Ewing Sarcoma Treatment–for health professionals (PDQ®)

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General Information About Ewing Sarcoma

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 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.[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 website.

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] 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.

Studies using immunohistochemical markers,[3] cytogenetics,[4,5] molecular genetics, and tissue culture [6] indicate that Ewing sarcoma is derived from a primordial bone marrow–derived 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.

Incidence

The incidence of Ewing sarcoma has remained unchanged for 30 years.[9] 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.[10,11]

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.[12,13] Based on data from 1,426 patients entered on European Intergroup Cooperative Ewing Sarcoma Studies, 59% of patients are male and 41% are female.[14]

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%).[15]
  • Skull (2%).

For extraosseous primary tumors, the most common primary sites of disease include the following:[16,17]

  • 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. This has not been associated with metastasis, surgical outcome, or survival.[18] Approximately 25% of patients with Ewing sarcoma have metastatic disease at the time of diagnosis.[9]

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).[19] 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
Characteristic Extraosseous Ewing Sarcoma Skeletal Ewing Sarcoma P Value
Mean age (range), years 20 (0–39) 16 (0–39) <.001
Male 53% 63% <.001
White 85% 93% <.001
Axial primary sites 73% 54% <.001
Pelvic primary sites 20% 27% .001

Diagnostic Evaluation

The following tests and procedures may be used to diagnose or stage Ewing sarcoma:

  • Physical exam 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).

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.[20-22]
  • 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.[22,23]
  • Age: Infants and younger patients have a better prognosis than do patients aged 15 years and older.[13,20-22,24]

    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).[25-27] A retrospective review of two consecutive German trials for Ewing sarcoma identified 47 patients older than 40 years.[28] 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 do boys with Ewing sarcoma.[10,21]
  • 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.[21]
  • 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 the lung have a better prognosis than do patients with extrapulmonary metastatic sites.[20,22,29] 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.[30]

    Patients with metastasis to only bone seem to have a better outcome than do patients with metastases to both bone and lung.[31,32]

    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.[33]

  • 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 overall survival for patients with secondary Ewing sarcoma, 43.5%; patients with primary Ewing sarcoma, 64.2%).[34]
  • 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.[35]
  • 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 or peripheral blood was associated with an increased risk of relapse.[36]
  • Other biological factors: Overexpression of the p53 protein, Ki67 expression, and loss of 16q may be adverse prognostic factors.[37-39] High expression of microsomal glutathione S-transferase, an enzyme associated with resistance to doxorubicin, is associated with inferior outcome for Ewing sarcoma.[40]

    The Children's Oncology Group performed a prospective analysis of TP53 mutations and/or CDKN2A deletions in patients with Ewing sarcoma; no correlation was found with event-free survival (EFS).[41]

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.[42]
  • Histopathology: The degree of neural differentiation is not a prognostic factor in Ewing sarcoma.[43,44]
  • 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,[45] two large series have shown that the EWSR1-ETS translocation breakpoint site is not an adverse prognostic factor.[46,47]

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.[48-51] Female gender and younger age predict a good histologic response to preoperative therapy.[52] For patients who receive preinduction- and postinduction-chemotherapy PET scans, decreased PET uptake after chemotherapy correlated with good histologic response and better outcome.[53,54]

Patients with poor response to presurgical chemotherapy have an increased risk for local recurrence.[55]

References
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  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. Suvà 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]
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  11. Beck R, Monument MJ, Watkins WS, et al.: EWS/FLI-responsive GGAA microsatellites exhibit polymorphic differences between European and African populations. Cancer Genet 205 (6): 304-12, 2012. [PUBMED Abstract]
  12. 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]
  13. van den Berg H, Dirksen U, Ranft A, et al.: Ewing tumors in infants. Pediatr Blood Cancer 50 (4): 761-4, 2008. [PUBMED Abstract]
  14. Paulussen M, Craft AW, Lewis I, et al.: Results of the EICESS-92 Study: two randomized trials of Ewing's sarcoma treatment--cyclophosphamide compared with ifosfamide in standard-risk patients and assessment of benefit of etoposide added to standard treatment in high-risk patients. J Clin Oncol 26 (27): 4385-93, 2008. [PUBMED Abstract]
  15. Froeb D, Ranft A, Boelling T, et al.: Ewing sarcoma of the hand or foot. Klin Padiatr 224 (6): 348-52, 2012. [PUBMED Abstract]
  16. 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]
  17. Rowe RG, Thomas DG, Schuetze SM, et al.: Ewing sarcoma of the kidney: case series and literature review of an often overlooked entity in the diagnosis of primary renal tumors. Urology 81 (2): 347-53, 2013. [PUBMED Abstract]
  18. Brasme JF, Chalumeau M, Oberlin O, et al.: Time to diagnosis of Ewing tumors in children and adolescents is not associated with metastasis or survival: a prospective multicenter study of 436 patients. J Clin Oncol 32 (18): 1935-40, 2014. [PUBMED Abstract]
  19. 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]
  20. 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]
  21. 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]
  22. 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]
  23. 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]
  24. De Ioris MA, Prete A, Cozza R, et al.: Ewing sarcoma of the bone in children under 6 years of age. PLoS One 8 (1): e53223, 2013. [PUBMED Abstract]
  25. 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]
  26. 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]
  27. 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]
  28. 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]
  29. 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]
  30. 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]
  31. 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]
  32. 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]
  33. 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]
  34. 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]
  35. 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]
  36. 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]
  37. 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]
  38. 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]
  39. 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]
  40. 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]
  41. 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]
  42. 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]
  43. 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]
  44. 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]
  45. 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]
  46. 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]
  47. 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]
  48. 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]
  49. 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]
  50. 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]
  51. 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]
  52. 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]
  53. 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]
  54. 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]
  55. 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 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.

Cytogenetic and Molecular Changes in 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).[2] The EWSR1 gene is a member of the TET family [TLS/EWS/TAF15] of RNA-binding proteins.[3] 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.[4] Rarely, TLS, another TET family member, can substitute for EWSR1.[5] 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.[6]

Three publications 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. In addition, these publications 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. 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.[7-9]

These 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.[10] 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 tumor, clear cell sarcoma, extraskeletal myxoid chondrosarcoma, and myxoid liposarcoma, all of which may be positive with a EWS fluorescence in situ hybridization split apart probe.

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. The molecular profile of these tumors is different from the profile of EWS-FLI1 translocated 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. 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.[11-14]

Table 2. EWS and TLS Fusions and Translocations in Ewing Sarcoma
TET Family Partner Fusion With ETS-like Oncogene Partner Translocation Comment
aThese partners are not members of the ETS family of oncogenes.
EWS EWSR1-FLI1 t(11;22)(q24;q12) Most common; ~85% to 90% of cases
EWSR1-ERG t(21:22)(q22;q12) Second most common; ~10% of cases
EWSR1-ETV1 t(7;22)(p22;q12) Rare
EWSR1-ETV4 t(17;22)(q12;q12) Rare
EWSR1-FEV t(2;22)(q35;q12) Rare
EWSR1-NFATc2a t(20;22)(q13;q12) Rare
EWSR1-POU5F1a t(6;22)(p21;q12)  
EWSR1-SMARCA5a t(4;22)(q31;q12) Rare
EWSR1-ZSGa t(6;22)(p21;q12)  
EWSR1-SP3a t(2;22)(q31;q12) Rare
TLS (also called FUS) TLS-ERG t(16;21)(p11;q22) Rare
TLS-FEV t(2;16)(q35;p11) Rare
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. 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]
  8. 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]
  9. 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]
  10. 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]
  11. 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]
  12. 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]
  13. 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]
  14. 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]

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 fluorodeoxyglucose (FDG-PET) or 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 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. In one institutional study, 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] FDG-PET/CT is more accurate than 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 total) 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] 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]

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 Group Standard Treatment Options
Localized Ewing sarcoma Chemotherapy
Local control measures:
  Surgery
  Radiation therapy
Metastatic Ewing sarcoma Chemotherapy
Surgery
Radiation therapy
Recurrent Ewing sarcoma Chemotherapy (not considered standard treatment)
Radiation therapy (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).[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 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 did alternating cycles at 3-week intervals (5-year EFS, 65%).[23]
  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. They found significantly increased toxicity without an improvement in outcome with the addition of carboplatin.[24][Level of evidence: 2Dii]

Local Control 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.[25] Radiation therapy is an effective alternative modality for local control in cases where the functional 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.[25] 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 radiation plus surgery.[26]

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.

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. However, 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.[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.

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 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 may 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.[27]

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.[19,28-40]

Evidence (high-dose therapy with stem cell rescue):

  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.[33]
    • 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.[41][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.

The role of high-dose therapy followed by stem cell rescue is being investigated in the prospective, randomized Euro-Ewing trial (EURO-EWING-INTERGROUP-EE99) for patients who present with metastases and patients with localized tumors with poor response to initial chemotherapy.

Ewing Sarcoma/Specific Sites

Multiple analyses have evaluated diagnostic findings, treatment, and outcome of patients with bone lesions at the following anatomic primary sites:

  • Pelvis.[42-44]
  • Femur.[45,46]
  • Humerus.[47,48]
  • Hand and foot.[49,50]
  • Chest wall/rib.[51-54]
  • Head and neck.[55]
  • Spine/sacrum.[56-59]

Extraosseous Ewing Sarcoma

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.

From 1987 to 2004, 111 patients with nonmetastatic extraosseous Ewing sarcoma were enrolled on the RMS-88 and RMS-96 protocols.[60] 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.

Two hundred thirty-six patients with extraosseous Ewing sarcoma were entered on studies of the German Pediatric Oncology Group.[61] 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 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. 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 who received the anthracycline-containing regimen had a significantly better EFS and OS than did patients who did not receive anthracyclines.[62,63] Two North American Ewing sarcoma trials have included patients with extraosseous Ewing sarcoma.[23,64] The outcome of patients with extraosseous Ewing sarcoma is no different than the outcome for patients with bone Ewing sarcoma.

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 is often used for these patients because there are no data to suggest which patients could be treated less aggressively.[65,66] 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.[67][Level of evidence: 3iiD]

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  49. 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]
  50. 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]
  51. 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]
  52. 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]
  53. 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]
  54. 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]
  55. Windfuhr JP: Primitive neuroectodermal tumor of the head and neck: incidence, diagnosis, and management. Ann Otol Rhinol Laryngol 113 (7): 533-43, 2004. [PUBMED Abstract]
  56. 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]
  57. Marco RA, Gentry JB, Rhines LD, et al.: Ewing's sarcoma of the mobile spine. Spine 30 (7): 769-73, 2005. [PUBMED Abstract]
  58. 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]
  59. 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]
  60. Spiller M, Bisogno G, Ferrari A, et al.: Prognostic factors in localized extraosseus Ewing family tumors. [Abstract] Pediatr Blood Cancer 46 (10) : A-PD.024, 434, 2006.
  61. Ladenstein R, Pötschger U, Jürgens H, et al.: Comparison of treatment concepts for extraosseus Ewing tumors (EET) within consecutive trials of two GPOH Cooperative Study Groups. [Abstract] Pediatr Blood Cancer 45 (10) : A-P.C.004, 450, 2005.
  62. 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]
  63. 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]
  64. 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]
  65. 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]
  66. 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]
  67. 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]

Treatment of Localized Ewing Sarcoma

Standard Treatment Options for Localized Ewing Sarcoma

Standard treatment options for localized Ewing sarcoma include the following:

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.[2,9,11]
  2. Dactinomycin is no longer used for Ewing sarcoma in the United States but continues to be used in the Euro-Ewing studies.
  3. Increased dose intensity of doxorubicin during the initial months of therapy was associated with an improved outcome in a meta-analysis performed before the standard use of IE.[12]
  4. 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.[13]
  5. 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.[14] Unlike the single-institution trial, this trial did not maintain the dose intensity of cyclophosphamide for the duration of treatment.[13]

In a Children's Oncology Group (COG) trial (COG-AEWS0031), 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.

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.
  • 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]

European investigators are studying whether treatment intensification (i.e., high-dose chemotherapy with stem cell rescue) will improve outcome for patients with a poor histologic response.

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.

Pathologic fracture at the time of diagnosis does not preclude surgical resection and is not associated with adverse outcome.[19]

Radiation therapy

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.[1,2,20]

The radiation dose may be adjusted depending on the extent of residual disease after the initial surgical procedure. 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]

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.[21] 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.[22] 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.[23]

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.[14]

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.[24] (Refer to the Late Effects of Treatment for Ewing Sarcoma section of this summary for more information.)

Treatment Options Under Clinical Evaluation for Localized Ewing Sarcoma

The following is an example of an international clinical trial that is currently being conducted. Information about ongoing clinical trials is available from the NCI website.

Treatment options under clinical evaluation for localized Ewing sarcoma include the following:

  • COG-AEWS1031; RTOG 1127 (NCT01231906) (Combination Chemotherapy in Treating Patients With Nonmetastatic Extracranial Ewing Sarcoma): This study is randomly assigning patients with newly diagnosed nonmetastatic Ewing sarcoma to either standard interval-compressed VDC/IE or the experimental arm consisting of interval-compressed therapy with the addition of vincristine, cyclophosphamide, and topotecan (VTC [VTC/VDC/IE]). The primary objective is to evaluate the effect of a new treatment regimen on EFS and OS. Patients younger than 50 years are eligible. This study is available in North America through the COG and in the United States for medical and radiation oncologists through the Radiation Therapy Oncology Group or the Cancer Trials Support Unit.

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with localized Ewing sarcoma/peripheral primitive neuroectodermal tumor. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

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. Smith MA, Ungerleider RS, Horowitz ME, et al.: Influence of doxorubicin dose intensity on response and outcome for patients with osteogenic sarcoma and Ewing's sarcoma. J Natl Cancer Inst 83 (20): 1460-70, 1991. [PUBMED Abstract]
  13. 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]
  14. 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]
  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. 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]
  20. 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]
  21. 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]
  22. 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]
  23. 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]
  24. 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]

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:

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 sem 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 impact of high-dose chemotherapy with peripheral blood stem cell support for patients with isolated lung metastases is unknown and is being studied in the EURO-EWING-INTERGROUP-EE99 trial, for which results are pending.[16]
  • 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.[20]
  • 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).[21][Level of evidence: 3iiiDiv] Further investigation is needed to determine irinotecan dosing and combinations with other agents for patients with Ewing sarcoma.

Treatment Options Under Clinical Evaluation for Metastatic Ewing Sarcoma

The following is an example of an international clinical trial that is currently being conducted. Information about ongoing clinical trials is available from the NCI website.

Treatment options under clinical evaluation for metastatic Ewing sarcoma include the following:

  • AEWS1221; NCI-2014-02380 (NCT02306161) (Combination Chemotherapy With or Without Ganitumab in Treating Patients With Newly Diagnosed Metastatic Ewing Sarcoma): This phase II study is randomly assigning newly diagnosed patients with metastatic Ewing sarcoma to multiagent chemotherapy (vincristine, doxorubicin, cyclophosphamide, ifosfamide, and etoposide) with or without the addition of ganitumab (AMG 479). Stereotactic body radiation therapy is being evaluated to sites of bone metastases at a dose of 40 Gy in five fractions. This is a shorter course of therapy than is the standard treatment.

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with metastatic Ewing sarcoma/peripheral primitive neuroectodermal tumor. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

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. 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]
  21. 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]

The overall prognosis for patients with recurrent Ewing sarcoma is poor; 5-year survival after recurrence is approximately 10% to 15%.[2,4,5]; [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 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.[6][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:

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.[7-12]

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.[7,9]
  2. In one retrospective series, 20 patients received temozolomide and irinotecan after recurrence. Five patients achieved a complete response and seven patients achieved a partial response.[11]
  3. The combination of docetaxel either with gemcitabine or irinotecan has achieved objective responses in relapsed Ewing sarcoma.[13][Level of evidence: 3iiA]; [14,15][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).[16][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.[17] Residual disease in the lung may be surgically removed.

Other therapies

Other therapies that have been studied in the treatment of recurrent Ewing sarcoma include the following:

  • 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.[18,19]; [20][Level of evidence: 3iiA]; [21][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.[18,22,23]

  • 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.[24-27][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 Ewing sarcoma patients.[28,29] 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),[30] GD2,[31] CD99 (MIC2 antigens),[32] and STEAP1 (six-transmembrane epithelial antigens of the prostate).[33] Some are in early-phase testing in sarcoma patients.[30]

Treatment Options Under Clinical Evaluation for Recurrent Ewing Sarcoma

The following are examples of international clinical trials that are currently being conducted. Information about ongoing clinical trials is available from the NCI website.

Treatment options under clinical evaluation for recurrent Ewing sarcoma include the following:

  • SARC028; NCI-2015-00320 (NCT02301039) (A Phase II Study of the Anti-PD1 Antibody Pembrolizumab [MK-3475] in Patients With Advanced Sarcomas): The objective response rate to the anti-PD1 inhibitor pembrolizumab will be assessed in patients with refractory, recurrent, and/or metastatic high-grade soft tissue sarcomas and bone sarcomas. Patients aged 18 years and older with soft tissue sarcomas and patients aged 12 years and older with bone sarcomas are eligible.
  • NCT02173093 (Activated T cells armed with GD2 Bispecific Antibody in Children and Young Adults with Neuroblastoma and Osteosarcoma): Patients with GD2-positive tumors are also eligible.
  • ADVL1412 (NCT02304458) (Nivolumab With or Without Ipilimumab in Treating Younger Patients With Recurrent or Refractory Solid Tumors or Sarcomas): Nivolumab is an anti-PD1 inhibitor that is being studied alone and in combination with ipilimumab in relapsed sarcoma patients, including patients with Ewing sarcoma.
  • ADVL1411 (NCT02116777) (BMN-673 and Temozolomide in Treating Younger Patients With Refractory or Recurrent Malignancies): In this study, the PARP inhibitor BMN-673 is combined with low-dose short duration temozolomide. This is based on the in vitro and mouse human tumor xenograft models, which showed impressive activity in a broad range of pediatric cancers, including Ewing sarcoma.[34]

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with recurrent Ewing sarcoma/peripheral primitive neuroectodermal tumor. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

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. 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]
  5. 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]
  6. 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]
  7. 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]
  8. 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]
  9. 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]
  10. 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]
  11. 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]
  12. 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]
  13. 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]
  14. 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]
  15. 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]
  16. 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]
  17. 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]
  18. 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]
  19. 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]
  20. 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]
  21. 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]
  22. 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]
  23. Eapen M: Response to Dr Gilman. Bone Marrow Transplant 42 (11): 763, 2008.
  24. 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]
  25. 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]
  26. 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]
  27. 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]
  28. 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]
  29. 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]
  30. 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]
  31. 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]
  32. 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]
  33. 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]
  34. Smith MA, Reynolds CP, Kang MH, et al.: Synergistic activity of PARP inhibition by talazoparib (BMN 673) with temozolomide in pediatric cancer models in the pediatric preclinical testing program. Clin Cancer Res 21 (4): 819-32, 2015. [PUBMED Abstract]

Late Effects of Treatment for Ewing Sarcoma

Patients treated for Ewing sarcoma have a significantly higher risk of developing subsequent neoplasms than do 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,[1]; [2][Level of evidence: 3iiiDi] although some dose-intensive regimens appear to be associated with a higher risk of hematological malignancy.[3,4]; [5][Level of evidence: 3ii] Treatment-related AML and MDS arise most commonly at 2 to 5 years after diagnosis.

Survivors of Ewing sarcoma remain at increased risk of developing a subsequent solid tumor throughout their lifetime. Sarcomas usually occur within the previous radiation field.[6,7] The risk of developing a sarcoma after radiation therapy is dose-dependent, with higher doses associated with an increased risk of sarcoma development.[1]; [2][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, 5.8–12.2). 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.[8]

(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, Petersen IA, et al.: Ewing's sarcoma and the development of secondary malignancies. Clin Orthop (415): 82-9, 2003. [PUBMED Abstract]
  2. Goldsby R, Burke C, Nagarajan R, et al.: Second solid malignancies among children, adolescents, and young adults diagnosed with malignant bone tumors after 1976: follow-up of a Children's Oncology Group cohort. Cancer 113 (9): 2597-604, 2008. [PUBMED Abstract]
  3. Bhatia S, Krailo MD, Chen Z, et al.: Therapy-related myelodysplasia and acute myeloid leukemia after Ewing sarcoma and primitive neuroectodermal tumor of bone: A report from the Children's Oncology Group. Blood 109 (1): 46-51, 2007. [PUBMED Abstract]
  4. Kushner BH, Heller G, Cheung NK, et al.: High risk of leukemia after short-term dose-intensive chemotherapy in young patients with solid tumors. J Clin Oncol 16 (9): 3016-20, 1998. [PUBMED Abstract]
  5. Navid F, Billups C, Liu T, et al.: Second cancers in patients with the Ewing sarcoma family of tumours. Eur J Cancer 44 (7): 983-91, 2008. [PUBMED Abstract]
  6. 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]
  7. Hawkins MM, Wilson LM, Burton HS, et al.: Radiotherapy, alkylating agents, and risk of bone cancer after childhood cancer. J Natl Cancer Inst 88 (5): 270-8, 1996. [PUBMED Abstract]
  8. Ginsberg JP, Goodman P, Leisenring W, et al.: Long-term survivors of childhood Ewing sarcoma: report from the childhood cancer survivor study. J Natl Cancer Inst 102 (16): 1272-83, 2010. [PUBMED Abstract]

Changes to This Summary (08/13/2015)

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.

This summary was comprehensively reviewed and extensively revised.

This summary was reformatted.

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:

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  • 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 (Dana-Farber Cancer Institute/Boston Children's Hospital)
  • 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 Center and Blood Disorders Service 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 Web site's Contact Form. 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.

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The preferred citation for this PDQ summary is:

National Cancer Institute: PDQ® Ewing Sarcoma Treatment. Bethesda, MD: National Cancer Institute. Date last modified <MM/DD/YYYY>. Available at: http://www.cancer.gov/types/bone/hp/ewing-treatment-pdq. Accessed <MM/DD/YYYY>.

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