PURPOSE: Ewing 2008R3 was conducted in 12 countries and evaluated the effect of treosulfan and melphalan high-dose chemotherapy (TreoMel-HDT) followed by reinfusion of autologous hematopoietic stem cells on event-free survival (EFS) and overall survival in high-risk Ewing sarcoma (EWS). METHODS: Phase III, open-label, prospective, multicenter, randomized controlled clinical trial. Eligible patients had disseminated EWS with metastases to bone and/or other sites, excluding patients with only pulmonary metastases. Patients received six cycles of vincristine, ifosfamide, doxorubicin, and etoposide induction and eight cycles of vincristine, actinomycin D, and cyclophosphamide consolidation therapy. Patients were randomly assigned to receive additional TreoMel-HDT or no further treatment (control). The random assignment was stratified by number of bone metastases (1, 2-5, and > 5). The one-sided adaptive-inverse-normal-4-stage-design was changed after the first interim analysis via Müller-Schäfer method. RESULTS: Between 2009 and 2018, 109 patients were randomly assigned, and 55 received TreoMel-HDT. With a median follow-up of 3.3 years, there was no significant difference in EFS between TreoMel-HDT and control in the adaptive design (hazard ratio [HR] 0.85; 95% CI, 0.55 to 1.32, intention-to-treat). Three-year EFS was 20.9% (95% CI, 11.5 to 37.9) in TreoMel-HDT and 19.2% (95% CI, 10.8 to 34.4) in control patients. The results were similar in the per-protocol collective. Males treated with TreoMel-HDT had better EFS compared with controls: median 1.0 years (95% CI, 0.8 to 2.2) versus 0.6 years (95% CI, 0.5 to 0.9); P = .035; HR 0.52 (0.28 to 0.97). Patients age < 14 years benefited from TreoMel-HDT with a 3-years EFS of 39.3% (95% CI, 20.4 to 75.8%) versus 9% (95% CI, 2.4 to 34); P = .016; HR 0.40 (0.19 to 0.87). These effects were similar in the per-protocol collective. This observation is supported by comparable results from the nonrandomized trial EE99R3. CONCLUSION: In patients with very high-risk EWS, additional TreoMel-HDT was of no benefit for the entire cohort of patients. TreoMel-HDT may be of benefit for children age < 14 years.

Intracranial Ewing sarcoma (EwS) is rare and publications on primary or metastatic intracranial EwS are minimal. The aim of this study was to describe incidence, clinical behavior, treatment, and factors associated with outcome in patients with primary intracranial EwS or patients with a primary extracranial EwS and cerebral metastases at diagnosis. We reviewed all patients with primary or with metastatic intracranial EwS at diagnosis registered in the International Clinical Trial Euro-E.W.I.N.G.99 (EE99). In total, 17 of 1435 patients (1.2%) presented with primary intracranial EwS; 3 of them had metastatic disease. Four patients (0.3%) with primary extracranial EwS presented with intracranial metastatic lesions. The 3-year event-free survival (EFS) was 64% and overall survival (OS) was 70% in patients with a primary intracranial EwS. Local control in patients with primary intracranial EwS consisted of surgery (6%), radiotherapy (RT) (18%), or both modalities (76%). Univariate analysis showed that patients < 15 years of age had significantly better outcome (EFS: 72%; OS: 76%) compared to those aged above 15 years (EFS: 13%; OS: 25%). In conclusion, primary intracranial EwS and extracranial EwS with cerebral metastases at diagnosis is rare, yet survival is comparable with local and metastatic EwS elsewhere in the body. Age and stage of disease are important prognostic factors. Besides chemotherapeutic treatment, local control with surgical resection combined with RT is recommended whenever feasible.

Background: Magnetic resonance imaging (MRI) is the modality of choice for local staging and response evaluation of Ewing sarcoma (EwS). Aim of this study was to determine the relevance of tumor volume response (TVR) in relation to histological response (HisRes) and survival, in order to evaluate if early modification of chemotherapy might be indicated in patients with inadequate TVR.Methods: Three dimensional (3D)‐tumor volume data at diagnosis, during early induction phase (1‐3 courses of chemotherapy; n = 195) and/or late induction phase (4‐6 courses; n = 175) from 241 localized patients were retrospectively analyzed. A distinction was made between adequate response (reduction ≥67%) and inadequate response (reduction <67% or progression). Correlations between TVR, HisRes, event free survival (EFS), and overall survival (OS) were analyzed using chi‐square tests, log‐rank tests, and the Cox‐regression model.Results: Early adequate TVR, noted in 41% of patients, did not correlate with EFS (P = 0.92) or OS (P = 0.38). During late induction phase 62% of patients showed an adequate TVR. EFS for patients with late adequate TVR was better (78%) than for those with inadequate late TVR (61%) (P = 0.01); OS was 80% and 69% (P = 0.26), respectively. No correlation was found between TVR and HisRes. Multivariate analysis showed that poor HisRes, pelvic location and late inadequate TVR were associated with poor outcome.Conclusions: Early inadequate TVR does not predict adverse outcome; therefore, changing the treatment to second line chemotherapy is not indicated in case of inadequate early TVR. Late adequate TVR and good HisRes correlate with better EFS; patients with late inadequate TVR might benefit from augmented therapy.

Introduction: Pretreatment prognostic factors in newly diagnosed osteosarcoma are important for clinical management and stratifying patients in clinical trials. Such factors include the presence of metastases, primary tumor size, and site. Factors surrounded by controversy include pathological fracture, histologic subtype, and P‐glycoprotein expression. No prognostic tumor biomarker has been established. We performed a systematic review with the aim to compile available evidence for pretreatment prognostic factors and define optimal cut‐off values for patient stratification or further validation in the upcoming European FOSTER‐CabOS trial.Methods: Predefined search terms were used to search PubMed, Web‐of‐science, and Embase for all studies investigating pretreatment prognostic factors in newly diagnosed osteosarcoma patients published 2000–2023. After applying strict inclusion and exclusion criteria, 49 papers were included.Results: We found 14 factors investigated in at least two separate studies or in a single study using one discovery and at least one validation cohort.Conclusions: We confirmed the prognostic value of patient age, presence of metastasis, tumor size, and site (axial vs. appendicular). Future studies of these factors should focus on specific patient populations and defining optimal cut‐off values. Although serum level of alkaline phosphatase and lactate dehydrogenase were associated with outcome, it remains unclear if they are independent of other prognostic factors. The prognostic value remains unclear for sex, pathological fracture, histologic subtype, and P‐glycoprotein expression. We could not establish any new prognostic biomarker. However, circulating tumor DNA in plasma and the G1/G2 RNA signature in diagnostic tumor biopsies show promise and will be further validated in the upcoming FOSTER‐CabOS trial.

Purpose: The phase III, open-label, prospective, multicenter, randomized Ewing 2008R1 trial (EudraCT2008-003658-13) was conducted in 12 countries to evaluate the effect of zoledronic acid (ZOL) maintenance therapy compared with no add-on regarding event-free survival (EFS, primary endpoint) and overall survival (OS) in standard-risk Ewing sarcoma (EWS).Patients and Methods: Eligible patients had localized EWS with either good histologic response to induction chemotherapy and/or small tumors (<200 mL). Patients received six cycles of VIDE induction and eight cycles of VAI (male) or eight cycles of VAC (female) consolidation. ZOL treatment started parallel to the sixth consolidation cycle. Randomization was stratified by tumor site (pelvis/other). The two-sided adaptive inverse–normal four-stage design (planned sample size 448 patients, significance level 5%, power 80%) was changed after the first interim analysis using the Müller–Schäfer method.Results: Between April 2010 and November 2018, 284 patients were randomized (142 ZOL/142 no add-on). With a median follow-up of 3.9 years, EFS was not significantly different between ZOL and no add-on group in the adaptive design (HR, 0.74; 95% CI, 0.43–1.28, P = 0.27, intention-to-treat). Three-year EFS rates were 84.0% (95% CI, 77.7%–90.8%) for ZOL vs. 81.7% (95% CI, 75.2%–88.8%) for no add-on. Results were similar in the per-protocol collective. OS was not different between groups. The 3-year OS was 92.8% (95% CI, 88.4%–97.5%) for ZOL and 94.6% (95% CI, 90.9%–98.6%) for no add-on. Noticeable more renal, neurologic, and gastrointestinal toxicities were observed for ZOL (P < 0.05). Severe renal toxicities occurred more often in the ZOL arm (P = 0.003).Conclusions: In patients with standard-risk localized EWS, there is no additional benefit from maintenance treatment with ZOL.