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Purpose: The R2Pulm trial was conducted to evaluate the effect of busulfan-melphalan high-dose chemotherapy with autologous stem-cell rescue (BuMel) without whole-lung irradiation (WLI) on event-free survival (main end point) and overall survival, compared with standard chemotherapy with WLI in Ewing sarcoma (ES) presenting with pulmonary and/or pleural metastases., Methods: From 2000 to 2015, we enrolled patients younger than 50 years of age with newly diagnosed ES and with only pulmonary or pleural metastases. Patients received chemotherapy with six courses of vincristine, ifosfamide, doxorubicin, and etoposide (VIDE) and one course of vincristine, dactinomycin, and ifosfamide (VAI) before either BuMel or seven courses of VAI and WLI (VAI plus WLI) by randomized assignment. The analysis was conducted as intention to treat. The estimates of the hazard ratio (HR), 95% CI, and P value were corrected for the three previous interim analyses by the inverse normal method., Results: Of 543 potentially eligible patients, 287 were randomly assigned to VAI plus WLI (n = 143) or BuMel (n = 144). Selected patients requiring radiotherapy to an axial primary site were excluded from randomization to avoid excess organ toxicity from interaction between radiotherapy and busulfan. Median follow-up was 8.1 years. We did not observe any significant difference in survival outcomes between treatment groups. Event-free survival was 50.6% versus 56.6% at 3 years and 43.1% versus 52.9% at 8 years, for VAI plus WLI and BuMel patients, respectively, resulting in an HR of 0.79 (95% CI, 0.56 to 1.10; P = .16). For overall survival, the HR was 1.00 (95% CI, 0.70 to 1.44; P = .99). Four patients died as a result of BuMel-related toxicity, and none died after VAI plus WLI. Significantly more patients in the BuMel arm experienced severe acute toxicities than in the VAI plus WLI arm., Conclusion: In ES with pulmonary or pleural metastases, there is no clear benefit from BuMel compared with conventional VAI plus WLI.

Background: The role of postoperative radiotherapy (PORT) in Ewing sarcoma (ES) is unclear. We assessed the impact of PORT on local control in patients with localised ES and good histological response to chemotherapy (<10% cells)., Patients and Methods: All randomised patients in the EE99-R1 trial (comparing two consolidation chemotherapy regimens) undergoing surgery after induction chemotherapy were included. Local relapse (LR) cumulative incidence was estimated using a competing risk approach. Impact of PORT was assessed in multivariable models, adjusted for country, age, tumour site and volume, quality of resection and histological response. We also evaluated the heterogeneity of PORT effect by patient and tumour characteristics., Results: One hundred forty-two (24%) of the 599 patients included from 1999 to 2009 received PORT (median dose: 45 Grays). With median follow-up of 6.2 years, 67 patients had an LR (with concomitant metastases in 28), leading to an 8-year LR-incidence = 11.9% (standard error [se] = 1.4%). Overall survival (OS) = 21% (se = 5%) 3 years after LR (31% in isolated LR). Controlling for possible confounders, we observed a statistically significant reduction of LR in patients treated by surgery + PORT compared to surgery alone (subdistribution-hazard ratio = 0.43, 95% confidence interval, 0.21-0.88, p = 0.02). The benefit of PORT was particularly marked for tumours larger than 200 ml at diagnosis and 100% necrosis. We observed a non-significant trend for benefit associated with PORT for disease-free, event-free and OS., Conclusion: Radiotherapy appears to improve local control. We now recommend PORT in case of incomplete removal of the tissues involved by the pre-chemotherapy tumour volume. Further studies are required to assess the balance between benefit and risks., (Copyright © 2016. Published by Elsevier Ltd.)

Ewing sarcoma (ES) is an aggressive sarcoma of bone and soft tissue occurring at any age with a peak incidence in adolescents and young adults. The treatment of ES relies on a multidisciplinary approach, coupling risk-adapted intensive neoadjuvant and adjuvant chemotherapies with surgery and/or radiotherapy for control of the primary site and possible metastatic disease. The optimization of ES multimodality therapeutic strategies has resulted from the efforts of several national and international groups in Europe and North America and from cooperation between pediatric and medical oncologists. Successive first-line trials addressed the efficacy of various cyclic combinations of drugs incorporating doxorubicin, vincristine, cyclophosphamide, ifosfamide, etoposide, and dactinomycin and identified prognostic factors now used to tailor therapies. The role of high-dose chemotherapy is still debated. Current 5-year overall survival for patients with localized disease is 65% to 75%. Patients with metastases have a 5-year overall survival < 30%, except for those with isolated pulmonary metastasis (approximately 50%). Patients with recurrence have a dismal prognosis. The many insights into the biology of the EWS-FLI1 protein in the initiation and progression of ES remain to be translated into novel therapeutic strategies. Current options and future approaches will be discussed., (© 2015 by American Society of Clinical Oncology.)

Deciphering the ways in which somatic mutations and germline susceptibility variants cooperate to promote cancer is challenging. Ewing sarcoma is characterized by fusions between EWSR1 and members of the ETS gene family, usually EWSR1-FLI1, leading to the generation of oncogenic transcription factors that bind DNA at GGAA motifs. A recent genome-wide association study identified susceptibility variants near EGR2. Here we found that EGR2 knockdown inhibited proliferation, clonogenicity and spheroidal growth in vitro and induced regression of Ewing sarcoma xenografts. Targeted germline deep sequencing of the EGR2 locus in affected subjects and controls identified 291 Ewing-associated SNPs. At rs79965208, the A risk allele connected adjacent GGAA repeats by converting an interspaced GGAT motif into a GGAA motif, thereby increasing the number of consecutive GGAA motifs and thus the EWSR1-FLI1-dependent enhancer activity of this sequence, with epigenetic characteristics of an active regulatory element. EWSR1-FLI1 preferentially bound to the A risk allele, which increased global and allele-specific EGR2 expression. Collectively, our findings establish cooperation between a dominant oncogene and a susceptibility variant that regulates a major driver of Ewing sarcomagenesis.

Background: Primary cutaneous/subcutaneous Ewing sarcoma (scEWS) is extremely rare. We describe clinical features, treatment, and outcome of this Ewing localization., Procedure: Retrospective study (1996-2012) on 56 patients., Results: Most primary scEWS occurred in late adolescent/young adult females (F/M = 1.9; median age 21.5 years), with primary tumor in the extremity/trunk (48.5%/39%). Only 35/56 samples had Real-Time-Polymerase-Chain-Reaction/Fluorescent-In-Situ-Hybridization analysis, 32/35 had EWS-translocation. Most of them exhibited known favorable prognostic factors: localized disease (54/56), initial tumor volume < 200 ml (51/53). Thirty and 25 patients received chemotherapy according to Euro-Ewing99 or a shorter/less intense chemotherapy regimen associated with milder toxicity. One patient had not received chemotherapy. Surgery was performed at diagnosis in 37 patients (18/37 marginal/intra-lesional resections) followed by secondary surgery in 8/37 (three remained marginal). Nineteen other patients had an initial biopsy followed by chemotherapy, 15/19 underwent late surgery (4/15 marginal/intra-lesional resections). Overall, 27/56 patients received radiotherapy. Median follow-up was six years (1-15). Two patients with metastatic disease progressed at metastatic sites. Four patients with localized disease experienced progression/relapse (local n = 3, metastatic n = 1). Survival was excellent: 5y-OS and 5y-EFS were 93.8% (95%CI = 83-98%) and 88.5% (95%CI-= 77-95), respectively., Conclusions: Unplanned primary surgery should be avoided to try to minimize potential long term sequels due to secondary surgery or radiotherapy. Biopsy with molecular analysis and staging should be performed at diagnosis to inform treatment recommendations. Patients with metastases should be treated aggressively as for other metastatic EWS. Further studies are necessary to clarify whether a less intensive chemotherapy regimen could be safely used in localized disease to minimize acute/late toxicities., (© 2015 Wiley Periodicals, Inc.)

The prognosis of primary disseminated multifocal metastatic Ewing's sarcoma (PDMES) is poor even if a slight improvement has been achieved with high-dose alkylating agent-containing chemotherapy. To enhance treatment efficacy, we assessed the feasibility, safety and efficacy of a tandem high-dose chemotherapy (HDC) regimen. In a single institution, patients with PDMES received six courses of vincristine/ifosfamide/doxorubicin/etoposide induction therapy, followed by high-dose thiotepa, and then melphalan-busulfan, 8 weeks apart. Surgical resection of primary tumour was carried out between the two HDC regimens and 70 days after the last HDC regimen for post-operative radiotherapy or irradiation alone. From October 2002 to 2009, 13 of the 18 consecutive patients with PDMES (72%) received the full treatment programme. The other five patients experienced early progression and died. Among the 13 patients, 11 relapsed after the end of the treatment programme within 6 months (2.2-11.9) from end of therapy. Only two patients are still alive in first complete remission after 9 years. The 3-year event-free survival (EFS) and overall survival (OS) rates were 11 and 22%, respectively. The median EFS and OS duration from the diagnosis were 13.4 and 17.3 months, respectively. Neither major complications nor treatment-related death occurred. The tandem-HDC regimen was feasible, with expected side effects, but it did not improve the outcome of patients with PDMES.

Curative therapies for Ewing sarcoma have been developed within cooperative groups. Consecutive clinical trials have systematically assessed the impact and timing of local therapy and the activity of cytotoxic drugs and their combinations. They have led to an increase of long-term disease-free survival to around 70% in patients with localized disease. Translational research in ES remains an area in which interdisciplinary and international cooperation is essential for future progress. This article reviews current state-of-the art therapy, with a focus on trials performed in Europe, and summarizes novel strategies to further advance both the cure rates and quality of survival., (© Georg Thieme Verlag KG Stuttgart · New York.)

Unlabelled: Ewing sarcoma is a primary bone tumor initiated by EWSR1-ETS gene fusions. To identify secondary genetic lesions that contribute to tumor progression, we performed whole-genome sequencing of 112 Ewing sarcoma samples and matched germline DNA. Overall, Ewing sarcoma tumors had relatively few single-nucleotide variants, indels, structural variants, and copy-number alterations. Apart from whole chromosome arm copy-number changes, the most common somatic mutations were detected in STAG2 (17%), CDKN2A (12%), TP53 (7%), EZH2, BCOR, and ZMYM3 (2.7% each). Strikingly, STAG2 mutations and CDKN2A deletions were mutually exclusive, as confirmed in Ewing sarcoma cell lines. In an expanded cohort of 299 patients with clinical data, we discovered that STAG2 and TP53 mutations are often concurrent and are associated with poor outcome. Finally, we detected subclonal STAG2 mutations in diagnostic tumors and expansion of STAG2-immunonegative cells in relapsed tumors as compared with matched diagnostic samples., Significance: Whole-genome sequencing reveals that the somatic mutation rate in Ewing sarcoma is low. Tumors that harbor STAG2 and TP53 mutations have a particularly dismal prognosis with current treatments and require alternative therapies. Novel drugs that target epigenetic regulators may constitute viable therapeutic strategies in a subset of patients with mutations in chromatin modifiers., (©2014 American Association for Cancer Research.)

Purpose: Relative efficacy and toxicity of cyclophosphamide compared with ifosfamide are debatable. The Euro-EWING99-R1 trial asked whether cyclophosphamide may replace ifosfamide in combination with vincristine and dactinomycin (vincristine, dactinomycin, and cyclophosphamide [VAC] v vincristine, dactinomycin, and ifosfamide [VAI]) after an intensive induction chemotherapy containing vincristine, ifosfamide, doxorubicin, and etoposide (VIDE) in standard-risk localized disease (NCT00020566)., Methods: Standard-risk Ewing sarcomas were localized tumors with either a good histologic response to chemotherapy (< 10% cells) or small tumors (< 200 mL) resected at diagnosis or receiving radiotherapy alone as local treatment. Patients entered the trial after six VIDE+1 VAI courses. Allocated treatment was either 7 VAC courses with 1.5 g/m(2) of cyclophosphamide or seven VAI-courses with 6 g/m(2) ifosfamide. The limit of noninferiority was set at -8.5% for the 3-year event-free survival rate (EFS), equivalent to 1.43 in terms of the hazard ratio of event (HR(event))., Results: This large international trial recruited 856 patients between February 2000 and March 2010 (n = 431 receiving VAC and n = 425 receiving VAI). With a median follow-up of 5.9 years, the 3-year EFSs were 75.4% and 78.2%, respectively, the 3-year EFS difference was -2.8% (91.4% CI, -7.8 to 2.2%), the HR(event) was 1.12 (91.4% CI, 0.89 to 1.41), and the HR(death) was 1.09 (91.4% CI, 0.84 to 1.42; intention-to-treat). The HR(event) was 1.22 (91.4% CI, 0.96 to 1.54) on the per-protocol population. Major treatment modifications were significantly less frequent in the VAC arm (< 1%) than in the VAI arm (7%), mainly resulting from toxicity. Patients experienced more frequent thrombocytopenia in the VAC arm (45% v 35%) but fewer grade 2 to 4 acute tubular toxicities (16% v 31%)., Conclusion: Cyclophosphamide may be able to replace ifosfamide in consolidation treatment of standard-risk Ewing sarcoma. However, some uncertainty surrounding the noninferiority of VAC compared with VAI remains at this stage. The ongoing comparative evaluation of long-term renal and gonadal toxicity is crucial to decisions regarding future patients., (© 2014 by American Society of Clinical Oncology.)

Purpose: The time to diagnosis (TtD) of Ewing tumors is one of the longest among pediatric tumors. Its precise consequences, however, have not been studied well. We analyzed the distribution of TtD for Ewing tumors in children and adolescents and its association with clinical features, tumor characteristics, surgical outcome, and long-term survival., Patients and Methods: We analyzed prospectively collected data from two multicenter clinical trials of patients younger than 21 years old who had Ewing bone tumors treated in France between 1988 and 2000. Clinical and tumoral features, TtD, and outcome associations were studied by univariable and multivariable analyses., Results: The median TtD for the 436 patients was 70 days (interquartile range, 27 to 146 days), with no significant decrease during the study period (P > .2). The factors associated with long TtD were older age and some tumor sites (pelvis, extremities of limbs). Increased tumor volume and decreased histologic response to chemotherapy were associated with long TtD on univariable analysis (P < .05) but not after adjustment. Presence of a nerve or spinal-cord compression at diagnosis, presence or site of metastasis, surgical treatment, mutilating surgery, complete resection, or survival were not associated with TtD., Conclusion: TtD of Ewing tumors was long, especially for adolescents and for certain tumor sites, and did not improve over time. But TtD was not associated with metastasis, surgical outcome, or survival. These findings could be used to comfort parents at diagnosis and in expert testimony produced for malpractice claims., (© 2014 by American Society of Clinical Oncology.)

Objectives: To evaluate both local outcome and sequelae of non-metastatic spinal Ewing tumours (EWT)., Patients and Methods: A French cohort of patients ≤ 50years with localised spinal EWT treated between 1988 and 2009, was analysed in regard to tumour characteristics (e.g. volume, vertebral compartment, spinal cord compression, paraspinal soft tissue invasion), local treatment modalities (surgery (S) and margin quality, radiotherapy (RT) dose), response to treatment (e.g. histological response to neoadjuvant chemotherapy (CT)), tumour local control (LC) and sequelae., Results: Seventy-five patients treated in successive trials were evaluated for LC: SFOP-EW88 (n=14), SFOP-EW93 (n=17) and EuroEwing99 (n=44). Fifty-seven patients (79%) presented initial neurological compression and 69% had inaugural decompressive S. Local treatment modality was S+RT (n=50), RT alone (n=19) and S alone (n=6). Surgery was mainly intralesional (66%). Local recurrences had occurred in 19 patients (14 local, 5 loco-regional) with a median interval of 25 months (1-50). After a 7 year median follow-up (1-22 years), the 5-year LC, relapse-free survival (RFS) and overall survival (OS) reached 78.0% (95%CI: 62.6-84.6), 57.0% (95%CI: 45.2-68.9) and 70.0% (95%CI: 59.1-81.0), respectively. Vertebral compartment involved was the only prognostic factor (5-year LC rate 100% versus 71% for favourable and unfavourable compartment, p<0.03). Among 41 five-year survivors, we observed spinal curvature deformation (35%), growth retardation (28%), spinal reduction mobility (40%), spinal pain (25%) and neurological sequelae (32%) without any significant association with a particular local procedure., Conclusion: RT is the backbone of a successful local treatment of spinal EWT. The place of S remains a pending question. Its actual benefit will likely evolve with new available RT techniques., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Background: Phase II trials demonstrate the activity of cisplatin in patients with refractory Ewing sarcoma family tumours (ESFT) and also the feasibility of giving cisplatin with oral VP16 in a variety of different cancers. This trial was conducted to evaluate the activity and toxicity profile of this combination delivered as outpatient therapy in patients with refractory/relapsed ESFT., Methods: Cisplatin was administered on days 1, 8 and 15 and days 29, 36 and 43 (70 mg/m(2)/dose for patients <21 years of age and 50 mg/m(2)/dose ≥21 years). VP16 was administered at a dose of 50 mg/m(2) on days 1-15 and days 29-43 inclusive. A three-stage Fleming statistical design was used for analysis., Results: Between January 2003 and October 2006, 45 patients aged between 5 and 46 years (median 19) were enrolled. Thirty-eight were evaluable for response. Patients had previously received one to three lines of chemotherapy (median = one). Seventy-three per cent of the patients had grade 3/4 neutropenia, 20 % developed fever, 40 % had grade 3/4 anaemia, 68 % grade 3/4 thrombocytopenia and 16 % grade 2/3 ototoxicity. Measured response after 2 cycles: 0 CR, 7 PR (18 %), 13 SD (34 %), 18 PD (48 %). There was excellent concordance between unidimensional and bidimensional criteria in 31 of 33 responses (94 %). PFS at 1 year was 39 %, with a median PFS of 6 months. Overall survival at 1 year was 44 %; median survival was 11 months., Conclusions: Cisplatin combined with oral VP16 is well tolerated and has acceptable side effects, but limited clinical activity in refractory/relapsed ESFT.

Aim of the Study: To determine whether a risk factor adapted chemotherapy would improve the outcome of non-metastatic bone Ewing's sarcoma., Methods: Standard risk tumours (SR, good histological response to chemotherapy or small unresected tumours) received the previous EW88 chemotherapy. Ifosfamide/etoposide (IE) were introduced after 3 courses of cyclophosphamide/doxorubicine when tumour regression was <50% or during consolidation therapy for the intermediate risk tumours (IR, intermediate histological response 5-30% residual cells or large unresected tumours >100ml). High risk tumours (HR, histological poor response >30% residual cells or clinical poor response <50% for unresectable tumours), received IE prior high dose busulfan/melphalan with stem cell rescue., Results: From 1993 to 1999, 214 patients were enrolled. 5 y-EFS and OS were 60% (95% confidence interval (CI), 53-66) and 69% (95% CI, 63-75), respectively. 116 (54%), 46 (21%), 48 (22%) patients were considered as SR, IR and HR of relapse, respectively. No advantage to IE was observed in the IR group. As compared to previous study, tumour with poor histological response to induction chemotherapy seemed to benefit from the consolidation strategy including busulfan/melphalan: EFS were 45% (95% CI, 30-60) and 20% (95% CI, 7-43) for EW93 and EW88, respectively. Despite a risk-adapted strategy, histological response to chemotherapy remains the main prognostic factor in resected tumours, while initial tumour volume is the main prognostic factor for unresected tumours., Conclusion: These results showing a potential benefit of a consolidation strategy including busulfan/melphalan as compared to conventional chemotherapy needed confirmation by a randomised trial and were one of the bases of the ongoing EuroEwing99., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Ewing sarcoma, a pediatric tumor characterized by EWSR1-ETS fusions, is predominantly observed in populations of European ancestry. We performed a genome-wide association study (GWAS) of 401 French individuals with Ewing sarcoma, 684 unaffected French individuals and 3,668 unaffected individuals of European descent and living in the United States. We identified candidate risk loci at 1p36.22, 10q21 and 15q15. We replicated these loci in two independent sets of cases and controls. Joint analysis identified associations with rs9430161 (P = 1.4 × 10(-20); odds ratio (OR) = 2.2) located 25 kb upstream of TARDBP, rs224278 (P = 4.0 × 10(-17); OR = 1.7) located 5 kb upstream of EGR2 and, to a lesser extent, rs4924410 at 15q15 (P = 6.6 × 10(-9); OR = 1.5). The major risk haplotypes were less prevalent in Africans, suggesting that these loci could contribute to geographical differences in Ewing sarcoma incidence. TARDBP shares structural similarities with EWSR1 and FUS, which encode RNA binding proteins, and EGR2 is a target gene of EWSR1-ETS. Variants at these loci were associated with expression levels of TARDBP, ADO (encoding cysteamine dioxygenase) and EGR2.

Purpose: To improve the poor prognosis of patients with primary disseminated multifocal Ewing sarcomas (PDMES) with a dose-intense treatment concept., Patients and Methods: From 1999 to 2005, 281 patients with PDMES were enrolled onto the Euro-EWING 99 R3 study. Median age was 16.2 years (range, 0.4 to 49 years). Recommended treatment consisted of six cycles of vincristine, ifosfamide, doxorubicin, and etoposide (VIDE), one cycle of vincristine, dactinomycin, and ifosfamide (VAI), local treatment (surgery and/or radiotherapy), and high-dose busulfan-melphalan followed by autologous stem-cell transplantation (HDT/SCT)., Results: After a median follow-up of 3.8 years, event-free survival (EFS) and overall survival (OS) at 3 years for all 281 patients were 27% +/- 3% and 34% +/- 4% respectively. Six VIDE cycles were completed by 250 patients (89%); 169 patients (60%) received HDT/SCT. The estimated 3-year EFS from the start of HDT/SCT was 45% for 46 children younger than 14 years. Cox regression analyses demonstrated increased risk at diagnosis for patients older than 14 years (hazard ratio [HR] = 1.6), a primary tumor volume more than 200 mL (HR = 1.8), more than one bone metastatic site (HR = 2.0), bone marrow metastases (HR = 1.6), and additional lung metastases (HR = 1.5). An up-front risk score based on these HR factors identified three groups with EFS rates of 50% for score or= 5 (70 patients; P < .0001)., Conclusion: PDMES patients may survive with intensive multimodal therapy. Age, tumor volume, and extent of metastatic spread are relevant risk factors. A score based on these factors may facilitate risk-adapted treatment approaches.

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.

Purpose: To evaluate the outcome of children with an extraosseous Ewing tumor (EOE) according to treatment., Patients and Methods: Children with EOE were treated either with the strategy used for malignant mesenchymal tumors (MMTs) by the International Society of Pediatric Oncology (SIOP) or with the French Society of Pediatric Oncology (SFOP) regimen used for osseous Ewing tumors (OET). The MMT strategy included vincristine/actinomycin for small and resected tumors or ifosfamide/vincristine/actinomycin for unfavorable sites or unresectable tumors. Surgical excision was to be attempted after four courses, followed by local irradiation in case of residue. Osseous Ewing (OE) protocol included three courses of cyclophosphamide/doxorubicin followed either by two similar courses in case of good response or two courses of ifosfamide/etoposide in case of no response. After resection of the primary, treatment included conventional chemotherapy in case of good histologic response and high-dose chemotherapy and radiotherapy for poor response. All diagnosis specimens were reviewed by the panel., Results: Between 1989 and 1999, 63 patients were registered. Characteristics of patients treated by both protocols were similar. Five-year overall survival (OS) and event-free survival (EFS) of those treated with the OE protocol are 83% and 75%, respectively, which is significantly better than the OS and EFS of those treated with the MMT strategy (59% and 44%, respectively; P = .04 and .008, respectively). The size of the primary and the type of protocol influenced patients' EFS. In multivariate analysis, only the regimen had an impact on OS and EFS., Conclusion: Our study shows that patients with EOE should be treated with OE regimens, probably because of the use of anthracyclines.

To retrospectively evaluate the incidence of tumour cell contamination of peripheral blood stem cell (PBSC) collections and to correlate these data with the clinical outcome after high-dose chemotherapy (HDCT) with stem cell rescue in patients with a high-risk Ewing tumour. Peripheral blood stem cell collections obtained from 171 patients were analysed. Tumour contamination was assessed by reverse transcriptase-polymerase chain reaction (RT-PCR). The files of 88 patients who underwent HDCT followed by PBSC reinfusion were reviewed in detail, and their outcome compared to the PBSC RT-PCR results. Seven of 88 PBSC collections (8%) contained tumour cells as detected by RT-PCR. Peripheral blood stem cells were collected after a median of five cycles of chemotherapy. No clinical factor predictive of tumour cell contamination of PBSC harvest could be identified. Event-free survival (EFS) and overall survival (OS) of the whole study population were 45.3 % and 51.8 % at 3 years from the date of the graft, respectively. Forty-five patients relapsed with a median time of 15 months after graft, only four of whom had tumour cell contamination of the PBSC harvest. Tumour cell contamination of PBSC collection is rare and does not seem to be associated with a significantly poorer EFS or OS in this high-risk population.

Purpose: To improve the prognosis for patients with metastatic Ewing sarcoma/primitive neuroectodermal tumors (ES/PNET) using conventional chemotherapy and consolidation high-dose chemotherapy (HDCT) containing busulfan and melphalan., Patients and Methods: Ninety-seven unselected patients with newly diagnosed metastatic ES/PNET received induction chemotherapy that included five cycles of cyclophosphamide 150 mg/m2/d for 7 days, doxorubicin 35 mg/m2/d once, followed by two cycles of ifosfamide 1.8 g/m2/d for 5 days, and etoposide 100 mg/m2/d for 5 days. Patients in complete or very good partial remission received HDCT with busulfan total dose 600 mg/m2 and melphalan 140 mg/m2 followed by autologous blood stem cells. Local therapy (surgery and/or radiation therapy) was performed before or after HDCT., Results: Ninety-seven patients were enrolled from 1991 to 1999 (median age, 12.3 years; range, 0.2 to 25 years). Among them, 75 received HDCT. The 5-year event-free survival (EFS) rate for all 97 patients was 37% and the overall survival (OS) rate was 38%. The EFS after HDCT was 47%. The EFS for the 44 patients with lung-only metastases was 52%, whereas it was 36% for patients with bone metastases without bone marrow involvement. Among the 23 patients with bone marrow metastases, only one survived. The multivariate analysis for both EFS and for OS identified three independent prognostic factors: age, fever at diagnosis, and bone marrow involvement., Conclusion: Compared with conventional chemotherapy, HDCT may yield benefits for patients with lung-only metastases or bone metastases. These results warrant confirmation in a randomized trial and provide part of the background data for the ongoing Euro-Ewing study.

Background: The EUROpean Ewing tumour Working Initiative of National Groups 1999 (EURO-E.W.I.N.G. 99) protocol prescribes six courses of vincristine, ifosfamide, doxorubicin, and etoposide (VIDE) as intensive induction chemotherapy for Ewing tumors (ET). Granulocyte-colony stimulating factor (G-CSF) is recommended. Adverse reactions (AR) were evaluated; quality assurance of data collection reviewed., Procedure: Safety data from 4,746 courses of VIDE in 851 patients less than 50 years with ET were collected using a checklist and evaluated using descriptive statistics with sub-groups including gender, age, and tumor volume, analyzed by Wilcoxon and Kruskal-Wallis tests., Results: Myelosuppression and infections were the major AR but with appropriate supportive therapy targeted dose intensity was maintained. Five VIDE-related deaths with three due to sepsis were reported. Renal and cardiac toxicity were reflected by glomerular filtration rate (GFR) <39 ml/min/1.73 m2 in 0.1%, tubular phosphate reabsorption < or = 0.80 in 1.9%, and left ventricular shortening fracture <28% in 2.5% VIDE courses. Statistically significant gender-associated AR concerning hemoglobin and platelets were observed with females > males as were age-associated AR concerning hemoglobin, WBC, platelets, stomatitis, and vomiting with AR decreasing with age, that is, children > adolescents > adults. No association of AR to tumor volume was found. In VIDE courses with and without G-CSF, neutropenia-related fever in 60.8% and 65.8%, and infection in 54.7% and 61.0% courses, respectively, were recorded., Conclusions: AR under VIDE remained within the expected range. Some AR, for example, hematotoxicity were significantly influenced by age and gender but not by tumor volume. G-CSF did not significantly influence neutropenia-related fever and infection. Solicited safety collection with checklists adequately reflects the burden per course., (Copyright 2006 Wiley-Liss, Inc.)

To determine which factors impact on quality of life of patients with bone tumor, we used the Children Health Questionnaire French version. Thirty-seven patients (25 males, 19 osteosarcoma, 18 Ewing sarcoma) were studied. At assessment, median age was 15 years, median follow-up was 4 years. Mean scores were 60, 81, 76, 74, 70, 87 for general health, physical functioning, pain, mental health, self-esteem, and family activity, respectively. Lower results were observed for mental health in girls, for physical functioning, and self-esteem in patients with endoprosthesis, and for family activity and pain in patients who had relapsed.

Purpose: The presence of metastasis is a major prognostic factor in Ewing tumor (ET). The relapse pattern of patients with localized tumors has long indicated that cases with disseminated ET cells escape detection at diagnosis. ET cells are characterized by specific gene fusions that can be detected with high sensitivity and specificity by reverse transcriptase polymerase chain reaction (RT-PCR)., Patients and Methods: RT-PCR targeting EWS-FLI-1 or EWS-ERG transcripts was used to search for occult tumor cells in peripheral blood (PB) and bone marrow (BM) at diagnosis in 172 patients with ET, and the prognostic significance of this parameter was assessed., Results: As we suggested previously in a smaller series of patients, RT-PCR positivity of the BM was correlated with a high risk of adverse outcome in the overall study population (P =.007). More interestingly, among patients with otherwise localized tumors, BM micrometastasis also predicted significantly poorer disease-free survival rates (P =.043). The presence of circulating tumor cells (CTC) was more frequently observed in patients with large tumors (P =.006). CTC were associated with a poor outcome among patients with clinically localized disease (P =.045). Patients with clinically localized disease and peripheral occult tumor cells as evidenced by BM and/or PB RT-PCR positivity had axial or proximal tumors and experienced relapses at a systemic rather than at a local level., Conclusion: Patients with localized ET and BM micrometastasis or CTC are comparable to patients with metastases in terms of the localization of the primary tumor, outcome, and relapse pattern.

From 1984 to 1997, 57 consecutive patients with non-metastatic Ewing's sarcoma of the ribs were treated according to multimodal French Society of Pediatric Oncology (SFOP) protocols EW 84, EW 88 and EW 93. The results of treatment were reviewed and analysed. Median age was 12 years. 34 patients had large tumours (greatest tumour dimension > or = 8 cm); pleural effusion was noted in 26. A tumour-positive margin after surgery was noted in 15 patients. Histological response after chemotherapy was assessed in 34 patients. 34 patients received radiation therapy. With a median follow-up of 5 years, the projected overall and relapse-free survival rates were 69 and 62%, respectively. The major site of relapse was local. None of the following was significant in predicting relapse: tumour size, gender, age at diagnosis, existence of pleural effusion, level of rib tumour, rib component, type of local control, surgical margin (positive or negative). Response to chemotherapy was the sole significant prognostic factor (P=0.004). Patients with pleural effusion had a higher percentage of relapse if they were treated without local radiation therapy. Our study confirms the prognostic significance of response to initial chemotherapy. Radiation therapy may be withheld in selected cases, but seems necessary in patients with pleural effusion.

Purpose: (1) To improve survival rates in patients with Ewing's sarcoma (ES) or peripheral neuroectodermal tumours (PNET) using semi-continuous chemotherapy and aiming to perform surgery in all; (2) To identify early prognostic factors to tailor therapy for future studies., Patients and Methods: One hundred and forty-one patients were entered onto the trial between January 1988 and December 1991. Induction therapy consisted of five courses of Cytoxan, 150 mg/m(2) x 7 days, followed by Doxorubicin, 35 mg/m(2) i.v on day 8 given at short intervals. Surgery was recommended whenever possible. The delivery of radiation therapy was based on the quality of resection and the histological response to CT. Maintenance chemotherapy consisted of vincristine + actinomycin and cytoxan + doxorubicin. The total duration of therapy was 10 months., Results: After a median follow-up of 8.5 years, the projected overall survival at 5 years was 66% and disease-free survival (DFS) was 58%. In patients treated by surgery, only the histological response to CT had an influence on survival: 75% DFS for patients with a good histological response (less than 5% of cells), 48% for intermediate responders and only 20% for poor responders (> or = 30% of cells), P < 0.0001. The initial tumor volume by itself had no influence on DFS in these patients. In contrast, the tumour volume had a strong impact on DFS in patients treated by radiation therapy alone. Age had no impact on outcome., Conclusion: Therapeutic trials for localized Ewing's sarcoma should be based on the histological response to chemotherapy or on the tumour volume according to the modality used for local therapy., ((c) 2001 Cancer Research Campaign)

The occurrence of secondary chromosome changes is frequent in Ewing tumors, in particular trisomies for chromosomes 8 and 12, and unbalanced (1;16) translocations leading to gains of 1q and losses of 16q. The prognostic value of these secondary aberrations has not been statistically demonstrated. We report here a CGH analysis of a series of 43 primary tumors corresponding to 21 localized and 22 metastatic tumors. For five of them, a sufficient amount of DNA for the CGH analysis was available from the frozen samples. For 19 samples, a preliminary step of DOP-PCR amplification of the DNA was necessary. For the last 19 tumors, DNA was obtained after DOP-PCR amplification of small amount of DNA contaminating the RNA. As a whole, the main chromosome imbalances previously described, such as trisomies for 1q, 8, and 12, were observed. It is noteworthy that the mean number of imbalances was more frequent in localized versus metastatic tumors. Gain of 1q was more frequent in metastatic than in localized tumors. Nevertheless, these two results do not reach statistical significance. Conversely, a statistically significant excess of copy number of chromosome 2 was observed in non-metastatic tumors, suggesting that this imbalance, which has never been previously reported, could be associated with more favorable tumor behavior.

Therapy in metastatic Ewing's sarcoma is reviewed using the methodology recommended by the guidelines project of the Federation of French Cancer Centres (FNCLCC) Standards, Options and Recommendation (SOR) Group. Twelve articles relating to conventional dose therapy and seven articles related to high-dose therapy were judged suitable for detailed appraisal. Rates of complete response (CR) at metastatic sites and local control were high using combinations of vincristine, actinomycin, cyclophosphamide and doxorubicin with radiation or surgery. With more recent regimens, including increased doses of alkylating agents and anthracyclines the relapse-free survival has increased from <15 to 20-30%. 'Megatherapy' regimens with haematopoietic stem cell rescue are tolerable in this patient group, but to date there is little evidence of any benefit. It appears that patients with isolated lung metastases do significantly better (approximately 40% EFS) than those presenting with combined sites such as bone, bone marrow and lung. The use of lung irradiation in children with lung metastases is associated with a reduced incidence of subsequent lung recurrence and a consistently better overall relapse-free survival (RFS).

Ewing sarcoma is an uncommon malignancy that has been frequently managed differently in childhood and adults. This is a review of the international experience that conducted to a common European study called Euro Ewing. This study was launched in 1999.

Background: Since January, 1984, 59 children with histologically confirmed Ewing sarcoma of the pelvic bone have been treated with three successive chemotherapy protocols recommended by the French Society of Pediatric Oncology. The purpose of the current study was to evaluate the role of surgery and/or radiotherapy in local progression-free, disease-free, and overall survivals (LPFS, DFS, and OS, respectively)., Procedure: We retrospectively examined 59 children treated for nonmetastatic, pelvic Ewing sarcoma over the last 12 years. All were first treated with chemotherapy according to the current French protocol. Six patients developed progressive disease before local treatment and were excluded for local control and survival analysis. Local treatment was surgery alone in 17 cases, radiation therapy in 27 cases, and surgery plus radiation therapy in 9 cases., Results: With a median of follow-up of 6.5 years, no significant differences in local control or survival were observed with the three chemotherapeutic protocols. Of the 53 patients evaluable for local control, 6 relapsed locally only, 8 had local and distant relapses, and 9 had distant metastases only. The 5-year OS rate was worst for patients with radiotherapy alone compared to those with surgery or combined modality treatment (44 % vs. 72 %, P = 0.043). The 5-year LPFS and DFS rates were worst in the radiotherapy-alone group but not significantly (63% vs. 79%, P = 0. 22 and 42% vs 71%, P =0.07, respectively). The importance of surgery to OS and DFS was confirmed by multivariate analysis (P = 0.026 and P = 0.048, respectively). One surviving patient was diagnosed with in-field fibrosarcoma, which was presumably radiation induced., Conclusions: Despite intensive, multiagent chemotherapy, survival from pelvic Ewing sarcoma has not improved over the past decade; however, the survival rate does not seem to be worse than that from Ewing sarcoma at other locations, insofar as at least 50% of the patients were cured. Surgery or a combination of surgery and radiation therapy are the best local treatment; exclusive radiation therapy should be reserved for patients with inoperable lesions or partially or nonchemosensitive tumors or when surgery would be an amputation., (Copyright 1999 Wiley-Liss, Inc.)

Purpose: Gene fusions that result from the chromosome translocations observed in Ewing's tumor (ET) provide tumor-specific markers that can be used to detect the presence of tumor cells in peripheral blood (PB), bone marrow (BM), and stem cell collection (SCC). These markers were used to evaluate, at diagnosis, a series of 67 ET patients., Patients and Methods: RNA was extracted from nucleated cells from PB and BM and a nested reverse-transcriptase polymerase chain reaction (RT-PCR) was performed to search for EWS-FLI-1 or EWS-ERG fusion transcripts that resulted from the t(11;22) or t(21;22) translocations, respectively., Results: At diagnosis, 16 of 62 (26%) patients had circulating tumor cells. This was not correlated with any clinical parameter. In contrast, Ewing's cells were detected by RT-PCR in BM in 14 of 43 (33%) patients and were associated with the presence of clinically detectable metastases and a statistically significant unfavorable outcome in univariate analysis. There was no correlation between the RT-PCR results in PB and in BM., Conclusion: These results suggested that the monitoring of BM but not of PB by RT-PCR might constitute an important criterion for the staging, at diagnosis, of patients with ET. Further studies should appreciate the relationship or independence of this marker toward other classical prognostic factors in ET, particularly to the presence of clinically detectable metastases.

Recently, Ewing's tumours have been shown to carry specific hybrid transcripts resulting from the fusion of the EWS gene with FLI-1 or ERG genes. Based on the sensitivity and specificity of the detection of these alterations by the reverse transcriptase-polymerase chain reaction technique, we have developed an assay to search for small numbers of Ewing cells in various sites from patients with Ewing's tumour. This method enables the detection of fewer than one tumour cell per million blood mononuclear cells. A total of 28 primary sites and 51 peripheral samples from 36 patients were investigated. Tumour cells could be detected in 4/18 blood samples, 4/15 bone marrow aspirates and 2/18 peripheral stem cell harvests. EWS/FLI-1 and EWS/ERG transcripts being observed in eight and two cases respectively. The type of fusion transcript detected in peripheral site(s) was identical to that observed in the primary site. At diagnosis 5/16 patients (31%) demonstrated either circulating tumour cells or/and occult bone marrow metastasis. After induction therapy, tumour cells were detected in 3/21 patients. This highly sensitive method should be a relevant tool to allow a more accurate clinical assessment of the dissemination of Ewing's tumours.

Purpose: Bone marrow (BM) status is a critical matter when intensified chemotherapy with bone marrow rescue is proposed to improve the survival of patients with poor prognosis Ewing's sarcoma (ES): metastatic or relapsing disease. A systematic bone marrow investigation was performed in all the patients with newly diagnosed ES or relapsing ES to assess their BM status., Patients and Methods: From January 1985 to February 1989, 59 untreated patients and five patients at the time of relapse had a bone marrow investigation under general anesthesia: two BM biopsies and two BM aspirates until May 1986, then two BM biopsies and 10 BM aspirates. The classical method of smearing each BM aspirate was compared to cytocentrifugation of the pool of BM samples after gradient density separation., Results: The BM was involved in 13 of 59 untreated patients. BM was the single site of metastatic spread in only one patient but was involved in 52% of the patients with metastatic disease at other sites. This involvement was focal in several patients and frequent discrepancies were noted between the aspirates and biopsies at the various sites explored. The number of positive cases of BM involvement discovered by the two methods is somewhat limited. However preliminary results indicate a superior rate of positive smears with the pool technique which did however fail to detect involvement in some cases., Conclusions: The present study indicates that 1) BM involvement is a frequent event in metastatic ES (52%); 2) is often multifocal and therefore requires extensive BM investigation; and 3) further investigation of the pool technique to facilitate the BM screening is warranted.

The role of radiolabeled meta-iodobenzyl-guanidine (mIBG) is established in the detection and the staging of neuroblastoma. We designed a study of mIBG scanning for patients with Ewing's sarcoma, a tumor for which a neuroectodermic origin has been proposed. We explored 15 children with round cell sarcoma of bone by a whole body scan carried out 24 hours after injection of 123-I mIBG. No patient demonstrated significant uptake either at the site of the primary or at the sites of metastases. These results suggest that despite its neural histogenesis Ewing's sarcoma is a member of the nonneuroblastoma neural crest tumors, which does not produce or store adrenergic metabolites.

Purpose: To undertake a new protocol with the goals of improving the chemotherapeutic treatment of pediatric Ewing's sarcoma by introducing ifosfamide, and to widen the indications for surgical resection of Ewing's tumor to obtain better local control and to reduce radiation doses., Patients and Methods: The French Society of Pediatric Oncology initiated its first cooperative Ewing's sarcoma study in 1978, using a four-drug regimen (cyclophosphamide, dactinomycin, Adriamycin [doxorubicin; Farmitalia Carlo Erba, Rueil-Malmaison, France], and vincristine). Ninety-five patients were included, and, at 5 years, the disease-free survival reached a plateau of 51%. After encouraging responses of recurrent soft tissue or bone sarcomas to ifosfamide, a second study began in 1984 using a new chemotherapy regimen in which cyclophosphamide was replaced by ifosfamide. Sixty-five patients were treated., Results: By February 1992, the median follow-up was 5.8 years. The estimated 5-year disease-free survival was 52%. We observed unexpected cardiac toxicity. Three patients experienced acute cardiac failure that was lethal in two cases. The acute toxicity of ifosfamide prompted us to stop the protocol. Retrospectively, the lack of efficacy reinforced our decision., Conclusion: We conclude that ifosfamide did not improve the outcome of the patients despite the fact that these two treatment regimens were not randomized.

Thirty-two children were treated for metastatic Ewing sarcoma by high-dose chemotherapy followed by autologous bone marrow transplantation. Fourteen patients entered phase II studies of high-dose alkylating agents. The response rate observed was 61%. High-dose chemotherapy was used as consolidation in complete remission of 18 patients. Disease free survival appears to be better than that observed under conventional altered chemotherapy. However, with only 4/18 long term survivors, these results remain unsatisfactory, taking into account the recent encouraging results of semi-continuous conventional chemotherapy.

A retrospective multifactorial analysis on 261 previously untreated patients with Ewing's sarcoma (Es) of bone has been carried out in order to ascertain the prognostic value of several histological variables on survival. Among those cases accepted as Es, 208 (80% of the patients) were considered to be "typical Es", while 40 (15%) displayed a large cell predominance, being subclassified as "atypical large cell Es". Furthermore, 13 patients (5%) possessed tumours of endothelial-like appearance. Eleven cases which displayed a mixed histological configuration were finally included within one of the three previous groups according to their predominant histological pattern. After adjustment for therapeutic regimens and initial location of the tumour, only two histological characteristics remain significant; i.e. the presence of necrosis (p = 0.002) and, to a lesser degree, the presence of filagree "en damier" pattern (p = 0.08), both of which are of poor prognostic value. From this study, it can be assumed that the morphological (and possibly histogenetical) heterogeneity of Es of bone has no prognostic influence on survival.

From April, 1978 to December, 1982, 87 cases of Ewing's sarcoma were registered in 12 centres of paediatric oncology in France. The results of a therapeutic protocol consisting of intensive chemotherapy (vincristine, cyclophosphamide and actinomycin with or without adriamycin) prior to tumoral irradiation, followed by maintenance chemotherapy are reported after 3 years' follow-up from the beginning of treatment. In localized sarcomas, complete remission (66/70) persisted without relapse or metastasis in 54% of the cases (78% in sarcomas of long bones, and 37% in sarcomas of short bones). In non-metastatic sarcomas of the ribs, the first remission persisted in 7/14 patients (50%). All these patients had been initially treated with chemotherapy, radiotherapy and surgical excision. These preliminary results emphasize the value of co-operative therapeutic trials in a rare tumour, demonstrate the effectiveness of the initial chemotherapy used against Ewing's sarcoma and are in favour of a combined treatment, including systematic excision, for Ewing's sarcomas affecting the ribs.

Phase II studies using ifosfamide both alone and combined with vindesine and cisplatin have shown the effectiveness of this drug in patients with Ewing's sarcoma (ES) who had relapsed during VAC (vincristine, actinomycin, cyclosphosphamide)/VAd (vincristine, Adriamycin) therapy. In November 1984, these results led the SFOP to adopt a protocol consisting of (1) initial chemotherapy with three cycles of IVA (ifosfamide, 3 g/m2 on days 1 and 2; actinomycin D, 750 mg/m2 on days 1-3; vincristine, 1.5 mg/m2 on day 1) alternating every 3 weeks with IVAd (vincristine on day 22; ifosfamide on days 21-23; Adriamycin, 60 mg/m2 on day 22); (2) radical surgery if possible; (3) local radiotherapy (RT); and (4) maintenance chemotherapy with alternating IVA and VAd (vincristine, Adriamycin) for up to 9 months. In May 1987, 87 patients with previously untreated ES entered the study; 61 had localized ES. To date, 54 patients with localized disease and 22 with metastatic disease have finished initial chemotherapy; 40 patients with localized disease have been evaluated. In all, 28 patients (70%) were in complete remission (17 patients) or had a tumor regression of greater than 50% 11 patients) and were considered to be good responders; 12 patients were considered to be poor responders. After local radiotherapy in all but 7 patients and surgical resection in 29, 52 of 54 were considered to be in clinical remission. A total of 13 patients with metastatic disease were good responders at the completion of the initial chemotherapy. These results confirm the efficacy of primary chemotherapy using ifosfamide for the treatment of ES.

Ninety-five children with localized Ewing's sarcoma were included in a prospective cooperative study. All patients received initial chemotherapy with the purpose of early prevention of metastases and improvement of the conditions of the subsequent local therapy, radiotherapy in all cases, surgical resection in selected cases. Clinical response to initial chemotherapy was evaluated in 67 patients who had measurable soft tissue mass or functional symptoms. This response appeared highly correlated with outcome as the disease-free survival was 57.3% for the 41 good responders and 9% for the 26 bad responders (P less than 0.00001), though 23 of these bad responders reached complete remission with radiotherapy. This study also confirms the prognostic significance for survival of the site of the primary tumor on axial skeleton or on limbs. Nevertheless, this factor had no predictive value for response to chemotherapy, which thus appears to be an independent factor.