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Dramatic improvements in survival have been achieved for children and adolescents with cancer. Between 1975 and 2010, childhood cancer mortality decreased by more than 50%. 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.
Studies using immunohistochemical markers, cytogenetics,[3,4] molecular genetics, and tissue culture  indicate that Ewing sarcoma is derived from a primordial bone marrow–derived mesenchymal stem cell.[6,7] Older terms such as peripheral primitive neuroectodermal tumor, Askin tumor (Ewing sarcoma of chest wall), and extraosseous Ewing sarcoma (often combined in the term Ewing sarcoma family of tumors) refer to this same tumor.
The incidence of Ewing sarcoma has remained unchanged for 30 years. The incidence for all ages is one case per 1 million people in the United States. In patients aged 10 to 19 years, the incidence is between nine and ten cases per 1 million people. The same analysis suggests that the incidence of Ewing sarcoma in the United States is nine times greater in whites than in African Americans, with an intermediate incidence in Asians.[9,10]
The relative paucity of Ewing sarcoma in people of African or Asian descent may be explained, in part, by a specific polymorphism in the EGR2 gene.
The median age of patients with Ewing sarcoma is 15 years, and more than 50% of patients are adolescents. Well-characterized cases of Ewing sarcoma in neonates and infants have been described.[11,12] Based on data from 1,426 patients entered on European Intergroup Cooperative Ewing Sarcoma Studies, 59% of patients are male and 41% are female.
Primary sites of bone disease include the following:
For extraosseous primary tumors, the most common primary sites of disease include the following:[15,16]
The median time from first symptom to diagnosis of Ewing sarcoma is often long, with a median interval reported from 2 to 5 months. Longer times are associated with older age and pelvic primary sites. Time from first symptom to diagnosis has not been associated with metastasis, surgical outcome, or survival. Approximately 25% of patients with Ewing sarcoma have metastatic disease at the time of diagnosis.
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). 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.
The following tests and procedures may be used to diagnose or stage Ewing sarcoma:
Refer to the Treatment Option Overview for Ewing Sarcoma section of this summary for information about diagnostic biopsy.
The two major types of prognostic factors for patients with Ewing sarcoma are grouped as follows:
Patients with metastatic disease confined to the lung have a better prognosis than do patients with extrapulmonary metastatic sites.[19,21,22,34] The number of pulmonary lesions does not seem to correlate with outcome, but patients with unilateral lung involvement do better than patients with bilateral lung involvement.
Patients with metastasis to only bone seem to have a better outcome than do patients with metastases to both bone and lung.[36,37]
Based on an analysis from the SEER database, regional lymph node involvement in patients is associated with an inferior overall outcome when compared with patients without regional lymph node involvement.
The COG performed a prospective analysis of TP53 mutations and/or CDKN2A deletions in patients with Ewing sarcoma; no correlation was found with EFS.
The following are not considered to be adverse prognostic factors for Ewing sarcoma:
Response to initial therapy factors
Multiple studies have shown that patients with minimal or no residual viable tumor after presurgical chemotherapy have a significantly better EFS than do patients with larger amounts of viable tumor.[53,54,55,56] Female sex and younger age predict a good histologic response to preoperative therapy. For patients who receive preinduction- and postinduction-chemotherapy PET scans, decreased PET uptake after chemotherapy correlated with good histologic response and better outcome.[58,59,60]
Patients with poor response to presurgical chemotherapy have an increased risk for local recurrence.
Detection of Ewing sarcoma in the peripheral blood
Several techniques to evaluate the presence of Ewing sarcoma in the peripheral blood have been proposed. Flow cytometry for cells that express the CD99 antigen was not sufficiently sensitive to serve as a reliable biomarker.[42,62] RT-PCR for the EWSR1-FLI1 translocation was also not considered a reliable biomarker.
A more sensitive technique that utilized patient-specific primers designed after identification of the specific translocation breakpoint in combination with droplet digital PCR reported a sensitivity of 0.018% to 0.009%. Levels of circulating cell-free DNA were higher in patients with metastatic disease than in patients with localized disease. A hybrid capture sequencing assay employing the introns at which EWSR1 and FLI1 fusions occur has also been developed to detect evidence of the EWSR1-FLI1 translocation in circulating cell-free DNA. Using this method, the translocation was detected in peripheral blood samples from 10 of 11 patients with Ewing sarcoma. Additional study is required to determine whether circulating cell-free DNA will have clinical utility as a biomarker for Ewing sarcoma to monitor disease status and response to therapy.
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.MIC2 positivity is not unique to Ewing sarcoma, and positivity by immunochemistry is found in several other tumors, including synovial sarcoma, non-Hodgkin lymphoma, and gastrointestinal stromal tumors.
The detection of a translocation involving the EWSR1 gene on chromosome 22 band q12 and any one of a number of partner chromosomes is the key feature in the diagnosis of Ewing sarcoma (refer to Table 2). The EWSR1 gene is a member of the TET family [TLS/EWS/TAF15] of RNA-binding proteins. 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. Rarely, TLS, another TET family member, can substitute for EWSR1. 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.
Three papers have described the genomic landscape of Ewing sarcoma and all show that these tumors have a relatively silent genome, with a paucity of mutations in pathways that might be amenable to treatment with novel targeted therapies.[6,7,8] These papers also identified mutations in STAG2, a member of the cohesin complex, in about 15% to 20% of the cases, and the presence of these mutations was associated with advanced-stage disease. CDKN2A deletions were noted in 12% to 22% of cases. Finally, TP53 mutations were identified in about 6% to 7% of cases and the coexistence of STAG2 and TP53 mutations is associated with a poor clinical outcome.[6,7,8]
Figure 1 below from a discovery cohort (n = 99) highlights the frequency of chromosome 8 gain, the co-occurrence of chromosome 1q gain and chromosome 16q loss, the mutual exclusivity of CDKN2A deletion and STAG2 mutation, and the relative paucity of recurrent single nucleotide variants for Ewing sarcoma.
Figure 1. A comprehensive profile of the genetic abnormalities in Ewing sarcoma and associated clinical information. Key clinical characteristics are indicated, including primary site, type of tissue, and metastatic status at diagnosis, follow-up, and last news. Below is the consistency of detection of gene fusions by RT-PCR and whole-genome sequencing (WGS). The numbers of structural variants (SV) and single-nucleotide variants (SNV) as well as indels are reported in grayscale. The presence of the main copy-number changes, chr 1q gain, chr 16 loss, chr 8 gain, chr 12 gain, and interstitial CDKN2A deletion is indicated. Listed last are the most significant mutations and their types. For gene mutations, "others" refers to: duplication of exon 22 leading to frameshift (STAG2), deletion of exon 2 to 11 (BCOR), and deletion of exons 1 to 6 (ZMYM3). Reprinted from Cancer Discovery, Copyright 2014, 4 (11), 1342–53, Tirode F, Surdez D, Ma X, et al., Genomic Landscape of Ewing Sarcoma Defines an Aggressive Subtype with Co-Association of STAG2 and TP53 mutations, with permission from AACR.
Ewing sarcoma translocations can all be found with standard cytogenetic analysis. A more rapid analysis looking for a break apart of the EWS gene is now frequently done to confirm the diagnosis of Ewing sarcoma molecularly. This test result must be considered with caution, however. Ewing sarcomas that utilize the TLS translocations will have negative tests because the EWSR1 gene is not translocated in those cases. In addition, other small round tumors also contain translocations of different ETS family members with EWSR1, such as desmoplastic small round cell tumor, clear cell sarcoma, extraskeletal myxoid chondrosarcoma, and myxoid liposarcoma, all of which may be positive with a EWS fluorescence in situ hybridization (FISH) break-apart probe. A detailed analysis of 85 patients with small round blue cell tumors that were negative for EWSR1 rearrangement by FISH with an EWSR1 break-apart probe identified eight patients with FUS rearrangements. Four patients who had EWSR1-ERG fusions were not detected by FISH with an EWSR1 break-apart probe. The authors do not recommend relying solely on EWSR1 break-apart probes for analyzing small round blue cell tumors with strong immunohistochemical positivity for CD99.
Undifferentiated small blue round cell sarcomas with the EWSR1-NFATc2 fusion have been studied with DNA methylation profiling; this revealed a homogeneous methylation cluster for these sarcomas with EWSR1-NFATc2 fusions, which clearly segregated them from the more common form of Ewing sarcoma with EWS-ETS translocations.
Small round blue cell tumors of bone and soft tissue that are histologically similar to Ewing sarcoma but do not have rearrangements of the EWSR1 gene have been analyzed and translocations have been identified. These include BCOR-CCNB3, CIC-DUX4, and CIC-FOX4.[12,13,14,15] 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 (refer to the Undifferentiated Round Cell Sarcomas With BCOR-CCNB3 Rearrangements and Undifferentiated Round Cell Sarcomas With CIC-DUX4 Rearrangements sections of this summary for more information). There are too few cases associated with each translocation to determine whether the prognosis for these small round blue cell tumors is distinct from the prognosis of Ewing sarcoma of similar stage and site.[12,13,14,15]
Some undifferentiated round cell sarcomas are characterized by paracentric inversion of chromosome X and a BCOR-CCNB3 rearrangement; alternative BCOR partners, including MAML3 and ZC3H7B, have also been reported. Despite clinical pathologic similarities to Ewing sarcoma, these tumors are biologically different by expression profiling and single-nucleotide polymorphism array analysis. (Refer to the Undifferentiated Round Cell Sarcomas With BCOR-CCNB3 Rearrangements section of this summary for more information about the treatment of this disease.)
Other undifferentiated round cell sarcomas are characterized by a CIC-DUX4 fusion resulting from a recurrent t(4;19) or t(10;19) and are the most common EWSR1-FUS fusion–negative undifferentiated round cell sarcomas. (Refer to the Undifferentiated Round Cell Sarcomas With CIC-DUX4 Rearrangements section of this summary for more information about the treatment of this disease.)
Genome-wide association studies have identified susceptibility loci for Ewing sarcoma at 1p36.22, 10q21, and 15q15.[18,19,20] Deep sequencing through the 10q21.3 region identified a polymorphism in the EGR2 gene, which appears to cooperate with and magnify the enhanced activity of the gene product of the EWSR1-FLI1 fusion that is seen in most patients with Ewing sarcoma. The polymorphism associated with the increased risk is found at a much higher frequency in whites than in blacks or Asians, possibly contributing to the epidemiology of the relative infrequency of Ewing sarcoma in the latter populations. Three new susceptibility loci have been identified at 6p25.1, 20p11.22, and 20p11.23.
Pretreatment staging studies for Ewing sarcoma may include the following:
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. Whole-body MRI may provide additional information that could potentially alter therapy planning. Additional pretreatment staging studies include bone scan and CT scan of the chest. In certain studies, determination of pretreatment tumor volume is an important variable.
Although 18F-FDG PET or 18F-FDG PET-CT are optional staging modalities, they have demonstrated high sensitivity and specificity in Ewing sarcoma and may provide additional information that alters therapy planning. In one institutional study, 18F-FDG PET had a very high correlation with bone scan; the investigators suggested that it could replace bone scan for the initial extent of disease evaluation. This finding was confirmed in a single-institution retrospective review. 18F-FDG PET-CT is more accurate than 18F-FDG PET alone in Ewing sarcoma.[5,6,7]
Bone marrow aspiration and biopsy have been considered the standard of care for Ewing sarcoma. However, two retrospective studies showed that for patients (N = 141) who were evaluated by bone scan and/or PET scan and lung CT without evidence of metastases, bone marrow aspirates and biopsies were negative in every case.[3,8] A single-institution retrospective review of 504 patients with Ewing sarcoma identified 12 patients with bone marrow metastasis. Only one patient was found to have bone marrow involvement without any other sites of metastatic disease, for an incidence of 1 per 367 (0.3%) in patients with clinically localized disease. The need for routine use of bone marrow aspirates and biopsies in patients without bone metastases is now in question.
For Ewing sarcoma, the tumor is defined as localized when, by clinical and imaging techniques, there is no spread beyond the primary site or regional lymph node involvement. Continuous extension into adjacent soft tissue may occur. If there is a question of regional lymph node involvement, pathologic confirmation is indicated.
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. 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.
Table 3 describes the treatment options for localized, metastatic, and recurrent Ewing sarcoma.
The successful treatment of patients with Ewing sarcoma requires systemic chemotherapy [3,4,5,6,7,8,9] in conjunction with surgery and/or radiation therapy for local tumor control.[10,11,12,13,14] 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.[15,16,17,18,19] 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.
Chemotherapy for Ewing Sarcoma
Multidrug chemotherapy for Ewing sarcoma always includes vincristine, doxorubicin, ifosfamide, and etoposide. Most protocols also use cyclophosphamide and some incorporate dactinomycin. The mode of administration and dose intensity of cyclophosphamide within courses differs markedly between protocols. A European Intergroup Cooperative Ewing Sarcoma Study (EICESS) trial suggested that 1.2 g of cyclophosphamide produced a similar event-free survival (EFS) compared with 6 g of ifosfamide in patients with lower-risk disease, and identified a trend toward better EFS for patients with localized Ewing sarcoma and higher-risk disease when treatment included etoposide (GER-GPOH-EICESS-92 [NCT00002516]).[Level of evidence: 1iiA]
Protocols in the United States generally alternate courses of vincristine, cyclophosphamide, and doxorubicin with courses of ifosfamide/etoposide, while European protocols generally combine vincristine, doxorubicin, and an alkylating agent with or without etoposide in a single treatment cycle. The duration of primary chemotherapy ranges from 6 months to approximately 1 year.
Local Control (Surgery and Radiation Therapy) for Ewing Sarcoma
Treatment approaches for Ewing sarcoma titrate therapeutic aggressiveness with the goal of maximizing local control while minimizing morbidity.
Surgery is the most commonly used form of local control. Radiation therapy is an effective alternative modality for local control in cases where the functional or cosmetic morbidity of surgery is deemed too high by experienced surgical oncologists. However, in the immature skeleton, radiation therapy can cause subsequent deformities that may be more morbid than deformities from surgery. When complete surgical resection with pathologically negative margins cannot be obtained, postoperative radiation therapy is indicated. A multidisciplinary discussion between the experienced radiation oncologist and the surgeon is necessary to determine the best treatment options for local control for a given case. For some marginally resectable lesions, a combined approach of preoperative radiation therapy followed by resection can be used.
Randomized trials that directly compare surgery and radiation therapy do not exist, and their relative roles remain controversial. Although retrospective institutional series suggest superior local control and survival with surgery than with radiation therapy, most of these studies are compromised by selection bias. An analysis using propensity scoring to adjust for clinical features that may influence the preference for surgery only, radiation only, or combined surgery and radiation demonstrated that similar EFS is achieved with each mode of local therapy after propensity adjustment. Data for patients with pelvic primary Ewing sarcoma from a North American intergroup trial showed no difference in local control or survival on the basis of local-control modality—surgery alone, radiation therapy alone, or surgery plus radiation therapy.
For patients who undergo gross-total resection with microscopic residual disease, a radiation therapy dose of 50.4 Gy is indicated; for patients treated with primary radiation therapy, the radiation dose is 55.8 Gy (45 Gy to the initial tumor volume and an additional 10.8 Gy to the postchemotherapy volume).[13,28]
Evidence (postoperative radiation therapy):
Thoracic primary tumors
In summary, surgery is chosen as definitive local therapy for suitable patients, but radiation therapy is appropriate for patients with unresectable disease or those who would experience functional or cosmetic compromise by definitive surgery. The possibility of impaired function or cosmesis needs to be measured against the possibility of second tumors in the radiation field. Adjuvant radiation therapy should be considered for patients with residual microscopic disease or inadequate margins.
When preoperative assessment has suggested a high probability that surgical margins will be close or positive, preoperative radiation therapy has achieved tumor shrinkage and allowed surgical resection with clear margins.
High-Dose Chemotherapy With Stem Cell Support for Ewing Sarcoma
For patients with a high risk of relapse with conventional treatments, certain investigators have utilized high-dose chemotherapy with hematopoietic stem cell transplant (HSCT) as consolidation treatment, in an effort to improve outcome.[19,31,32,33,34,35,36,37,38,39,40,41,42,43]
Evidence (high-dose therapy with stem cell support):
Both study arms were compromised by the potential for selection bias for patients who were eligible for and accepted randomization, which may limit the generalizability of the results. Only 40% of eligible patients were randomized.
The induction regimen employed in the EURO-EWING-INTERGROUP-EE99 trial was VIDE. This regimen is less dose intensive than the regimen employed in COG studies. This can be inferred from the intended dose intensity of the agents employed for the 21-week period that preceded randomization in the EURO-EWING-INTERGROUP-EE99 study (refer to Table 4). The lower dose intensity can also be inferred from the outcome of the EURO-EWING-INTERGROUP-EE99 study for patients in the localized disease stratum. Results from this study include the following:
The observation that high-dose therapy with autologous stem cell rescue improved outcomes for patients with a poor response to initial therapy in the EURO-EWING-INTERGROUP-EE99 study must be interpreted in this context. The advantage of high-dose therapy as consolidation for patients with a poor response to initial treatment with a less intensive regimen cannot be extrapolated to a population of patients who received a more intensive treatment regimen as initial therapy.
Extraosseous Ewing Sarcoma
Multiple analyses have evaluated diagnostic findings, treatment, and outcome of patients with bone lesions at the following anatomic primary sites:
Extraosseous Ewing sarcoma is biologically similar to Ewing sarcoma arising in bone. Historically, most children and young adults with extraosseous Ewing sarcoma were treated on protocols designed for the treatment of rhabdomyosarcoma. This is important because many of the treatment regimens for rhabdomyosarcoma do not include an anthracycline, which is a critical component of current treatment regimens for Ewing sarcoma. Currently, patients with extraosseous Ewing sarcoma are eligible for studies that include Ewing sarcoma of bone.
Evidence (treatment of extraosseous Ewing sarcoma):
Cutaneous Ewing sarcoma is a soft tissue tumor in the skin or subcutaneous tissue that seems to behave as a less-aggressive tumor than primary bone or soft tissue Ewing sarcoma. Tumors can form throughout the body, although the extremity is the most common site, and they are almost always localized.
Evidence (treatment of cutaneous Ewing sarcoma):
Special Considerations for the Treatment of Children With Cancer
Cancer in children and adolescents is rare, although the overall incidence of childhood cancer has been slowly increasing since 1975. 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:
(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. At these pediatric cancer centers, clinical trials are available for most types of cancer that occur in children and adolescents, and the opportunity to participate in these trials is offered to most patients and their families. Clinical trials for children and adolescents with cancer are generally designed to compare potentially better therapy with therapy that is currently accepted as standard. Most of the progress made in identifying curative therapies for childhood cancers has been achieved through clinical trials. Information about ongoing clinical trials is available from the NCI website.
Childhood and adolescent cancer survivors require close monitoring because cancer therapy side effects may persist or develop months or years after treatment. (Refer to the PDQ summary on Late Effects of Treatment for Childhood Cancer for specific information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors.)
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.[1,2,3,4,5,6,7,8] 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.
Current standard chemotherapy in the United States includes vincristine, doxorubicin, and cyclophosphamide (VDC), alternating with ifosfamide and etoposide (IE) or VDC/IE.; [Level of evidence: 1iiA]
In a Children's Oncology Group (COG) trial (COG-AEWS0031 [NCT00006734]), 568 patients with newly diagnosed localized extradural Ewing sarcoma were randomly assigned to receive chemotherapy (VDC/IE) given either every 2 weeks (interval compression) or every 3 weeks (standard). Patients randomly assigned to the every 2-week interval of treatment had an improved 5-year EFS (73% vs. 65%, P = .048). There was no increase in toxicity observed with the every 2-week schedule.
Local control can be achieved by surgery and/or radiation therapy. Decisions regarding the optimal modality for local control for an individual patient involve consideration of the following:
An analysis using propensity scoring (a method that adjusts for the inherent selection bias of the location and size of the tumor) to adjust for clinical features that may influence the preference for surgery only, radiation only, or combined surgery and radiation demonstrated that similar EFS rates are achieved with each mode of local therapy after propensity adjustment.
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.
Potential benefits of surgery include the following:
One arm of the prospective, randomized EURO-EWING-INTERGROUP-EE99 (NCT00020566) trial demonstrated a benefit of high-dose therapy with busulfan-melphalan followed by stem cell rescue compared with continued chemotherapy for patients with localized tumor and poor response to initial chemotherapy.
Pathologic fracture at the time of diagnosis does not preclude surgical resection and is not associated with adverse outcome.
Radiation therapy is usually employed in the following cases:
Radiation therapy is delivered in a setting in which stringent planning techniques are applied by those experienced in the treatment of Ewing sarcoma. Such an approach will result in local control of the tumor with acceptable morbidity in most patients.[1,2,21]
The radiation dose may be adjusted depending on the extent of residual disease after the initial surgical procedure. When no surgical resection is performed, radiation therapy is generally administered in fractionated doses totaling approximately 55.8 Gy to the prechemotherapy tumor volume. A randomized study of 40 patients with Ewing sarcoma using 55.8 Gy to the prechemotherapy tumor extent with a 2-cm margin compared with the same total-tumor dose after 39.6 Gy to the entire bone showed no difference in local control or EFS. Hyperfractionated radiation therapy has not been associated with improved local control or decreased morbidity.
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.
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. 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. 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.
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.
High-dose chemotherapy and autologous stem cell rescue
Evidence (high-dose chemotherapy and autologous stem cell rescue):
Both study arms were compromised by the potential for selection bias for patients who were eligible for and accepted randomization, which may limit the generalizability of the results. Only 40% of eligible patients were randomized.
The induction regimen employed in the EURO-EWING-INTERGROUP-EE99 trial included vincristine, ifosfamide, doxorubicin, and etoposide (VIDE). This regimen is less dose intensive than the regimen employed in COG studies. This can be inferred from the intended dose intensity of the agents employed for the 21-week period that preceded randomization in the EURO-EWING-INTERGROUP-EE99 study (refer to Table 4). The lower dose intensity can also be inferred from the outcome of the EURO-EWING-INTERGROUP-EE99 study for patients in the localized disease stratum. Results from this study include the following:
Current Clinical Trials
Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
Metastases at diagnosis are detected in approximately 25% of patients. 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:
Standard Treatment Options for Metastatic Ewing Sarcoma
Standard treatment options for metastatic Ewing sarcoma include the following:
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%.[5,6,7]
The following chemotherapy regimens have not shown benefit:
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):
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.
The radiation dose depends on the metastatic site of disease:
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.[2,3,10,16,17,18]; [Level of evidence: 3iiiDi] (Refer to the High-Dose Therapy With Stem Cell Rescue for Ewing Sarcoma section of this summary for more information.)
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. An analysis of the Surveillance, Epidemiology, and End Results database identified 1,351 patients who survived more than 60 months from diagnosis. Of these patients, 209 died, with 144 of the deaths (69%) attributed to recurrent, progressive Ewing sarcoma. Black race, male sex, older age at initial diagnosis, and primary tumors of the pelvis and axial skeleton were associated with a higher risk of late death. This analysis covered the period from 1973 to 2013, and the 1,351 patients represented only 38% of the patients in the original sample, which reflects the inferior treatment outcomes from the earlier era. It is possible that patients who reach the 5-year point after more contemporary treatment may not recapitulate this experience.
The overall prognosis for patients with recurrent Ewing sarcoma is poor; 5-year survival after recurrence is approximately 10% to 15%.[2,5,6]; [Level of evidence: 3iiA]
Prognostic factors include the following:
Treatment Options for Recurrent Ewing Sarcoma
The selection of treatment for patients with recurrent disease depends on many factors, including the following:
There is no standardized second-line treatment for relapsed or refractory Ewing sarcoma.
Treatment options for recurrent Ewing sarcoma include the following:
Combinations of chemotherapy, such as cyclophosphamide and topotecan or irinotecan and temozolomide with or without vincristine, are active in recurrent Ewing sarcoma and can be considered for these patients.[8,9,10,11,12,13]
These studies were retrospective, not prospective; prospective trials with clearly defined eligibility cohorts and intent-to-treat analyses are lacking. When combined, these studies accrued 99 patients and observed 3 complete remissions and 27 partial remissions. The objective response rate was 30%.
Most of these studies were retrospective, not prospective; there are only four prospective trials with well-defined eligibility cohorts and report by intent to treat. In addition, there is significant variability among the reports in doses and dose schedules of irinotecan and temozolomide and the use of additional agents. When combined, these studies accrued 176 patients and observed 18 complete remissions and 56 partial remissions. The objective response rate was 42%.
In the largest retrospective multicenter study of the combination of temozolomide and irinotecan in patients with recurrent and primary refractory Ewing sarcoma, 51 patients (66% of patients were aged ≥18 years; median age, 21 years) were treated with temozolomide (100 mg/m2 /day orally) and irinotecan (40 mg/m2 /day intravenously), on days 1 to 5, every 21 days. Twenty-five percent of the patients were in first relapse/progression, while the remainder of the patients were in second or greater relapse/progression.
Radiation therapy to bone lesions may provide palliation, although radical resection may improve outcome. Patients with pulmonary metastases who have not received radiation therapy to the lungs should be considered for whole-lung irradiation. Residual disease in the lung may be surgically removed.
High-dose chemotherapy with stem cell support
Aggressive attempts to control the disease, including myeloablative regimens, have been used, but there is no evidence at this time to conclude that myeloablative therapy is superior to standard chemotherapy.[29,30]; [Level of evidence: 3iiA]; [Level of evidence: 3iiiDiii]
Most published reports about the use of high-dose therapy and stem cell support for patients with high-risk Ewing sarcoma have significant flaws in methodology. The most common error is the comparison of this high-risk group with an inappropriate control group. Patients with Ewing sarcoma at high risk of treatment failure who received high-dose therapy are compared with patients who did not receive high-dose therapy. Patients who undergo high-dose therapy must respond to systemic therapy, remain alive and respond to treatment long enough to reach the time at which stem cell therapy can be applied, be free of comorbid toxicity that precludes high-dose therapy, and have an adequate stem cell collection. Patients who undergo high-dose therapy and stem cell support are a highly selected group; comparing this patient group with all patients with high-risk Ewing sarcoma is inappropriate and leads to the erroneous conclusion that this strategy improves outcome.
Surveys of patients undergoing allogeneic stem cell transplantation (SCT) for recurrent Ewing sarcoma did not show improved event-free survival when compared with autologous SCT and was associated with a higher complication rate.[29,33,34]
Other therapies that have been studied in the treatment of recurrent Ewing sarcoma include the following:
Treatment Options Under Clinical Evaluation for Recurrent Ewing Sarcoma
Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, refer to the ClinicalTrials.gov website.
The following are examples of national and/or institutional clinical trials that are currently being conducted:
Tumor tissue from progressive or recurrent disease must be available for molecular characterization. Patients with tumors that have molecular variants addressed by treatment arms included in the trial will be offered treatment on Pediatric MATCH. Additional information can be obtained on the NCI website and ClinicalTrials.gov website.
Undifferentiated Round Cell Sarcomas WithBCOR-CCNB3Rearrangements
Undifferentiated round cell sarcomas with BCOR-CCNB3 rearrangements account for about 5% of all EWSR1-negative rearranged sarcomas and more commonly affects males. More than 70% of cases occur in patients younger than 18 years (median age at diagnosis, 13–15 years).[1,2][Level of evidence: 3iiA] These tumors more commonly arise in the bones of the pelvis and extremities, and metastases are present in approximately 30% of cases.
Treatment of undifferentiated round cell sarcomas withBCOR-CCNB3rearrangements
When treated with Ewing sarcoma–like therapies, 75% of patients show significant treatment-associated pathologic responses. In one series of 36 cases, the 3-year and 5-year survival rates were 93% and 72%, respectively.[Level of evidence: 3iiA] In another series of 26 patients, the 5-year overall survival was 76.5%, and survival was better for patients who received induction therapy using an Ewing sarcoma–type regimen.[Level of evidence: 3iiA] Most of the tumors in these series arose in the bone.
Undifferentiated Round Cell Sarcomas WithCIC-DUX4Rearrangements
Undifferentiated round cell sarcomas with CIC-DUX4 rearrangements most commonly affect young adults, with 50% of cases occurring between the ages of 21 and 40 years. In a series of 115 cases, the median age at diagnosis was 32 years, and 22% of cases occurred in patients younger than 18 years.[2,4] This entity more commonly affects males and usually originates from the soft tissues of the trunk and extremities.
Treatment of undifferentiated round cell sarcomas withCIC-DUX4rearrangements
In a series of 115 cases of CIC-rearranged round cell sarcomas, 57 patients had adequate follow-up information. Nine patients presented with metastases, and 53% of patients with localized disease experienced a recurrence commonly involving the lung. Patients treated with neoadjuvant chemotherapy had an inferior survival compared with patients who were treated with up-front surgical resection; however, this difference might have been related to a larger tumor size at presentation in the former group. The 2-year and 5-year survival rates were 53% and 43%, respectively. These survival rates are significantly lower than the survival rates observed in patients with Ewing sarcoma. Further study is required to identify optimal treatments for this disease.
The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.
General Information About Ewing Sarcoma
Added Ahmed et al. as reference 27.
Genomics of Ewing Sarcoma
Added text to state that undifferentiated small blue round cell sarcomas with the EWSR1-NFATc2 fusion have been studied with DNA methylation profiling; this revealed a homogeneous methylation cluster for these sarcomas with EWSR1-NFATc2 fusions, which clearly segregated them from the more common form of Ewing sarcoma with EWS-ETS translocations (cited Koelsche et al. as reference 11).
Added text to state that some undifferentiated round cell sarcomas are characterized by paracentric inversion of chromosome X and a BCOR-CCNB3 rearrangement; alternative BCOR partners, including MAML3 and ZC3H7B, have also been reported. Despite clinical pathologic similarities to Ewing sarcoma, these tumors are biologically different by expression profiling and single-nucleotide polymorphism array analysis (cited Schaefer et al. as reference 16).
Added text to state that other undifferentiated round cell sarcomas are characterized by a CIC-DUX4 fusion resulting from a recurrent t(4;19) or t(10;19) and are the most common EWSR1-FUS fusion–negative undifferentiated round cell sarcomas (cited Antonescu et al. as reference 17).
Stage Information for Ewing Sarcoma
Added text to state that a single-institution retrospective review of 504 patients with Ewing sarcoma identified 12 patients with bone marrow metastasis. Only one patient was found to have bone marrow involvement without any other sites of metastatic disease, for an incidence of 1 per 367 in patients with clinically localized disease (cited Cesari et al. as reference 9).
Treatment Option Overview for Ewing Sarcoma
Revised text to state that for patients who undergo gross-total resection with microscopic residual disease, a radiation therapy dose of 50.4 Gy is indicated; for patients treated with primary radiation therapy, the radiation dose is 55.8 Gy.
Added Thoracic primary tumors as a new subsection.
Added text to state that only 40% of eligible patients were randomized in the EURO-EWING-INTERGROUP-EE99 trial.
Added text to state that the 3-year overall survival (OS) was 78.0% with busulfan-melphalan (BuMel) and 72.2% with continued chemotherapy in the EURO-EWING-INTERGROUP-EE99 trial.
Revised text to state that the probability for event-free survival (EFS) at 3 years for the favorable group was 76%, and OS at 3 years was 85%. Also revised text to state that for all patients with localized Ewing sarcoma, including patients with large primary tumors and patients with poor response to initial therapy treated on the COG-AEWS1031 trial, the 5-year probability for EFS was 73%, and the 5-year OS was 88%.
Revised Table 4 to include the cyclophosphamide equivalent doses in the EURO-EWING-INTERGROUP-EE99 and Children's Oncology Group trials.
Treatment of Localized Ewing Sarcoma
Added text to state that decisions regarding the optimal modality for local control for an individual patient involve several considerations, including the possibility of a complete resection with adequate margins after an initial period of systemic therapy, the predicted functional impact of a surgical procedure, the predicted morbidity after radiation therapy, and the possibility of increased risk of second malignant neoplasms after radiation therapy.
Added text to state that an analysis using propensity scoring to adjust for clinical features that may influence the preference for surgery only, radiation only, or combined surgery and radiation demonstrated that similar EFS rates are achieved with each mode of local therapy after propensity adjustment (cited DuBois et al. as reference 14).
Added text to state that the 3-year OS was 78.0% with BuMel and 72.2% with continued chemotherapy in the EURO-EWING-INTERGROUP-EE99 trial.
Revised text to state that the probability for EFS at 3 years for the favorable group was 76%, and OS at 3 years was 85%. Also revised text to state that for all patients with localized Ewing sarcoma, including patients with large primary tumors and patients with poor response to initial therapy treated on the COG-AEWS1031 trial, the 5-year probability for EFS was 73%, and the 5-year OS was 88%.
Treatment of Recurrent Ewing Sarcoma
Added text to state that the studies in Table 5 were retrospective, not prospective; prospective trials with clearly defined eligibility cohorts and intent-to-treat analyses are lacking.
Added text to state that most of the studies in Table 6 were retrospective, not prospective; there are only four prospective trials with well-defined eligibility cohorts and report by intent to treat. In addition, there is significant variability among the reports in doses and dose schedules of irinotecan and temozolomide and the use of additional agents.
Undifferentiated Round Cell (Ewing-like) Sarcomas
Added this new section.
This summary is written and maintained by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® - NCI's Comprehensive Cancer Database pages.
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:
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:
Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.
Levels of Evidence
Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Pediatric Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.
Permission to Use This Summary
PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as "NCI's PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary]."
The preferred citation for this PDQ summary is:
PDQ® Pediatric Treatment Editorial Board. PDQ Ewing Sarcoma Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/bone/hp/ewing-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389480]
Images in this summary are used with permission of the author(s), artist, and/or publisher for use within the PDQ summaries only. Permission to use images outside the context of PDQ information must be obtained from the owner(s) and cannot be granted by the National Cancer Institute. Information about using the illustrations in this summary, along with many other cancer-related images, is available in Visuals Online, a collection of over 2,000 scientific images.
Based on the strength of the available evidence, treatment options may be described as either "standard" or "under clinical evaluation." These classifications should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on Cancer.gov on the Managing Cancer Care page.
More information about contacting us or receiving help with the Cancer.gov website can be found on our Contact Us for Help page. Questions can also be submitted to Cancer.gov through the website's Email Us.
Last Revised: 2019-08-15
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