed by HDC and SCR. A second group matched for observation period and consisting of 26 patients with more than three involved bones at diagnosis was treated with the European Intergroup Cooperative Ewing Sarcoma Study-92 (EICESS-92) protocol (group B). These patients did not receive TB-MRI and consequently did not receive TB-MRI-governed ICI, or HDC and SCR. Survival in group A vs group B was 45 vs 8% at 5 years and 27 vs 8% at 10 years after diagnosis (log rank and Breslow: P <0.005). We conclude that TB-MRI-governed ICI followed by HDC and SCR in ET-MBM is feasible and warrants further evaluation in prospective studies.

Internationally, a single standard chemotherapy treatment for Ewing sarcoma is not defined. Because different chemotherapy regimens were standard in Europe and the USA for newly diagnosed Ewing sarcoma, and in the absence of novel agents to investigate, we aimed to compare these two strategies. EURO EWING 2012 was a European investigator-initiated, open-label, randomised, controlled phase 3 trial done in 10 countries. We included patients aged 2–49 years, with any histologically and genetically confirmed Ewing sarcoma of bone or soft tissue, or Ewing-like sarcomas. The eligibility criteria originally excluded patients with extrapulmonary metastatic disease, but this was amended in the protocol (version 3.0) in September, 2016. Patients were randomly assigned (1:1) to either the European regimen of vincristine, ifosfamide, doxorubicin, and etoposide induction, and consolidation using vincristine, actinomycin D, with ifosfamide or cyclophosphamide, or busulfan and melphalan (group 1); or the US regimen of vincristine, doxorubicin, cyclophosphamide, ifosfamide, and etoposide induction, plus ifosfamide and etoposide, and consolidation using vincristine and cyclophosphamide, or vincristine, actinomycin D, and ifosfamide, with busulfan and melphalan (group 2). All drugs were administered intravenously. The primary outcome measure was event-free survival. We used a Bayesian approach for the design, analysis, and interpretation of the results. Patients who received at least one dose of study treatment were considered in the safety analysis. The trial was registered with EudraCT, 2012-002107-17, and ISRCTN, 54540667. Between March 21, 2014, and May 1, 2019, 640 patients were entered into EE2012, 320 (50%) randomly allocated to each group. Median follow-up of surviving patients was 47 months (range 0–84). Event-free survival at 3 years was 61% with group 1 and 67% with group 2 (adjusted hazard ratio [HR] 0·71 [95% credible interval 0·55–0·92 in favour of group 1). The probability that the true HR was less than 1·0 was greater than 0·99. Febrile neutropenia as a grade 3–5 treatment toxicity occurred in 234 (74%) patients in group 1 and in 183 (58%) patients in group 2. More patients in group 1 (n=205 [64%]) required at least one platelet transfusion compared with those in group 2 (n=138 [43%]). Conversely, more patients required blood transfusions in group 2 (n=286 [89%]) than in group 1 (n=277 [87%]). Dose-intensive chemotherapy with vincristine, doxorubicin, cyclophosphamide, ifosfamide, and etoposide is more effective, less toxic, and shorter in duration for all stages of newly diagnosed Ewing sarcoma than vincristine, ifosfamide, doxorubicin, and etoposide induction and should now be the standard of care for Ewing sarcoma. The European Union's Seventh Framework Programme for Research, Technological Development, and Demonstration; The National Coordinating Centre in France, Centre Léon Bérard; SFCE; Ligue contre le cancer; Cancer Research UK.

Purpose The histological response to neoadjuvant chemotherapy is an important prognostic factor in patients with osteosarcoma (OS) and Ewing sarcoma (EWS). The aim of this study was to assess baseline primary tumour FDG uptake on PET/CT, and serum values of alkaline phosphatase (ALP) and lactate dehydrogenase (LDH), to establish whether these factors are correlated with tumour necrosis and prognosis. Methods Patients treated between 2009 and 2014 for localized EWS and OS, who underwent FDG PET/CT as part of their staging work-up, were included. The relationships between primary tumour SUVmax at baseline (SUV1), SUVmax after induction chemotherapy (SUV2), metabolic response calculated as [(SUV1 − SUV2)/SUV1)] × 100, LDH and ALP and tumour response/survival were analysed. A good response (GR) was defined as tumour necrosis >90 % in patients with OS, and grade II-III Picci necrosis (persitence of microscopic foci only or no viable tumor) in patients with Ewing sarcoma. Results The study included 77 patients, 45 with EWS and 32 with OS. A good histological response was achieved in 53 % of EWS patients, and 41 % of OS patients. The 3-year event-free survival (EFS) was 57 % in EWS patients and 48 % OS patients. The median SUV1 was 5.6 (range 0 – 17) in EWS patients and 7.9 (range 0 – 24) in OS patients ( p  = 0.006). In EWS patients the GR rate was 30 % in those with a high SUV1 (≥6) and 72 % in those with a lower SUV1 ( p  = 0.0004), and in OS patients the GR rate was 29 % in those with SUV1 ≥6 and 64 % in those with a lower SUV1 ( p  = 0.05). In the univariate analysis the 3-year EFS was significantly better in patients with a low ALP level (59 %) than in those with a high ALP level (22 %, p  = 0.02) and in patients with a low LDH level (62 %) than in those with a high LDH level (37 %, p  = 0.004). In EWS patients the 3-year EFS was 37 % in those with a high SUV1 and 75 % in those with a low SUV1 ( p  = 0.004), and in OS patients the 3-year EFS was 32 % in those with a high SUV1 and 66 % in those with a low SUV1 ( p  = 0.1). Histology, age and gender were not associated with survival. In the multivariate analysis, SUV1 was the only independent pretreatment prognostic factor to retain statistical significance ( p  = 0.017). SUV2 was assessed in 25 EWS patients: the median SUV2 was 1.9 (range 1 – 8). The GR rate was 20 % in patients with a high SUV2, and 67 % in those with a low SUV2 ( p  = 0.02). A good metabolic response (SUV reduction of ≥55 %) was associated with a 3-year EFS of 80 % and a poor metabolic response with a 3-year EFS of 20 % ( p  = 0.05). In the OS patients the median SUV2 was 2.7 (range 0 – 4.5). Neither SUV2 nor the metabolic response was associated with outcome in OS patients. Conclusion FDG PET/CT is a useful and noninvasive tool for identifying patients who are more likely to be resistant to chemotherapy. If this finding is confirmed in a larger series, SUV1, SUV2 and metabolic response could be proposed as factors for stratifying EWS patients to identify those with high-grade localized bone EWS who would benefit from risk-adapted induction chemotherapy.

Progress in the treatment of Ewing's sarcoma, the second most common bone tumour in children and adolescents, has improved survival from about 10% in the period before chemotherapy was introduced to about 75% today for patients with localised tumours. However, patients with metastases still fare badly, and the therapy carries short-term and long-term toxicities. Multidisciplinary care is indispensable for these patients. Molecular techniques and new imaging modalities are affecting the diagnosis and classification of patients with Ewing's sarcoma. Cooperative group studies have led to chemotherapy regimens using the same drugs (vincristine, doxorubicin, cyclophosphamide, ifosfamide, and etoposide), although the exact regimens differ in Europe and North America. The EWS–ETS family of gene fusions and their downstream effects in Ewing's sarcomas provide opportunities for new approaches to treatment. These include the inhibition of the fusion gene or its protein product, and pathways related to IGF1 and mTOR. Inhibition of tyrosine kinases, exploitation of non-apoptotic cell death, and interference with angiogenesis are promising new approaches. With many new approaches and relatively few patients, it will be challenging to integrate new and established treatments through clinical trials.

IntroductionEwing sarcoma is a rare paediatric cancer. Currently, there is no way of accurately predicting these patients’ survival at diagnosis. Disease type (ie, localised disease, lung/pleuropulmonary metastases and other metastases) is used to guide treatment decisions, with metastatic patients generally having worse outcomes than localised disease patients. However, not all patients fit this trend. An accurate prognostic model could be used to guide treatment decisions in clinical practice to avoid patients being incorrectly under or overtreated.Methods and analysisThis study aims to develop and internally validate prognostic models in newly diagnosed Ewing sarcoma patients, using the EE2012 clinical trial data set. The models will incorporate prognostic factors, identified from a literature review, to predict patients’ probability of event-free survival at clinically important time points. Three models will be developed, for comparison of their performance and stability, using different methods of model selection and penalisation for overfitting (full model or backwards selection applying uniform shrinkage; and lasso variable selection). The models will be internally validated using bootstrapping to give optimism-adjusted performance statistics (calibration and discrimination) and model stability results. Patient and clinical user groups will be asked to determine risk thresholds to guide treatment decisions in clinical practice based on the model. Decision curve analyses will examine clinical utility at these thresholds.Ethics and disseminationThis study is a secondary analysis of EE2012 clinical trial data. The EE2012 trial received ethical approval from the competent authorities (UK ethics reference approval number 12/NW/0827). This study is covered by the trial ethics in place. The results from this study will be published in peer-reviewed journals to act as a benchmark for future studies.Trial registration numberEudraCT number 2012-002107-17. ISRCTN number 92192408.

Background Primary Ewing sarcoma (ES) can sometimes present as a chest-wall tumor. Multidisciplinary management, including chemotherapy and local treatment consisting of surgery, radiotherapy (RT), or both, has improved the survival of patients with localized ES; however, the best approach to achieving local control remains controversial. Methods We retrospectively analyzed data from 198 patients with non-metastatic ES of the chest wall, who were registered in the database of the German Society of Pediatric Hematology and Oncology between July 1998 and April 2009. The majority of patients ( n  = 130) presented with rib tumors; 7 patients received RT only, 85 patients underwent surgery alone, and 106 patients were treated with a combination of surgery and RT. Results Overall survival in all patients was 78 and 71 % at 3 and 5 years, respectively. Event-free survival at 5 years (5-year EFS) was 57 % in the RT group, 73 % in the surgery group and 63 % in the surgery + RT group. In patients with complete resections, 5-year EFS did not improve with the addition of RT compared with surgery alone. There was no difference in the 5-year EFS in patients with partial (63 %) or total (64 %) resection of the affected ribs, and median follow-up was 4.71 years (range 0.40–13.48). Conclusions Complete tumor resection is the best way to achieve local control of ES of the chest wall; additional RT is only useful in patients with incomplete resection. The main limitation of this study was its retrospective nature, and the benefit of total resection of the affected ribs could not be proved.

BackgroundThe REGOBONE multi-cohort study explored the efficacy and safety of regorafenib for patients with advanced bone sarcomas; this report details the Ewing sarcoma (ES) cohort.MethodsPatients with relapsed ES progressing despite prior standard therapy, were randomised (2:1) to receive regorafenib or placebo. Patients on placebo could crossover to receive regorafenib after centrally confirmed progression. The primary endpoint was the progression-free rate at 8 weeks. With one-sided α of 0.05, and 80% power, at least 14/24 progression-free patients at 8 weeks were needed for success.ResultsFrom September 2014 to November 2019, 41 patients were accrued. 36 patients were evaluable for efficacy: 23 on regorafenib and 13 on placebo. Thirteen patients (56%; one-sided 95% CI [37.5%–[)) were progression-free at 8 weeks on regorafenib vs. 1 (7.7%; 95% CI [0.4%–[) on placebo. Median PFS was 11.4 weeks on regorafenib, and 3.9 weeks on placebo. Ten placebo patients crossed over to receive regorafenib after progression. The most common grade ≥3 regorafenib-related adverse events were pain (22%), asthenia (17%), thrombocytopenia (13%) and diarrhoea (13%).ConclusionAlthough the primary endpoint was not met statistically in this randomised cohort, there is evidence to suggest that regorafenib might modestly delay tumour progression in relapsed ES after failure of prior chemotherapy.

Background Ewing sarcoma (ES) is the second most common primary malignant bone tumor in children and adolescents. Tumor-associated macrophages (TAMs) are a key component of the tumor microenvironment. While increased TAMs infiltration is linked to poor prognosis in various solid tumors, limited data are available regarding their role in sarcomas. Methods This retrospective study aimed to evaluate the frequency, density, and prognostic impact of TAMs in pediatric patients with ES treated at the Pediatric Oncology Department, National Cancer Institute (NCI), Cairo University. Immunohistochemical analysis of CD68 and CD163 expression was performed on 74 tumor tissue samples from pediatric patients with ES, which helps us understand the density of TAMs. Results The study cohort comprised 74 patients with a median age of 12 years (range: 0.5–18 years) and a male-to-female ratio of 0.8:1. The 5-year overall survival (OS) and event-free survival (EFS) rates were 48% and 42.8%, respectively. CD68 expression showed significant correlations with age at diagnosis ( p  = 0.035) and tumor size ( p  = 0.031) and near-significant associations with skeletal tumor location ( p  = 0.052) and complete response following induction chemotherapy ( p  = 0.054). CD163 expression was significantly associated with age at diagnosis ( p  = 0.046). However, neither CD68 (≤ 60 vs. > 60) nor CD163 (≤ 90 vs. > 90) levels showed significant correlation with survival outcomes (OS or EFS). Initial primary tumor site, tumor stage, post-induction chemotherapy disease status, and histological response to induction chemotherapy were significant predictor of survival outcome. Conclusions TAM markers (CD68 and CD163) did not demonstrate a significant prognostic impact on survival. Larger-scale studies are warranted to more precisely determine the role of TAMs in pediatric ES.