Dramatic improvements in survival have been achieved for children and adolescents with cancer.[1] Between 1975 and 2020, childhood cancer mortality decreased by more than 50%.[1-3] For Ewing sarcoma, the 5-year survival rate has increased from 59% to a range of 75% to 80% for children younger than 15 years and from 20% to 65% for adolescents aged 15 to 19 years.[1,2]
Studies using immunohistochemical markers,[4] cytogenetics,[5,6] molecular genetics, and tissue culture [7] indicate that Ewing sarcoma originates from a primordial bone marrow–derived mesenchymal stem cell.[8,9] 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 World Health Organization (WHO) classification of tumors of soft tissue and bone was modified in 2020 to introduce a new chapter on undifferentiated small round cell sarcomas of bone and soft tissue. This chapter consists of Ewing sarcoma and three main categories, including round cell sarcomas with EWSR1::non-ETS fusions, CIC-rearranged sarcoma, and sarcomas with BCOR genetic alterations.[10]
Before the widespread availability of genomic testing, Ewing sarcoma was identified by the appearance of small round blue cells on light microscopic examination, along with positive staining for CD99 by immunohistochemistry. The identification of the recurring t(11;22) translocation in most Ewing sarcoma tumors led to the discovery that most tumors classified as Ewing sarcoma had a translocation that juxtaposed a portion of the EWSR1 gene to a portion of an ETS gene family member, resulting in a transforming transcript. Not all undifferentiated small round cell sarcomas of bone and soft tissue have such a translocation. Further research identified additional genetic changes, including tumors with translocations of the CIC gene or the BCOR gene. These groups of tumors occur much less frequently than Ewing sarcoma, and definitive clinical outcomes for these patients are based on smaller sample sizes and less homogeneous treatment; therefore, patient outcomes are harder to quantitate with precision. Most of these tumors have been treated with regimens designed for Ewing sarcoma, and there is consensus that they were often included in clinical trials for the treatment of Ewing sarcoma, sometimes as translocation-negative Ewing sarcoma. There is agreement that these tumors are sufficiently different from Ewing sarcoma. These tumors should be stratified and analyzed separately from Ewing sarcoma with the common translocation, even if they are treated with similar therapy. In this summary, they are described separately. For more information about these smaller groups of tumors, see the following sections:
The incidence of Ewing sarcoma has remained unchanged for 30 years.[11] The incidence for all ages is 1 case per 1 million people in the United States. In patients aged 10 to 19 years, the incidence is between 9 and 10 cases per 1 million people. The same analysis suggests that the incidence of Ewing sarcoma in the United States is nine times greater in White people than in Black people, with an intermediate incidence in Asian people.[12,13]
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.[14]
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.[15,16] Based on data from 1,426 patients entered on European Intergroup Cooperative Ewing Sarcoma Studies, 59% of patients are male and 41% are female.[17]
Conventional understanding of translocation-driven sarcoma such as Ewing sarcoma suggests that these patients do not have a genetic predisposition.[18] A retrospective European-focused and panancestry case-controlled analysis was performed. The purpose of this study was to screen for enrichment of pathogenic germline variants in 141 established cancer predisposition genes in 1,147 pediatric patients with sarcoma diagnoses (226 Ewing sarcomas, 438 osteosarcomas, 180 rhabdomyosarcomas, and 303 other sarcomas) relative to identically processed cancer-free control individuals. A distinct pattern of pathogenic germline variants was seen in Ewing sarcoma compared with other sarcoma types. FANCC was the only gene with an enrichment signal for heterozygous pathogenic variants in the European Ewing sarcoma discovery cohort (three individuals; odds ratio [OR], 12.6; 95% confidence interval [CI], 3.0–43.2; P = .003; false discovery rate, 0.40). This enrichment in FANCC heterozygous pathogenic variants was again observed in the European Ewing sarcoma validation cohort (three individuals; OR, 7.0; 95% CI, 1.7–23.6; P = .014).
Primary sites of bone disease include the following:
For extraosseous primary tumors, the most common primary sites of disease include the following:[20,21]
The time from the 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 the first symptom to diagnosis has not been associated with metastasis, surgical outcome, or survival.[22] Approximately 25% of patients with Ewing sarcoma have metastatic disease at the time of diagnosis.[11]
The Surveillance, Epidemiology, and End Results (SEER) Program database was used to compare patients younger than 40 years with Ewing sarcoma who presented with skeletal and extraosseous primary sites (see Table 1).[23] Patients with extraosseous Ewing sarcoma were more likely to be older, female, of non-White race, and have axial primary sites, and they were less likely to have pelvic primary sites than were patients with skeletal Ewing sarcoma.
Characteristic | Extraosseous Ewing Sarcoma | Skeletal Ewing Sarcoma | P Value |
---|---|---|---|
aAdapted from Applebaum et al.[23] | |||
Mean age (range), years | 20 (0–39) | 16 (0–39) | <.001 |
Male | 53% | 63% | <.001 |
White race | 85% | 93% | <.001 |
Axial primary sites | 73% | 54% | <.001 |
Pelvic primary sites | 20% | 27% | .001 |
The following tests and procedures may be used to diagnose or stage Ewing sarcoma:
For primary appendicular bone tumors, imaging of the entire involved bone is standardly performed to evaluate for skip metastasis. In one retrospective study, skip metastasis was seen in 15.8% of patients. The presence of skip metastasis was associated with an increased risk of distant metastatic disease.[24]
A systematic review of Ewing sarcoma studies was performed to assess the incidence of bone marrow metastasis and the role of fluorine F 18-fludeoxyglucose (18F-FDG) PET imaging to detect bone marrow metastasis.[25] The review reported a pooled incidence of bone marrow metastasis of 4.8% in all patients with newly diagnosed Ewing sarcoma and 17.5% in patients with metastatic disease. Only 1.2% of patients had bone marrow metastasis as their sole metastatic site. Compared with bone marrow biopsy and aspiration, 18F-FDG PET detection of bone marrow metastasis demonstrated pooled 100% sensitivity and 96% specificity, positive predictive value of 75%, and negative predictive value of 100%. In the era of 18F-FDG PET imaging, omission of bone marrow biopsy and aspiration may be considered in patients with otherwise localized disease after initial staging studies. For more information about diagnostic biopsy, see the Treatment Option Overview for Ewing Sarcoma section.
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.[26,28,29,42] 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.[43]
Patients with metastasis to only bone seem to have a better outcome than do patients with metastases to both bone and lung.[44,45]
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.[46]
In a study of 299 patients with Ewing sarcoma, 41 patients (14%) had STAG2 variants and 16 patients (5%) had TP53 variants.[53] There was no association with OS for patients with either the STAG2 or TP53 variant alone. However, the nine patients (3%) with tumors that had both STAG2 and TP53 variants had a significantly decreased OS rate (<20% at 4 years).
The COG analyzed STAG2 expression by immunohistochemistry in children with Ewing sarcoma who participated in frontline treatment trials.[62] STAG2 was lost in 29 of 108 patients with localized disease and in 6 of 27 patients with metastatic disease. Among patients who had immunohistochemistry and sequencing performed, no cases (0 of 17) with STAG2 expression had STAG2 variants, and 2 of 7 cases with STAG2 loss had STAG2 variants. Among patients with localized disease, the 5-year EFS rate was 54% (95% CI, 34%–70%) for those with STAG2 loss, compared with 75% (95% CI, 63%–84%) for those with STAG2 expression (P = .0034).
The following are not considered to be adverse prognostic factors for Ewing sarcoma:
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.[68-72]; [73][Level of evidence C2] In particular, patients with localized disease who have no viable tumor seen at the time of local-control surgery appear to have markedly favorable outcomes.[72]; [73][Level of evidence C2] Female sex and younger age predict a good histological response to preoperative therapy.[74] For patients who receive preinduction- and postinduction-chemotherapy PET scans, decreased PET uptake after chemotherapy correlated with good histological response and better outcome.[75-77]
Patients with poor response to presurgical chemotherapy have an increased risk of local recurrence.[78]
A retrospective analysis of risk factors for recurrence was performed in patients who received initial chemotherapy and underwent surgical resection of the primary tumor.[79][Level of evidence C1] Among 982 patients with a median follow-up of 7.6 years, the following was reported:
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.[59,80] RT-PCR for the EWSR1::FLI1 translocation was also not considered a reliable biomarker.[81]
A more sensitive technique that used patient-specific primers designed after identification of the specific translocation breakpoint in combination with droplet digital PCR reported a sensitivity of 0.009% to 0.018%.[82] 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.[83] 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.
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 pathological parameters.[1] CD99 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.
For more information about the cellular classification of other undifferentiated small round cell sarcomas, see the Undifferentiated Small Round Cell (Ewing-Like) Sarcomas section.
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 (see Table 2).[1] The EWSR1 gene is a member of the TET family [TLS/EWS/TAF15] of RNA-binding proteins.[2] The FLI1 gene is a member of the ETS family of DNA-binding genes. Characteristically, the amino terminus of the EWSR1 gene is juxtaposed with the carboxy terminus of the ETS family genes. 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, and FEV.[3] Rarely, FUS, another TET family member, can substitute for EWSR1.[4] Finally, there are a few rare cases in which EWSR1 has translocated with partners that are not members of the ETS family of oncogenes. The significance of these alternate partners is not known.
Besides these consistent aberrations involving the EWSR1 gene at 22q12, additional numerical and structural aberrations have been observed in Ewing sarcoma, including gains of chromosomes 2, 5, 8, 9, 12, and 15; the nonreciprocal translocation t(1;16)(q12;q11.2); and deletions on the short arm of chromosome 6. Trisomy 20 may be associated with a more aggressive subset of Ewing sarcoma.[5]
Three papers have described the genomic landscape of Ewing sarcoma and all show that these tumors have a relatively silent genome, with a paucity of variants in pathways that might be amenable to treatment with novel targeted therapies.[6-8] These papers identified recurring genomic alterations in several genes:
A discovery cohort (n = 99) highlighted 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 variant, and the relative paucity of recurrent single nucleotide variants for Ewing sarcoma.[6]
Ewing sarcoma translocations can all be found with standard cytogenetic analysis. A more rapid analysis looking for a break apart of the EWSR1 gene is now frequently done to confirm the diagnosis of Ewing sarcoma molecularly.[12] This test result must be considered with caution, however. Ewing sarcomas that utilize FUS 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 EWSR1 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.[13] 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.
Genome-wide association studies have identified susceptibility loci for Ewing sarcoma at 1p36.22, 10q21, and 15q15.[14-16] 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.[15] The polymorphism associated with the increased risk is found at a much higher frequency in White people than in Black or Asian people, 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.[16]
TET Family Partner | Fusion With ETS-Like Oncogene Partner | Translocation | Comment |
---|---|---|---|
aThese partners are not members of the ETS family of oncogenes. | |||
EWSR1 | EWSR1::FLI1 | t(11;22)(q24;q12) | Most common; approximately 85% to 90% of cases |
EWSR1::ERG | t(21;22)(q22;q12) | Second most common; approximately 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::PATZ1a | t(6;22)(p21;q12) | ||
EWSR1::SP3a | t(2;22)(q31;q12) | Rare | |
FUS | FUS::ERG | t(16;21)(p11;q22) | Rare |
FUS::FEV | t(2;16)(q35;p11) | Rare |
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.[1] Whole-body MRI may provide additional information that could potentially alter therapy planning.[2] Additional pretreatment staging studies include bone scan and CT scan of the chest. In certain studies, determination of pretreatment tumor volume is an important variable.
Although 18F-FDG PET or 18F-FDG PET-CT are optional staging modalities, they have demonstrated high sensitivity and specificity in Ewing sarcoma and may provide additional information that alters therapy planning. In one institutional study, 18F-FDG PET had a very high correlation with bone scan; the investigators suggested that it could replace bone scan for the initial extent of disease evaluation.[3] This finding was confirmed in a single-institution retrospective review.[4] 18F-FDG PET-CT is more accurate than 18F-FDG PET alone in Ewing sarcoma.[5-7]
Bone marrow aspiration and biopsy have been considered the standard of care for Ewing sarcoma. However, two retrospective studies showed that for patients (N = 141) who were evaluated by bone scan and/or PET scan and lung CT without evidence of metastases, bone marrow aspirates and biopsies were negative in every case.[3,8] A single-institution retrospective review of 504 patients with Ewing sarcoma identified 12 patients with bone marrow metastasis.[9] Only one patient was found to have bone marrow involvement without any other sites of metastatic disease, for an incidence of 1 per 367 (0.3%) in patients with clinically localized disease. The need for routine use of bone marrow aspirates and biopsies in patients without bone metastases is now in question.
For Ewing sarcoma, the tumor is defined as localized when, by clinical and imaging techniques, there is no spread beyond the primary site or regional lymph node involvement. Continuous extension into adjacent soft tissue may occur. If there is a question of regional lymph node involvement, pathological confirmation is indicated.
It is important that patients be evaluated by specialists from the appropriate disciplines (e.g., radiologists, medical oncologists, 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 subsequently be totally excised after initial systemic therapy or if a limb salvage procedure may be attempted. It is almost never appropriate to attempt a primary resection of Ewing sarcoma. With rare exceptions, Ewing sarcoma is sensitive to chemotherapy and will respond to initial systemic therapy. This therapy reduces the risk of tumor spread to surrounding tissues and makes ultimate surgery easier and safer. Biopsy should be from soft tissue as often as possible to avoid increasing the risk of fracture.[1] If the initial biopsy sample is obtained from bone, the pathologist must be notified to reserve some tissue without decalcification because decalcification denatures DNA and makes genomic profiling of tumor tissue impossible.[2] 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.[3]
Table 3 describes the treatment options for localized, metastatic, and recurrent Ewing sarcoma.
Treatment Group | Standard Treatment Options | |
---|---|---|
Localized Ewing sarcoma | Chemotherapy | |
Local-control measures: | ||
Surgery | ||
Radiation therapy | ||
High-dose chemotherapy with autologous stem cell rescue | ||
Metastatic Ewing sarcoma | Chemotherapy | |
Surgery | ||
Radiation therapy | ||
Recurrent Ewing sarcoma | Chemotherapy (not considered standard treatment) | |
Surgery (not considered standard treatment) | ||
Radiation therapy (not considered standard treatment) | ||
High-dose chemotherapy with stem cell support (not considered standard treatment) | ||
Other therapies (not considered standard treatment) |
The successful treatment of patients with Ewing sarcoma requires systemic chemotherapy [4-10] in conjunction with surgery and/or radiation therapy for local tumor control.[11-15] In general, patients receive chemotherapy before instituting local-control measures. In patients who undergo surgery, surgical margins and histological 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.[16-21] 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.[22]
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]).[23][Level of evidence A1]
Protocols in the United States generally alternate courses of vincristine, cyclophosphamide, and doxorubicin (VDC) with courses of ifosfamide and etoposide (IE),[8] while, for many years, European protocols generally combined vincristine, doxorubicin, and an alkylating agent with or without etoposide in a single treatment cycle.[10] After the completion of the randomized EURO EWING 2012 (EE2012) trial (see below), European investigators shifted to therapy with cycles of VDC alternating with cycles of IE.[24][Level of evidence B1] The duration of primary chemotherapy ranges from 6 months to approximately 1 year.
Evidence (chemotherapy):
Treatment approaches for Ewing sarcoma and therapeutic aggressiveness must be adjusted to maximize local control while also minimizing morbidity.
Surgery is the most commonly used form of local control.[30] 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.
Timing of local control may impact outcome. A retrospective review from the National Cancer Database identified 1,318 patients with Ewing sarcoma.[31] Patients who initiated local therapy at 6 to 15 weeks had a 5-year OS rate of 78.7% and a 10-year OS rate of 70.3%, and patients who initiated local therapy after 16 weeks had a 5-year OS rate of 70.4% and a 10-year OS rate of 57.1% (P < .001). The difference in OS according to time to local therapy was more important in patients who received radiation therapy alone.
For patients with metastatic Ewing sarcoma, any benefit of combined surgery and radiation therapy compared with either therapy alone for local control is relatively less substantial because the overall prognosis of these patients is much worse than the prognosis of patients who have localized disease.
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.[30] 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.[32]
The EURO-EWING-INTERGROUP-EE99 (NCT00020566) trial prospectively treated 180 patients with pelvic primary tumors without clinically detectable metastatic disease.[33][Level of evidence B4] A retrospective analysis of outcomes for these patients showed improved survival for patients whose tumors were treated with combined radiation therapy and surgery. The study did not prospectively define criteria for the selection of local-control modalities, and the investigators did not have access to information that would allow them to clarify why decisions for local-control modalities were made. In nonsacral tumors, combined local treatment was associated with a lower local recurrence probability (14% [95% CI, 5%–23%] vs. 33% [95% CI, 19%–47%] at 5 years; P = .015) and a higher OS probability (72% [95% CI, 61%–83%] vs. 47% [95% CI, 33%–62%] at 5 years; P = .024) compared with surgery alone. Even in a subgroup of patients with wide surgical margins and a good histological response to induction treatment, the combined local treatment was associated with a higher OS probability (87% [95% CI, 74%–100%] vs. 51% [95% CI, 33%–69%] at 5 years; P = .009) compared with surgery alone. In patients with bone tumors who underwent surgical treatment— after controlling for tumor site in the pelvis, tumor volume, and surgical margin status—patients who did not undergo complete removal of the affected bone (HR, 5.04; 95% CI, 2.07–12.24; P < .001), patients with a poor histological response to induction chemotherapy (HR, 3.72; 95% CI, 1.51–9.21; P = .004), and patients who did not receive additional radiation therapy (HR, 4.34; 95% CI, 1.71–11.05; P = .002) had a higher risk of death.
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).[14,34]
Evidence (postoperative radiation therapy):
Evidence (surgery):
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.[37]
For patients with a high risk of relapse with conventional treatments, certain investigators have used high-dose chemotherapy with hematopoietic stem cell transplant (HSCT) as consolidation treatment, in an effort to improve outcome.[19,38-50]
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 (see 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.
Chemotherapy Agent | Prescribed Dose Intensity (mg/week) | |
---|---|---|
EURO-EWING-INTERGROUP-EE99 Trial [25] | COG Interval Dose Compression [26] | |
COG = Children's Oncology Group. | ||
Vincristine | 0.5 mg/m2 | 0.43 mg/m2 |
Doxorubicin | 17.1 mg/m2 | 21.4 mg/m2 |
Ifosfamide | 3,000 mg/m2 | 2,150 mg/m2 |
Cyclophosphamide | 0 | 343 mg/m2 |
Cyclophosphamide equivalent dose (= cyclophosphamide dose + ifosfamide dose × 0.244) | 732 mg/m2 | 868 mg/m2 |
Multiple analyses have evaluated diagnostic findings, treatment, and outcome of patients with bone lesions at the following anatomical 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):
Cancer in children and adolescents is rare, although the overall incidence 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:
For specific information about supportive care for children and adolescents with cancer, see the summaries on Supportive and Palliative Care.
The American Academy of Pediatrics has outlined guidelines for pediatric cancer centers and their role in the treatment of pediatric patients with cancer.[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 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 current standard therapy. 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 side effects of cancer therapy may persist or develop months or years after treatment. For specific information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors, see Late Effects of Treatment for Childhood Cancer.
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] Patients with localized Ewing sarcoma who receive current treatment regimens achieve event-free survival (EFS) and overall survival (OS) rates of approximately 70% at 5 years after diagnosis.[9]
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 A1] With the outcome of the EURO EWING 2012 (EE2012) trial, which compared VDC/IE to VIDE (vincristine, ifosfamide, doxorubicin, etoposide), the VDC/IE regimen has become increasingly used internationally as initial therapy over the previous VIDE regimen.[11][Level of evidence B1] For more information about the EE2012 trial, see the Chemotherapy for Ewing Sarcoma section.
Evidence (chemotherapy):
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.[17]
Surgery is generally the preferred approach if the lesion is resectable.[18,19] The superiority of resection for local control has never been tested in a prospective randomized trial. The apparent superiority may represent selection bias.
A single-institution retrospective analysis of 78 patients with Ewing sarcoma suggested that pathological fracture at initial presentation was associated with inferior EFS and OS.[22][Level of evidence C1] Another study found that pathological fracture at the time of diagnosis did not preclude surgical resection and was not associated with adverse outcome.[23]
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.[1,2,24]
The radiation dose may be adjusted depending on the extent of residual disease after the initial surgical procedure. When no surgical resection is performed, radiation therapy is generally administered in fractionated doses totaling approximately 55.8 Gy to the prechemotherapy tumor volume. A randomized study of 40 patients with Ewing sarcoma using 55.8 Gy to the prechemotherapy tumor extent with a 2-cm margin compared with the same total-tumor dose after 39.6 Gy to the entire bone showed no difference in local control or EFS.[3] Hyperfractionated radiation therapy has not been associated with improved local control or decreased morbidity.[1]
Preoperative radiation therapy is an approach that can be used when surgical resection is deemed possible but with the likelihood of microscopic residual disease. A panel of international expert clinicians used a three-stage modified Delphi technique to develop consensus statements about local treatment. The panel reached a strong consensus that preoperative radiation therapy may be given when an inadequate (marginal) margin at resection is foreseen on imaging.[25]
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 had no evidence of microscopic residual disease after surgical resection.[14]
For patients who are deemed to have unresectable disease after induction chemotherapy, radiation therapy is given, using the same doses as those administered for patients with partially resected disease.[26] Patients who have unresectable disease are typically those with extremity tumors that have persistent encasement of the neurovascular bundles and/or morbid surgical excision entailing loss of functionality. In a phase III randomized controlled clinical trial of patients with unresectable disease, patients were randomly assigned to receive either standard-dose radiation therapy (55.8 Gy in 1.8 Gy fractions) or escalated-dose radiation therapy (70.2 Gy in 1.8 Gy fractions).[26] From 2005 to 2015, the study accrued 47 patients who received standard-dose radiation therapy and 48 patients who received escalated-dose radiation therapy (interquartile age, 13–23 years). The median largest tumor dimension was 9.7 cm. At a median follow-up of 67 months, the 5-year local control rate was significantly better in the escalated arm than in the standard arm (76.4% vs. 49.4%; P = .02). The differences in disease-free survival (DFS) and OS at 5 years did not achieve statistical significance (DFS rates, 46.7% vs. 31.8%; P = .22; OS rates, 58.8% vs. 45.4%; P = .08), possibly because the rate of metastatic disease was not changed. A skin toxicity grade of more than 2 was greater in the high-dose arm (10.4% vs. 2.1%; P = .08).
In a single-institution nonrandomized study, patients who had primary tumors 8 cm or larger were treated with higher-dose radiation therapy (median dose, 64.8 Gy). The 5-year cumulative incidence of local failure rate was 6.6%, which compares favorably to other published local failure rates in this group of patients.[27]
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.[28] 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 larger than 8 cm in length.[29] Among patients with pelvic tumors, a larger tumor volume, a periacetabular tumor site, and the use of definitive radiation therapy only (rather than a combined-modality approach) were associated with higher rates of local failure.[30] 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.[31]
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%. Patients 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.[32]
Evidence (high-dose chemotherapy with 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 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 (see 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.
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Approximately 25% of patients with Ewing sarcoma have metastases at diagnosis.[1] The prognosis of patients with metastatic disease is poor. With current therapies, patients who present with metastatic disease have a 6-year event-free survival (EFS) rate of approximately 28% and an overall survival (OS) rate of approximately 30%.[2,3] For patients with lung/pleural metastases only, the 6-year EFS rate is approximately 40% when using bilateral lung irradiation.[2,4] In contrast, patients with bone/bone marrow metastases have a 4-year EFS rate of approximately 28%, and patients with combined lung and bone/bone marrow metastases have a 4-year EFS rate of approximately 14%.[4,5]
The following factors independently predict a poor outcome in patients presenting with metastatic disease:[3]
Standard treatment options for metastatic Ewing sarcoma include the following:
For patients with metastatic Ewing sarcoma, standard treatment that uses alternating cycles of vincristine/doxorubicin/cyclophosphamide and ifosfamide/etoposide (VDC/IE) 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:
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 the tumor with acceptable morbidity in most patients.[14]
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.[2,3,11,17-19]; [20][Level of evidence C2] For more information, see the High-Dose Therapy With Stem Cell Rescue for Ewing Sarcoma section.
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Recurrence of Ewing sarcoma is most common within 2 years of initial diagnosis (approximately 80%).[1,2] However, late relapses occurring more than 5 years from initial diagnosis are more common in Ewing sarcoma (13%; 95% confidence interval, 9.4%–16.5%) than in other pediatric solid tumors.[3] An analysis of the Surveillance, Epidemiology, and End Results (SEER) Program database identified 1,351 patients who survived more than 60 months from diagnosis.[4] Of these patients, 209 died; 144 of the deaths (69%) were 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; the 5-year survival rate after recurrence is approximately 10% to 15%.[2,5,6]; [1][Level of evidence C1] Patients with relapsed or progressive Ewing sarcoma with measurable disease have a 6-month event-free survival (EFS) rate of 13%.[7][Level of evidence C1]
Prognostic factors include the following:
The selection of treatment for patients with recurrent disease depends on many factors, including the following:
There is no standardized second-line treatment for patients with relapsed or refractory Ewing sarcoma. Most patients in first relapse are treated with conventional systemic chemotherapy. Patients who demonstrate a response to therapy may undergo local control to sites of recurrence.
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.[9-14]
Study Reference | Trial Phase (Total No. of Patients) | Median Age (Range) (y) | CR/PR | RR | Cyclophosphamide (mg/m2)/Topotecan (mg/m2) × d | Other Agents |
---|---|---|---|---|---|---|
II = phase II trial; CR = complete response; PR = partial response; R = retrospective; RR = objective response rate; VCR = vincristine. | ||||||
Saylors et al.[9] | II (17) | 13.8 (1–21) | 1/3 | 29% | 250 × 5/0.75 × 5 | None |
Hunold et al.[11] | R (54) | 17.4 (3–49) | 0/16 | 30% | 250 × 5/0.75 × 5 | None |
Farhat et al.[15] | R (14) | 11 (2–19) | 0/3 | 21% | 250 × 5/0.75 × 5 | None |
Kebudi et al.[16] | R (14) | 13 (3–16) | 2/5 | 50% | 250 × 5/0.75 × 5 | VCR |
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%.
Study Reference | Trial Phase (Total No. of Patients) | Median Age (Range) (y) | CR/PR | RR | Temozolomide (mg/m2)/Irinotecan (mg/m2) × d × wk | Other Agents |
---|---|---|---|---|---|---|
I = phase I trial; II = phase II trial; Acta Onc = Acta Oncologica; An Ped = Annals of Pediatrics; Clin Cancer Res = Clinical Cancer Research; Exp Opin = Expert Opinion Investigational Drugs; Clin Transl Oncol = Clinical and Translational Oncology; BEV = bevacizumab; CR = complete response; IV = intravenous; N/A = not applicable; PBC = Pediatric Blood and Cancer; Ped Hem Onc = Pediatric Hematology and Oncology; PO = oral; PR = partial response; R = retrospective trial; RR = objective response rate; TMS = temsirolimus; UK = unknown; VCR = vincristine. | ||||||
Wagner et al. (PBC, 2007) [12] | R (16) | 18 (7–33) | 1/3 | 29% | 100 × 5/IV 10–20 × 5 × 2 | None |
Casey et al. (PBC, 2009) [13] | R (19) | 19.5 (2–40) | 5/7 | 63% | 100 × 5/IV 20 × 5 × 2 | None |
Hernandez-Marques et al. (An Ped, 2013) [17] | R (8) | 13 (6–18) | 0/3 | 37% | 80–100 × 5/IV 10–20 × 5 × 2 | None |
Raciborska et al. (PBC, 2013) [14] | R (22) | 14.3 | 5/7 | 54% | 125 × 5/IV 50 × 5 | VCR |
McKnall-Knapp et al. (PBC, 2010) [18] | I (1) | N/A | 0/1 | 100% | 100 × 5/IV 20 × 5 × 2 | VCR |
Wagner et al. (PBC, 2010) [19] | I (5) | (<21) | 1/1 | 40% | 100–150 × 5/PO 35–90 × 5 | VCR |
Wagner et al. (PBC, 2013) [20] | I (2) | 20, 22 | 1/1 | 100% | 150 × 5/PO 90 × 5 | VCR, BEV |
Bagatell et al. (PBC, 2014) [21] | I (7) | (<21) | 0/1 | 14% | 100–150 × 5/PO 50–90 × 5 | TMS |
Kurucu et al. (Ped Hem Onc, 2015) [22] | R (20) | 14 (1–18) | UK | 55% | 100 × 5/IV 20 × 5 × 2 | None |
Anderson et al. (Exp Opin, 2008) [23] | R (25) | 15 | 7/9 | 64% | 100 × 5/IV 10 × 5 × 2 | None |
Palmerini et al. (Acta Onc, 2018) [24] | R (51) | 21 (3–65) | 5/12 | 34% | 100 × 5/IV 40 × 5 | None |
Salah et al. (Clin Transl Oncol, 2021) [25] | R (53) | 20 (5–45) | 1/11 | 28% | 100 × 5/IV 40 × 5 in 21 patients; IV 50 × 5 in 24 patients; IV 20 × 5 × 2 in 6 patients | None |
Xu et al. (Clin Cancer Res, 2023) [26] 5-day schedule: | II (24) | 16.5 ± 7.9 | 1 CR/4 PR | 20.8% | 100 × 5/50 × 5 | VCR 1.4 mg/m2 day 1 |
Xu et al. (Clin Cancer Res, 2023) [26] 10-day schedule: | II (22) | 15.2 ± 6.3 | 1 CR/11 PR | 54.5% | 100 × 5/20 × 5 × 2 | VCR 1.4 mg/m2 days 1 and 8 |
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 275 patients and observed 21 complete remissions and 82 partial remissions. The objective response rate was 37.5%.
Evidence (chemotherapy):
Treatment with aggressive surgery (such as amputation or hemipelvectomy) may be considered for patients with nonmetastatic locally recurrent disease, even if the prognosis is limited.[32]
The role of pulmonary metastasectomy in patients with relapsed disease and isolated lung metastases is controversial.[33,34]
In the relapsed setting, radiation therapy may be used (similar to first-line strategies) for patients who relapsed after the beginning of front-line therapy and/or who present only with pulmonary metastases.[33]; [35][Level of evidence C1] 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 and/or treated with stereotactic body radiation therapy.[33]; [35][Level of evidence C1]; [36] Residual disease in the lung may be surgically removed.
Palliation of painful lesions in children with recurrent or progressive disease can be achieved using a short course (10 or fewer fractions) of radiation therapy. In a retrospective study of 213 children with various malignancies, who were treated with such short course radiation therapy, 85% of patients had complete or partial pain relief, with low levels of toxicity.[37]
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.[38-40]; [41][Level of evidence C2]
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 who underwent allogeneic hematopoietic stem cell transplant (HSCT) for recurrent Ewing sarcoma did not show improved EFS when compared with patients who underwent autologous HSCT, and allogeneic HSCT was associated with a higher complication rate.[38,42,43]
Other therapies that have been studied in the treatment of recurrent Ewing sarcoma include the following:
A prospective, randomized, double-blind trial compared regorafenib with placebo in patients with recurrent Ewing sarcoma.[60] Of 36 patients who were evaluable for efficacy, 23 received regorafenib and 13 received placebo. The patients randomly assigned to regorafenib had an 8-week PFS rate of 56%, compared with 7.7% for patients randomly assigned to placebo. The median PFS was 11.4 weeks for patients who received regorafenib and 3.9 weeks for patients who received placebo. The response rate was 13% in patients treated with regorafenib. Ten patients in the placebo group crossed over to receive regorafenib after progression. Although the results were not significant, the authors suggested that this trial provided some evidence of benefit for the use of regorafenib in patients with relapsed Ewing sarcoma.
In addition to this single-agent experience, regorafenib was shown to be tolerable on a sequential schedule with vincristine and irinotecan in 21 pediatric patients. Five patients with relapsed Ewing sarcoma were included as part of this phase I trial. Three of five patients had partial responses with this regimen.[61]
Sequencing of recurrent and refractory Ewing sarcoma tumors from pediatric (n = 79) and young adult patients (n = 25) enrolled in the National Cancer Institute (NCI)-COG Pediatric Molecular Analysis for Therapeutic Choice (MATCH) trial revealed genomic alterations that were considered actionable for treatment on MATCH study arms in 8 of 104 tumors (7.7%), including EZH2 variants in 2 of 104 tumors (1.9%).[64]
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There are undifferentiated small round cell sarcomas of bone and soft tissue that do not have the EWSR1::ETS gene family member translocations and appear to be biologically distinctive from Ewing sarcoma with EWSR1::ETS gene family member translocations. This includes tumors with translocations of the CIC gene or the BCOR gene, as well as tumors with EWSR1 translocations involving non-ETS gene family members. These groups occur much less frequently than Ewing sarcoma, and descriptions of clinical outcomes for these patients are based on smaller sample sizes and less homogeneous treatment; therefore, patient outcomes are hard to quantitate with precision. Most of these tumors have been treated with regimens designed for Ewing sarcoma, and there is consensus that they were often included in past clinical trials for the treatment of Ewing sarcoma, sometimes called translocation-negative Ewing sarcoma. There is agreement that these tumors are sufficiently different from Ewing sarcoma; they should be stratified and analyzed separately from Ewing sarcoma with the common translocations, even if they are treated with similar therapy. The summary of these entities are presented below and follows the categorization of the 2020 World Health Organization (WHO) Classification of Tumours: Soft Tissue and Bone Tumours (5th edition).[1]
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).[2,3][Level of evidence C1] These tumors more commonly arise in the bones of the pelvis and extremities, and metastases are present in approximately 30% of cases.
The most common types of undifferentiated small round cell sarcoma with BCOR rearrangements are those with the BCOR::CCNB3 rearrangement.[2,4] The BCOR::MAML3 rearrangement is less commonly observed, but tumors with this translocation appear to have biological characteristics that are similar to tumors with the BCOR::CCNB3 rearrangement.[2,5,6]
BCOR internal tandem duplications (ITD) involving exon 15 are observed in infantile undifferentiated round cell sarcomas and primitive myxoid mesenchymal tumors of infancy (PMMTI).[7-9] These two entities have significant histological overlap as well as similar transcriptional profiles, and they are distinguished by more prominent myxoid stroma in PMMTI. BCOR ITD may be occasionally observed in undifferentiated round cell sarcomas arising in older children.[9]
BCOR ITD have been reported in 90% of cases of clear cell sarcoma of the kidney, with a smaller subset harboring YWHAE::NUTM2B/E or BCOR::CCNB3 gene fusions.[10,11] For more information, see the Clear Cell Sarcoma of the Kidney section in Wilms Tumor and Other Childhood Kidney Tumors Treatment.
The transcriptional profiles induced by BCOR gene fusions, BCOR ITD, and YWHAE::NUTM2B/E fusions appear to be similar to each other and distinctive from that of Ewing sarcoma.[2,6,7] As an example, elevated BCOR expression is observed across all of these entities, which can be useful in distinguishing these entities from other undifferentiated small round cell tumors.
When treated with Ewing sarcoma–like therapies, 75% of patients show significant treatment-associated pathological responses. In one series of 36 cases, the 3-year and 5-year survival rates were 93% and 72%, respectively.[2][Level of evidence C1] In another series of 26 patients, the 5-year overall survival (OS) rate was 76.5%, and survival was better for patients who received induction therapy using an Ewing sarcoma–type regimen.[12][Level of evidence C1] Most of the tumors in these series arose in the bone. A retrospective survey of European cancer centers identified 148 patients with undifferentiated small round cell sarcomas who did not have an Ewing sarcoma–related fusion gene.[13] Of the 148 patients, 88 (60%) had CIC-rearranged sarcomas (median age, 32 years; range 7–78 years), 33 (22%) had BCOR::CCNB3-rearranged sarcomas (median age, 17 years; range 5–91 years), and 27 (18%) had unclassified undifferentiated small round cell sarcomas (median age, 37 years; range 4–70 years). Of the 148 patients, 101 (68.2%) presented with localized disease and 47 (31.8%) had metastasis at diagnosis. Male prevalence, younger age, bone primary site, and low rate of synchronous metastases were observed in BCOR::CCNB3-rearranged cases. The local treatment was surgery for 67 patients (45%) and surgery and radiation therapy for 52 patients (35%). Chemotherapy was given to 122 patients (82%). At a 42.7-month median follow-up, the 3-year OS rate was 92.2% for patients with BCOR::CCNB3-rearranged sarcomas, 39.6% for patients with CIC-rearranged sarcomas, and 78.7% (P < .0001) for patients with unclassified undifferentiated small round cell sarcomas.
A multi-institution retrospective analysis of patients aged 0 to 24 years identified 29 patients with sarcomas and CIC gene fusions and 25 patients with BCOR-associated sarcomas (18 with BCOR::CCNB3 gene fusions and 7 with BCOR-ITD).[14] Using a diverse range of treatments, the 3-year event-free survival (EFS) rates were 44.0% (95% confidence interval [CI], 28.7%–67.5%) for patients with CIC gene fusions and 41.2% (95% CI, 25.4%–67.0%) for patients with BCOR alterations (P = .97).
Undifferentiated small 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.[3,15] This entity more commonly affects males and usually originates from the soft tissues of the trunk and extremities.
CIC-rearranged sarcomas most commonly have a CIC gene fusion with DUX4, resulting from either a t(4;19)(q35;q13) or a t(10;19)(q26;q13) translocation.[16,17] CIC is located at chromosome 19q13.1 and DUX4 is located on either chromosome 4q35 or 10q26.3. Sarcomas with the CIC::DUX4 rearrangement have a transcriptional profile and DNA methylation profile that differs from that of Ewing sarcoma, supporting their characterization as a distinct entity.[6,18,19] For example, nearly all sarcomas with CIC::DUX4 rearrangements express WT1 and ETV4, in contrast to Ewing sarcoma and BCOR-rearranged tumors, making immunohistochemistry for these proteins useful in distinguishing between these diagnoses.[15,18]
In a series of 115 cases of CIC-rearranged small round cell sarcomas, 57 patients had adequate follow-up information.[15] 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 than did patients who were treated with up-front surgical resection. However, this difference in survival 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.
An international retrospective cohort study further highlighted the poor outcomes for patients with CIC-rearranged sarcomas. The 3-year OS rate was only 39.6%, which was significantly worse than outcomes for patients with other undifferentiated round cell sarcomas.[13] Likewise, 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.
In another series of 79 patients with CIC-rearranged round cell sarcomas, outcomes were likewise poor, with a median OS of 18 months.[20] Patients treated with Ewing sarcoma-based chemotherapy regimens had nominally higher response rates compared with patients treated with soft tissue sarcoma-based regimens. However, OS rates were similar between these two groups.
A multi-institution retrospective analysis of patients aged 0 to 24 years identified 29 patients with sarcomas and CIC gene fusions and 25 patients with BCOR-associated sarcomas (18 with BCOR::CCNB3 gene fusions and 7 with BCOR-ITD).[14] Using a diverse range of treatments, the 3-year EFS rates were 44.0% (95% CI, 28.7%–67.5%) for patients with CIC gene fusions and 41.2% (95% CI, 25.4%–67.0%) for patients with BCOR alterations (P = .97).
Undifferentiated small round cell sarcomas with CIC::NUTM1 rearrangements have been described and occur much less frequently than undifferentiated round cell sarcomas with CIC::DUX4 rearrangements.[21-23] These tumors occur in younger patients, and primary tumors occur in the central nervous system (CNS) and in the periphery. The histological appearance of these tumors is similar to CIC::DUX4-rearranged sarcomas. The prognosis of patients with these tumors is reported to be very poor despite treatment with surgery, multiagent chemotherapy, and radiation therapy.
In one report, three children had tumors with ATXN1::NUTM2A or ATXN1L::NUTM2A fusions.[24] Two of the patients were infants with CNS lesions, and the third patient was a neonate with skin involvement and multiple masses throughout the peritoneal cavity. The authors suggested that ATXN1- or ATXN1L-associated fusions disrupted their interaction with CIC and decreased the transcription repressor complex, leading to downstream PEA3 family gene overexpression.
Sarcomas with EWSR1::NFATC2 and FUS::NFATC2 fusions typically arise in long bones, show a strong male predominance, and are more common in adults than in children.[25,26] These entities have transcriptional and DNA methylation profiles that distinguish them from Ewing sarcoma and other small round cell sarcomas.[6,19] Additionally, the transcriptional profiles for EWSR1::NFATC2 and FUS::NFATC2 differ from each other,[6] although the significance of this observation is unclear. The two entities also differ in that amplification of the EWSR1::NFATC2 gene fusion is commonly observed, but the FUS::NFATC2 gene fusion is generally not amplified.[19,25,27] Sarcomas with EWSR1::NFATC2 and FUS::NFATC2 fusions have metastatic potential and appear to be poorly responsive to chemotherapy regimens that are commonly used to treat other sarcomas.[25,26]
EWSR1::NFATC2 and FUS::NFATC2 rearrangements are also observed in a substantial proportion of solitary bone cysts (also known as simple bone cysts), a benign condition that typically presents in the metadiaphyses of the long bones of skeletally immature individuals.[28,29] Therefore, the presence of either EWSR1::NFATC2 or FUS::NFATC2 fusions should not be taken as an indicator of malignancy, but rather needs to be interpreted considering the clinical setting.
Sarcomas with the EWSR1::PATZ1 fusion are very uncommon. In the small number of cases described, there appears to be gender balance, a propensity for presentation at truncal primary sites (particularly the chest), and a median age of presentation of between 40 to 50 years, with cases rarely occurring in the pediatric age range.[30,31] Sarcomas with the EWSR1::PATZ1 fusion have gene expression and DNA methylation profiles that distinguish them from other sarcomas,[6,19] and CDKN2A deletions appear to commonly occur as secondary genomic alterations.[30,31]
The EWSR1::PATZ1 fusion has been described more commonly in brain tumors. It has been suggested that this fusion may define a novel form of glioblastoma.[32] In a series of 11 cases of EWSR1::PATZ1 fusion–associated tumors, 3 were primary brain tumors, 7 were sarcomas, and 1 was classified as a soft tissue sarcoma in the CNS.[30] Patients were between the ages of 11 and 81 years. Treatment details were reported for only three adult patients, two of whom had mixed responses to chemotherapy followed by disease progression, and one patient who did not receive chemotherapy.
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.
Added text about the results of one study that retrospectively analyzed a single-institution's experience with visceral Ewing sarcoma. The study focused on surgical management and compared the outcomes of patients with visceral Ewing sarcoma with those of patients with osseous and soft tissue Ewing sarcoma (cited Wallace et al. as reference 30).
Treatment of Localized Ewing Sarcoma
Added text about the results of the European Ewing 2008R1 trial that evaluated 284 patients with standard-risk Ewing sarcoma who received chemotherapy. During the sixth cycle of consolidation, patients were randomly assigned to therapy with either the addition of zoledronic acid for nine 28-day cycles or no maintenance therapy (cited Koch et al. as reference 16).
Added text to state that in a single-institution nonrandomized study, patients who had primary tumors 8 cm or larger were treated with higher-dose radiation therapy. The 5-year cumulative incidence of local failure rate was 6.6%, which compares favorably to other published local failure rates in this group of patients (cited Kacar et al. as reference 27).
Treatment of Recurrent Ewing Sarcoma
Added text about the results of a prospective, randomized, double-blind trial that compared regorafenib with placebo in patients with recurrent Ewing sarcoma (cited Duffaud et al. as reference 60).
Added text to state that in addition to single-agent experience, regorafenib was shown to be tolerable on a sequential schedule with vincristine and irinotecan in 21 pediatric patients. Five patients with relapsed Ewing sarcoma were included as part of this phase I trial. Three of five patients had partial responses with this regimen (cited Casanova et al. as reference 61).
Added cabozantinib as a multitargeted kinase inhibitor that has been studied in the treatment of recurrent Ewing sarcoma. Also added text to state that a real-world evidence analysis included 16 patients with relapsed or refractory Ewing sarcoma who were treated with cabozantinib. Four patients had objective responses (cited Peretz Soroka et al. as reference 63).
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® Cancer Information for Health Professionals pages.
This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of childhood Ewing sarcoma and undifferentiated small round cell sarcomas of bone and soft tissue. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.
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PDQ® Pediatric Treatment Editorial Board. PDQ Ewing Sarcoma and Undifferentiated Small Round Cell Sarcomas of Bone and Soft Tissue 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]
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