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Purpose For over 30 years, the place of consolidation high-dose chemotherapy in Ewing sarcoma (ES) has been controversial. A randomized study was conducted to determine whether consolidation high-dose chemotherapy improved survival in patients with localized ES at high risk for relapse. Methods Randomization between busulfan and melphalan (BuMel) or standard chemotherapy (vincristine, dactinomycin, and ifosfamide [VAI], seven courses) was offered to patients if they were younger than 50 years of age with poor histologic response (≥ 10% viable cells) after receiving vincristine, ifosfamide, doxorubicin, and etoposide (six courses); or had a tumor volume at diagnosis ≥ 200 mL if unresected, or initially resected, or resected after radiotherapy. A 15% improvement in 3-year event-free survival (EFS) was sought (hazard ratio [HR], 0.60). Results Between 2000 and 2015, 240 patients classified as high risk (median age, 17.1 years) were randomly assigned to VAI (n = 118) or BuMel (n = 122). Seventy-eight percent entered the trial because of poor histologic response after chemotherapy alone. Median follow-up was 7.8 years. In an intent-to-treat analysis, the risk of event was significantly decreased by BuMel compared with VAI: HR, 0.64 (95% CI, 0.43 to 0.95; P = .026); 3- and 8-year EFS were, respectively, 69.0% (95% CI, 60.2% to 76.6%) versus 56.7% (95% CI, 47.6% to 65.4%) and 60.7% (95% CI, 51.1% to 69.6%) versus 47.1% (95% CI, 37.7% to 56.8%). Overall survival (OS) also favored BuMel: HR, 0.63 (95% CI, 0.41 to 0.95; P = .028); 3- and 8-year OS were, respectively, 78.0% (95% CI, 69.6% to 84.5%) versus 72.2% (95% CI, 63.3% to 79.6%) and 64.5% (95% CI, 54.4% to 73.5%) versus 55.6% (95% CI, 45.8% to 65.1%). Results were consistent in the sensitivity analysis. Two patients died as a result of BuMel-related toxicity, one after standard chemotherapy. Significantly more BuMel patients experienced severe acute toxicities from this course of chemotherapy compared with multiple VAI courses. Conclusion BuMel improved EFS and OS when given after vincristine, ifosfamide, doxorubicin, and etoposide induction in localized ES with predefined high-risk factors. For this group of patients, BuMel may be an important addition to the standard of care.

Purpose Significantly improved survival rates in patients with Ewing sarcoma have raised interest in accessing the quality of long-term survivorship. In this study, subjective and objective measurement tools, preclassified as physical or mental scores, were used to assess clinicofunctional outcome and physical activity after intensive bone tumor treatment. Methods Long-term outcome of 618 survivors from consecutive Ewing sarcoma trials was assessed by the Toronto Extremity Salvage Score, Short-Form Health Survey (SF-36), Brief Symptom Inventory (BSI), and Rosenberg Self-Esteem Scale questionnaires and by the accelerometric StepWatch 3 Activity Monitor. Prospective measurements were correlated retrospectively with standardized primary trial data. Results were compared with 316 nonrandom healthy peers by using effect sizes ( d). Median observation time was 12.9 years from primary diagnosis (range, 3.7 to 31.2 years). Results Absolute subjective scores were moderate to good for survivors. Compared with control subjects, unfavorable outcome was shown on physical Toronto Extremity Salvage Score, SF-36 Physical Component Summary, and BSI-Somatization scales (| d| ≥ 0.50; P < .01), in contrast to SF-36 Mental Component Summary, BSI-Anxiety, BSI-Depression, and Rosenberg Self-Esteem Scale mental scales (| d| ≤ 0.31). Survivors were less active than control subjects, as demonstrated by a step count difference of 1,742 steps per day ( d = −0.43; P < .01); however, on average, the recommended level for an active lifestyle was achieved (≥ 10,000 steps). Location of pelvic tumor was the major inferior disease-specific prognostic factor in physical scores ( P < .01), whereas nondisease-specific inferior factors in questionnaires were older age and female sex ( P < .01). Conclusion Survivors of Ewing sarcoma apparently returned to a normal life with minor limitations. Observed reductions in physical scores should be a focus in future research to optimize treatment strategies to reduce a negative impact on the quality of survivorship.

11523 Background: Ewing 2008R1 (EudraCT2008-003658-13, Sponsor UKM) was conducted in 12 countries. It evaluated the effect of zolendronic acid (ZOL) maintenance therapy on event-free (EFS, primary endpoint) and overall survival (OS) from randomization in standard risk Ewing Sarcoma (EwS). Methods: Phase III, open label, prospective, multi-center, randomized controlled clinical trial. Eligible patients (pts) had localized EwS with either good histological response to induction chemotherapy and/or small tumors ( < 200ml). Pts received 6 cycles VIDE induction and 8 VAI (male) or 8 VAC consolidation (female) and were randomized to receive either 9 cycles of maintenance ZOL or no further treatment (control;ctrl). ZOL cycles started parallel to the 6th consolidation cycle. Randomization was stratified by tumor site (pelvis/no pelvis). Two-sided adaptive inverse-normal 4-stage design, changed after the 1st interim analysis via Müller-Schäfer method. Initial sample size 448 pts, type I error rate 5%, power 80%. Results: 284 pts were randomized between 2009 and 2018 (142 ZOL / 142 ctrl). With a median follow-up of 3.9 years, the primary endpoint EFS was not significantly different between the ZOL and ctrl group in the adaptive design (HR 0.74, 95% CI 0.43-1.28, intention to treat). 3-year (3y) EFS rates were 84.0% (95% CI 77.7-90.8%) for ZOL vs 81.7% (95% CI 75.2-88.8%) for ctrl. Results were similar in the per protocol collective. Cause-specific HR for local recurrence in ZOL was csHR 0.30 (95% CI 0.08 -1.09; p = 0.07), for metastatic progress/new metastases csHR 1.0 (CI 0.5-2.2), for combined relapse/progress csHR 0.3 (95% CI 0.1-1.7), for second malignancies csHR 4.0 (95% CI 0.45-36.1) compared to ctrl. The 3y OS was 92.8% (95% CI 88.4-97.5%) for ZOL and 94.6% (95% CI 90.9-98.6%) for ctrl. For ZOL the 5y OS was 87.3% (95% CI 80.7-94.5%) and 89% (95% CI 83.7-95.9%) for ctrl. Noticeable more renal, neurological and gut toxicities were observed for ZOL (p < 0.05), with severe renal toxicities occurring more often in the ZOL arm (p = 0.003). Conclusions: In patients with standard risk localized Ewing Sarcoma there is no benefit from maintenance treatment with zoledronic acid, but significant side effects were observed. Clinical trial information: NCT00987636 .

Purpose EWS-ETS fusion genes are the driving force in Ewing's sarcoma pathogenesis. Because of the variable breakpoint locations in the involved genes, there is heterogeneity in fusion RNA and protein architecture. Since previous retrospective studies suggested prognostic differences among patients expressing different EWS-FLI1 fusion types, the impact of fusion RNA architecture on disease progression and relapse was studied prospectively within the Euro-E.W.I.N.G. 99 clinical trial. Patients and Methods Among 1,957 patients who registered before January 1, 2007, 703 primary tumors were accessible for the molecular biology study. Fusion type was assessed by polymerase chain reaction on frozen (n = 578) or paraffin-embedded materials (n = 125). The primary end point was the time to disease progression or relapse. Results After exclusion of noninformative patients, 565 patients were entered into the prognostic factor analysis comparing type 1 (n = 296), type 2 (n = 133), nontype 1/nontype 2 EWS-FLI1 (n = 91) and EWS-ERG fusions (n = 45). Median follow-up time was 4.5 years. The distribution of sex, age, tumor volume, tumor site, disease extension, or histologic response did not differ between the four fusion type groups. We did not observe any significant prognostic value of the fusion type on the risk of progression or relapse. The only slight difference was that the risk of progression or relapse associated with nontype 1/nontype 2 EWS-FLI1 fusions was 1.38 (95% CI, 0.96 to 2.0) times higher than risk associated with other fusion types, but it was not significant (P = .10). Conclusion In contrast to retrospective studies, the prospective evaluation did not confirm a prognostic benefit for type 1 EWS-FLI1 fusions.

117 Background: With improved survival rates of patients with Ewing sarcoma the quality of long-term survivorship needs to be addressed. In this study, general recovery and restitution of function following intensive bone tumor treatment were analyzed by assessing the clinico-functional outcome and physical activity using self-reporting and objective measurement tools. Methods: Long-term outcome of 224 former patients with lower extremity Ewing sarcoma, registered between 1980 and 2009 in consecutive clinical trials of the GPOH, were assessed using the TESS, SF-36, BSI, and RSES questionnaire scales, and the accelerometric StepWatch Activity Monitor (SAM). To compare results with healthy subjects, 111 non-random peer controls were selected. Median observation time was 13.8 years from primary diagnosis (range 4.1-31.2). Results: Absolute values from the questionnaire scores indicated no major clinical findings in former patients. Compared to controls, unfavorable outcomes were however seen on physical TESS (d=-0.85), PCS (SF-36) (d=-1.08) and BSI-S scores (d=0.65) (P10000 steps). Comparing local therapy modality, physical scores for SAM, TESS, PCS were 10978, 91.2, T=50.2 for patients treated with surgery (N=101), 11097, 90.0, T=48.6 in patients with combined modality treatment (N=108), and 10093, 92.8, T=50.0 for patients with definite radiotherapy (N=15) (P=0.648; P=0.580; P=0.368). Conclusions: Survivors of primary lower extremity Ewing sarcoma exhibited moderately reduced self-reported and objectively measured physical outcome scores. Continuous long-term observation will be important in order to identify disease-specific prognostic factors for these patient-oriented outcomes.

11026Background: Local recurrence (LR) is associated with very poor prognosis in ES patients. We sought to identify factors associated with LR in patients undergoing multimodal treatment. Methods: ...

11000Background: EE99R2Loc (ISRCTN61438620) was conducted in 12 countries, by 4 cooperative groups: GPOH, SFCE/GSF, UK-CCLG, and EORTC. It evaluated effects on event-free (EFS, main endpoint) and o...

10529 Background: Since 1980 patients with Ewing sarcoma have been treated according to consecutive protocols (CESS) of the German Society of Pediatric Oncology and Hematology (GPOH). Rising surviv...

10529 Background: Since 1980 patients with Ewing sarcoma have been treated according to consecutive protocols (CESS) of the German Society of Pediatric Oncology and Hematology (GPOH)(supported by D...

10031 Background: The randomized Euro-EWING99-R1 trial assessed noninferiority of cyclophosphamide- vs ifosfamide-based consolidation regimens (VAC vs VAI) in SR localized ES patients. Overall, efficacy of VAC was deemed acceptable compared to VAI, with hazard ratio of event HR = 1.12 [0.89 - 1.41]. Based on its gender-stratified randomization, influence of gender on efficacy and acute toxicity were additionally explored. Methods: Impact of gender on EFS, acute toxicity by course, switches between treatment arms, and cumulative dose of alkylating agents was evaluated in multivariable models, including terms to test for heterogeneity of treatment effect by gender. Analysis was performed on the intention to treat population. Results: 856 patients (509 males, 347 females) were recruited between 2000 and 2010: 425 VAI and 431 VAC. EFS did not significantly differ between genders (p=0.33), but a marginal interaction was seen between treatment and gender (p=0.083): VAC was associated with poorer EFS in males than VAI, HR(VAC/VAI) = 1.34 [0.96 - 1.86], whereas, in females, VAC was slightly better than VAI, HR = 0.83 [0.54 - 1.28]. Similarly, males had a worse EFS than females with VAC, HR(M/F) = 1.42 [0.97 – 2.08], whereas results by gender were very similar with VAI, HR = 0.91 [0.62 – 1.33]. Severe hematological toxicity was more frequent with VAC than VAI whereas tubular renal impairment was more frequent with VAI. Severe toxicity was more frequent in females than in males, whatever the toxicity type, with no significant interaction between treatment and gender effect. 30 patients switched from VAI to VAC (21 F, 9 M) mostly due to renal toxicity, and 3 from VAC to VAI (1 F, 2 M). A reduction of alkylating agent cumulative dose >20% was more frequent in females (15% vs 9%, p=0.01), with no major difference between VAI and VAC (13% vs 10%, p=0.21). Conclusions: The marginal interaction between gender and type of alkylating agent on EFS has to be validated on external data. Differences of acute toxicity rate and compliance are not sufficient explanation. Effects of gender-dependant polymorphism/activity of metabolic enzymes (e.g. known for CYP2B6) of ifosfamide vs cyclophosphamide should be explored. Clinical trial information: NCT00020566.

e15050 Background: The aim of this analysis was to identify parameters to predict additional vascular procedures during RTR in a multicenter setting in patients (pts) with GCT after chemotherapy. M...

9517 Background: Anthracyclines and alkylating agents are the main effective drugs known for ES. Ifosfamide and cyclophosphamide are widely used, have different toxicity profiles and unknown relati...

e20516 Background: Ewing Sarcoma rarely occurs in the head and neck region, representing less than 5% of all Ewing sarcoma cases. Consequently, data of the clinical background and outcome are quite...

10546 Background: High-dose chemotherapy (HDC) is widely used in consolidation treatment of Ewing sarcoma patients with primary disseminated or recurrent disease. Standard busulfan-based regimens are not compatible with radiotherapy to central axis sites. Treosulfan is a newly-developed bifunctional alkylating agent that has been shown to be safe in current trials of the German Society for Pediatric Hematology and Oncology (GPOH) even in heavily pre-treated patients including axial radiation. Methods: Event-free survival (EFS) and overall survival (OS) for 21 patients with primary disseminated disease (PDD) and survival after relapse for 11 relapse patients recruited from the EURO-E.W.I.N.G.99 trial 1998–2007 were analyzed. PDD-patients had received VIDE induction prior to treosulfan-based HDC (treosulfan: 36g/m2; melphalan: 140mg/m2) followed by autologous stem cell transplantation. Median follow up was 1.72 yrs. Relapse patients had received appropriate second line chemotherapy regimens prior to treosulfan-based HDC. Median follow up after relapse was 2.26 yrs. Results: Seventeen of 21 (81%) PDD-patients had a central axis site of the primary tumor, 8 patients (38%) presented with a pelvic tumor. Metastatic sites were: bone (76%), bone marrow (22%), CNS (10%), liver (15%), lymphnode (29%), other (16%), and additionally lung metastases in 57%. 1y-EFS was 0.70 (SE=.10), 2y-EFS was 0.27 (SE=0.10), and 3y-EFS was 0.16 (SE=.09). 1y-OS was 0.84 (SE=.08), 2y-OS was 0.46 (SE=.13), and 3y-OS was 0.32 (SE=.12). In the cohort of 11 relapse patients two patients (18%) had a local relapse, 3 (27%) a combined relapse, and 6 (55%) a systemic relapse. Six of 11 (55%) relapse patients had a late relapse >2 yrs from diagnosis. Survival after relapse at 3yrs was 0.70 (SE=.15). Conclusions: Treosulfan-based HDC is an alternative approach in high-risk Ewing tumor patients especially after relapse to consolidate a second remission. Further investigation and comparison to other standard HDC regimens is needed. No significant financial relationships to disclose.

10039 Background: High dose (HD) chemotherapy using a busulfan-containing regimen has been proven advantageous for some high risk Ewing tumor (ET) patients. HD busulfan is not compatible with radiotherapy to central axis sites. Treosulfan is a bifunctional alkylating agent, structurally related to busulfan, that has shown to be safe even in heavily pretreated patients and patients at risk to treatment related toxicity. Methods: In vitro: In order to compare the cytotoxicity of busulfan and treosulfan, growth inhibition was tested by a modified (4,5-dimethylthiazol-2-yl)2,5-diphenyltetrazolium-bromide (MTT) assay. In vivo: 11 patients with primary disseminated ET and contraindication for busulfan HD treatment and 11 patients with relapsed ET were referred to HD treosulfan (36 g/m2) and melphalan (140 mg/m2) followed by autologous stem cell rescue. Results: In vitro: Busulfan and treosulfan were cytotoxic in a time and dose dependent manner. Treosulfan was 15-fold more cytotoxic compared to busulfan. In vivo: The median age in patients with disseminated ET was 14.3 years, in relapsed ET 22.7 years. Sex distribution was equal. Response status prior to HD treosulfan was: stable disease in 4, partial response in 6, complete remission in 8, progressive disease in 1, not documented in 3 patients. Median follow up time in patients with disseminated ET was 0.91 years. All patients are alive. Four patients have relapsed within 2 years after HD treatment. Median follow up time in relapsed ET was 1.35 years. Seven patients are in remission, one patient is under treatment and two patients have died after relapse. HD was well tolerated with mucositis °3 in seven, °4 in three, stomatitis °3 in four, °4 in three , neutropenic infection °3 in three and reversible myelitis in one patient. Conclusions: Treosulfan HD treatment is a feasible therapeutic option without overt acute toxicity for patients with advanced ET. Efficacy and late effects remain to be evaluated. No significant financial relationships to disclose.

10012 Background: Ewing tumor treatment has resulted in long term survival rates of approx. 70% in localized, and 30% in metastatic disease. Survival following relapse has remained poor with survival rates well below 30%. Methods: All histological proven Ewing tumor patients from three consecutive GPOH trials since 1981 (CESS81 & CESS86 & EICESS92; N=1,549) were included to conduct a meta-analyses of time to and type of recurrence. The follow up has been recently updated in 2006 resulting in a maximum observation period of 25 years. The cumulative incidences of the types of first relapse excluding progress under therapy were computed with competing risk analysis. Multivariate stepwise regression analyses according to the Cox proportional hazard model researched the influences of time to and type of relapse on survival after relapse. Results: More than 70% of first recurrences occurred within 2 years, and 85% within 3 years from initial diagnosis. Most common relapses were systemic with a 3-year cumulative incidence of approx. 0.10 each for lung metastases, bone metastases and multisystem metastases including other sites, followed by local and combined relapses both with a 3-year cumulative incidence of approx. 0.05. Multivariate analyses identified both early (2.5 (p No significant financial relationships to disclose.