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NCI/PDQ^® Health professionals: Ewing Sarcoma Treatment (PDQ®)

National Cancer Institute
Last Modified: November 26, 2012

TABLE OF CONTENTS

• General Information
  • Origin and Incidence of Ewing Sarcoma
  • Prognostic Factors for Ewing Sarcoma
    • Pretreatment factors
    • Treatment response factors to preoperative therapy

• Cellular Classification
  • Cytogenetic Changes in Ewing Sarcoma

• Stage Information

• Treatment Option Overview
  • Chemotherapy for Ewing Sarcoma
    • Local control for Ewing sarcoma
  • High-Dose Therapy With Stem Cell Rescue for Ewing Sarcoma
  • Ewing Sarcoma/Specific Sites
  • Extraosseous Ewing Sarcoma
  • Subsequent Neoplasms

• Ewing Sarcoma: Localized Tumors
  • Standard Treatment Options
  • Treatment Options Under Clinical Evaluation
  • Current Clinical Trials

• Ewing Sarcoma: Metastatic Tumors
  • Standard Treatment Options
  • Treatment Options Under Clinical Evaluation
  • Current Clinical Trials

• Ewing Sarcoma: Recurrent Tumors
  • Standard Treatment Options
  • Treatment Options Under Clinical Evaluation
  • Current Clinical Trials

• Changes to This Summary (11/26/2012)

• About This PDQ® Summary
  • Purpose of This Summary
  • Reviewers and Updates
  • Levels of Evidence
  • Permission to Use This Summary
  • Disclaimer
  • Contact Us

• Get More Information From NCI

General Information

Fortunately, cancer in children and adolescents is rare, although the overall incidence of childhood cancer has been slowly increasing since 1975. 1 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 primary care physician, pediatric surgical subspecialists, radiation oncologists, pediatric oncologists/hematologists, rehabilitation specialists, pediatric nurse specialists, social workers, and others to ensure that children receive treatment, supportive care, and rehabilitation that will achieve optimal survival and quality of life. 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. 2 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/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 Web site.

Dramatic improvements in survival have been achieved for children and adolescents with cancer. 1 Between 1975 and 2002, childhood cancer mortality has decreased by more than 50%. For Ewing sarcoma, the 5-year survival rate has increased over the same time from 59% to 76% for children younger than 15 years and from 20% to 49% for adolescents aged 15 to 19 years. 1 Childhood and adolescent cancer survivors require close follow-up 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.

Origin and Incidence of Ewing Sarcoma

Studies using immunohistochemical markers, 3 cytogenetics, 4 5 molecular genetics, and tissue culture 6 indicate that Ewing sarcoma is derived from a primordial bone marrowderived mesenchymal stem cell. 7 8 Older terms such as 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.

The incidence of Ewing sarcoma is approximately three cases per 1 million per year and has remained unchanged for 30 years. 9 Data from the Surveillance, Epidemiology, and End Results (SEER) registries report an overall incidence of Ewing sarcoma of one case per 1 million in the U.S. population. The incidence in patients aged 10 to 19 years is between nine and ten cases per 1 million. The same analysis suggests that the incidence of Ewing sarcoma in the United States is nine times greater in Caucasians than in African Americans. 10

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 (EI-CESS), 59% of patients are male and 41% are female. Primary sites of bone disease include the following:

• Lower extremity (41%).
• Pelvis (26%).
• Chest wall (16%).
• Upper extremity (9%).
• Spine (6%).
• Skull (2%). 13

For extraosseous primary tumors, the most common primary sites of disease include the following:

• Trunk (32%).
• Extremity (26%).
• Head and neck (18%).
• Retroperitoneum (16%).
• Other sites (9%). 13

Approximately 25% of patients will have metastatic disease at diagnosis. 9

The U.S. NCI SEER database was used to compare patients younger than 40 years with Ewing sarcoma who presented with skeletal and extraosseous primary sites. 14 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 when compared with patients with skeletal Ewing sarcoma.

Prognostic Factors for Ewing Sarcoma

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

• Pretreatment.
• Treatment response.

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. 15 16 17 Patients with tumors of the sacrum have a very poor prognosis. 18
• 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. 17 19
• Age: Infants and younger patients (aged <15 years) have a better prognosis than adolescents aged 15 years or older, young adults, or adults. 12 15 16 17 In North American studies, patients younger than 10 years have a better outcome than those aged 10 to 17 years at diagnosis (relative risk [RR], 1.4). Patients older than 18 years have an inferior outcome (RR, 2.5). 20 A retrospective review of two consecutive German trials for Ewing sarcoma identified 47 patients older than 40 years. 21 With adequate multimodal therapy, survival was comparable to the survival observed in adolescents treated on the same trials.
• Gender: Girls with Ewing sarcoma have a better prognosis than boys. 10 16
• Serum lactate dehydrogenase (LDH): Increased serum LDH levels prior to treatment are associated with inferior prognosis. Increased LDH levels are also correlated with large primary tumors and metastatic disease. 16
• Metastases: Any metastatic disease defined by standard imaging techniques or bone marrow aspirate/biopsy by morphology is an adverse prognostic factor. The presence or absence of metastatic disease is the single most powerful predictor of outcome. Metastases at diagnosis are detected in about 25% of patients. 9 Patients with metastatic disease confined to lung have a better prognosis than patients with extrapulmonary metastatic sites. 15 17 22 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. 23 Patients with metastasis to bone only seem to have a better outcome than patients with metastases to both bone and lung. 24 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. 25
• Standard cytogenetics: Complex karyotype (defined as the presence of 5 or more independent chromosome abnormalities at diagnosis) and modal chromosome numbers lower than 50 appear to have adverse prognostic significance. 26
• Detectable fusion transcripts in morphologically normal marrow: Reverse transcriptase polymerase chain reaction 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 was associated with an increased risk of relapse. 27
• Other biological factors: Overexpression of the p53 protein, Ki67 expression, and loss of 16q may be adverse prognostic factors. 28 29 30 High expression of microsomal glutathione S-transferase, an enzyme associated with resistance to doxorubicin, is associated with inferior outcome for Ewing sarcoma. 31

The following are not considered to be adverse prognostic factors for Ewing sarcoma:

• Pathologic fracture: Pathologic fractures do not appear to be a prognostic factor. 32
• Histopathology: The degree of neural differentiation is not a prognostic factor in Ewing sarcoma. 33 34
• Molecular pathology: The EWS-FL1 translocation associated with Ewing sarcoma can occur at several potential breakpoints in each of the genes which join to form the novel segment of DNA. Once thought to be significant, 35 two large series have shown the EWS-FL1 translocation breakpoint site is not an adverse prognostic factor. 36 37

Treatment response factors to preoperative therapy

Multiple studies have shown that patients with minimal or no residual viable tumor after presurgical chemotherapy have a significantly better event-free survival compared with patients with larger amounts of viable tumor. 38 39 40 41 Female gender and younger age predict a good histologic response to preoperative therapy. 42 For patients who receive preinduction and postinduction chemotherapy positron emission tomography (PET) scans, decreased PET uptake following chemotherapy correlated with good histologic response and better outcome. 43 44 Patients with poor response to presurgical chemotherapy have an increased risk for local recurrence. 45

References:

1. Smith MA, Seibel NL, Altekruse SF, et al.: Outcomes for children and adolescents with cancer: challenges for the twenty-first century. J Clin Oncol 28 (15): 2625-34, 2010. [PUBMED Abstract]
2. Guidelines for the pediatric cancer center and role of such centers in diagnosis and treatment. American Academy of Pediatrics Section Statement Section on Hematology/Oncology. Pediatrics 99 (1): 139-41, 1997. [PUBMED Abstract]
3. Olsen SH, Thomas DG, Lucas DR: Cluster analysis of immunohistochemical profiles in synovial sarcoma, malignant peripheral nerve sheath tumor, and Ewing sarcoma. Mod Pathol 19 (5): 659-68, 2006. [PUBMED Abstract]
4. 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]
5. Dagher R, Pham TA, Sorbara L, et al.: Molecular confirmation of Ewing sarcoma. J Pediatr Hematol Oncol 23 (4): 221-4, 2001. [PUBMED Abstract]
6. Llombart-Bosch A, Carda C, Peydro-Olaya A, et al.: Soft tissue Ewing's sarcoma. Characterization in established cultures and xenografts with evidence of a neuroectodermic phenotype. Cancer 66 (12): 2589-601, 1990. [PUBMED Abstract]
7. Suví ML, Riggi N, Stehle JC, et al.: Identification of cancer stem cells in Ewing's sarcoma. Cancer Res 69 (5): 1776-81, 2009. [PUBMED Abstract]
8. Tirode F, Laud-Duval K, Prieur A, et al.: Mesenchymal stem cell features of Ewing tumors. Cancer Cell 11 (5): 421-9, 2007. [PUBMED Abstract]
9. 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]
10. Jawad MU, Cheung MC, Min ES, et al.: Ewing sarcoma demonstrates racial disparities in incidence-related and sex-related differences in outcome: an analysis of 1631 cases from the SEER database, 1973-2005. Cancer 115 (15): 3526-36, 2009. [PUBMED Abstract]
11. Kim SY, Tsokos M, Helman LJ: Dilemmas associated with congenital ewing sarcoma family tumors. J Pediatr Hematol Oncol 30 (1): 4-7, 2008. [PUBMED Abstract]
12. van den Berg H, Dirksen U, Ranft A, et al.: Ewing tumors in infants. Pediatr Blood Cancer 50 (4): 761-4, 2008. [PUBMED Abstract]
13. Raney RB, Asmar L, Newton WA Jr, et al.: Ewing's sarcoma of soft tissues in childhood: a report from the Intergroup Rhabdomyosarcoma Study, 1972 to 1991. J Clin Oncol 15 (2): 574-82, 1997. [PUBMED Abstract]
14. Applebaum MA, Worch J, Matthay KK, et al.: Clinical features and outcomes in patients with extraskeletal Ewing sarcoma. Cancer 117 (13): 3027-32, 2011. [PUBMED Abstract]
15. Cotterill SJ, Ahrens S, Paulussen M, et al.: Prognostic factors in Ewing's tumor of bone: analysis of 975 patients from the European Intergroup Cooperative Ewing's Sarcoma Study Group. J Clin Oncol 18 (17): 3108-14, 2000. [PUBMED Abstract]
16. Bacci G, Longhi A, Ferrari S, et al.: Prognostic factors in non-metastatic Ewing's sarcoma tumor of bone: an analysis of 579 patients treated at a single institution with adjuvant or neoadjuvant chemotherapy between 1972 and 1998. Acta Oncol 45 (4): 469-75, 2006. [PUBMED Abstract]
17. Rodríguez-Galindo C, Liu T, Krasin MJ, et al.: Analysis of prognostic factors in ewing sarcoma family of tumors: review of St. Jude Children's Research Hospital studies. Cancer 110 (2): 375-84, 2007. [PUBMED Abstract]
18. 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]
19. Ahrens S, Hoffmann C, Jabar S, et al.: Evaluation of prognostic factors in a tumor volume-adapted treatment strategy for localized Ewing sarcoma of bone: the CESS 86 experience. Cooperative Ewing Sarcoma Study. Med Pediatr Oncol 32 (3): 186-95, 1999. [PUBMED Abstract]
20. 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]
21. 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]
22. 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]
23. 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]
24. 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]
25. 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]
26. 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]
27. 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]
28. 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]
29. 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]
30. 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]
31. 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]
32. 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]
33. 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]
34. 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]
35. 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]
36. 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]
37. 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]
38. 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]
39. 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]
40. Wunder JS, Paulian G, Huvos AG, et al.: The histological response to chemotherapy as a predictor of the oncological outcome of operative treatment of Ewing sarcoma. J Bone Joint Surg Am 80 (7): 1020-33, 1998. [PUBMED Abstract]
41. 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]
42. Ferrari S, Bertoni F, Palmerini E, et al.: Predictive factors of histologic response to primary chemotherapy in patients with Ewing sarcoma. J Pediatr Hematol Oncol 29 (6): 364-8, 2007. [PUBMED Abstract]
43. Hawkins DS, Schuetze SM, Butrynski JE, et al.: [18F]Fluorodeoxyglucose positron emission tomography predicts outcome for Ewing sarcoma family of tumors. J Clin Oncol 23 (34): 8828-34, 2005. [PUBMED Abstract]
44. Denecke T, Hundsdírfer 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]
45. Lin PP, Jaffe N, Herzog CE, et al.: Chemotherapy response is an important predictor of local recurrence in Ewing sarcoma. Cancer 109 (3): 603-11, 2007. [PUBMED Abstract]

Cellular Classification

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 suggesting diagnosis of 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. 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. 2

Cytogenetic Changes in Ewing Sarcoma

Cytogenetic studies of Ewing sarcoma have identified a consistent alteration of the EWSR1 locus (a member of the TET family [TLS/EWS/TAF15] of RNA binding proteins) on chromosome 22 band q12 that may involve other chromosomes, including 11 or 21. 3 Characteristically, the amino terminus of the EWSR1 gene is juxtaposed with the carboxy terminus of another gene. In most cases (90%), the carboxy terminus is provided by FLI1, a member of the Ets family of transcription factor genes located on chromosome 11 band q24. Other Ets family members that may combine with the EWSR1 gene in order of frequency are ERG, located on chromosome 21; ETV1, located on chromosome 7; and E1AF, located on chromosome 17; these result in the following translocations: t(21;22), 4 t(7;22), and t(17;22), respectively. Rarely, other TET family members can substitute for EWS. 5 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 tumors. 6

A molecular test (i.e., reverse transcriptase polymerase chain reaction [PCR] and restriction analysis of PCR products), currently available on a research basis only, now offers the opportunity to markedly simplify the definition of Ewing sarcoma. 7 8 The molecular assay can be performed on relatively small amounts of tissue obtained by minimally invasive biopsies and is capable of providing results faster than cytogenetic analysis.

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]
2. 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]
3. 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]
4. 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]
5. Sankar S, Lessnick SL: Promiscuous partnerships in Ewing's sarcoma. Cancer Genet 204 (7): 351-65, 2011. [PUBMED Abstract]
6. 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]
7. Meier VS, Kí¼hne T, Jundt G, et al.: Molecular diagnosis of Ewing tumors: improved detection of EWS-FLI-1 and EWS-ERG chimeric transcripts and rapid determination of exon combinations. Diagn Mol Pathol 7 (1): 29-35, 1998. [PUBMED Abstract]
8. Dagher R, Pham TA, Sorbara L, et al.: Molecular confirmation of Ewing sarcoma. J Pediatr Hematol Oncol 23 (4): 221-4, 2001. [PUBMED Abstract]

Stage Information

For patients with confirmed Ewing sarcoma, pretreatment staging studies should include magnetic resonance imaging (MRI) and/or computed tomography (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 should include bone scan, CT scan of the chest, and bone marrow aspiration and biopsy. A staging modality under evaluation but not required on current clinical trials is molecular analysis of bone marrow for the presence of fusion transcript. In certain studies, determination of pretreatment tumor volume is an important variable.

Although positron emission tomography using fluorodeoxyglucose (FDG-PET) or 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. FDG-PET/CT is more accurate than FDG-PET alone in Ewing sarcoma. 3 4 5

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, an excisional biopsy should be performed.

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. Vílker 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]
4. 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]
5. Treglia G, Salsano M, Stefanelli A, et al.: Diagnostic accuracy of F-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]

Treatment Option Overview

Patients should be evaluated by specialists from the appropriate disciplines (e.g., radiologist, chemotherapist, pathologist, surgical or orthopedic oncologist, and radiation oncologist) as early as possible. Appropriate imaging studies of the site should be obtained prior to biopsy. The surgical or orthopedic oncologist who will perform the definitive surgery should be involved prior to or during the biopsy so that the incision can be placed in an acceptable location. 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 radiation oncologist and pathologist should be consulted prior to biopsy/surgery in order to be sure that the incision will not compromise the radiation port and so that multiple types of 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 for molecular biology and cytogenetics is obtained. 2

The successful treatment of patients with Ewing sarcoma requires systemic chemotherapy 3 4 5 6 7 8 9 in conjunction with either surgery or radiation therapy or both modalities for local tumor control. 10 11 12 13 14 In general, patients receive preoperative chemotherapy prior to instituting local control measures. In patients who undergo surgery, surgical margins and histologic response are considered in planning postoperative therapy. Most patients with metastatic disease have a good initial response to preoperative chemotherapy; however, in most cases, the disease is only partially controlled or recurs. 15 16 17 18 Patients with lung as the sole metastatic site have a better prognosis than patients with metastases to bone and/or bone marrow. Adequate local control for metastatic sites, particularly bone metastases, may be an important issue.

Chemotherapy for Ewing Sarcoma

Multidrug chemotherapy for Ewing sarcoma always includes vincristine, doxorubicin, ifosfamide, and etoposide. Most protocols use cyclophosphamide as well. Certain protocols 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 grams of cyclophosphamide produced a similar event-free survival (EFS) compared with 6 grams 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). 19[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. A randomized clinical trial (COG-AEWS0031 [NCT00006734]) from the Children's Oncology Group showed that for patients presenting without metastases, 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 alternating cycles at 3-week intervals (5-year EFS, 65%). 20

Local control for Ewing sarcoma

Treatment approaches for Ewing sarcoma titrate therapeutic aggressiveness with the goal of maximizing local control while minimizing morbidity.

While surgery is effective and appropriate for patients who can undergo complete resection with acceptable morbidity, children who have unresectable tumors or who would suffer loss of function are treated with radiation therapy alone. Those who undergo gross resections with microscopic residual disease may benefit from adjuvant radiation therapy. Randomized trials that directly compare both modalities do not exist, and their relative roles remain controversial. Although retrospective institutional series suggest superior local control and survival with surgery rather than radiation therapy, most of these studies are compromised by selection bias. 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 modalitysurgery alone, radiation therapy alone, or radiation plus surgery. 21

For patients who undergo gross total resection with microscopic residual disease, the value of adjuvant radiation therapy is controversial. Investigations addressing this issue are retrospective and nonrandomized, limiting their value. Investigators from St. Jude Children's Research Hospital reported 39 patients with localized Ewing sarcoma who received both surgery and radiation. Local failure for patients with positive and negative margins was 17% and 5%, respectively, and overall survival (OS) was 71% and 94%, respectively. 13 However, in a large retrospective Italian study, 45 Gy adjuvant radiation therapy for patients with inadequate margins did not appear to improve either local control or disease-free survival. 14 It is not known whether higher doses of radiation therapy could improve outcome. These investigators concluded that patients who are anticipated to have suboptimal surgery should be considered for definitive radiation therapy.

Thus, 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 compromise by definitive surgery. The possibility of impaired function needs to be measured against the possibility of second tumors in the radiation field (see below). Adjuvant radiation therapy should be considered for patients with residual microscopic disease, inadequate margins, or who have viable tumor in the resected specimen and close 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. 22

High-Dose Therapy With Stem Cell Rescue 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. 23 24 25 26 27 28 29 30 31 32 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. The study showed no benefit for HSCT compared with historical controls. 28 A retrospective review using international bone marrow transplant registries compared outcome after treatment with reduced-intensity conditioning to high-intensity conditioning followed by allogeneic stem cell transplant for patients with Ewing sarcoma at high risk for relapse. 33[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. 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. The role of high-dose therapy followed by stem cell rescue is being investigated in a Euro-Ewing clinical trial (EURO-EWING-INTERGROUP-EE99) for patients that present with pulmonary metastases.

Ewing Sarcoma/Specific Sites

Separate journal articles have been written that discuss diagnostic findings, treatment, and outcome of patients with bone lesions at the following sites:

• Pelvis. 34 35 36
• Femur. 37 38
• Humerus. 39 40
• Hand and foot. 41 42
• Chest wall/rib. 43 44 45 46
• Head and neck. 47
• Spine/sacrum. 48 49 50 51

Extraosseous Ewing Sarcoma

Extraosseous Ewing sarcoma is biologically similar to Ewing sarcoma arising in bone. Until recently, 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.

From 1987 to 2004, 111 patients with nonmetastatic extraosseous Ewing sarcoma were enrolled on the RMS-88 and RMS-96 protocols. 52 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 and OS were 59% and 69%, respectively. 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.

Two hundred thirty-six patients with extraosseous Ewing sarcoma were entered on studies of the German Pediatric Oncology Group. 53 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 236 patients had metastases at diagnosis. Chemotherapy consisted of vincristine, doxorubicin, cyclophosphamide, and actinomycin (VACA); CEVAIE; or vincristine, ifosfamide, doxorubicin, and etoposide (VIDE). The 5-year EFS and OS were 49% and 60%, respectively. 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. 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). Patients receiving the anthracycline-containing regimen had a significantly better EFS and OS compared with patients receiving no anthracyclines. 54 55

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. 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 should be used for these patients because there are no data to suggest which patients could be treated less aggressively. 56 57

Subsequent Neoplasms

Patients treated for Ewing sarcoma have a significantly higher risk of developing subsequent neoplasms than patients in the general population.

Treatment-related acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) have generally been reported to occur in 1% to 2% of survivors of Ewing sarcoma, 58; 59[Level of evidence: 3iiiDi] although some dose-intensive regimens appear to be associated with a higher risk of hematological malignancy. 60 61; 62[Level of evidence: 3ii] Treatment-related AML and MDS arise most commonly at 2 to 5 years following diagnosis.

Survivors of Ewing sarcoma remain at increased risk of developing a subsequent solid tumor throughout their lifetime. Sarcomas usually occur within the prior radiation field. 63 64 The risk of developing a sarcoma following radiation therapy is dose-dependent, with higher doses associated with an increased risk of sarcoma development. 58; 59[Level of evidence: 3iiiDi] The cumulative incidence of subsequent neoplasms in children treated for Ewing sarcoma between 1970 and 1986 at 25 years after diagnosis was 9.0% (confidence interval, 5.812.2). Most of these patients received radiation therapy; comparable long-term data do not yet exist for significant numbers of patients who did not receive radiation therapy. 65

(Refer to the PDQ® summary on Late Effects of Treatment for Childhood Cancer for a full discussion of the late effects of cancer treatment in children and adolescents.)

References:

1. 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]
2. Hoffer FA, Gianturco LE, Fletcher JA, et al.: Percutaneous biopsy of peripheral primitive neuroectodermal tumors and Ewing's sarcomas for cytogenetic analysis. AJR Am J Roentgenol 162 (5): 1141-2, 1994. [PUBMED Abstract]
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4. Shankar AG, Pinkerton CR, Atra A, et al.: Local therapy and other factors influencing site of relapse in patients with localised Ewing's sarcoma. United Kingdom Children's Cancer Study Group (UKCCSG). Eur J Cancer 35 (12): 1698-704, 1999. [PUBMED Abstract]
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6. 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]
7. 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]
8. Thacker MM, Temple HT, Scully SP: Current treatment for Ewing's sarcoma. Expert Rev Anticancer Ther 5 (2): 319-31, 2005. [PUBMED Abstract]
9. Juergens C, Weston C, Lewis I, et al.: Safety assessment of intensive induction with vincristine, ifosfamide, doxorubicin, and etoposide (VIDE) in the treatment of Ewing tumors in the EURO-E.W.I.N.G. 99 clinical trial. Pediatr Blood Cancer 47 (1): 22-9, 2006. [PUBMED Abstract]
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12. Bacci G, Ferrari S, Longhi A, et al.: Role of surgery in local treatment of Ewing's sarcoma of the extremities in patients undergoing adjuvant and neoadjuvant chemotherapy. Oncol Rep 11 (1): 111-20, 2004. [PUBMED Abstract]
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