Wednesday, August 21, 2019

Ewing Sarcoma Treatment (PDQ®)–Health Professional Version - National Cancer Institute

Ewing Sarcoma Treatment (PDQ®)–Health Professional Version - National Cancer Institute

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Ewing Sarcoma Treatment (PDQ®)–Health Professional Version

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General Information About Ewing Sarcoma

Dramatic improvements in survival have been achieved for children and adolescents with cancer.[1] Between 1975 and 2010, childhood cancer mortality decreased by more than 50%.[1] For Ewing sarcoma, the 5-year survival rate has increased over the same time from 59% to 78% for children younger than 15 years and from 20% to 60% for adolescents aged 15 to 19 years.[1]
Studies using immunohistochemical markers,[2] cytogenetics,[3,4] molecular genetics, and tissue culture [5] indicate that Ewing sarcoma is derived from a primordial bone marrow–derived mesenchymal stem cell.[6,7] Older terms such as peripheral primitive neuroectodermal tumor, Askin tumor (Ewing sarcoma of chest wall), and extraosseous Ewing sarcoma (often combined in the term Ewing sarcoma family of tumors) refer to this same tumor.

Incidence

The incidence of Ewing sarcoma has remained unchanged for 30 years.[8] The incidence for all ages is one case per 1 million people in the United States. In patients aged 10 to 19 years, the incidence is between nine and ten cases per 1 million people. The same analysis suggests that the incidence of Ewing sarcoma in the United States is nine times greater in whites than in African Americans, with an intermediate incidence in Asians.[9,10]
The relative paucity of Ewing sarcoma in people of African or Asian descent may be explained, in part, by a specific polymorphism in the EGR2 gene.
The median age of patients with Ewing sarcoma is 15 years, and more than 50% of patients are adolescents. Well-characterized cases of Ewing sarcoma in neonates and infants have been described.[11,12] Based on data from 1,426 patients entered on European Intergroup Cooperative Ewing Sarcoma Studies, 59% of patients are male and 41% are female.[13]

Clinical Presentation

Primary sites of bone disease include the following:
  • Lower extremity (41%).
  • Pelvis (26%).
  • Chest wall (16%).
  • Upper extremity (9%).
  • Spine (6%).
  • Hand and foot (3%).[14]
  • Skull (2%).
For extraosseous primary tumors, the most common primary sites of disease include the following:[15,16]
  • Trunk (32%).
  • Extremity (26%).
  • Head and neck (18%).
  • Retroperitoneum (16%).
  • Other sites (9%).
The median time from first symptom to diagnosis of Ewing sarcoma is often long, with a median interval reported from 2 to 5 months. Longer times are associated with older age and pelvic primary sites. Time from first symptom to diagnosis has not been associated with metastasis, surgical outcome, or survival.[17] Approximately 25% of patients with Ewing sarcoma have metastatic disease at the time of diagnosis.[8]
The Surveillance, Epidemiology, and End Results (SEER) database was used to compare patients younger than 40 years with Ewing sarcoma who presented with skeletal and extraosseous primary sites (refer to Table 1).[18] Patients with extraosseous Ewing sarcoma were more likely to be older, female, nonwhite, and have axial primary sites, and were less likely to have pelvic primary sites than were patients with skeletal Ewing sarcoma.
Table 1. Characteristics of Children With Extraosseous Ewing Sarcoma and Skeletal Ewing Sarcoma
CharacteristicExtraosseous Ewing SarcomaSkeletal Ewing SarcomaP Value
Mean age (range), years20 (0–39)16 (0–39)<.001
Male53%63%<.001
White85%93%<.001
Axial primary sites73%54%<.001
Pelvic primary sites20%27%.001

Diagnostic Evaluation

The following tests and procedures may be used to diagnose or stage Ewing sarcoma:
  • Physical examination and history.
  • Magnetic resonance imaging (MRI).
  • Computed tomography (CT) scan.
  • Positron emission tomography (PET) scan.
  • Bone scan.
  • Bone marrow aspiration and biopsy.
  • X-ray.
  • Complete blood count.
  • Blood chemistry studies, such as lactate dehydrogenase (LDH).
Refer to the Treatment Option Overview for Ewing Sarcoma section of this summary for information about diagnostic biopsy.

Prognostic Factors

The two major types of prognostic factors for patients with Ewing sarcoma are grouped as follows:

Pretreatment factors

  • Site of tumor: Patients with Ewing sarcoma in the distal extremities have the best prognosis. Patients with Ewing sarcoma in the proximal extremities have an intermediate prognosis, followed by patients with central or pelvic sites.[19-22]
  • Extraskeletal versus skeletal primary tumors: The Children's Oncology Group (COG) performed a retrospective analysis from two large cooperative trials that used similar treatment regimens.[23] They identified 213 patients with extraskeletal primary tumors and 826 patients with skeletal primary tumors. Patients with extraskeletal primary tumors were more likely to have an axial primary site, less likely to have large primary tumors, and had a statistically significant better prognosis than did patients with skeletal primary tumors.
  • Tumor size or volume: Tumor size or volume has been shown to be an important prognostic factor in most studies. Cutoffs of a volume of 100 mL or 200 mL and/or single dimension greater than 8 cm are used to define larger tumors. Larger tumors tend to occur in unfavorable sites.[21,22,24]
  • Age: Infants and younger patients have a better prognosis than do patients aged 15 years and older, as noted in the following studies:[12,19,20,22,25-27]
    • In North American studies, patients younger than 10 years had a better outcome than those aged 10 to 17 years at diagnosis (relative risk [RR], 1.4). Patients older than 18 years had an inferior outcome (RR, 2.5).[28-30]
    • A retrospective review of two consecutive German trials for Ewing sarcoma identified 47 patients older than 40 years.[31] With adequate multimodal therapy, survival was comparable to the survival observed in adolescents treated on the same trials.
    • Review of the SEER database from 1973 to 2011 identified 1,957 patients with Ewing sarcoma.[32] Thirty-nine of these patients (2.0%) were younger than 12 months at diagnosis. Infants were less likely to receive radiation therapy and more likely to have soft tissue primary sites. Early death was more common in infants, but the overall survival (OS) did not differ significantly from that of older patients.
    • A European retrospective review identified 2,635 patients with Ewing sarcoma of bone.[33] Sites of primary and metastatic tumors differed according to the age groups of young children (0–9 years), early adolescence (10–14 years), late adolescence (15–19 years), young adults (20–24 years), and adults (older than 24 years). Young children had the most striking differences in site of disease, with a lower proportion of pelvic primary and axial tumors. Young children also presented less often with metastatic disease at diagnosis.
  • Sex: Girls with Ewing sarcoma have a better prognosis than do boys with Ewing sarcoma.[9,20,22]
  • Serum LDH: Increased serum LDH levels before treatment are associated with inferior prognosis. Increased LDH levels are also correlated with large primary tumors and metastatic disease.[20]
  • Metastases: The presence or absence of metastatic disease is the single most powerful predictor of outcome. Any metastatic disease defined by standard imaging techniques or bone marrow aspirate/biopsy by morphology is an adverse prognostic factor. Metastases at diagnosis are detected in about 25% of patients.[8]
    Patients with metastatic disease confined to the lung have a better prognosis than do patients with extrapulmonary metastatic sites.[19,21,22,34] The number of pulmonary lesions does not seem to correlate with outcome, but patients with unilateral lung involvement do better than patients with bilateral lung involvement.[35]
    Patients with metastasis to only bone seem to have a better outcome than do patients with metastases to both bone and lung.[36,37]
    Based on an analysis from the SEER database, regional lymph node involvement in patients is associated with an inferior overall outcome when compared with patients without regional lymph node involvement.[38]
  • Pathologic fracture: A single-institution retrospective analysis of 78 patients with Ewing sarcoma suggested that pathologic fracture at initial presentation was associated with inferior event-free survival (EFS) and OS.[39][Level of evidence: 3iiA]
  • Previous treatment for cancer: In the SEER database, 58 patients with Ewing sarcoma who were diagnosed after treatment for a previous malignancy (2.1% of patients with Ewing sarcoma) were compared with 2,756 patients with Ewing sarcoma as a first cancer over the same period. Patients with Ewing sarcoma as a second malignant neoplasm were older (secondary Ewing sarcoma, mean age of 47.8 years; primary Ewing sarcoma, mean age of 22.5 years), more likely to have a primary tumor in an axial or extraskeletal site, and had a worse prognosis (5-year OS for patients with secondary Ewing sarcoma, 43.5%; patients with primary Ewing sarcoma, 64.2%).[40]
  • Standard cytogenetics: Complex karyotype (defined as the presence of five or more independent chromosome abnormalities at diagnosis) and modal chromosome numbers lower than 50 appear to have adverse prognostic significance.[41]
  • Detectable fusion transcripts in morphologically normal marrow: Reverse transcription–polymerase chain reaction (RT-PCR) can be used to detect fusion transcripts in bone marrow. In a single retrospective study utilizing patients with normal marrow morphology and no other metastatic site, fusion transcript detection in marrow or peripheral blood was associated with an increased risk of relapse.[42]
  • Other biological factors: Overexpression of the p53 protein, Ki67 expression, and loss of 16q may be adverse prognostic factors.[43-45] High expression of microsomal glutathione S-transferase, an enzyme associated with resistance to doxorubicin, is associated with inferior outcome for Ewing sarcoma.[46]
    The COG performed a prospective analysis of TP53 mutations and/or CDKN2A deletions in patients with Ewing sarcoma; no correlation was found with EFS.[47]
The following are not considered to be adverse prognostic factors for Ewing sarcoma:
  • Histopathology: The degree of neural differentiation is not a prognostic factor in Ewing sarcoma.[48,49]
  • Molecular pathology: The EWSR1-ETS translocation associated with Ewing sarcoma can occur at several potential breakpoints in each of the genes that join to form the novel segment of DNA. Once thought to be significant,[50] two large series have shown that the EWSR1-ETS translocation breakpoint site is not an adverse prognostic factor.[51,52]

Response to initial therapy factors

Multiple studies have shown that patients with minimal or no residual viable tumor after presurgical chemotherapy have a significantly better EFS than do patients with larger amounts of viable tumor.[53-56] Female sex and younger age predict a good histologic response to preoperative therapy.[57] For patients who receive preinduction- and postinduction-chemotherapy PET scans, decreased PET uptake after chemotherapy correlated with good histologic response and better outcome.[58-60]
Patients with poor response to presurgical chemotherapy have an increased risk for local recurrence.[61]
Detection of Ewing sarcoma in the peripheral blood
Several techniques to evaluate the presence of Ewing sarcoma in the peripheral blood have been proposed. Flow cytometry for cells that express the CD99 antigen was not sufficiently sensitive to serve as a reliable biomarker.[42,62] RT-PCR for the EWSR1-FLI1 translocation was also not considered a reliable biomarker.[63]
A more sensitive technique that utilized patient-specific primers designed after identification of the specific translocation breakpoint in combination with droplet digital PCR reported a sensitivity of 0.018% to 0.009%.[64] Levels of circulating cell-free DNA were higher in patients with metastatic disease than in patients with localized disease. A hybrid capture sequencing assay employing the introns at which EWSR1 and FLI1 fusions occur has also been developed to detect evidence of the EWSR1-FLI1 translocation in circulating cell-free DNA.[65] Using this method, the translocation was detected in peripheral blood samples from 10 of 11 patients with Ewing sarcoma. Additional study is required to determine whether circulating cell-free DNA will have clinical utility as a biomarker for Ewing sarcoma to monitor disease status and response to therapy.
References
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  29. Granowetter L, Womer R, Devidas M, et al.: Dose-intensified compared with standard chemotherapy for nonmetastatic Ewing sarcoma family of tumors: a Children's Oncology Group Study. J Clin Oncol 27 (15): 2536-41, 2009. [PUBMED Abstract]
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  31. Pieper S, Ranft A, Braun-Munzinger G, et al.: Ewing's tumors over the age of 40: a retrospective analysis of 47 patients treated according to the International Clinical Trials EICESS 92 and EURO-E.W.I.N.G. 99. Onkologie 31 (12): 657-63, 2008. [PUBMED Abstract]
  32. Wong T, Goldsby RE, Wustrack R, et al.: Clinical features and outcomes of infants with Ewing sarcoma under 12 months of age. Pediatr Blood Cancer 62 (11): 1947-51, 2015. [PUBMED Abstract]
  33. Worch J, Ranft A, DuBois SG, et al.: Age dependency of primary tumor sites and metastases in patients with Ewing sarcoma. Pediatr Blood Cancer : e27251, 2018. [PUBMED Abstract]
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  35. Paulussen M, Ahrens S, Craft AW, et al.: Ewing's tumors with primary lung metastases: survival analysis of 114 (European Intergroup) Cooperative Ewing's Sarcoma Studies patients. J Clin Oncol 16 (9): 3044-52, 1998. [PUBMED Abstract]
  36. Paulussen M, Ahrens S, Burdach S, et al.: Primary metastatic (stage IV) Ewing tumor: survival analysis of 171 patients from the EICESS studies. European Intergroup Cooperative Ewing Sarcoma Studies. Ann Oncol 9 (3): 275-81, 1998. [PUBMED Abstract]
  37. Ladenstein R, Pötschger U, Le Deley MC, et al.: Primary disseminated multifocal Ewing sarcoma: results of the Euro-EWING 99 trial. J Clin Oncol 28 (20): 3284-91, 2010. [PUBMED Abstract]
  38. Applebaum MA, Goldsby R, Neuhaus J, et al.: Clinical features and outcomes in patients with Ewing sarcoma and regional lymph node involvement. Pediatr Blood Cancer 59 (4): 617-20, 2012. [PUBMED Abstract]
  39. Schlegel M, Zeumer M, Prodinger PM, et al.: Impact of Pathological Fractures on the Prognosis of Primary Malignant Bone Sarcoma in Children and Adults: A Single-Center Retrospective Study of 205 Patients. Oncology 94 (6): 354-362, 2018. [PUBMED Abstract]
  40. Applebaum MA, Goldsby R, Neuhaus J, et al.: Clinical features and outcomes in patients with secondary Ewing sarcoma. Pediatr Blood Cancer 60 (4): 611-5, 2013. [PUBMED Abstract]
  41. Roberts P, Burchill SA, Brownhill S, et al.: Ploidy and karyotype complexity are powerful prognostic indicators in the Ewing's sarcoma family of tumors: a study by the United Kingdom Cancer Cytogenetics and the Children's Cancer and Leukaemia Group. Genes Chromosomes Cancer 47 (3): 207-20, 2008. [PUBMED Abstract]
  42. Schleiermacher G, Peter M, Oberlin O, et al.: Increased risk of systemic relapses associated with bone marrow micrometastasis and circulating tumor cells in localized ewing tumor. J Clin Oncol 21 (1): 85-91, 2003. [PUBMED Abstract]
  43. Abudu A, Mangham DC, Reynolds GM, et al.: Overexpression of p53 protein in primary Ewing's sarcoma of bone: relationship to tumour stage, response and prognosis. Br J Cancer 79 (7-8): 1185-9, 1999. [PUBMED Abstract]
  44. López-Guerrero JA, Machado I, Scotlandi K, et al.: Clinicopathological significance of cell cycle regulation markers in a large series of genetically confirmed Ewing's sarcoma family of tumors. Int J Cancer 128 (5): 1139-50, 2011. [PUBMED Abstract]
  45. Ozaki T, Paulussen M, Poremba C, et al.: Genetic imbalances revealed by comparative genomic hybridization in Ewing tumors. Genes Chromosomes Cancer 32 (2): 164-71, 2001. [PUBMED Abstract]
  46. Scotlandi K, Remondini D, Castellani G, et al.: Overcoming resistance to conventional drugs in Ewing sarcoma and identification of molecular predictors of outcome. J Clin Oncol 27 (13): 2209-16, 2009. [PUBMED Abstract]
  47. Lerman DM, Monument MJ, McIlvaine E, et al.: Tumoral TP53 and/or CDKN2A alterations are not reliable prognostic biomarkers in patients with localized Ewing sarcoma: a report from the Children's Oncology Group. Pediatr Blood Cancer 62 (5): 759-65, 2015. [PUBMED Abstract]
  48. Parham DM, Hijazi Y, Steinberg SM, et al.: Neuroectodermal differentiation in Ewing's sarcoma family of tumors does not predict tumor behavior. Hum Pathol 30 (8): 911-8, 1999. [PUBMED Abstract]
  49. Luksch R, Sampietro G, Collini P, et al.: Prognostic value of clinicopathologic characteristics including neuroectodermal differentiation in osseous Ewing's sarcoma family of tumors in children. Tumori 85 (2): 101-7, 1999 Mar-Apr. [PUBMED Abstract]
  50. de Alava E, Kawai A, Healey JH, et al.: EWS-FLI1 fusion transcript structure is an independent determinant of prognosis in Ewing's sarcoma. J Clin Oncol 16 (4): 1248-55, 1998. [PUBMED Abstract]
  51. van Doorninck JA, Ji L, Schaub B, et al.: Current treatment protocols have eliminated the prognostic advantage of type 1 fusions in Ewing sarcoma: a report from the Children's Oncology Group. J Clin Oncol 28 (12): 1989-94, 2010. [PUBMED Abstract]
  52. Le Deley MC, Delattre O, Schaefer KL, et al.: Impact of EWS-ETS fusion type on disease progression in Ewing's sarcoma/peripheral primitive neuroectodermal tumor: prospective results from the cooperative Euro-E.W.I.N.G. 99 trial. J Clin Oncol 28 (12): 1982-8, 2010. [PUBMED Abstract]
  53. Paulussen M, Ahrens S, Dunst J, et al.: Localized Ewing tumor of bone: final results of the cooperative Ewing's Sarcoma Study CESS 86. J Clin Oncol 19 (6): 1818-29, 2001. [PUBMED Abstract]
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  59. Denecke T, Hundsdörfer P, Misch D, et al.: Assessment of histological response of paediatric bone sarcomas using FDG PET in comparison to morphological volume measurement and standardized MRI parameters. Eur J Nucl Med Mol Imaging 37 (10): 1842-53, 2010. [PUBMED Abstract]
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  62. Dubois SG, Epling CL, Teague J, et al.: Flow cytometric detection of Ewing sarcoma cells in peripheral blood and bone marrow. Pediatr Blood Cancer 54 (1): 13-8, 2010. [PUBMED Abstract]
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  64. Shukla NN, Patel JA, Magnan H, et al.: Plasma DNA-based molecular diagnosis, prognostication, and monitoring of patients with EWSR1 fusion-positive sarcomas. JCO Precis Oncol 2017: , 2017. [PUBMED Abstract]
  65. Klega K, Imamovic-Tuco A, Ha G, et al.: Detection of Somatic Structural Variants Enables Quantification and Characterization of Circulating Tumor DNA in Children With Solid Tumors. JCO Precis Oncol 2018: , 2018. [PUBMED Abstract]

Cellular Classification of Ewing Sarcoma

Ewing sarcoma belongs to the group of neoplasms commonly referred to as small, round, blue-cell tumors of childhood. The individual cells of Ewing sarcoma contain round-to-oval nuclei, with fine dispersed chromatin without nucleoli. Occasionally, cells with smaller, more hyperchromatic, and probably degenerative nuclei are present, giving a light cell/dark cell pattern. The cytoplasm varies in amount, but in the classic case, it is clear and contains glycogen, which can be highlighted with a periodic acid-Schiff stain. The tumor cells are tightly packed and grow in a diffuse pattern without evidence of structural organization. Tumors with the requisite translocation that show neuronal differentiation are not considered a separate entity, but rather, part of a continuum of differentiation.
The MIC2 gene product, CD99, is a surface membrane protein that is expressed in most cases of Ewing sarcoma and is useful in diagnosing these tumors when the results are interpreted in the context of clinical and pathologic parameters.[1] MIC2 positivity is not unique to Ewing sarcoma, and positivity by immunochemistry is found in several other tumors, including synovial sarcoma, non-Hodgkin lymphoma, and gastrointestinal stromal tumors.
References
  1. Parham DM, Hijazi Y, Steinberg SM, et al.: Neuroectodermal differentiation in Ewing's sarcoma family of tumors does not predict tumor behavior. Hum Pathol 30 (8): 911-8, 1999. [PUBMED Abstract]

Genomics of Ewing Sarcoma

The detection of a translocation involving the EWSR1 gene on chromosome 22 band q12 and any one of a number of partner chromosomes is the key feature in the diagnosis of Ewing sarcoma (refer to Table 2).[1] The EWSR1 gene is a member of the TET family [TLS/EWS/TAF15] of RNA-binding proteins.[2] The FLI1 gene is a member of the ETS family of DNA-binding genes. Characteristically, the amino terminus of the EWSR1 gene is juxtaposed with the carboxy terminus of the STS family gene. In most cases (90%), the carboxy terminus is provided by FLI1, a member of the family of transcription factor genes located on chromosome 11 band q24. Other family members that may combine with the EWSR1 gene are ERG, ETV1, ETV4 (also termed E1AF), and FEV.[3] Rarely, TLS, another TET family member, can substitute for EWSR1.[4] Finally, there are a few rare cases in which EWSR1 has translocated with partners that are not members of the ETS family of oncogenes. The significance of these alternate partners is not known.
Besides these consistent aberrations involving the EWSR1 gene at 22q12, additional numerical and structural aberrations have been observed in Ewing sarcoma, including gains of chromosomes 2, 5, 8, 9, 12, and 15; the nonreciprocal translocation t(1;16)(q12;q11.2); and deletions on the short arm of chromosome 6. Trisomy 20 may be associated with a more aggressive subset of Ewing sarcoma.[5]
Three papers have described the genomic landscape of Ewing sarcoma and all show that these tumors have a relatively silent genome, with a paucity of mutations in pathways that might be amenable to treatment with novel targeted therapies.[6-8] These papers also identified mutations in STAG2, a member of the cohesin complex, in about 15% to 20% of the cases, and the presence of these mutations was associated with advanced-stage disease. CDKN2A deletions were noted in 12% to 22% of cases. Finally, TP53 mutations were identified in about 6% to 7% of cases and the coexistence of STAG2 and TP53 mutations is associated with a poor clinical outcome.[6-8]
Figure 1 below from a discovery cohort (n = 99) highlights the frequency of chromosome 8 gain, the co-occurrence of chromosome 1q gain and chromosome 16q loss, the mutual exclusivity of CDKN2A deletion and STAG2 mutation, and the relative paucity of recurrent single nucleotide variants for Ewing sarcoma.[6]
ENLARGEChart showing a comprehensive profile of the genetic abnormalities in Ewing sarcoma and associated clinical information.
Figure 1. A comprehensive profile of the genetic abnormalities in Ewing sarcoma and associated clinical information. Key clinical characteristics are indicated, including primary site, type of tissue, and metastatic status at diagnosis, follow-up, and last news. Below is the consistency of detection of gene fusions by RT-PCR and whole-genome sequencing (WGS). The numbers of structural variants (SV) and single-nucleotide variants (SNV) as well as indels are reported in grayscale. The presence of the main copy-number changes, chr 1q gain, chr 16 loss, chr 8 gain, chr 12 gain, and interstitial CDKN2A deletion is indicated. Listed last are the most significant mutations and their types. For gene mutations, “others” refers to: duplication of exon 22 leading to frameshift (STAG2), deletion of exon 2 to 11 (BCOR), and deletion of exons 1 to 6 (ZMYM3). Reprinted from Cancer Discovery, Copyright 2014, 4 (11), 1342–53, Tirode F, Surdez D, Ma X, et al., Genomic Landscape of Ewing Sarcoma Defines an Aggressive Subtype with Co-Association of STAG2 and TP53 mutations, with permission from AACR.
Ewing sarcoma translocations can all be found with standard cytogenetic analysis. A more rapid analysis looking for a break apart of the EWS gene is now frequently done to confirm the diagnosis of Ewing sarcoma molecularly.[9] This test result must be considered with caution, however. Ewing sarcomas that utilize the TLS translocations will have negative tests because the EWSR1 gene is not translocated in those cases. In addition, other small round tumors also contain translocations of different ETS family members with EWSR1, such as desmoplastic small round cell tumor, clear cell sarcoma, extraskeletal myxoid chondrosarcoma, and myxoid liposarcoma, all of which may be positive with a EWSfluorescence in situ hybridization (FISH) break-apart probe. A detailed analysis of 85 patients with small round blue cell tumors that were negative for EWSR1 rearrangement by FISH with an EWSR1 break-apart probe identified eight patients with FUS rearrangements.[10] Four patients who had EWSR1-ERG fusions were not detected by FISH with an EWSR1break-apart probe. The authors do not recommend relying solely on EWSR1 break-apart probes for analyzing small round blue cell tumors with strong immunohistochemical positivity for CD99.
Undifferentiated small blue round cell sarcomas with the EWSR1-NFATc2 fusion have been studied with DNA methylation profiling; this revealed a homogeneous methylation cluster for these sarcomas with EWSR1-NFATc2 fusions, which clearly segregated them from the more common form of Ewing sarcoma with EWS-ETS translocations.[11]
Small round blue cell tumors of bone and soft tissue that are histologically similar to Ewing sarcoma but do not have rearrangements of the EWSR1 gene have been analyzed and translocations have been identified. These include BCOR-CCNB3, CIC-DUX4, and CIC-FOX4.[12-15] The molecular profile of these tumors is different from the profile of EWS-FLI1translocated Ewing sarcoma, and limited evidence suggests that they have a different clinical behavior. In almost all cases, the patients were treated with therapy designed for Ewing sarcoma on the basis of the histologic and immunohistologic similarity to Ewing sarcoma (refer to the Undifferentiated Round Cell Sarcomas With BCOR-CCNB3 Rearrangements and Undifferentiated Round Cell Sarcomas With CIC-DUX4 Rearrangements sections of this summary for more information). There are too few cases associated with each translocation to determine whether the prognosis for these small round blue cell tumors is distinct from the prognosis of Ewing sarcoma of similar stage and site.[12-15]
Some undifferentiated round cell sarcomas are characterized by paracentric inversion of chromosome X and a BCOR-CCNB3 rearrangement; alternative BCOR partners, including MAML3 and ZC3H7B, have also been reported.[16] Despite clinical pathologic similarities to Ewing sarcoma, these tumors are biologically different by expression profiling and single-nucleotide polymorphism array analysis. (Refer to the Undifferentiated Round Cell Sarcomas With BCOR-CCNB3 Rearrangements section of this summary for more information about the treatment of this disease.)
Other undifferentiated round cell sarcomas are characterized by a CIC-DUX4 fusion resulting from a recurrent t(4;19) or t(10;19) and are the most common EWSR1-FUS fusion–negative undifferentiated round cell sarcomas.[17] (Refer to the Undifferentiated Round Cell Sarcomas With CIC-DUX4 Rearrangements section of this summary for more information about the treatment of this disease.)
Genome-wide association studies have identified susceptibility loci for Ewing sarcoma at 1p36.22, 10q21, and 15q15.[18-20] Deep sequencing through the 10q21.3 region identified a polymorphism in the EGR2 gene, which appears to cooperate with and magnify the enhanced activity of the gene product of the EWSR1-FLI1 fusion that is seen in most patients with Ewing sarcoma.[19] The polymorphism associated with the increased risk is found at a much higher frequency in whites than in blacks or Asians, possibly contributing to the epidemiology of the relative infrequency of Ewing sarcoma in the latter populations. Three new susceptibility loci have been identified at 6p25.1, 20p11.22, and 20p11.23.[20]
Table 2. EWS and TLS Fusions and Translocations in Ewing Sarcoma
TET Family PartnerFusion With ETS-like Oncogene PartnerTranslocationComment
aThese partners are not members of the ETS family of oncogenes.
EWSEWSR1-FLI1t(11;22)(q24;q12)Most common; ~85% to 90% of cases
EWSR1-ERGt(21;22)(q22;q12)Second most common; ~10% of cases
EWSR1-ETV1t(7;22)(p22;q12)Rare
EWSR1-ETV4t(17;22)(q12;q12)Rare
EWSR1-FEVt(2;22)(q35;q12)Rare
EWSR1-NFATc2at(20;22)(q13;q12)Rare
EWSR1-POU5F1at(6;22)(p21;q12) 
EWSR1-SMARCA5at(4;22)(q31;q12)Rare
EWSR1-ZSGat(6;22)(p21;q12) 
EWSR1-SP3at(2;22)(q31;q12)Rare
TLS (also called FUS)TLS-ERGt(16;21)(p11;q22)Rare
TLS-FEVt(2;16)(q35;p11)Rare
References
  1. Delattre O, Zucman J, Melot T, et al.: The Ewing family of tumors--a subgroup of small-round-cell tumors defined by specific chimeric transcripts. N Engl J Med 331 (5): 294-9, 1994. [PUBMED Abstract]
  2. Urano F, Umezawa A, Yabe H, et al.: Molecular analysis of Ewing's sarcoma: another fusion gene, EWS-E1AF, available for diagnosis. Jpn J Cancer Res 89 (7): 703-11, 1998. [PUBMED Abstract]
  3. Hattinger CM, Rumpler S, Strehl S, et al.: Prognostic impact of deletions at 1p36 and numerical aberrations in Ewing tumors. Genes Chromosomes Cancer 24 (3): 243-54, 1999. [PUBMED Abstract]
  4. Sankar S, Lessnick SL: Promiscuous partnerships in Ewing's sarcoma. Cancer Genet 204 (7): 351-65, 2011. [PUBMED Abstract]
  5. Roberts P, Burchill SA, Brownhill S, et al.: Ploidy and karyotype complexity are powerful prognostic indicators in the Ewing's sarcoma family of tumors: a study by the United Kingdom Cancer Cytogenetics and the Children's Cancer and Leukaemia Group. Genes Chromosomes Cancer 47 (3): 207-20, 2008. [PUBMED Abstract]
  6. Tirode F, Surdez D, Ma X, et al.: Genomic landscape of Ewing sarcoma defines an aggressive subtype with co-association of STAG2 and TP53 mutations. Cancer Discov 4 (11): 1342-53, 2014. [PUBMED Abstract]
  7. Crompton BD, Stewart C, Taylor-Weiner A, et al.: The genomic landscape of pediatric Ewing sarcoma. Cancer Discov 4 (11): 1326-41, 2014. [PUBMED Abstract]
  8. Brohl AS, Solomon DA, Chang W, et al.: The genomic landscape of the Ewing Sarcoma family of tumors reveals recurrent STAG2 mutation. PLoS Genet 10 (7): e1004475, 2014. [PUBMED Abstract]
  9. Monforte-Muñoz H, Lopez-Terrada D, Affendie H, et al.: Documentation of EWS gene rearrangements by fluorescence in-situ hybridization (FISH) in frozen sections of Ewing's sarcoma-peripheral primitive neuroectodermal tumor. Am J Surg Pathol 23 (3): 309-15, 1999. [PUBMED Abstract]
  10. Chen S, Deniz K, Sung YS, et al.: Ewing sarcoma with ERG gene rearrangements: A molecular study focusing on the prevalence of FUS-ERG and common pitfalls in detecting EWSR1-ERG fusions by FISH. Genes Chromosomes Cancer 55 (4): 340-9, 2016. [PUBMED Abstract]
  11. Koelsche C, Kriegsmann M, Kommoss FKF, et al.: DNA methylation profiling distinguishes Ewing-like sarcoma with EWSR1-NFATc2 fusion from Ewing sarcoma. J Cancer Res Clin Oncol 145 (5): 1273-1281, 2019. [PUBMED Abstract]
  12. Pierron G, Tirode F, Lucchesi C, et al.: A new subtype of bone sarcoma defined by BCOR-CCNB3 gene fusion. Nat Genet 44 (4): 461-6, 2012. [PUBMED Abstract]
  13. Specht K, Sung YS, Zhang L, et al.: Distinct transcriptional signature and immunoprofile of CIC-DUX4 fusion-positive round cell tumors compared to EWSR1-rearranged Ewing sarcomas: further evidence toward distinct pathologic entities. Genes Chromosomes Cancer 53 (7): 622-33, 2014. [PUBMED Abstract]
  14. Sugita S, Arai Y, Tonooka A, et al.: A novel CIC-FOXO4 gene fusion in undifferentiated small round cell sarcoma: a genetically distinct variant of Ewing-like sarcoma. Am J Surg Pathol 38 (11): 1571-6, 2014. [PUBMED Abstract]
  15. Cohen-Gogo S, Cellier C, Coindre JM, et al.: Ewing-like sarcomas with BCOR-CCNB3 fusion transcript: a clinical, radiological and pathological retrospective study from the Société Française des Cancers de L'Enfant. Pediatr Blood Cancer 61 (12): 2191-8, 2014. [PUBMED Abstract]
  16. Schaefer IM, Fletcher CDM: Recent advances in the diagnosis of soft tissue tumours. Pathology 50 (1): 37-48, 2018. [PUBMED Abstract]
  17. Antonescu CR, Owosho AA, Zhang L, et al.: Sarcomas With CIC-rearrangements Are a Distinct Pathologic Entity With Aggressive Outcome: A Clinicopathologic and Molecular Study of 115 Cases. Am J Surg Pathol 41 (7): 941-949, 2017. [PUBMED Abstract]
  18. Postel-Vinay S, Véron AS, Tirode F, et al.: Common variants near TARDBP and EGR2 are associated with susceptibility to Ewing sarcoma. Nat Genet 44 (3): 323-7, 2012. [PUBMED Abstract]
  19. Grünewald TG, Bernard V, Gilardi-Hebenstreit P, et al.: Chimeric EWSR1-FLI1 regulates the Ewing sarcoma susceptibility gene EGR2 via a GGAA microsatellite. Nat Genet 47 (9): 1073-8, 2015. [PUBMED Abstract]
  20. Machiela MJ, Grünewald TGP, Surdez D, et al.: Genome-wide association study identifies multiple new loci associated with Ewing sarcoma susceptibility. Nat Commun 9 (1): 3184, 2018. [PUBMED Abstract]

Stage Information for Ewing Sarcoma

Pretreatment staging studies for Ewing sarcoma may include the following:
  • Magnetic resonance imaging (MRI).
  • Computed tomography (CT) scan of the primary site and chest.
  • Positron emission tomography using fluorine F 18-fludeoxyglucose (18F-FDG PET) or 18F-FDG PET-CT.
  • Bone scan.
  • Bone marrow aspiration and biopsy.
For patients with confirmed Ewing sarcoma, pretreatment staging studies include MRI and/or CT scan, depending on the primary site. Despite the fact that CT and MRI are both equivalent in terms of staging, use of both imaging modalities may help radiation therapy planning.[1] Whole-body MRI may provide additional information that could potentially alter therapy planning.[2] Additional pretreatment staging studies include bone scan and CT scan of the chest. In certain studies, determination of pretreatment tumor volume is an important variable.
Although 18F-FDG PET or 18F-FDG PET-CT are optional staging modalities, they have demonstrated high sensitivity and specificity in Ewing sarcoma and may provide additional information that alters therapy planning. In one institutional study, 18F-FDG PET had a very high correlation with bone scan; the investigators suggested that it could replace bone scan for the initial extent of disease evaluation.[3] This finding was confirmed in a single-institution retrospective review.[4] 18F-FDG PET-CT is more accurate than 18F-FDG PET alone in Ewing sarcoma.[5-7]
Bone marrow aspiration and biopsy have been considered the standard of care for Ewing sarcoma. However, two retrospective studies showed that for patients (N = 141) who were evaluated by bone scan and/or PET scan and lung CT without evidence of metastases, bone marrow aspirates and biopsies were negative in every case.[3,8] A single-institution retrospective review of 504 patients with Ewing sarcoma identified 12 patients with bone marrow metastasis.[9] Only one patient was found to have bone marrow involvement without any other sites of metastatic disease, for an incidence of 1 per 367 (0.3%) in patients with clinically localized disease. The need for routine use of bone marrow aspirates and biopsies in patients without bone metastases is now in question.
For Ewing sarcoma, the tumor is defined as localized when, by clinical and imaging techniques, there is no spread beyond the primary site or regional lymph node involvement. Continuous extension into adjacent soft tissue may occur. If there is a question of regional lymph node involvement, pathologic confirmation is indicated.
References
  1. Meyer JS, Nadel HR, Marina N, et al.: Imaging guidelines for children with Ewing sarcoma and osteosarcoma: a report from the Children's Oncology Group Bone Tumor Committee. Pediatr Blood Cancer 51 (2): 163-70, 2008. [PUBMED Abstract]
  2. Mentzel HJ, Kentouche K, Sauner D, et al.: Comparison of whole-body STIR-MRI and 99mTc-methylene-diphosphonate scintigraphy in children with suspected multifocal bone lesions. Eur Radiol 14 (12): 2297-302, 2004. [PUBMED Abstract]
  3. Newman EN, Jones RL, Hawkins DS: An evaluation of [F-18]-fluorodeoxy-D-glucose positron emission tomography, bone scan, and bone marrow aspiration/biopsy as staging investigations in Ewing sarcoma. Pediatr Blood Cancer 60 (7): 1113-7, 2013. [PUBMED Abstract]
  4. Ulaner GA, Magnan H, Healey JH, et al.: Is methylene diphosphonate bone scan necessary for initial staging of Ewing sarcoma if 18F-FDG PET/CT is performed? AJR Am J Roentgenol 202 (4): 859-67, 2014. [PUBMED Abstract]
  5. Völker T, Denecke T, Steffen I, et al.: Positron emission tomography for staging of pediatric sarcoma patients: results of a prospective multicenter trial. J Clin Oncol 25 (34): 5435-41, 2007. [PUBMED Abstract]
  6. Gerth HU, Juergens KU, Dirksen U, et al.: Significant benefit of multimodal imaging: PET/CT compared with PET alone in staging and follow-up of patients with Ewing tumors. J Nucl Med 48 (12): 1932-9, 2007. [PUBMED Abstract]
  7. Treglia G, Salsano M, Stefanelli A, et al.: Diagnostic accuracy of ¹⁸F-FDG-PET and PET/CT in patients with Ewing sarcoma family tumours: a systematic review and a meta-analysis. Skeletal Radiol 41 (3): 249-56, 2012. [PUBMED Abstract]
  8. Kopp LM, Hu C, Rozo B, et al.: Utility of bone marrow aspiration and biopsy in initial staging of Ewing sarcoma. Pediatr Blood Cancer 62 (1): 12-5, 2015. [PUBMED Abstract]
  9. Cesari M, Righi A, Colangeli M, et al.: Bone marrow biopsy in the initial staging of Ewing sarcoma: Experience from a single institution. Pediatr Blood Cancer : e27653, 2019. [PUBMED Abstract]

Treatment Option Overview for Ewing Sarcoma

It is important that patients be evaluated by specialists from the appropriate disciplines (e.g., radiologists, chemotherapists, pathologists, surgical or orthopedic oncologists, and radiation oncologists) as early as possible.
Appropriate imaging studies of the site are obtained before biopsy. To ensure that the incision is placed in an acceptable location, the surgical or orthopedic oncologist who will perform the definitive surgery is involved in the decision regarding biopsy-incision placement. This is especially important if it is thought that the lesion can be totally excised or if a limb salvage procedure may be attempted. Biopsy should be from soft tissue as often as possible to avoid increasing the risk of fracture.[1] The pathologist is consulted before biopsy/surgery to ensure that the incision will not compromise the radiation port and that multiple types of adequate tissue samples are obtained. It is important to obtain fresh tissue, whenever possible, for cytogenetics and molecular pathology. A second option is to perform a needle biopsy, as long as adequate tissue is obtained for molecular biology and cytogenetics.[2]
Table 3 describes the treatment options for localized, metastatic, and recurrent Ewing sarcoma.
Table 3. Standard Treatment Options for Ewing Sarcoma
Treatment GroupStandard Treatment Options
Localized Ewing sarcomaChemotherapy
Local-control measures:
 Surgery
 Radiation therapy
 High-dose chemotherapy and autologous stem cell rescue
Metastatic Ewing sarcomaChemotherapy
Surgery
Radiation therapy
Recurrent Ewing sarcomaChemotherapy (not considered standard treatment)
Radiation therapy (not considered standard treatment)
High-dose chemotherapy with stem cell support (not considered standard treatment)
Other therapies (not considered standard treatment)
The successful treatment of patients with Ewing sarcoma requires systemic chemotherapy [3-9] in conjunction with surgery and/or radiation therapy for local tumor control.[10-14] In general, patients receive chemotherapy before instituting local-control measures. In patients who undergo surgery, surgical margins and histologic response are considered in planning postoperative therapy. Patients with metastatic disease often have a good initial response to preoperative chemotherapy, but in most cases, the disease is only partially controlled or recurs.[15-19] Patients with lung as the only metastatic site have a better prognosis than do patients with metastases to bone and/or bone marrow. Adequate local control for metastatic sites, particularly bone metastases, may be an important issue.[20]

Chemotherapy for Ewing Sarcoma

Multidrug chemotherapy for Ewing sarcoma always includes vincristine, doxorubicin, ifosfamide, and etoposide. Most protocols also use cyclophosphamide and some incorporate dactinomycin. The mode of administration and dose intensity of cyclophosphamide within courses differs markedly between protocols. A European Intergroup Cooperative Ewing Sarcoma Study (EICESS) trial suggested that 1.2 g of cyclophosphamide produced a similar event-free survival (EFS) compared with 6 g of ifosfamide in patients with lower-risk disease, and identified a trend toward better EFS for patients with localized Ewing sarcoma and higher-risk disease when treatment included etoposide (GER-GPOH-EICESS-92 [NCT00002516]).[21][Level of evidence: 1iiA]
Protocols in the United States generally alternate courses of vincristine, cyclophosphamide, and doxorubicin with courses of ifosfamide/etoposide,[7] while European protocols generally combine vincristine, doxorubicin, and an alkylating agent with or without etoposide in a single treatment cycle.[9] The duration of primary chemotherapy ranges from 6 months to approximately 1 year.
Evidence (chemotherapy):
  1. An international consortium of European countries conducted the EURO-EWING-INTERGROUP-EE99 (NCT00020566) trial from 2000 to 2010.[22][Level of evidence: 1iiA] All patients received induction therapy with six cycles of vincristine, ifosfamide, doxorubicin, and etoposide (VIDE), followed by local control, and then one cycle of vincristine, dactinomycin, and ifosfamide (VAI). Patients were classified as standard risk if they had localized disease and good histologic response to therapy or if they had localized tumors less than 200 mL in volume at presentation; they were treated with radiation therapy alone as local treatment. Standard-risk patients (n = 856) were randomly assigned to receive either maintenance therapy with seven cycles of vincristine, dactinomycin, and cyclophosphamide (VAC) or VAI.
    • There was no significant difference in EFS or overall survival (OS) between the VAC arm and the VAI arm.
    • Three-year EFS for this low-risk population was 77%.
    • Acute renal toxicity was lower in the VAC arm than in the VAI arm, but long-term renal function outcome and fertility analyses are still pending.
    • It is difficult to compare this outcome with that of other large series because the study population excluded patients with poor response to initial therapy or patients with tumors more than 200 mL in volume who received local-control therapy with radiation alone. All other published series report results for all patients who present without clinically detectable metastasis; thus, these other series included patients with poor response and patients with larger primary tumors treated with radiation alone, all of whom were excluded from the EURO-EWING-INTERGROUP-EE99 study.
  2. A Children's Oncology Group (COG) study (COG-AEWS0031 [NCT00006734]) randomly assigned patients presenting without metastases to cycles of cyclophosphamide, doxorubicin, and vincristine alternating with cycles of ifosfamide and etoposide at either 2-week or 3-week intervals.[23]
    • The administration of cycles of cyclophosphamide, doxorubicin, and vincristine alternating with cycles of ifosfamide and etoposide at 2-week intervals achieved superior EFS (5-year EFS, 73%) than did alternating cycles at 3-week intervals (5-year EFS, 65%).
  3. The Brazilian Cooperative Study Group performed a multi-institutional trial that incorporated carboplatin into a risk-adapted intensive regimen in 175 children with localized or metastatic Ewing sarcoma.[24][Level of evidence: 2Dii]
    • The investigators found significantly increased toxicity without an improvement in outcome with the addition of carboplatin.
  4. The COG conducted a pilot study of the addition of cycles of cyclophosphamide and topotecan to cycles of cyclophosphamide/doxorubicin/vincristine and ifosfamide/etoposide administered in an interval-compressed (2-week instead of 3-week intervals) schedule.[25][Level of evidence: 2Di]
    • Therapy was well tolerated, and the 5-year EFS for 35 patients was 80%. This pilot study became the experimental arm of COG-AEWS1031 (NCT01231906).

Local Control (Surgery and Radiation Therapy) for Ewing Sarcoma

Treatment approaches for Ewing sarcoma titrate therapeutic aggressiveness with the goal of maximizing local control while minimizing morbidity.
Surgery is the most commonly used form of local control.[26] Radiation therapy is an effective alternative modality for local control in cases where the functional or cosmetic morbidity of surgery is deemed too high by experienced surgical oncologists. However, in the immature skeleton, radiation therapy can cause subsequent deformities that may be more morbid than deformities from surgery. When complete surgical resection with pathologically negative margins cannot be obtained, postoperative radiation therapy is indicated. A multidisciplinary discussion between the experienced radiation oncologist and the surgeon is necessary to determine the best treatment options for local control for a given case. For some marginally resectable lesions, a combined approach of preoperative radiation therapy followed by resection can be used.
Randomized trials that directly compare surgery and radiation therapy do not exist, and their relative roles remain controversial. Although retrospective institutional series suggest superior local control and survival with surgery than with radiation therapy, most of these studies are compromised by selection bias. An analysis using propensity scoring to adjust for clinical features that may influence the preference for surgery only, radiation only, or combined surgery and radiation demonstrated that similar EFS is achieved with each mode of local therapy after propensity adjustment.[26] Data for patients with pelvic primary Ewing sarcoma from a North American intergroup trial showed no difference in local control or survival on the basis of local-control modality—surgery alone, radiation therapy alone, or surgery plus radiation therapy.[27]
For patients who undergo gross-total resection with microscopic residual disease, a radiation therapy dose of 50.4 Gy is indicated; for patients treated with primary radiation therapy, the radiation dose is 55.8 Gy (45 Gy to the initial tumor volume and an additional 10.8 Gy to the postchemotherapy volume).[13,28]
Evidence (postoperative radiation therapy):
  1. Investigators from St. Jude Children’s Research Hospital reported 39 patients with localized Ewing sarcoma who received both surgery and radiation.[13]
    • Local failure for patients with positive margins was 17% and OS was 71%. Local failure for patients with negative margins was 5% and OS was 94%.
  2. In a large retrospective Italian study, 45 Gy of adjuvant radiation therapy for patients with inadequate margins did not appear to improve either local control or disease-free survival (DFS).[14] These investigators concluded that patients who are anticipated to have suboptimal surgery should be considered for definitive radiation therapy or receive full-dose radiation therapy.
  3. The EURO-EWING-INTERGROUP-EE99 (NCT00020566) study reported the outcomes of 599 patients who presented with localized disease and had surgical resection after initial chemotherapy with at least 90% necrosis of the primary tumor.[28][Level of evidence: 3iiDi] The protocol recommended postoperative radiation therapy for patients with inadequate surgical margins, vertebral primary tumors, or thoracic tumors with pleural effusion, but the decision to use postoperative radiation therapy was left to the institutional investigator.
    • Patients who received postoperative radiation therapy (n = 142) had a lower risk of failure than did patients who did not receive postoperative radiation therapy, even after controlling for known prognostic factors, including age, sex, tumor site, clinical response, quality of resection, and histologic necrosis. Most of the improvement was seen in a decreased risk of local recurrence. The improvement was greater in patients who had large tumors (>200 mL) and were assessed to have 100% necrosis than in patients who were assessed to have 90% to 100% necrosis.
    • There is a clear interaction between systemic therapy and local-control modalities for both local control and DFS. The induction regimen used in the EURO-EWING-INTERGROUP-EE99 study is less intense than the induction regimen used in contemporaneous protocols in the COG, and it is not appropriate to extrapolate the results from the EURO-EWING-INTERGROUP-EE99 study to different systemic chemotherapy regimens.

Thoracic primary tumors

Evidence (surgery):
  1. The treatment and outcomes for 62 patients with thoracic Ewing sarcoma were reported from the Cooperative Weichteilsarkom Studiengruppe CWS-81, -86, -91, -96, and -2002P trials.[29]
    • The 5-year OS rate was 58.7% (95% confidence interval [CI], 52.7%–64.7%), and the EFS rate was 52.8% (95% CI, 46.8%–58.8%).
    • Patients with intrathoracic tumor localization (n = 24) had a worse outcome (EFS, 37.5% [95% CI, 27.5%–37.5%]) than did patients with chest wall tumors (n = 38; EFS, 62.3% [95% CI, 54.3%–70.3%]; P = .008).
    • Patients aged 10 years and younger (n = 38) had a better survival (EFS, 65.7% [95% CI, 57.7%–73.7%]) than did patients older than 10 years (EFS, 31.3% [95% CI, 21.3%–41.3%]; P = .01).
    • Tumor size of less than or equal to 5 cm (n = 15) was associated with significantly better survival (EFS, 93.3% [95% CI, 87.3%–99.3%]) compared with a tumor size greater than 5 cm (n = 47; EFS, 40% [95% CI, 33%–47%]; P = .002).
    • Primary resections were carried out in 36 patients, 75% of which were incomplete, resulting in inferior EFS (P = .006).
    • Complete secondary resections were performed in 22 of 40 patients.
In summary, surgery is chosen as definitive local therapy for suitable patients, but radiation therapy is appropriate for patients with unresectable disease or those who would experience functional or cosmetic compromise by definitive surgery. The possibility of impaired function or cosmesis needs to be measured against the possibility of second tumors in the radiation field. Adjuvant radiation therapy should be considered for patients with residual microscopic disease or inadequate margins.
When preoperative assessment has suggested a high probability that surgical margins will be close or positive, preoperative radiation therapy has achieved tumor shrinkage and allowed surgical resection with clear margins.[30]

High-Dose Chemotherapy With Stem Cell Support for Ewing Sarcoma

For patients with a high risk of relapse with conventional treatments, certain investigators have utilized high-dose chemotherapy with hematopoietic stem cell transplant (HSCT) as consolidation treatment, in an effort to improve outcome.[19,31-43]
Evidence (high-dose therapy with stem cell support):
  1. In a prospective study, patients with bone and/or bone marrow metastases at diagnosis were treated with aggressive chemotherapy, surgery, and/or radiation and HSCT if a good initial response was achieved.[36]
    • The study showed no benefit for HSCT compared with historical controls.
  2. A retrospective review using international bone marrow transplant registries compared the outcomes after treatment with either reduced-intensity conditioning or high-intensity conditioning followed by allogeneic SCT for patients with Ewing sarcoma at high risk for relapse.[44][Level of evidence: 3iiiA]
    • There was no difference in outcome, and the authors concluded that this suggested the absence of a clinically relevant graft-versus-tumor effect against Ewing sarcoma tumor cells with current approaches.
  3. Multiple small studies that report benefit for HSCT have been published but are difficult to interpret because only patients who have a good initial response to standard chemotherapy are considered for HSCT.
  4. The role of high-dose therapy with busulfan-melphalan (BuMel) followed by stem cell rescue was investigated in the prospective, randomized EURO-EWING-INTERGROUP-EE99 (NCT00020566) trial for two distinct groups:[45]
    1. Patients who presented with isolated pulmonary metastases (R2pulm).
    2. Patients with localized tumors with poor response to initial chemotherapy (<90% necrosis) or with large tumors (>200 mL) (R2loc).
      Both study arms were compromised by the potential for selection bias for patients who were eligible for and accepted randomization, which may limit the generalizability of the results. Only 40% of eligible patients were randomized.
      • Among R2pulm patients, there was no difference in 3-year EFS (55.7% with BuMel vs. 50.3% with continued chemotherapy and whole-lung radiation; P = .21).
      • Among R2loc patients, 3-year EFS was superior with BuMel compared with continued chemotherapy (66.9% vs. 53.1%; P = .019). The 3-year OS was 78.0% with BuMel and 72.2% with continued chemotherapy (P = .028).
    The induction regimen employed in the EURO-EWING-INTERGROUP-EE99 trial was VIDE. This regimen is less dose intensive than the regimen employed in COG studies. This can be inferred from the intended dose intensity of the agents employed for the 21-week period that preceded randomization in the EURO-EWING-INTERGROUP-EE99 study (refer to Table 4). The lower dose intensity can also be inferred from the outcome of the EURO-EWING-INTERGROUP-EE99 study for patients in the localized disease stratum. Results from this study include the following:
    • Patients assigned to the most favorable risk stratum, R1, were patients with small primary tumors, less than 200 mL in volume. In addition, patients who had poor response to the initial six cycles of therapy with VIDE, as assessed by pathology or radiology, were removed from the R1 stratum and assigned to the R2 stratum. As a result, the R1 stratum includes only patients with small primary tumors and favorable response to initial therapy. The probability for EFS at 3 years for this favorable group was 76%, and the OS at 3 years was 85%.[22]
    • For all patients with localized Ewing sarcoma, including patients with large primary tumors and patients with poor response to initial therapy treated on the COG-AEWS1031 (NCT01231906) trial, the 5-year probability for EFS was 73%, and the 5-year OS was 88%.[23]
    The observation that high-dose therapy with autologous stem cell rescue improved outcomes for patients with a poor response to initial therapy in the EURO-EWING-INTERGROUP-EE99 study must be interpreted in this context. The advantage of high-dose therapy as consolidation for patients with a poor response to initial treatment with a less intensive regimen cannot be extrapolated to a population of patients who received a more intensive treatment regimen as initial therapy.
    Table 4. Comparison of the Dose Intensity of the EURO-EWING-INTERGROUP-EE99 Trial Versus COG Interval Dose Compression
    Chemotherapy AgentPrescribed Dose Intensity (mg/week)
     EURO-EWING-INTERGROUP-EE99 TrialCOG Interval Dose Compression
    COG = Children's Oncology Group.
    Vincristine0.5 mg/m20.43 mg/m2
    Doxorubicin17.1 mg/m221.4 mg/m2
    Ifosfamide3,000 mg/m22,150 mg/m2
    Cyclophosphamide0343 mg/m2
    Cyclophosphamide equivalent dose (= cyclophosphamide dose + ifosfamide dose × 0.244)732 mg/m2868 mg/m2

Extraosseous Ewing Sarcoma

Multiple analyses have evaluated diagnostic findings, treatment, and outcome of patients with bone lesions at the following anatomic primary sites:
Extraosseous Ewing sarcoma is biologically similar to Ewing sarcoma arising in bone. Historically, most children and young adults with extraosseous Ewing sarcoma were treated on protocols designed for the treatment of rhabdomyosarcoma. This is important because many of the treatment regimens for rhabdomyosarcoma do not include an anthracycline, which is a critical component of current treatment regimens for Ewing sarcoma. Currently, patients with extraosseous Ewing sarcoma are eligible for studies that include Ewing sarcoma of bone.
Evidence (treatment of extraosseous Ewing sarcoma):
  1. From 1987 to 2004, 111 patients with nonmetastatic extraosseous Ewing sarcoma were enrolled on the RMS-88 and RMS-96 protocols.[64] Patients with initial complete tumor resection received ifosfamide, vincristine, and actinomycin (IVA) while patients with residual tumor received IVA plus doxorubicin (VAIA) or IVA plus carboplatin, epirubicin, and etoposide (CEVAIE). Seventy-six percent of patients received radiation.
    • The 5-year EFS was 59% and OS was 69%.
    • In a multivariate analysis, independent adverse prognostic factors included axial primary, tumor size greater than 10 cm, Intergroup Rhabdomyosarcoma Studies Group III, and lack of radiation therapy.
  2. Two hundred thirty-six patients with extraosseous Ewing sarcoma were entered on studies of the German Pediatric Oncology Group.[65] The median age at diagnosis was 15 years and 133 patients were male. Primary tumor site was either extremity (n = 62) or central site (n = 174). Sixty of the 236 patients had metastases at diagnosis. Chemotherapy consisted of vincristine, doxorubicin, cyclophosphamide, and actinomycin (VACA), CEVAIE, or VIDE.
    • The 5-year EFS was 49% and OS was 60%.
    • Five-year survival was 70% for patients with localized disease and 33% for patients with metastasis at diagnosis.
    • OS in patients with localized disease did not seem related to tumor site or size.
  3. In a retrospective French study, patients with extraosseous Ewing sarcoma were treated using a rhabdomyosarcoma regimen (no anthracyclines) or a Ewing sarcoma regimen (includes anthracyclines).[66,67]
    • Patients who received the anthracycline-containing regimen had a significantly better EFS and OS than did patients who did not receive anthracyclines.
  4. Two North American Ewing sarcoma trials have included patients with extraosseous Ewing sarcoma.[23,68] In a review of data from the POG-9354 (INT-0154) and EWS0031 (NCT00006734) studies, 213 patients with extraosseous Ewing sarcoma and 826 patients with Ewing sarcoma of bone were identified.[69][Level of evidence: 3iiDi]
    • The hazard ratio of extraosseous Ewing sarcoma was superior (0.62), and extraosseous Ewing sarcoma was a favorable risk factor, independent of age, race, and primary site.
Cutaneous Ewing sarcoma is a soft tissue tumor in the skin or subcutaneous tissue that seems to behave as a less-aggressive tumor than primary bone or soft tissue Ewing sarcoma. Tumors can form throughout the body, although the extremity is the most common site, and they are almost always localized.
Evidence (treatment of cutaneous Ewing sarcoma):
  1. In a review of 78 reported cases, some lacking molecular confirmation, the OS was 91%. Adequate local control, defined as a complete resection with negative margins, radiation therapy, or a combination, significantly reduced the incidence of relapse. Standard chemotherapy for Ewing sarcoma is often used for these patients because there are no data to suggest which patients could be treated less aggressively.[70,71]
  2. A series of 56 patients with cutaneous or subcutaneous Ewing sarcoma confirmed the excellent outcome with the use of standard systemic therapy and local control. Attempted primary definitive surgery often resulted in the need for either radiation therapy or more function-compromising surgery, supporting the recommendation of biopsy only as initial surgery, rather than upfront unplanned resection.[72][Level of evidence: 3iiD]

Special Considerations for the Treatment of Children With Cancer

Cancer in children and adolescents is rare, although the overall incidence of childhood cancer has been slowly increasing since 1975.[73] Children and adolescents with cancer should be referred to medical centers that have a multidisciplinary team of cancer specialists with experience treating the cancers that occur during childhood and adolescence. This multidisciplinary team approach incorporates the skills of the following health care professionals and others to ensure that children receive treatment, supportive care, and rehabilitation that will achieve optimal survival and quality of life:
  • Primary care physicians.
  • Pediatric surgeons.
  • Radiation oncologists.
  • Pediatric oncologists/hematologists.
  • Rehabilitation specialists.
  • Pediatric nurse specialists.
  • Social workers.
  • Child-life professionals.
  • Psychologists.
(Refer to the PDQ Supportive and Palliative Care summaries for specific information about supportive care for children and adolescents with cancer.)
Guidelines for pediatric cancer centers and their role in the treatment of pediatric patients with cancer have been outlined by the American Academy of Pediatrics.[74] At these pediatric cancer centers, clinical trials are available for most types of cancer that occur in children and adolescents, and the opportunity to participate in these trials is offered to most patients and their families. Clinical trials for children and adolescents with cancer are generally designed to compare potentially better therapy with therapy that is currently accepted as standard. Most of the progress made in identifying curative therapies for childhood cancers has been achieved through clinical trials. Information about ongoing clinical trials is available from the NCI website.
Childhood and adolescent cancer survivors require close monitoring because cancer therapy side effects may persist or develop months or years after treatment. (Refer to the PDQ summary on Late Effects of Treatment for Childhood Cancer for specific information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors.)
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  22. Le Deley MC, Paulussen M, Lewis I, et al.: Cyclophosphamide compared with ifosfamide in consolidation treatment of standard-risk Ewing sarcoma: results of the randomized noninferiority Euro-EWING99-R1 trial. J Clin Oncol 32 (23): 2440-8, 2014. [PUBMED Abstract]
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  25. Mascarenhas L, Felgenhauer JL, Bond MC, et al.: Pilot Study of Adding Vincristine, Topotecan, and Cyclophosphamide to Interval-Compressed Chemotherapy in Newly Diagnosed Patients With Localized Ewing Sarcoma: A Report From the Children's Oncology Group. Pediatr Blood Cancer 63 (3): 493-8, 2016. [PUBMED Abstract]
  26. DuBois SG, Krailo MD, Gebhardt MC, et al.: Comparative evaluation of local control strategies in localized Ewing sarcoma of bone: a report from the Children's Oncology Group. Cancer 121 (3): 467-75, 2015. [PUBMED Abstract]
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  30. Wagner TD, Kobayashi W, Dean S, et al.: Combination short-course preoperative irradiation, surgical resection, and reduced-field high-dose postoperative irradiation in the treatment of tumors involving the bone. Int J Radiat Oncol Biol Phys 73 (1): 259-66, 2009. [PUBMED Abstract]
  31. Kushner BH, Meyers PA: How effective is dose-intensive/myeloablative therapy against Ewing's sarcoma/primitive neuroectodermal tumor metastatic to bone or bone marrow? The Memorial Sloan-Kettering experience and a literature review. J Clin Oncol 19 (3): 870-80, 2001. [PUBMED Abstract]
  32. Marina N, Meyers PA: High-dose therapy and stem-cell rescue for Ewing's family of tumors in second remission. J Clin Oncol 23 (19): 4262-4, 2005. [PUBMED Abstract]
  33. Burdach S: Treatment of advanced Ewing tumors by combined radiochemotherapy and engineered cellular transplants. Pediatr Transplant 8 (Suppl 5): 67-82, 2004. [PUBMED Abstract]
  34. McTiernan A, Driver D, Michelagnoli MP, et al.: High dose chemotherapy with bone marrow or peripheral stem cell rescue is an effective treatment option for patients with relapsed or progressive Ewing's sarcoma family of tumours. Ann Oncol 17 (8): 1301-5, 2006. [PUBMED Abstract]
  35. Burdach S, Meyer-Bahlburg A, Laws HJ, et al.: High-dose therapy for patients with primary multifocal and early relapsed Ewing's tumors: results of two consecutive regimens assessing the role of total-body irradiation. J Clin Oncol 21 (16): 3072-8, 2003. [PUBMED Abstract]
  36. Meyers PA, Krailo MD, Ladanyi M, et al.: High-dose melphalan, etoposide, total-body irradiation, and autologous stem-cell reconstitution as consolidation therapy for high-risk Ewing's sarcoma does not improve prognosis. J Clin Oncol 19 (11): 2812-20, 2001. [PUBMED Abstract]
  37. Oberlin O, Rey A, Desfachelles AS, et al.: Impact of high-dose busulfan plus melphalan as consolidation in metastatic Ewing tumors: a study by the Société Française des Cancers de l'Enfant. J Clin Oncol 24 (24): 3997-4002, 2006. [PUBMED Abstract]
  38. Hawkins D, Barnett T, Bensinger W, et al.: Busulfan, melphalan, and thiotepa with or without total marrow irradiation with hematopoietic stem cell rescue for poor-risk Ewing-Sarcoma-Family tumors. Med Pediatr Oncol 34 (5): 328-37, 2000. [PUBMED Abstract]
  39. Rosenthal J, Bolotin E, Shakhnovits M, et al.: High-dose therapy with hematopoietic stem cell rescue in patients with poor prognosis Ewing family tumors. Bone Marrow Transplant 42 (5): 311-8, 2008. [PUBMED Abstract]
  40. Burdach S, Thiel U, Schöniger M, et al.: Total body MRI-governed involved compartment irradiation combined with high-dose chemotherapy and stem cell rescue improves long-term survival in Ewing tumor patients with multiple primary bone metastases. Bone Marrow Transplant 45 (3): 483-9, 2010. [PUBMED Abstract]
  41. Gaspar N, Rey A, Bérard PM, et al.: Risk adapted chemotherapy for localised Ewing's sarcoma of bone: the French EW93 study. Eur J Cancer 48 (9): 1376-85, 2012. [PUBMED Abstract]
  42. Drabko K, Raciborska A, Bilska K, et al.: Consolidation of first-line therapy with busulphan and melphalan, and autologous stem cell rescue in children with Ewing's sarcoma. Bone Marrow Transplant 47 (12): 1530-4, 2012. [PUBMED Abstract]
  43. Loschi S, Dufour C, Oberlin O, et al.: Tandem high-dose chemotherapy strategy as first-line treatment of primary disseminated multifocal Ewing sarcomas in children, adolescents and young adults. Bone Marrow Transplant 50 (8): 1083-8, 2015. [PUBMED Abstract]
  44. Thiel U, Wawer A, Wolf P, et al.: No improvement of survival with reduced- versus high-intensity conditioning for allogeneic stem cell transplants in Ewing tumor patients. Ann Oncol 22 (7): 1614-21, 2011. [PUBMED Abstract]
  45. Whelan J, Le Deley MC, Dirksen U, et al.: High-Dose Chemotherapy and Blood Autologous Stem-Cell Rescue Compared With Standard Chemotherapy in Localized High-Risk Ewing Sarcoma: Results of Euro-E.W.I.N.G.99 and Ewing-2008. J Clin Oncol : JCO2018782516, 2018. [PUBMED Abstract]
  46. Hoffmann C, Ahrens S, Dunst J, et al.: Pelvic Ewing sarcoma: a retrospective analysis of 241 cases. Cancer 85 (4): 869-77, 1999. [PUBMED Abstract]
  47. Sucato DJ, Rougraff B, McGrath BE, et al.: Ewing's sarcoma of the pelvis. Long-term survival and functional outcome. Clin Orthop (373): 193-201, 2000. [PUBMED Abstract]
  48. Bacci G, Ferrari S, Mercuri M, et al.: Multimodal therapy for the treatment of nonmetastatic Ewing sarcoma of pelvis. J Pediatr Hematol Oncol 25 (2): 118-24, 2003. [PUBMED Abstract]
  49. Bacci G, Ferrari S, Longhi A, et al.: Local and systemic control in Ewing's sarcoma of the femur treated with chemotherapy, and locally by radiotherapy and/or surgery. J Bone Joint Surg Br 85 (1): 107-14, 2003. [PUBMED Abstract]
  50. Ozaki T, Hillmann A, Hoffmann C, et al.: Ewing's sarcoma of the femur. Prognosis in 69 patients treated by the CESS group. Acta Orthop Scand 68 (1): 20-4, 1997. [PUBMED Abstract]
  51. Ayoub KS, Fiorenza F, Grimer RJ, et al.: Extensible endoprostheses of the humerus after resection of bone tumours. J Bone Joint Surg Br 81 (3): 495-500, 1999. [PUBMED Abstract]
  52. Bacci G, Palmerini E, Staals EL, et al.: Ewing's sarcoma family tumors of the humerus: outcome of patients treated with radiotherapy, surgery or surgery and adjuvant radiotherapy. Radiother Oncol 93 (2): 383-7, 2009. [PUBMED Abstract]
  53. Casadei R, Magnani M, Biagini R, et al.: Prognostic factors in Ewing's sarcoma of the foot. Clin Orthop (420): 230-8, 2004. [PUBMED Abstract]
  54. Anakwenze OA, Parker WL, Wold LE, et al.: Ewing's sarcoma of the hand. J Hand Surg Eur Vol 34 (1): 35-9, 2009. [PUBMED Abstract]
  55. Shamberger RC, Laquaglia MP, Krailo MD, et al.: Ewing sarcoma of the rib: results of an intergroup study with analysis of outcome by timing of resection. J Thorac Cardiovasc Surg 119 (6): 1154-61, 2000. [PUBMED Abstract]
  56. Sirvent N, Kanold J, Levy C, et al.: Non-metastatic Ewing's sarcoma of the ribs: the French Society of Pediatric Oncology Experience. Eur J Cancer 38 (4): 561-7, 2002. [PUBMED Abstract]
  57. Shamberger RC, LaQuaglia MP, Gebhardt MC, et al.: Ewing sarcoma/primitive neuroectodermal tumor of the chest wall: impact of initial versus delayed resection on tumor margins, survival, and use of radiation therapy. Ann Surg 238 (4): 563-7; discussion 567-8, 2003. [PUBMED Abstract]
  58. Schuck A, Ahrens S, Konarzewska A, et al.: Hemithorax irradiation for Ewing tumors of the chest wall. Int J Radiat Oncol Biol Phys 54 (3): 830-8, 2002. [PUBMED Abstract]
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  60. Venkateswaran L, Rodriguez-Galindo C, Merchant TE, et al.: Primary Ewing tumor of the vertebrae: clinical characteristics, prognostic factors, and outcome. Med Pediatr Oncol 37 (1): 30-5, 2001. [PUBMED Abstract]
  61. Marco RA, Gentry JB, Rhines LD, et al.: Ewing's sarcoma of the mobile spine. Spine 30 (7): 769-73, 2005. [PUBMED Abstract]
  62. Schuck A, Ahrens S, von Schorlemer I, et al.: Radiotherapy in Ewing tumors of the vertebrae: treatment results and local relapse analysis of the CESS 81/86 and EICESS 92 trials. Int J Radiat Oncol Biol Phys 63 (5): 1562-7, 2005. [PUBMED Abstract]
  63. Bacci G, Boriani S, Balladelli A, et al.: Treatment of nonmetastatic Ewing's sarcoma family tumors of the spine and sacrum: the experience from a single institution. Eur Spine J 18 (8): 1091-5, 2009. [PUBMED Abstract]
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  66. Castex MP, Rubie H, Stevens MC, et al.: Extraosseous localized ewing tumors: improved outcome with anthracyclines--the French society of pediatric oncology and international society of pediatric oncology. J Clin Oncol 25 (10): 1176-82, 2007. [PUBMED Abstract]
  67. Dantonello TM, Int-Veen C, Harms D, et al.: Cooperative trial CWS-91 for localized soft tissue sarcoma in children, adolescents, and young adults. J Clin Oncol 27 (9): 1446-55, 2009. [PUBMED Abstract]
  68. Granowetter L, Womer R, Devidas M, et al.: Dose-intensified compared with standard chemotherapy for nonmetastatic Ewing sarcoma family of tumors: a Children's Oncology Group Study. J Clin Oncol 27 (15): 2536-41, 2009. [PUBMED Abstract]
  69. Cash T, McIlvaine E, Krailo MD, et al.: Comparison of clinical features and outcomes in patients with extraskeletal versus skeletal localized Ewing sarcoma: A report from the Children's Oncology Group. Pediatr Blood Cancer 63 (10): 1771-9, 2016. [PUBMED Abstract]
  70. Collier AB 3rd, Simpson L, Monteleone P: Cutaneous Ewing sarcoma: report of 2 cases and literature review of presentation, treatment, and outcome of 76 other reported cases. J Pediatr Hematol Oncol 33 (8): 631-4, 2011. [PUBMED Abstract]
  71. Terrier-Lacombe MJ, Guillou L, Chibon F, et al.: Superficial primitive Ewing's sarcoma: a clinicopathologic and molecular cytogenetic analysis of 14 cases. Mod Pathol 22 (1): 87-94, 2009. [PUBMED Abstract]
  72. Di Giannatale A, Frezza AM, Le Deley MC, et al.: Primary cutaneous and subcutaneous Ewing sarcoma. Pediatr Blood Cancer 62 (9): 1555-61, 2015. [PUBMED Abstract]
  73. Smith MA, Altekruse SF, Adamson PC, et al.: Declining childhood and adolescent cancer mortality. Cancer 120 (16): 2497-506, 2014. [PUBMED Abstract]
  74. Corrigan JJ, Feig SA; American Academy of Pediatrics: Guidelines for pediatric cancer centers. Pediatrics 113 (6): 1833-5, 2004. [PUBMED Abstract]

Treatment of Localized Ewing Sarcoma

Standard Treatment Options for Localized Ewing Sarcoma

Standard treatment options for localized Ewing sarcoma include the following:
  1. Chemotherapy.
  2. Local-control measures:
Because most patients with apparently localized disease at diagnosis have occult metastatic disease, multidrug chemotherapy and local disease control with surgery and/or radiation therapy is indicated in the treatment of all patients.[1-8] Current regimens for the treatment of localized Ewing sarcoma achieve event-free survival (EFS) and overall survival (OS) of approximately 70% at 5 years after diagnosis.[9]

Chemotherapy

Current standard chemotherapy in the United States includes vincristine, doxorubicin, and cyclophosphamide (VDC), alternating with ifosfamide and etoposide (IE) or VDC/IE.[9]; [10][Level of evidence: 1iiA]
Evidence (chemotherapy):
  1. IE has shown activity in Ewing sarcoma, and a large randomized clinical trial and a nonrandomized trial demonstrated that outcome was improved when IE was alternated with VDC.[9,11]
  2. Dactinomycin is no longer used for Ewing sarcoma in the United States but continues to be used in the Euro-Ewing studies.
  3. The use of high-dose VDC has shown promising results in small numbers of patients. A single-institution study of 44 patients treated with high-dose VDC and IE showed an 82% 4-year EFS.[12]
  4. However, in an intergroup trial of the Pediatric Oncology Group and the Children's Cancer Group, which compared an alkylator dose-intensified VDC/IE regimen with standard alkylator doses of the same VDC/IE regimen, no differences in outcome were observed.[13] Unlike the single-institution trial, this trial did not maintain the dose intensity of cyclophosphamide for the duration of treatment.[12]
In a Children's Oncology Group (COG) trial (COG-AEWS0031 [NCT00006734]), 568 patients with newly diagnosed localized extradural Ewing sarcoma were randomly assigned to receive chemotherapy (VDC/IE) given either every 2 weeks (interval compression) or every 3 weeks (standard). Patients randomly assigned to the every 2-week interval of treatment had an improved 5-year EFS (73% vs. 65%, P = .048). There was no increase in toxicity observed with the every 2-week schedule.[10]

Local-control measures

Local control can be achieved by surgery and/or radiation therapy. Decisions regarding the optimal modality for local control for an individual patient involve consideration of the following:
  • The possibility of complete resection with adequate margins after an initial period of systemic therapy.
  • The predicted functional impact of a surgical procedure.
  • The predicted morbidity after radiation therapy.
  • The possibility of increased risk of second malignant neoplasms after radiation therapy.
An analysis using propensity scoring (a method that adjusts for the inherent selection bias of the location and size of the tumor) to adjust for clinical features that may influence the preference for surgery only, radiation only, or combined surgery and radiation demonstrated that similar EFS rates are achieved with each mode of local therapy after propensity adjustment.[14]
Surgery
Surgery is generally the preferred approach if the lesion is resectable.[15,16] The superiority of resection for local control has never been tested in a prospective randomized trial. The apparent superiority may represent selection bias.
  1. In past studies, smaller, more peripheral tumors were more likely to be treated with surgery, and larger, more central tumors were more likely to be treated with radiation therapy.[17]
  2. An Italian retrospective study showed that surgery improved outcome only in extremity tumors, although the number of patients with central axis Ewing sarcoma who achieved adequate margins was small.[8]
  3. In a series of 39 patients treated at St. Jude Children's Research Hospital who received both surgery and radiation, the 8-year local failure rate was 5% for patients with negative surgical margins and 17% for those with positive margins.[5]
  4. Data for patients with pelvic primary Ewing sarcoma from a North American intergroup trial showed no difference in local control or survival based on local-control modality—surgery alone, radiation therapy alone, or radiation plus surgery.[18]
Potential benefits of surgery include the following:
  • If a very young child has Ewing sarcoma, surgery may be a less-morbid therapy than radiation therapy because of the retardation of bone growth caused by radiation.
  • Treatment with surgery may allow for the omission of radiation therapy, which might be associated with an increased risk of subsequent neoplasms.
  • Another potential benefit for surgical resection of the primary tumor is related to the amount of necrosis in the resected tumor. Patients with residual viable tumor in the resected specimen have a worse outcome than those with complete necrosis. In a French Ewing study (EW88), EFS for patients with less than 5% viable tumor was 75%, EFS for patients with 5% to 30% viable tumor was 48%, and EFS for patients with more than 30% viable tumor was 20%.[17]
One arm of the prospective, randomized EURO-EWING-INTERGROUP-EE99 (NCT00020566) trial demonstrated a benefit of high-dose therapy with busulfan-melphalan followed by stem cell rescue compared with continued chemotherapy for patients with localized tumor and poor response to initial chemotherapy.[19]
Pathologic fracture at the time of diagnosis does not preclude surgical resection and is not associated with adverse outcome.[20]
Radiation therapy
Radiation therapy is usually employed in the following cases:
  • Patients who do not have a surgical option that preserves function.
  • Patients whose tumors have been excised but with inadequate margins.
Radiation therapy is delivered in a setting in which stringent planning techniques are applied by those experienced in the treatment of Ewing sarcoma. Such an approach will result in local control of the tumor with acceptable morbidity in most patients.[1,2,21]
The radiation dose may be adjusted depending on the extent of residual disease after the initial surgical procedure. When no surgical resection is performed, radiation therapy is generally administered in fractionated doses totaling approximately 55.8 Gy to the prechemotherapy tumor volume. A randomized study of 40 patients with Ewing sarcoma using 55.8 Gy to the prechemotherapy tumor extent with a 2-cm margin compared with the same total-tumor dose after 39.6 Gy to the entire bone showed no difference in local control or EFS.[3] Hyperfractionated radiation therapy has not been associated with improved local control or decreased morbidity.[1]
For patients with residual disease after an attempt at surgical resection, the Intergroup Ewing Sarcoma Study (INT-0091) recommended 45 Gy to the original disease site plus a 10.8 Gy boost for patients with gross residual disease and 45 Gy plus a 5.4 Gy boost for patients with microscopic residual disease. No radiation therapy was recommended for those who have no evidence of microscopic residual disease after surgical resection.[13]
Comparison of proton-beam radiation therapy and intensity-modulated radiation therapy (IMRT) treatment plans has shown that proton-beam radiation therapy can spare more normal tissue adjacent to Ewing sarcoma primary tumors than IMRT.[22] Follow-up remains relatively short, and there are no data available to determine whether the reduction in dose to adjacent tissue will result in improved functional outcome or reduce the risk of secondary malignancy. Because patient numbers are small and follow-up is relatively short, it is not possible to determine whether the risk of local recurrence might be increased by reducing radiation dose in tissue adjacent to the primary tumor.
Higher rates of local failure are seen in patients older than 14 years who have tumors more than 8 cm in length.[23] A retrospective analysis of patients with Ewing sarcoma of the chest wall compared patients who received hemithorax radiation therapy with those who received radiation therapy to the chest wall only. Patients with pleural invasion, pleural effusion, or intraoperative contamination were assigned to hemithorax radiation therapy. EFS was longer for patients who received hemithorax radiation, but the difference was not statistically significant. In addition, most patients with primary vertebral tumors did not receive hemithorax radiation and had a lower probability for EFS.[24]
Radiation therapy is associated with the development of subsequent neoplasms. A retrospective study noted that patients who received 60 Gy or more had an incidence of second malignancy of 20%. Those who received 48 Gy to 60 Gy had an incidence of 5%, and those who received less than 48 Gy did not develop a second malignancy.[25]
High-dose chemotherapy and autologous stem cell rescue
Evidence (high-dose chemotherapy and autologous stem cell rescue):
  1. The role of high-dose therapy with busulfan-melphalan (BuMel) followed by stem cell rescue was investigated in the prospective, randomized EURO-EWING-INTERGROUP-EE99 (NCT00020566) trial for two distinct groups:[19]
    1. Patients who presented with isolated pulmonary metastases (R2pulm).
    2. Patients with localized tumors with poor response to initial chemotherapy (<90% necrosis) or with large tumors (>200 mL) (R2loc).
      Both study arms were compromised by the potential for selection bias for patients who were eligible for and accepted randomization, which may limit the generalizability of the results. Only 40% of eligible patients were randomized.
      • Among R2pulm patients, there was no difference in 3-year EFS (55.7% with BuMel vs. 50.3% with continued chemotherapy and whole-lung radiation; P = .21).
      • Among R2loc patients, 3-year EFS was superior with BuMel compared with continued chemotherapy (66.9% vs. 53.1%; P = .019). The 3-year OS was 78.0% with BuMel and 72.2% with continued chemotherapy (P = .028).
    The induction regimen employed in the EURO-EWING-INTERGROUP-EE99 trial included vincristine, ifosfamide, doxorubicin, and etoposide (VIDE). This regimen is less dose intensive than the regimen employed in COG studies. This can be inferred from the intended dose intensity of the agents employed for the 21-week period that preceded randomization in the EURO-EWING-INTERGROUP-EE99 study (refer to Table 4). The lower dose intensity can also be inferred from the outcome of the EURO-EWING-INTERGROUP-EE99 study for patients in the localized disease stratum. Results from this study include the following:
    • Patients assigned to the most favorable risk stratum, R1, were patients with small primary tumors, less than 200 mL in volume. In addition, patients who had poor response to the initial six cycles of therapy with VIDE, as assessed by pathology or radiology, were removed from the R1 stratum and assigned to the R2 stratum. As a result, the R1 stratum includes only patients with small primary tumors and favorable response to initial therapy. The probability for EFS at 3 years for this favorable group was 76%, and OS at 3 years was 85%.[26]
    • For all patients with localized Ewing sarcoma, including patients with large primary tumors and patients with poor response to initial therapy treated on the COG-AEWS1031 (NCT01231906) trial, the 5-year probability for EFS was 73%, and the 5-year OS was 88%.[10]
    The observation that high-dose therapy with autologous stem cell rescue improved outcomes for patients with a poor response to initial therapy in the EURO-EWING-INTERGROUP-EE99 study must be interpreted in this context. The advantage of high-dose therapy as consolidation for patients with a poor response to initial treatment with a less intensive regimen cannot be extrapolated to a population of patients who received a more intensive treatment regimen as initial therapy.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
References
  1. Dunst J, Jürgens H, Sauer R, et al.: Radiation therapy in Ewing's sarcoma: an update of the CESS 86 trial. Int J Radiat Oncol Biol Phys 32 (4): 919-30, 1995. [PUBMED Abstract]
  2. Donaldson SS, Torrey M, Link MP, et al.: A multidisciplinary study investigating radiotherapy in Ewing's sarcoma: end results of POG #8346. Pediatric Oncology Group. Int J Radiat Oncol Biol Phys 42 (1): 125-35, 1998. [PUBMED Abstract]
  3. Craft A, Cotterill S, Malcolm A, et al.: Ifosfamide-containing chemotherapy in Ewing's sarcoma: The Second United Kingdom Children's Cancer Study Group and the Medical Research Council Ewing's Tumor Study. J Clin Oncol 16 (11): 3628-33, 1998. [PUBMED Abstract]
  4. Nilbert M, Saeter G, Elomaa I, et al.: Ewing's sarcoma treatment in Scandinavia 1984-1990--ten-year results of the Scandinavian Sarcoma Group Protocol SSGIV. Acta Oncol 37 (4): 375-8, 1998. [PUBMED Abstract]
  5. Krasin MJ, Davidoff AM, Rodriguez-Galindo C, et al.: Definitive surgery and multiagent systemic therapy for patients with localized Ewing sarcoma family of tumors: local outcome and prognostic factors. Cancer 104 (2): 367-73, 2005. [PUBMED Abstract]
  6. Bacci G, Forni C, Longhi A, et al.: Long-term outcome for patients with non-metastatic Ewing's sarcoma treated with adjuvant and neoadjuvant chemotherapies. 402 patients treated at Rizzoli between 1972 and 1992. Eur J Cancer 40 (1): 73-83, 2004. [PUBMED Abstract]
  7. Rosito P, Mancini AF, Rondelli R, et al.: Italian Cooperative Study for the treatment of children and young adults with localized Ewing sarcoma of bone: a preliminary report of 6 years of experience. Cancer 86 (3): 421-8, 1999. [PUBMED Abstract]
  8. Bacci G, Longhi A, Briccoli A, et al.: The role of surgical margins in treatment of Ewing's sarcoma family tumors: experience of a single institution with 512 patients treated with adjuvant and neoadjuvant chemotherapy. Int J Radiat Oncol Biol Phys 65 (3): 766-72, 2006. [PUBMED Abstract]
  9. Grier HE, Krailo MD, Tarbell NJ, et al.: Addition of ifosfamide and etoposide to standard chemotherapy for Ewing's sarcoma and primitive neuroectodermal tumor of bone. N Engl J Med 348 (8): 694-701, 2003. [PUBMED Abstract]
  10. Womer RB, West DC, Krailo MD, et al.: Randomized controlled trial of interval-compressed chemotherapy for the treatment of localized Ewing sarcoma: a report from the Children's Oncology Group. J Clin Oncol 30 (33): 4148-54, 2012. [PUBMED Abstract]
  11. Ferrari S, Mercuri M, Rosito P, et al.: Ifosfamide and actinomycin-D, added in the induction phase to vincristine, cyclophosphamide and doxorubicin, improve histologic response and prognosis in patients with non metastatic Ewing's sarcoma of the extremity. J Chemother 10 (6): 484-91, 1998. [PUBMED Abstract]
  12. Kolb EA, Kushner BH, Gorlick R, et al.: Long-term event-free survival after intensive chemotherapy for Ewing's family of tumors in children and young adults. J Clin Oncol 21 (18): 3423-30, 2003. [PUBMED Abstract]
  13. Granowetter L, Womer R, Devidas M, et al.: Dose-intensified compared with standard chemotherapy for nonmetastatic Ewing sarcoma family of tumors: a Children's Oncology Group Study. J Clin Oncol 27 (15): 2536-41, 2009. [PUBMED Abstract]
  14. DuBois SG, Krailo MD, Gebhardt MC, et al.: Comparative evaluation of local control strategies in localized Ewing sarcoma of bone: a report from the Children's Oncology Group. Cancer 121 (3): 467-75, 2015. [PUBMED Abstract]
  15. Hoffmann C, Ahrens S, Dunst J, et al.: Pelvic Ewing sarcoma: a retrospective analysis of 241 cases. Cancer 85 (4): 869-77, 1999. [PUBMED Abstract]
  16. Shamberger RC, Laquaglia MP, Krailo MD, et al.: Ewing sarcoma of the rib: results of an intergroup study with analysis of outcome by timing of resection. J Thorac Cardiovasc Surg 119 (6): 1154-61, 2000. [PUBMED Abstract]
  17. Oberlin O, Deley MC, Bui BN, et al.: Prognostic factors in localized Ewing's tumours and peripheral neuroectodermal tumours: the third study of the French Society of Paediatric Oncology (EW88 study). Br J Cancer 85 (11): 1646-54, 2001. [PUBMED Abstract]
  18. Yock TI, Krailo M, Fryer CJ, et al.: Local control in pelvic Ewing sarcoma: analysis from INT-0091--a report from the Children's Oncology Group. J Clin Oncol 24 (24): 3838-43, 2006. [PUBMED Abstract]
  19. Whelan J, Le Deley MC, Dirksen U, et al.: High-Dose Chemotherapy and Blood Autologous Stem-Cell Rescue Compared With Standard Chemotherapy in Localized High-Risk Ewing Sarcoma: Results of Euro-E.W.I.N.G.99 and Ewing-2008. J Clin Oncol : JCO2018782516, 2018. [PUBMED Abstract]
  20. Bramer JA, Abudu AA, Grimer RJ, et al.: Do pathological fractures influence survival and local recurrence rate in bony sarcomas? Eur J Cancer 43 (13): 1944-51, 2007. [PUBMED Abstract]
  21. Krasin MJ, Rodriguez-Galindo C, Billups CA, et al.: Definitive irradiation in multidisciplinary management of localized Ewing sarcoma family of tumors in pediatric patients: outcome and prognostic factors. Int J Radiat Oncol Biol Phys 60 (3): 830-8, 2004. [PUBMED Abstract]
  22. Rombi B, DeLaney TF, MacDonald SM, et al.: Proton radiotherapy for pediatric Ewing's sarcoma: initial clinical outcomes. Int J Radiat Oncol Biol Phys 82 (3): 1142-8, 2012. [PUBMED Abstract]
  23. Fuchs B, Valenzuela RG, Sim FH: Pathologic fracture as a complication in the treatment of Ewing's sarcoma. Clin Orthop (415): 25-30, 2003. [PUBMED Abstract]
  24. Schuck A, Ahrens S, Konarzewska A, et al.: Hemithorax irradiation for Ewing tumors of the chest wall. Int J Radiat Oncol Biol Phys 54 (3): 830-8, 2002. [PUBMED Abstract]
  25. Kuttesch JF Jr, Wexler LH, Marcus RB, et al.: Second malignancies after Ewing's sarcoma: radiation dose-dependency of secondary sarcomas. J Clin Oncol 14 (10): 2818-25, 1996. [PUBMED Abstract]
  26. Le Deley MC, Paulussen M, Lewis I, et al.: Cyclophosphamide compared with ifosfamide in consolidation treatment of standard-risk Ewing sarcoma: results of the randomized noninferiority Euro-EWING99-R1 trial. J Clin Oncol 32 (23): 2440-8, 2014. [PUBMED Abstract]

Treatment of Metastatic Ewing Sarcoma

Metastases at diagnosis are detected in approximately 25% of patients.[1] The prognosis of patients with metastatic disease is poor. Current therapies for patients who present with metastatic disease achieve 6-year event-free survival (EFS) of approximately 28% and overall survival (OS) of approximately 30%.[2,3] For patients with lung/pleural metastases only, 6-year EFS is approximately 40% when utilizing bilateral lung irradiation.[2,4] In contrast, patients with bone/bone marrow metastases have a 4-year EFS of approximately 28% and patients with combined lung and bone/bone marrow metastases have a 4-year EFS of approximately 14%.[4,5]
The following factors independently predict a poor outcome in patients presenting with metastatic disease:[3]
  • Age older than 14 years.
  • Primary tumor volume of more than 200 mL.
  • More than one bone metastatic site.
  • Bone marrow metastases.
  • Additional lung metastases.

Standard Treatment Options for Metastatic Ewing Sarcoma

Standard treatment options for metastatic Ewing sarcoma include the following:
  1. Chemotherapy.
  2. Surgery.
  3. Radiation therapy.

Chemotherapy

Standard treatment for patients with metastatic Ewing sarcoma utilizing alternating vincristine, doxorubicin, cyclophosphamide, and ifosfamide/etoposide combined with adequate local-control measures applied to both primary and metastatic sites often results in complete or partial responses; however, the overall cure rate is 20%.[5-7]
The following chemotherapy regimens have not shown benefit:
  • In the Intergroup Ewing Sarcoma Study, patients with metastatic disease showed no benefit from the addition of ifosfamide and etoposide to a standard regimen of vincristine, doxorubicin, cyclophosphamide, and dactinomycin.[7]
  • In another Intergroup study, increasing dose intensity of cyclophosphamide, ifosfamide, and doxorubicin did not improve outcome compared with regimens utilizing standard-dose intensity. This regimen increased toxicity and risk of second malignancy without improving EFS or OS.[2]
  • Intensification of ifosfamide to 2.8 g/m2 per day for 5 days did not improve outcome when administered with standard chemotherapy in patients with newly diagnosed metastatic Ewing sarcoma.[8][Level of evidence: 3iiiDi]

Surgery and radiation therapy

Systematic use of surgery and radiation therapy for metastatic sites may improve overall outcome in patients with extrapulmonary metastases.
Evidence (surgery and radiation therapy):
  1. In a retrospective data analysis of 120 patients with multifocal metastatic Ewing sarcoma, patients receiving local treatment of both primary tumor and metastases had a better outcome than patients receiving local treatment of primary tumor only or with no local treatment (3-year EFS, 39% vs. 17% and 14%, P < .001).[9]
  2. A similar trend for better outcome with irradiation of all sites of metastatic disease was seen in three retrospective analyses of smaller groups of patients receiving radiation therapy to all tumor sites.[10-12]
    These results must be interpreted with caution. The patients who received local-control therapy to all known sites of metastatic disease were selected by the treating investigator, not randomly assigned. Patients with so many metastases that radiation to all sites would result in bone marrow failure were not selected to receive radiation to all sites of metastatic disease. Patients who did not achieve control of the primary tumor did not go on to have local control of all sites of metastatic disease. There was a selection bias such that while all patients in these reports had multiple sites of metastatic disease, the patients who had surgery and/or radiation therapy to all sites of clinically detectable metastatic disease had better responses to systemic therapy and fewer sites of metastasis than did patients who did not undergo similar therapy of metastatic sites.
Radiation therapy, delivered in a setting in which stringent planning techniques are applied by those experienced in the treatment of Ewing sarcoma, should be considered. Such an approach will result in local control of tumor with acceptable morbidity in most patients.[13]
The radiation dose depends on the metastatic site of disease:
  • Bone and soft tissue. Stereotactic body radiation therapy has been used to treat metastatic sites in bone and soft tissue. The median total curative/definitive stereotactic body radiation therapy dose delivered was 40 Gy in five fractions (range, 30–60 Gy in 3–10 fractions). The median total palliative stereotactic body radiation therapy dose delivered was 40 Gy in five fractions (range, 16–50 Gy in 1–10 fractions). These short-course regimens with large-dose fractions are biologically equivalent to higher doses delivered with smaller-dose fractions given over longer treatment courses.[14][Level of evidence: 3iiiC]
  • Pulmonary. For all patients with pulmonary metastases, whole-lung irradiation should be considered, even if complete resolution of overt pulmonary metastatic disease has been achieved with chemotherapy.[4,5,15] Radiation doses are modulated based on the amount of lung to be irradiated and on pulmonary function. Doses between 12 Gy and 15 Gy are generally used if whole lungs are treated.

Other therapies

More intensive therapies, many of which incorporate high-dose chemotherapy with or without total-body irradiation in conjunction with stem cell support, have not shown improvement in EFS rates for patients with bone and/or bone marrow metastases.[2,3,10,16-18]; [19][Level of evidence: 3iiiDi] (Refer to the High-Dose Therapy With Stem Cell Rescue for Ewing Sarcoma section of this summary for more information.)
  • High-dose chemotherapy with stem cell support. One of the largest studies was the EURO-EWING-INTERGROUP-EE99 R3 trial that enrolled 281 patients with primary disseminated metastatic Ewing sarcoma. Patients were treated with six cycles of vincristine, ifosfamide, doxorubicin, and etoposide followed by high-dose therapy and autologous stem cell transplant and demonstrated a 3-year EFS of 27% and OS of 34%. Factors such as the presence and number of bone lesions, primary tumor volume greater than 200 mL, age older than 14 years, additional pulmonary metastases, and bone marrow involvement were identified as independent prognostic factors.[3][Level of evidence: 3iiDi] The role of high-dose therapy with busulfan-melphalan (BuMel) followed by stem cell rescue was investigated in the prospective, randomized EURO-EWING-INTERGROUP-EE99 (NCT00020566) trial. Among patients with isolated pulmonary metastases, there was no difference in 3-year EFS (55.7% with BuMel vs. 50.3% with continued chemotherapy and whole-lung radiation therapy; P = .21).[20]
  • Melphalan. Melphalan, at nonmyeloablative doses, proved to be an active agent in an upfront window study for patients with metastatic disease at diagnosis; however, the cure rate remained extremely low.[21]
  • Irinotecan. Irinotecan was administered as a single agent in an upfront window for newly diagnosed metastatic Ewing sarcoma patients and showed modest activity (partial response in 5 of 24 patients).[22][Level of evidence: 3iiiDiv] Further investigation is needed to determine irinotecan dosing and combinations with other agents for patients with Ewing sarcoma.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
References
  1. Esiashvili N, Goodman M, Marcus RB Jr: Changes in incidence and survival of Ewing sarcoma patients over the past 3 decades: Surveillance Epidemiology and End Results data. J Pediatr Hematol Oncol 30 (6): 425-30, 2008. [PUBMED Abstract]
  2. Miser JS, Goldsby RE, Chen Z, et al.: Treatment of metastatic Ewing sarcoma/primitive neuroectodermal tumor of bone: evaluation of increasing the dose intensity of chemotherapy--a report from the Children's Oncology Group. Pediatr Blood Cancer 49 (7): 894-900, 2007. [PUBMED Abstract]
  3. Ladenstein R, Pötschger U, Le Deley MC, et al.: Primary disseminated multifocal Ewing sarcoma: results of the Euro-EWING 99 trial. J Clin Oncol 28 (20): 3284-91, 2010. [PUBMED Abstract]
  4. Paulussen M, Ahrens S, Craft AW, et al.: Ewing's tumors with primary lung metastases: survival analysis of 114 (European Intergroup) Cooperative Ewing's Sarcoma Studies patients. J Clin Oncol 16 (9): 3044-52, 1998. [PUBMED Abstract]
  5. Paulussen M, Ahrens S, Burdach S, et al.: Primary metastatic (stage IV) Ewing tumor: survival analysis of 171 patients from the EICESS studies. European Intergroup Cooperative Ewing Sarcoma Studies. Ann Oncol 9 (3): 275-81, 1998. [PUBMED Abstract]
  6. Pinkerton CR, Bataillard A, Guillo S, et al.: Treatment strategies for metastatic Ewing's sarcoma. Eur J Cancer 37 (11): 1338-44, 2001. [PUBMED Abstract]
  7. Miser JS, Krailo MD, Tarbell NJ, et al.: Treatment of metastatic Ewing's sarcoma or primitive neuroectodermal tumor of bone: evaluation of combination ifosfamide and etoposide--a Children's Cancer Group and Pediatric Oncology Group study. J Clin Oncol 22 (14): 2873-6, 2004. [PUBMED Abstract]
  8. Magnan H, Goodbody CM, Riedel E, et al.: Ifosfamide dose-intensification for patients with metastatic Ewing sarcoma. Pediatr Blood Cancer 62 (4): 594-7, 2015. [PUBMED Abstract]
  9. Haeusler J, Ranft A, Boelling T, et al.: The value of local treatment in patients with primary, disseminated, multifocal Ewing sarcoma (PDMES). Cancer 116 (2): 443-50, 2010. [PUBMED Abstract]
  10. Burdach S, Thiel U, Schöniger M, et al.: Total body MRI-governed involved compartment irradiation combined with high-dose chemotherapy and stem cell rescue improves long-term survival in Ewing tumor patients with multiple primary bone metastases. Bone Marrow Transplant 45 (3): 483-9, 2010. [PUBMED Abstract]
  11. Paulino AC, Mai WY, Teh BS: Radiotherapy in metastatic ewing sarcoma. Am J Clin Oncol 36 (3): 283-6, 2013. [PUBMED Abstract]
  12. Casey DL, Wexler LH, Meyers PA, et al.: Radiation for bone metastases in Ewing sarcoma and rhabdomyosarcoma. Pediatr Blood Cancer 62 (3): 445-9, 2015. [PUBMED Abstract]
  13. Donaldson SS, Torrey M, Link MP, et al.: A multidisciplinary study investigating radiotherapy in Ewing's sarcoma: end results of POG #8346. Pediatric Oncology Group. Int J Radiat Oncol Biol Phys 42 (1): 125-35, 1998. [PUBMED Abstract]
  14. Brown LC, Lester RA, Grams MP, et al.: Stereotactic body radiotherapy for metastatic and recurrent ewing sarcoma and osteosarcoma. Sarcoma 2014: 418270, 2014. [PUBMED Abstract]
  15. Spunt SL, McCarville MB, Kun LE, et al.: Selective use of whole-lung irradiation for patients with Ewing sarcoma family tumors and pulmonary metastases at the time of diagnosis. J Pediatr Hematol Oncol 23 (2): 93-8, 2001. [PUBMED Abstract]
  16. Meyers PA, Krailo MD, Ladanyi M, et al.: High-dose melphalan, etoposide, total-body irradiation, and autologous stem-cell reconstitution as consolidation therapy for high-risk Ewing's sarcoma does not improve prognosis. J Clin Oncol 19 (11): 2812-20, 2001. [PUBMED Abstract]
  17. Burdach S, Meyer-Bahlburg A, Laws HJ, et al.: High-dose therapy for patients with primary multifocal and early relapsed Ewing's tumors: results of two consecutive regimens assessing the role of total-body irradiation. J Clin Oncol 21 (16): 3072-8, 2003. [PUBMED Abstract]
  18. Thiel U, Wawer A, Wolf P, et al.: No improvement of survival with reduced- versus high-intensity conditioning for allogeneic stem cell transplants in Ewing tumor patients. Ann Oncol 22 (7): 1614-21, 2011. [PUBMED Abstract]
  19. Loschi S, Dufour C, Oberlin O, et al.: Tandem high-dose chemotherapy strategy as first-line treatment of primary disseminated multifocal Ewing sarcomas in children, adolescents and young adults. Bone Marrow Transplant 50 (8): 1083-8, 2015. [PUBMED Abstract]
  20. Whelan J, Le Deley MC, Dirksen U, et al.: High-Dose Chemotherapy and Blood Autologous Stem-Cell Rescue Compared With Standard Chemotherapy in Localized High-Risk Ewing Sarcoma: Results of Euro-E.W.I.N.G.99 and Ewing-2008. J Clin Oncol : JCO2018782516, 2018. [PUBMED Abstract]
  21. Luksch R, Grignani G, Fagioli F, et al.: Response to melphalan in up-front investigational window therapy for patients with metastatic Ewing's family tumours. Eur J Cancer 43 (5): 885-90, 2007. [PUBMED Abstract]
  22. Morland B, Platt K, Whelan JS: A phase II window study of irinotecan (CPT-11) in high risk Ewing sarcoma: a Euro-E.W.I.N.G. study. Pediatr Blood Cancer 61 (3): 442-5, 2014. [PUBMED Abstract]

Treatment of Recurrent Ewing Sarcoma

Recurrence of Ewing sarcoma is most common within 2 years of initial diagnosis (approximately 80%).[1,2] However, late relapses occurring more than 5 years from initial diagnosis are more common in Ewing sarcoma (13%; 95% confidence interval, 9.4%–16.5%) than in other pediatric solid tumors.[3] An analysis of the Surveillance, Epidemiology, and End Results database identified 1,351 patients who survived more than 60 months from diagnosis.[4] Of these patients, 209 died, with 144 of the deaths (69%) attributed to recurrent, progressive Ewing sarcoma. Black race, male sex, older age at initial diagnosis, and primary tumors of the pelvis and axial skeleton were associated with a higher risk of late death. This analysis covered the period from 1973 to 2013, and the 1,351 patients represented only 38% of the patients in the original sample, which reflects the inferior treatment outcomes from the earlier era. It is possible that patients who reach the 5-year point after more contemporary treatment may not recapitulate this experience.
The overall prognosis for patients with recurrent Ewing sarcoma is poor; 5-year survival after recurrence is approximately 10% to 15%.[2,5,6]; [1][Level of evidence: 3iiA]
Prognostic factors include the following:
  • Time to recurrence. Time to recurrence is the most important prognostic factor. Patients whose Ewing sarcoma recurred more than 2 years from initial diagnosis had a 5-year survival of 30% versus 7% for patients whose Ewing sarcoma recurred within 2 years.[1,2]
  • Local and distant recurrence. Patients with both local recurrence and distant metastases have a worse outcome than do patients with either isolated local recurrence or metastatic recurrence alone.[1,2]
  • Isolated pulmonary recurrence. Isolated pulmonary recurrence was not an important prognostic factor in a North American series.[1] In the Italian/Scandinavian experience, younger age, longer disease-free interval, and lung-only recurrence were associated with longer progression-free survival (PFS) after recurrence. In this experience, patients with Ewing sarcoma that recurred after initial therapy, which included high-dose therapy with autologous stem cell rescue, were less likely to achieve a second complete remission.[7][Level of evidence: 3iiDiii]

Treatment Options for Recurrent Ewing Sarcoma

The selection of treatment for patients with recurrent disease depends on many factors, including the following:
  • Site of recurrence.
  • Previous treatment.
  • Individual patient considerations.
There is no standardized second-line treatment for relapsed or refractory Ewing sarcoma.
Treatment options for recurrent Ewing sarcoma include the following:
  1. Chemotherapy.
  2. Radiation therapy.
  3. High-dose chemotherapy with stem cell support.
  4. Other therapies.

Chemotherapy

Combinations of chemotherapy, such as cyclophosphamide and topotecan or irinotecan and temozolomide with or without vincristine, are active in recurrent Ewing sarcoma and can be considered for these patients.[8-13]
Table 5. Results from Studies that Used Cyclophosphamide and Topotecan Regimens to Treat Patients With Relapsed and/or Refractory Ewing Sarcoma
ENLARGE
Study ReferenceTrial Phase (Total No. of Patients)Median Age (Range) (y)CR/PRRRCyclophosphamide (mg/m2)/Topotecan (mg/m2) × dOther Agents
II = phase II trial; CR = complete response; PR = partial response; R = retrospective; RR = objective response rate; VCR = vincristine.
Saylors et al.[8]II (17)13.8 (1–21)1/329%250 × 5/0.75 × 5None
Hunold et al.[10]R (54)17.4 (3–49)0/1630%250 × 5/0.75 × 5None
Farhat et al.[14]R (14)11 (2–19)0/321%250 × 5/0.75 × 5None
Kebudi et al.[15]R (14)13 (3–16)2/550%250 × 5/0.75 × 5VCR
These studies were retrospective, not prospective; prospective trials with clearly defined eligibility cohorts and intent-to-treat analyses are lacking. When combined, these studies accrued 99 patients and observed 3 complete remissions and 27 partial remissions. The objective response rate was 30%.
Table 6. Results from Studies that Used Temozolomide and Irinotecan Regimens to Treat Patients With Relapsed and/or Refractory Ewing Sarcoma
ENLARGE
Study ReferenceTrial Phase (Total No. of Patients)Median Age (Range) (y)CR/PRRRTemozolomide (mg/m2)/Irinotecan (mg/m2) × d × wkOther Agents
I = phase I trial; BEV = bevacizumab; CR = complete response; IV = intravenous; PO = oral; PR = partial response; R = retrospective trial; RR = objective response rate; TMS = temsirolimus; UK = unknown; VCR = vincristine.
Wagner et al.[11]R (16)18 (7–33)1/329%100 × 5/IV 10–20 × 5 × 2None
Casey et al.[12]R (19)19.5 (2–40)5/763%100 × 5/IV 20 × 5 × 2None
Hernandez-Marques et al.[16]R (8)13 (6–18)0/337%80–100 × 5/IV 10–20 × 5 × 2None
Raciborska et al.[13]R (22)14.35/754%125 × 5/IV 50 × 5VCR
McKnall-Knapp et al.[17]I (1)N/A0/1100%100 × 5/IV 20 × 5 × 2VCR
Wagner et al.[18]I (5)(<21)1/140%100–150 × 5/PO 35–90 × 5VCR
Wagner et al.[19]I (2)20, 221/1100%150 × 5/PO 90 × 5VCR, BEV
Bagatell et al.[20]I (7)(<21)0/114%100–150 × 5/PO 50–90 × 5TMS
Kurucu et al.[21]R (20)14 (1–18)UK55%100 × 5/IV 20 × 5 × 2None
Anderson et al.[22]R (25)157/964%100 × 5/IV 10 × 5 × 2None
Palmerini et al.[23]R (51)21 (3–65)5/1234%100 × 5/IV 40 × 5None
Most of these studies were retrospective, not prospective; there are only four prospective trials with well-defined eligibility cohorts and report by intent to treat. In addition, there is significant variability among the reports in doses and dose schedules of irinotecan and temozolomide and the use of additional agents. When combined, these studies accrued 176 patients and observed 18 complete remissions and 56 partial remissions. The objective response rate was 42%.
Evidence (chemotherapy):
  1. One phase II study of topotecan and cyclophosphamide showed a response in 6 of 17 patients with Ewing sarcoma; 16 of 49 patients had a clinical response in a similar trial in Germany.[8,10]
  2. Several retrospective studies have demonstrated the activity of temozolomide and irinotecan in patients with recurrent Ewing sarcoma.[12,21,23]
    In the largest retrospective multicenter study of the combination of temozolomide and irinotecan in patients with recurrent and primary refractory Ewing sarcoma, 51 patients (66% of patients were aged ≥18 years; median age, 21 years) were treated with temozolomide (100 mg/m2/day orally) and irinotecan (40 mg/m2/day intravenously), on days 1 to 5, every 21 days. Twenty-five percent of the patients were in first relapse/progression, while the remainder of the patients were in second or greater relapse/progression.[23]
    • Five patients (10%) achieved complete remissions, 12 patients (24%) achieved partial remissions, and 19 patients (37%) had stable disease, with a disease control rate of 71%.
    • On univariate analysis, the only two factors predicting response to temozolomide and irinotecan in PFS were performance score and lactate dehydrogenase levels.
    • Two patients were rechallenged with temozolomide and irinotecan after disease remission was induced. Both patients achieved partial remissions on rechallenge; one patient's remission lasted at least 15 cycles and the other remission lasted 22 cycles.[23]
  3. The combination of docetaxel either with gemcitabine or irinotecan has achieved objective responses in relapsed Ewing sarcoma.[24][Level of evidence: 3iiA]; [25,26][Level of evidence: 3iiiDiv]
  4. High-dose ifosfamide (3 g/m2 per day for 5 days = 15 g/m2) has shown activity in patients whose Ewing sarcoma recurred after therapy that included standard ifosfamide (1.8 g/m2 per day for 5 days = 9 g/m2).[27][Level of evidence: 3iiiDiv]

Radiation therapy

Radiation therapy to bone lesions may provide palliation, although radical resection may improve outcome.[2] Patients with pulmonary metastases who have not received radiation therapy to the lungs should be considered for whole-lung irradiation.[28] Residual disease in the lung may be surgically removed.

High-dose chemotherapy with stem cell support

Aggressive attempts to control the disease, including myeloablative regimens, have been used, but there is no evidence at this time to conclude that myeloablative therapy is superior to standard chemotherapy.[29,30]; [31][Level of evidence: 3iiA]; [32][Level of evidence: 3iiiDiii]
Most published reports about the use of high-dose therapy and stem cell support for patients with high-risk Ewing sarcoma have significant flaws in methodology. The most common error is the comparison of this high-risk group with an inappropriate control group. Patients with Ewing sarcoma at high risk of treatment failure who received high-dose therapy are compared with patients who did not receive high-dose therapy. Patients who undergo high-dose therapy must respond to systemic therapy, remain alive and respond to treatment long enough to reach the time at which stem cell therapy can be applied, be free of comorbid toxicity that precludes high-dose therapy, and have an adequate stem cell collection. Patients who undergo high-dose therapy and stem cell support are a highly selected group; comparing this patient group with all patients with high-risk Ewing sarcoma is inappropriate and leads to the erroneous conclusion that this strategy improves outcome.
Surveys of patients undergoing allogeneic stem cell transplantation (SCT) for recurrent Ewing sarcoma did not show improved event-free survival when compared with autologous SCT and was associated with a higher complication rate.[29,33,34]

Other therapies

Other therapies that have been studied in the treatment of recurrent Ewing sarcoma include the following:
  • Monoclonal antibody therapy. Monoclonal antibodies against the insulin-like growth factor 1 receptor (IGF1R) are reported to produce objective responses in metastatic recurrent Ewing sarcoma in roughly 10% of cases.[35-38][Level of evidence: 3iiDiv] In these studies, it was suggested that time-to-progression was prolonged compared with historical controls. Objective responses have been reported in studies combining the mTOR inhibitor temsirolimus with an IGF1R antibody. Stratification by IGF1R expression by immunohistochemistry in one of the studies did not predict clinical outcome in patients with Ewing sarcoma.[39,40] Further studies are needed to identify patients who are likely to benefit from IGF1R therapy.
  • Immunotherapy. Immunotherapy with antigen-specific T cells is being studied in patients with Ewing sarcoma because immune-mediated killing does not rely on pathways used by conventional therapies to which such tumors are often resistant. Several potential chimeric antigen receptors target antigens that have been identified for Ewing sarcomas. These include HER2 (human epidermal growth factor receptor 2),[41] GD2,[42] CD99 (MIC2 antigens),[43] and STEAP1 (six-transmembrane epithelial antigens of the prostate).[44] Some are in early-phase testing in sarcoma patients.[41] Treatment with single-agent checkpoint inhibitors in patients with Ewing sarcoma has demonstrated limited efficacy.[45,46]

Treatment Options Under Clinical Evaluation for Recurrent Ewing Sarcoma

Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, refer to the ClinicalTrials.gov website.
The following are examples of national and/or institutional clinical trials that are currently being conducted:
  • APEC1621 (NCT03155620) (Pediatric MATCH: Targeted Therapy Directed by Genetic Testing in Treating Pediatric Patients with Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphomas, or Histiocytic Disorders): NCI–Children's Oncology Group Pediatric Molecular Analysis for Therapeutic Choice (MATCH), referred to as Pediatric MATCH, will match targeted agents with specific molecular changes identified using a next-generation sequencing targeted assay of more than 4,000 different mutations across more than 160 genes in refractory and recurrent solid tumors. Children and adolescents aged 1 to 21 years are eligible for the trial.
    Tumor tissue from progressive or recurrent disease must be available for molecular characterization. Patients with tumors that have molecular variants addressed by treatment arms included in the trial will be offered treatment on Pediatric MATCH. Additional information can be obtained on the NCI website and ClinicalTrials.gov website.
  • ADVL1622 (NCT02867592) (Cabozantinib-S-Malate in Treating Younger Patients with Recurrent, Refractory, or Newly Diagnosed Sarcomas, Wilms Tumor, or Other Rare Tumors): This is an open-label, two-stage, phase II trial of cabozantinib in selective solid tumors, including Ewing sarcoma. Cabozantinib is an oral small molecule inhibitor of multiple tyrosine kinases, including MET, VEGFR2, and RET, which are potential therapeutic targets in many pediatric and adult solid tumors.
  • ADVL1412 (NCT02304458) (Nivolumab With or Without Ipilimumab in Treating Younger Patients With Recurrent or Refractory Solid Tumors or Sarcomas): Nivolumab is an anti–programmed death receptor-1 antibody and checkpoint inhibitor that is being studied in combination with ipilimumab in treating patients with relapsed sarcoma, including patients with Ewing sarcoma.
  • ADVL1615 (NCT03323034) (Pevonedistat, Irinotecan Hydrochloride, and Temozolomide in Treating Patients With Recurrent or Refractory Solid Tumors or Lymphoma): This is a phase I study of pevonedistat in combination with temozolomide and irinotecan. Pevonedistat is a novel first-in-class Nedd8 activating enzyme (NAE) inhibitor that blocks the degradation of a subset of proteins that would normally be degraded by the 26S proteasome. Pevonedistat is more specific than previous proteasome inhibitors because it blocks the degradation of cullin-RING ligases, narrowing the targets to only a handful of key regulatory proteins important in cell survival. Preclinical, antitumor activity has been observed in Ewing sarcoma.
  • TK216-01 (NCT02657005) (TK216 in Patients With Relapsed or Refractory Ewing Sarcoma): TK216 is a novel agent that directly targets the EWSR1-FLI1 interaction with a partner protein RNA helicase A and, in turn, downregulates transcriptional activity of the EWSR1-FLI1 fusion protein.[47,48] This is a first-in-human study of TK216 in patients with Ewing sarcoma. The study is designed to establish initial safety and efficacy data to assess the potential of TK216 for further development.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
References
  1. Leavey PJ, Mascarenhas L, Marina N, et al.: Prognostic factors for patients with Ewing sarcoma (EWS) at first recurrence following multi-modality therapy: A report from the Children's Oncology Group. Pediatr Blood Cancer 51 (3): 334-8, 2008. [PUBMED Abstract]
  2. Stahl M, Ranft A, Paulussen M, et al.: Risk of recurrence and survival after relapse in patients with Ewing sarcoma. Pediatr Blood Cancer 57 (4): 549-53, 2011. [PUBMED Abstract]
  3. Wasilewski-Masker K, Liu Q, Yasui Y, et al.: Late recurrence in pediatric cancer: a report from the Childhood Cancer Survivor Study. J Natl Cancer Inst 101 (24): 1709-20, 2009. [PUBMED Abstract]
  4. Davenport JR, Vo KT, Goldsby R, et al.: Conditional Survival and Predictors of Late Death in Patients With Ewing Sarcoma. Pediatr Blood Cancer 63 (6): 1091-5, 2016. [PUBMED Abstract]
  5. Barker LM, Pendergrass TW, Sanders JE, et al.: Survival after recurrence of Ewing's sarcoma family of tumors. J Clin Oncol 23 (19): 4354-62, 2005. [PUBMED Abstract]
  6. Bacci G, Longhi A, Ferrari S, et al.: Pattern of relapse in 290 patients with nonmetastatic Ewing's sarcoma family tumors treated at a single institution with adjuvant and neoadjuvant chemotherapy between 1972 and 1999. Eur J Surg Oncol 32 (9): 974-9, 2006. [PUBMED Abstract]
  7. Ferrari S, Luksch R, Hall KS, et al.: Post-relapse survival in patients with Ewing sarcoma. Pediatr Blood Cancer 62 (6): 994-9, 2015. [PUBMED Abstract]
  8. Saylors RL 3rd, Stine KC, Sullivan J, et al.: Cyclophosphamide plus topotecan in children with recurrent or refractory solid tumors: a Pediatric Oncology Group phase II study. J Clin Oncol 19 (15): 3463-9, 2001. [PUBMED Abstract]
  9. McTiernan A, Driver D, Michelagnoli MP, et al.: High dose chemotherapy with bone marrow or peripheral stem cell rescue is an effective treatment option for patients with relapsed or progressive Ewing's sarcoma family of tumours. Ann Oncol 17 (8): 1301-5, 2006. [PUBMED Abstract]
  10. Hunold A, Weddeling N, Paulussen M, et al.: Topotecan and cyclophosphamide in patients with refractory or relapsed Ewing tumors. Pediatr Blood Cancer 47 (6): 795-800, 2006. [PUBMED Abstract]
  11. Wagner LM, McAllister N, Goldsby RE, et al.: Temozolomide and intravenous irinotecan for treatment of advanced Ewing sarcoma. Pediatr Blood Cancer 48 (2): 132-9, 2007. [PUBMED Abstract]
  12. Casey DA, Wexler LH, Merchant MS, et al.: Irinotecan and temozolomide for Ewing sarcoma: the Memorial Sloan-Kettering experience. Pediatr Blood Cancer 53 (6): 1029-34, 2009. [PUBMED Abstract]
  13. Raciborska A, Bilska K, Drabko K, et al.: Vincristine, irinotecan, and temozolomide in patients with relapsed and refractory Ewing sarcoma. Pediatr Blood Cancer 60 (10): 1621-5, 2013. [PUBMED Abstract]
  14. Farhat R, Raad R, Khoury NJ, et al.: Cyclophosphamide and topotecan as first-line salvage therapy in patients with relapsed ewing sarcoma at a single institution. J Pediatr Hematol Oncol 35 (5): 356-60, 2013. [PUBMED Abstract]
  15. Kebudi R, Cakir FB, Gorgun O, et al.: A modified protocol with vincristine, topotecan, and cyclophosphamide for recurrent/progressive ewing sarcoma family tumors. Pediatr Hematol Oncol 30 (3): 170-7, 2013. [PUBMED Abstract]
  16. Hernández-Marqués C, Lassaletta-Atienza A, Ruiz Hernández A, et al.: [Irinotecan plus temozolomide in refractory or relapsed pediatric solid tumors]. An Pediatr (Barc) 79 (2): 68-74, 2013. [PUBMED Abstract]
  17. McNall-Knapp RY, Williams CN, Reeves EN, et al.: Extended phase I evaluation of vincristine, irinotecan, temozolomide, and antibiotic in children with refractory solid tumors. Pediatr Blood Cancer 54 (7): 909-15, 2010. [PUBMED Abstract]
  18. Wagner LM, Perentesis JP, Reid JM, et al.: Phase I trial of two schedules of vincristine, oral irinotecan, and temozolomide (VOIT) for children with relapsed or refractory solid tumors: a Children's Oncology Group phase I consortium study. Pediatr Blood Cancer 54 (4): 538-45, 2010. [PUBMED Abstract]
  19. Wagner L, Turpin B, Nagarajan R, et al.: Pilot study of vincristine, oral irinotecan, and temozolomide (VOIT regimen) combined with bevacizumab in pediatric patients with recurrent solid tumors or brain tumors. Pediatr Blood Cancer 60 (9): 1447-51, 2013. [PUBMED Abstract]
  20. Bagatell R, Norris R, Ingle AM, et al.: Phase 1 trial of temsirolimus in combination with irinotecan and temozolomide in children, adolescents and young adults with relapsed or refractory solid tumors: a Children's Oncology Group Study. Pediatr Blood Cancer 61 (5): 833-9, 2014. [PUBMED Abstract]
  21. Kurucu N, Sari N, Ilhan IE: Irinotecan and temozolamide treatment for relapsed Ewing sarcoma: a single-center experience and review of the literature. Pediatr Hematol Oncol 32 (1): 50-9, 2015. [PUBMED Abstract]
  22. Anderson P, Kopp L, Anderson N, et al.: Novel bone cancer drugs: investigational agents and control paradigms for primary bone sarcomas (Ewing's sarcoma and osteosarcoma). Expert Opin Investig Drugs 17 (11): 1703-15, 2008. [PUBMED Abstract]
  23. Palmerini E, Jones RL, Setola E, et al.: Irinotecan and temozolomide in recurrent Ewing sarcoma: an analysis in 51 adult and pediatric patients. Acta Oncol 57 (7): 958-964, 2018. [PUBMED Abstract]
  24. Fox E, Patel S, Wathen JK, et al.: Phase II study of sequential gemcitabine followed by docetaxel for recurrent Ewing sarcoma, osteosarcoma, or unresectable or locally recurrent chondrosarcoma: results of Sarcoma Alliance for Research Through Collaboration Study 003. Oncologist 17 (3): 321, 2012. [PUBMED Abstract]
  25. Mora J, Cruz CO, Parareda A, et al.: Treatment of relapsed/refractory pediatric sarcomas with gemcitabine and docetaxel. J Pediatr Hematol Oncol 31 (10): 723-9, 2009. [PUBMED Abstract]
  26. Yoon JH, Kwon MM, Park HJ, et al.: A study of docetaxel and irinotecan in children and young adults with recurrent or refractory Ewing sarcoma family of tumors. BMC Cancer 14: 622, 2014. [PUBMED Abstract]
  27. Ferrari S, del Prever AB, Palmerini E, et al.: Response to high-dose ifosfamide in patients with advanced/recurrent Ewing sarcoma. Pediatr Blood Cancer 52 (5): 581-4, 2009. [PUBMED Abstract]
  28. Rodriguez-Galindo C, Billups CA, Kun LE, et al.: Survival after recurrence of Ewing tumors: the St Jude Children's Research Hospital experience, 1979-1999. Cancer 94 (2): 561-9, 2002. [PUBMED Abstract]
  29. Burdach S, van Kaick B, Laws HJ, et al.: Allogeneic and autologous stem-cell transplantation in advanced Ewing tumors. An update after long-term follow-up from two centers of the European Intergroup study EICESS. Stem-Cell Transplant Programs at Düsseldorf University Medical Center, Germany and St. Anna Kinderspital, Vienna, Austria. Ann Oncol 11 (11): 1451-62, 2000. [PUBMED Abstract]
  30. Burdach S, Meyer-Bahlburg A, Laws HJ, et al.: High-dose therapy for patients with primary multifocal and early relapsed Ewing's tumors: results of two consecutive regimens assessing the role of total-body irradiation. J Clin Oncol 21 (16): 3072-8, 2003. [PUBMED Abstract]
  31. Rasper M, Jabar S, Ranft A, et al.: The value of high-dose chemotherapy in patients with first relapsed Ewing sarcoma. Pediatr Blood Cancer 61 (8): 1382-6, 2014. [PUBMED Abstract]
  32. Gardner SL, Carreras J, Boudreau C, et al.: Myeloablative therapy with autologous stem cell rescue for patients with Ewing sarcoma. Bone Marrow Transplant 41 (10): 867-72, 2008. [PUBMED Abstract]
  33. Gilman AL, Oesterheld J: Myeloablative chemotherapy with autologous stem cell rescue for Ewing sarcoma. Bone Marrow Transplant 42 (11): 761; author reply 763, 2008. [PUBMED Abstract]
  34. Eapen M: Response to Dr Gilman. Bone Marrow Transplant 42 (11): 763, 2008.
  35. Malempati S, Weigel B, Ingle AM, et al.: Phase I/II trial and pharmacokinetic study of cixutumumab in pediatric patients with refractory solid tumors and Ewing sarcoma: a report from the Children's Oncology Group. J Clin Oncol 30 (3): 256-62, 2012. [PUBMED Abstract]
  36. Juergens H, Daw NC, Geoerger B, et al.: Preliminary efficacy of the anti-insulin-like growth factor type 1 receptor antibody figitumumab in patients with refractory Ewing sarcoma. J Clin Oncol 29 (34): 4534-40, 2011. [PUBMED Abstract]
  37. Pappo AS, Patel SR, Crowley J, et al.: R1507, a monoclonal antibody to the insulin-like growth factor 1 receptor, in patients with recurrent or refractory Ewing sarcoma family of tumors: results of a phase II Sarcoma Alliance for Research through Collaboration study. J Clin Oncol 29 (34): 4541-7, 2011. [PUBMED Abstract]
  38. Tap WD, Demetri G, Barnette P, et al.: Phase II study of ganitumab, a fully human anti-type-1 insulin-like growth factor receptor antibody, in patients with metastatic Ewing family tumors or desmoplastic small round cell tumors. J Clin Oncol 30 (15): 1849-56, 2012. [PUBMED Abstract]
  39. Naing A, LoRusso P, Fu S, et al.: Insulin growth factor-receptor (IGF-1R) antibody cixutumumab combined with the mTOR inhibitor temsirolimus in patients with refractory Ewing's sarcoma family tumors. Clin Cancer Res 18 (9): 2625-31, 2012. [PUBMED Abstract]
  40. Schwartz GK, Tap WD, Qin LX, et al.: Cixutumumab and temsirolimus for patients with bone and soft-tissue sarcoma: a multicentre, open-label, phase 2 trial. Lancet Oncol 14 (4): 371-82, 2013. [PUBMED Abstract]
  41. Ahmed N, Brawley VS, Hegde M, et al.: Human Epidermal Growth Factor Receptor 2 (HER2) -Specific Chimeric Antigen Receptor-Modified T Cells for the Immunotherapy of HER2-Positive Sarcoma. J Clin Oncol 33 (15): 1688-96, 2015. [PUBMED Abstract]
  42. Pule MA, Savoldo B, Myers GD, et al.: Virus-specific T cells engineered to coexpress tumor-specific receptors: persistence and antitumor activity in individuals with neuroblastoma. Nat Med 14 (11): 1264-70, 2008. [PUBMED Abstract]
  43. Scotlandi K, Baldini N, Cerisano V, et al.: CD99 engagement: an effective therapeutic strategy for Ewing tumors. Cancer Res 60 (18): 5134-42, 2000. [PUBMED Abstract]
  44. Grunewald TG, Diebold I, Esposito I, et al.: STEAP1 is associated with the invasive and oxidative stress phenotype of Ewing tumors. Mol Cancer Res 10 (1): 52-65, 2012. [PUBMED Abstract]
  45. D'Angelo SP, Mahoney MR, Van Tine BA, et al.: Nivolumab with or without ipilimumab treatment for metastatic sarcoma (Alliance A091401): two open-label, non-comparative, randomised, phase 2 trials. Lancet Oncol 19 (3): 416-426, 2018. [PUBMED Abstract]
  46. Tawbi HA, Burgess M, Bolejack V, et al.: Pembrolizumab in advanced soft-tissue sarcoma and bone sarcoma (SARC028): a multicentre, two-cohort, single-arm, open-label, phase 2 trial. Lancet Oncol 18 (11): 1493-1501, 2017. [PUBMED Abstract]
  47. Erkizan HV, Kong Y, Merchant M, et al.: A small molecule blocking oncogenic protein EWS-FLI1 interaction with RNA helicase A inhibits growth of Ewing's sarcoma. Nat Med 15 (7): 750-6, 2009. [PUBMED Abstract]
  48. Lamhamedi-Cherradi SE, Menegaz BA, Ramamoorthy V, et al.: An Oral Formulation of YK-4-279: Preclinical Efficacy and Acquired Resistance Patterns in Ewing Sarcoma. Mol Cancer Ther 14 (7): 1591-604, 2015. [PUBMED Abstract]

Undifferentiated Round Cell (Ewing-like) Sarcomas

Undifferentiated Round Cell Sarcomas With BCOR-CCNB3Rearrangements

Clinical presentation

Undifferentiated round cell sarcomas with BCOR-CCNB3 rearrangements account for about 5% of all EWSR1-negative rearranged sarcomas and more commonly affects males. More than 70% of cases occur in patients younger than 18 years (median age at diagnosis, 13–15 years).[1,2][Level of evidence: 3iiA] These tumors more commonly arise in the bones of the pelvis and extremities, and metastases are present in approximately 30% of cases.

Treatment of undifferentiated round cell sarcomas with BCOR-CCNB3rearrangements

When treated with Ewing sarcoma–like therapies, 75% of patients show significant treatment-associated pathologic responses. In one series of 36 cases, the 3-year and 5-year survival rates were 93% and 72%, respectively.[1][Level of evidence: 3iiA] In another series of 26 patients, the 5-year overall survival was 76.5%, and survival was better for patients who received induction therapy using an Ewing sarcoma–type regimen.[3][Level of evidence: 3iiA] Most of the tumors in these series arose in the bone.

Undifferentiated Round Cell Sarcomas With CIC-DUX4Rearrangements

Clinical presentation

Undifferentiated round cell sarcomas with CIC-DUX4 rearrangements most commonly affect young adults, with 50% of cases occurring between the ages of 21 and 40 years. In a series of 115 cases, the median age at diagnosis was 32 years, and 22% of cases occurred in patients younger than 18 years.[2,4] This entity more commonly affects males and usually originates from the soft tissues of the trunk and extremities.

Treatment of undifferentiated round cell sarcomas with CIC-DUX4rearrangements

In a series of 115 cases of CIC-rearranged round cell sarcomas, 57 patients had adequate follow-up information.[4] Nine patients presented with metastases, and 53% of patients with localized disease experienced a recurrence commonly involving the lung. Patients treated with neoadjuvant chemotherapy had an inferior survival compared with patients who were treated with up-front surgical resection; however, this difference might have been related to a larger tumor size at presentation in the former group. The 2-year and 5-year survival rates were 53% and 43%, respectively. These survival rates are significantly lower than the survival rates observed in patients with Ewing sarcoma. Further study is required to identify optimal treatments for this disease.
References
  1. Kao YC, Owosho AA, Sung YS, et al.: BCOR-CCNB3 Fusion Positive Sarcomas: A Clinicopathologic and Molecular Analysis of 36 Cases With Comparison to Morphologic Spectrum and Clinical Behavior of Other Round Cell Sarcomas. Am J Surg Pathol 42 (5): 604-615, 2018. [PUBMED Abstract]
  2. Machado I, Navarro S, Llombart-Bosch A: Ewing sarcoma and the new emerging Ewing-like sarcomas: (CIC and BCOR-rearranged-sarcomas). A systematic review. Histol Histopathol 31 (11): 1169-81, 2016. [PUBMED Abstract]
  3. Cohen-Gogo S, Cellier C, Coindre JM, et al.: Ewing-like sarcomas with BCOR-CCNB3 fusion transcript: a clinical, radiological and pathological retrospective study from the Société Française des Cancers de L'Enfant. Pediatr Blood Cancer 61 (12): 2191-8, 2014. [PUBMED Abstract]
  4. Antonescu CR, Owosho AA, Zhang L, et al.: Sarcomas With CIC-rearrangements Are a Distinct Pathologic Entity With Aggressive Outcome: A Clinicopathologic and Molecular Study of 115 Cases. Am J Surg Pathol 41 (7): 941-949, 2017. [PUBMED Abstract]

Changes to This Summary (08/15/2019)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.
General Information About Ewing Sarcoma
Added Ahmed et al. as reference 27.
Genomics of Ewing Sarcoma
Added text to state that undifferentiated small blue round cell sarcomas with the EWSR1-NFATc2 fusion have been studied with DNA methylation profiling; this revealed a homogeneous methylation cluster for these sarcomas with EWSR1-NFATc2 fusions, which clearly segregated them from the more common form of Ewing sarcoma with EWS-ETStranslocations (cited Koelsche et al. as reference 11).
Added text to state that some undifferentiated round cell sarcomas are characterized by paracentric inversion of chromosome X and a BCOR-CCNB3 rearrangement; alternative BCOR partners, including MAML3 and ZC3H7B, have also been reported. Despite clinical pathologic similarities to Ewing sarcoma, these tumors are biologically different by expression profiling and single-nucleotide polymorphism array analysis (cited Schaefer et al. as reference 16).
Added text to state that other undifferentiated round cell sarcomas are characterized by a CIC-DUX4 fusion resulting from a recurrent t(4;19) or t(10;19) and are the most common EWSR1-FUS fusion–negative undifferentiated round cell sarcomas (cited Antonescu et al. as reference 17).
Stage Information for Ewing Sarcoma
Added text to state that a single-institution retrospective review of 504 patients with Ewing sarcoma identified 12 patients with bone marrow metastasis. Only one patient was found to have bone marrow involvement without any other sites of metastatic disease, for an incidence of 1 per 367 in patients with clinically localized disease (cited Cesari et al. as reference 9).
Treatment Option Overview for Ewing Sarcoma
Revised text to state that for patients who undergo gross-total resection with microscopic residual disease, a radiation therapy dose of 50.4 Gy is indicated; for patients treated with primary radiation therapy, the radiation dose is 55.8 Gy.
Added Thoracic primary tumors as a new subsection.
Added text to state that only 40% of eligible patients were randomized in the EURO-EWING-INTERGROUP-EE99 trial.
Added text to state that the 3-year overall survival (OS) was 78.0% with busulfan-melphalan (BuMel) and 72.2% with continued chemotherapy in the EURO-EWING-INTERGROUP-EE99 trial.
Revised text to state that the probability for event-free survival (EFS) at 3 years for the favorable group was 76%, and OS at 3 years was 85%. Also revised text to state that for all patients with localized Ewing sarcoma, including patients with large primary tumors and patients with poor response to initial therapy treated on the COG-AEWS1031 trial, the 5-year probability for EFS was 73%, and the 5-year OS was 88%.
Revised Table 4 to include the cyclophosphamide equivalent doses in the EURO-EWING-INTERGROUP-EE99 and Children's Oncology Group trials.
Treatment of Localized Ewing Sarcoma
Added text to state that decisions regarding the optimal modality for local control for an individual patient involve several considerations, including the possibility of a complete resection with adequate margins after an initial period of systemic therapy, the predicted functional impact of a surgical procedure, the predicted morbidity after radiation therapy, and the possibility of increased risk of second malignant neoplasms after radiation therapy.
Added text to state that an analysis using propensity scoring to adjust for clinical features that may influence the preference for surgery only, radiation only, or combined surgery and radiation demonstrated that similar EFS rates are achieved with each mode of local therapy after propensity adjustment (cited DuBois et al. as reference 14).
Added text to state that only 40% of eligible patients were randomized in the EURO-EWING-INTERGROUP-EE99 trial.
Added text to state that the 3-year OS was 78.0% with BuMel and 72.2% with continued chemotherapy in the EURO-EWING-INTERGROUP-EE99 trial.
Revised text to state that the probability for EFS at 3 years for the favorable group was 76%, and OS at 3 years was 85%. Also revised text to state that for all patients with localized Ewing sarcoma, including patients with large primary tumors and patients with poor response to initial therapy treated on the COG-AEWS1031 trial, the 5-year probability for EFS was 73%, and the 5-year OS was 88%.
Treatment of Recurrent Ewing Sarcoma
Added text to state that the studies in Table 5 were retrospective, not prospective; prospective trials with clearly defined eligibility cohorts and intent-to-treat analyses are lacking.
Added text to state that most of the studies in Table 6 were retrospective, not prospective; there are only four prospective trials with well-defined eligibility cohorts and report by intent to treat. In addition, there is significant variability among the reports in doses and dose schedules of irinotecan and temozolomide and the use of additional agents.
Undifferentiated Round Cell (Ewing-like) Sarcomas
Added this new section.
This summary is written and maintained by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® - NCI's Comprehensive Cancer Database pages.

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of childhood Ewing sarcoma. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).
Board members review recently published articles each month to determine whether an article should:
  • be discussed at a meeting,
  • be cited with text, or
  • replace or update an existing article that is already cited.
Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.
The lead reviewers for Ewing Sarcoma Treatment are:
  • Holcombe Edwin Grier, MD
  • Andrea A. Hayes-Jordan, MD, FACS, FAAP (University of North Carolina - Chapel Hill School of Medicine)
  • Karen J. Marcus, MD (Dana-Farber Cancer Institute/Boston Children's Hospital)
  • Paul A. Meyers, MD (Memorial Sloan-Kettering Cancer Center)
  • Thomas A. Olson, MD (Aflac Cancer and Blood Disorders Center of Children's Healthcare of Atlanta - Egleston Campus)
  • Nita Louise Seibel, MD (National Cancer Institute)
Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

Levels of Evidence

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Pediatric Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

Permission to Use This Summary

PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as “NCI’s PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary].”
The preferred citation for this PDQ summary is:
PDQ® Pediatric Treatment Editorial Board. PDQ Ewing Sarcoma Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/bone/hp/ewing-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389480]
Images in this summary are used with permission of the author(s), artist, and/or publisher for use within the PDQ summaries only. Permission to use images outside the context of PDQ information must be obtained from the owner(s) and cannot be granted by the National Cancer Institute. Information about using the illustrations in this summary, along with many other cancer-related images, is available in Visuals Online, a collection of over 2,000 scientific images.

Disclaimer

Based on the strength of the available evidence, treatment options may be described as either “standard” or “under clinical evaluation.” These classifications should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on Cancer.gov on the Managing Cancer Care page.

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