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Fortunately, 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 primary care physician, pediatric surgical subspecialists, radiation oncologists, pediatric oncologists/hematologists, rehabilitation specialists, pediatric nurse specialists, social workers, and others to ensure that children receive treatment, supportive care, and rehabilitation that will achieve optimal survival and quality of life. Refer to the PDQ Supportive and Palliative Care summaries for specific information about supportive care for children and adolescents with cancer.
Guidelines for pediatric cancer centers and their role in the treatment of pediatric patients with cancer have been outlined by the American Academy of Pediatrics. At these pediatric cancer centers, clinical trials are available for most types of cancer that occur in children and adolescents, and the opportunity to participate in these trials is offered to most patients/families. Clinical trials for children and adolescents with cancer are generally designed to compare potentially better therapy with therapy that is currently accepted as standard. Most of the progress made in identifying curative therapies for childhood cancers has been achieved through clinical trials. Information about ongoing clinical trials is available from the NCI Web site.
Dramatic improvements in survival have been achieved for children and adolescents with cancer. 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. Childhood and adolescent cancer survivors require close follow-up because cancer therapy side effects may persist or develop months or years after treatment. Refer to the PDQ summary on Late Effects of Treatment for Childhood Cancer for specific information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors.
Origin and Incidence of Ewing Sarcoma
Studies using immunohistochemical markers, cytogenetics,[5,6] molecular genetics, and tissue culture  indicate that Ewing sarcoma is derived from a primordial bone marrow–derived mesenchymal stem cell.[8,9] Older terms such as primitive neuroectodermal tumor, Askin tumor (Ewing sarcoma of chest wall), and extraosseous Ewing sarcoma (often combined in the term Ewing sarcoma family of tumors) refer to this same tumor.
The incidence of Ewing sarcoma is approximately three cases per 1 million per year and has remained unchanged for 30 years. Data from the U.S. National Cancer Institute (NCI) Surveillance, Epidemiology, and End Results (SEER) registries report an overall incidence of Ewing sarcoma of one case per 1 million in the U.S. population. The incidence in patients aged 10 to 19 years is between nine and ten cases per 1 million. The same analysis suggests that the incidence of Ewing sarcoma in the United States is nine times greater in Caucasians than in African Americans.
The median age of patients with Ewing sarcoma is 15 years, and more than 50% of patients are adolescents. Well-characterized cases of Ewing sarcoma in neonates and infants have been described.[12,13] Based on data from 1,426 patients entered on European Intergroup Cooperative Ewing Sarcoma Studies (EI-CESS), 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:
Approximately 25% of patients will have metastatic disease at diagnosis.
The SEER database was used to compare patients younger than 40 years with Ewing sarcoma who presented with skeletal and extraosseous primary sites. Patients with extraosseous Ewing sarcoma were more likely to be older, female, nonwhite, and have axial primary sites and were less likely to have pelvic primary sites when compared with patients with skeletal Ewing sarcoma.
Prognostic Factors for Ewing Sarcoma
The two major types of prognostic factors for patients with Ewing sarcoma are as follows:
The following are not considered to be adverse prognostic factors for Ewing sarcoma:
Treatment response factors to preoperative therapy
Multiple studies have shown that patients with minimal or no residual viable tumor after presurgical chemotherapy have a significantly better event-free survival compared with patients with larger amounts of viable tumor.[43,44,45,46] Female gender and younger age predict a good histologic response to preoperative therapy. For patients who receive preinduction and postinduction chemotherapy positron emission tomography (PET) scans, decreased PET uptake after chemotherapy correlated with good histologic response and better outcome.[48,49] Patients with poor response to presurgical chemotherapy have an increased risk for local recurrence.
Ewing sarcoma belongs to the group of neoplasms commonly referred to as small, round, blue-cell tumors of childhood. The individual cells of Ewing sarcoma contain round-to-oval nuclei with fine dispersed chromatin without nucleoli. Occasionally, cells with smaller, more hyperchromatic, and probably degenerative nuclei are present, giving a light cell/dark cell pattern. The cytoplasm varies in amount, but in the classic case, it is clear and contains glycogen, which can be highlighted with a periodic acid-Schiff stain. The tumor cells are tightly packed and grow in a diffuse pattern without evidence of structural organization. Tumors with the requisite translocation that show neuronal differentiation are not considered a separate entity, but rather, part of a continuum of differentiation.
The MIC2 gene product, CD99, is a surface membrane protein that is expressed in most cases of Ewing sarcoma and is useful in suggesting diagnosis of these tumors when the results are interpreted in the context of clinical and pathologic parameters.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.
Cytogenetic Changes in Ewing Sarcoma
Cytogenetic studies of Ewing sarcoma have identified a consistent alteration of the EWSR1 locus (a member of the TET family [TLS/EWS/TAF15] of RNA binding proteins) on chromosome 22 band q12 that may involve other chromosomes, including 11 or 21. Characteristically, the amino terminus of the EWSR1 gene is juxtaposed with the carboxy terminus of another gene. In most cases (90%), the carboxy terminus is provided by FLI1, a member of the Ets family of transcription factor genes located on chromosome 11 band q24. Other Ets family members that may combine with the EWSR1 gene in order of frequency are ERG, located on chromosome 21; ETV1, located on chromosome 7; and E1AF, located on chromosome 17; these result in the following translocations: t(21;22), t(7;22), and t(17;22), respectively. Rarely, other TET family members can substitute for EWS. Besides these consistent aberrations involving the EWSR1 gene at 22q12, additional numerical and structural aberrations have been observed in Ewing sarcoma, including gains of chromosomes 2, 5, 8, 9, 12, and 15; the nonreciprocal translocation t(1;16)(q12;q11.2); and deletions on the short arm of chromosome 6. Trisomy 20 may be associated with a more aggressive subset of Ewing sarcoma tumors.
A molecular test (i.e., reverse transcriptase polymerase chain reaction [PCR] and restriction analysis of PCR products), currently available on a research basis only, now offers the opportunity to markedly simplify the definition of Ewing sarcoma.[7,8] The molecular assay can be performed on relatively small amounts of tissue obtained by minimally invasive biopsies and is capable of providing results faster than cytogenetic analysis.
For patients with confirmed Ewing sarcoma, pretreatment staging studies should include magnetic resonance imaging (MRI) and/or computed tomography (CT) scan, depending on the primary site. Despite the fact that CT and MRI are both equivalent in terms of staging, use of both imaging modalities may help radiation therapy planning. Whole-body MRI may provide additional information that could potentially alter therapy planning. Additional pretreatment staging studies should include bone scan, CT scan of the chest, and bone marrow aspiration and biopsy. A staging modality under evaluation but not required on current clinical trials is molecular analysis of bone marrow for the presence of fusion transcript. In certain studies, determination of pretreatment tumor volume is an important variable.
Although positron emission tomography using fluorodeoxyglucose (FDG-PET) or FDG-PET/CT are optional staging modalities, they have demonstrated high sensitivity and specificity in Ewing sarcoma and may provide additional information that alters therapy planning. In one institutional study, FDG-PET had a very high correlation with bone scan; the investigators suggested that it could replace bone scan for the initial extent of disease evaluation. This finding was confirmed in a single-institution retrospective review. FDG-PET/CT is more accurate than FDG-PET alone in Ewing sarcoma.[5,6,7]
For Ewing sarcoma, the tumor is defined as localized when, by clinical and imaging techniques, there is no spread beyond the primary site or regional lymph node involvement. Continuous extension into adjacent soft tissue may occur. If there is a question of regional lymph node involvement, an excisional biopsy should be performed.
Patients should be evaluated by specialists from the appropriate disciplines (e.g., radiologist, chemotherapist, pathologist, surgical or orthopedic oncologist, and radiation oncologist) as early as possible. Appropriate imaging studies of the site should be obtained before biopsy. The surgical or orthopedic oncologist who will perform the definitive surgery should be involved before or during the biopsy so that the incision can be placed in an acceptable location. This is especially important if it is thought that the lesion can be totally excised or if a limb salvage procedure may be attempted. Biopsy should be from soft tissue as often as possible to avoid increasing the risk of fracture. The radiation oncologist and pathologist should be consulted before biopsy/surgery in order to be sure that the incision will not compromise the radiation port and so that multiple types of tissue samples are obtained. It is important to obtain fresh tissue, whenever possible, for cytogenetics and molecular pathology. A second option is to perform a needle biopsy as long as adequate tissue for molecular biology and cytogenetics is obtained.
The successful treatment of patients with Ewing sarcoma requires systemic chemotherapy [3,4,5,6,7,8,9] in conjunction with either surgery or radiation therapy or both modalities for local tumor control.[10,11,12,13,14] In general, patients receive preoperative chemotherapy before instituting local control measures. In patients who undergo surgery, surgical margins and histologic response are considered in planning postoperative therapy. Most patients with metastatic disease have a good initial response to preoperative chemotherapy; however, in most cases, the disease is only partially controlled or recurs.[15,16,17,18] Patients with lung as the sole metastatic site have a better prognosis than patients with metastases to bone and/or bone marrow. Adequate local control for metastatic sites, particularly bone metastases, may be an important issue.
Chemotherapy for Ewing Sarcoma
Multidrug chemotherapy for Ewing sarcoma always includes vincristine, doxorubicin, ifosfamide, and etoposide. Most protocols use cyclophosphamide as well. Certain protocols incorporate dactinomycin. The mode of administration and dose intensity of cyclophosphamide within courses differs markedly between protocols. A European Intergroup Cooperative Ewing Sarcoma Study (EICESS) trial suggested that 1.2 grams of cyclophosphamide produced a similar event-free survival (EFS) compared with 6 grams of ifosfamide in patients with lower-risk disease, and identified a trend toward better EFS for patients with localized Ewing sarcoma and higher-risk disease when treatment included etoposide (GER-GPOH-EICESS-92).[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. A randomized clinical trial (COG-AEWS0031 [NCT00006734]) from the Children's Oncology Group showed that for patients presenting without metastases, the administration of cycles of cyclophosphamide, doxorubicin, and vincristine alternating with cycles of ifosfamide and etoposide at 2-week intervals achieved superior EFS (5-year EFS, 73%) than alternating cycles at 3-week intervals (5-year EFS, 65%).
Local control for Ewing sarcoma
Treatment approaches for Ewing sarcoma titrate therapeutic aggressiveness with the goal of maximizing local control while minimizing morbidity.
While surgery is effective and appropriate for patients who can undergo complete resection with acceptable morbidity, children who have unresectable tumors or who would suffer loss of function are treated with radiation therapy alone. Those who undergo gross resections with microscopic residual disease may benefit from adjuvant radiation therapy. Randomized trials that directly compare both modalities do not exist, and their relative roles remain controversial. Although retrospective institutional series suggest superior local control and survival with surgery rather than radiation therapy, most of these studies are compromised by selection bias. Data for patients with pelvic primary Ewing sarcoma from a North American intergroup trial showed no difference in local control or survival based on local-control modality—surgery alone, radiation therapy alone, or radiation plus surgery.
For patients who undergo gross total resection with microscopic residual disease, the value of adjuvant radiation therapy is controversial. Investigations addressing this issue are retrospective and nonrandomized, limiting their value. Investigators from St. Jude Children's Research Hospital reported 39 patients with localized Ewing sarcoma who received both surgery and radiation. Local failure for patients with positive and negative margins was 17% and 5%, respectively, and overall survival (OS) was 71% and 94%, respectively. However, in a large retrospective Italian study, 45 Gy adjuvant radiation therapy for patients with inadequate margins did not appear to improve either local control or disease-free survival. It is not known whether higher doses of radiation therapy could improve outcome. These investigators concluded that patients who are anticipated to have suboptimal surgery should be considered for definitive radiation therapy.
Thus, surgery is chosen as definitive local therapy for suitable patients, but radiation therapy is appropriate for patients with unresectable disease or those who would experience functional compromise by definitive surgery. The possibility of impaired function needs to be measured against the possibility of second tumors in the radiation field (see below). Adjuvant radiation therapy should be considered for patients with residual microscopic disease, inadequate margins, or who have viable tumor in the resected specimen and close margins.
When preoperative assessment has suggested a high probability that surgical margins will be close or positive, preoperative radiation therapy has achieved tumor shrinkage and allowed surgical resection with clear margins.
High-Dose Therapy With Stem Cell Rescue for Ewing Sarcoma
For patients with a high risk of relapse with conventional treatments, certain investigators have utilized high-dose chemotherapy with hematopoietic stem cell transplant (HSCT) as consolidation treatment, in an effort to improve outcome.[23,24,25,26,27,28,29,30,31,32,33,34] In a prospective study, patients with bone and/or bone marrow metastases at diagnosis were treated with aggressive chemotherapy, surgery, and/or radiation and HSCT if a good initial response was achieved. The study showed no benefit for HSCT compared with historical controls. A retrospective review using international bone marrow transplant registries compared outcome after treatment with reduced-intensity conditioning to high-intensity conditioning followed by allogeneic stem cell transplant for patients with Ewing sarcoma at high risk for relapse.[Level of evidence: 3iiiA] There was no difference in outcome and the authors concluded that this suggested the absence of a clinically relevant graft-versus-tumor effect against Ewing sarcoma tumor cells with current approaches. Multiple small studies that report benefit for HSCT have been published but are difficult to interpret because only patients who have a good initial response to standard chemotherapy are considered for HSCT. The role of high-dose therapy followed by stem cell rescue is being investigated in a Euro-Ewing clinical trial (EURO-EWING-INTERGROUP-EE99) for patients that present with pulmonary metastases.
Ewing Sarcoma/Specific Sites
Separate journal articles have been written that discuss diagnostic findings, treatment, and outcome of patients with bone lesions at the following sites:
Extraosseous Ewing Sarcoma
Extraosseous Ewing sarcoma is biologically similar to Ewing sarcoma arising in bone. Until recently, most children and young adults with extraosseous Ewing sarcoma were treated on protocols designed for the treatment of rhabdomyosarcoma. This is important because many of the treatment regimens for rhabdomyosarcoma do not include an anthracycline, which is a critical component of current treatment regimens for Ewing sarcoma. Currently, patients with extraosseous Ewing sarcoma are eligible for studies that include Ewing sarcoma of bone.
From 1987 to 2004, 111 patients with nonmetastatic extraosseous Ewing sarcoma were enrolled on the RMS-88 and RMS-96 protocols. Patients with initial complete tumor resection received ifosfamide, vincristine, and actinomycin (IVA) while patients with residual tumor received IVA plus doxorubicin (VAIA) or IVA plus carboplatin, epirubicin, and etoposide (CEVAIE). Seventy-six percent of patients received radiation. The 5-year EFS and OS were 59% and 69%, respectively. In a multivariate analysis, independent adverse prognostic factors included axial primary, tumor size greater than 10 cm, Intergroup Rhabdomyosarcoma Studies Group III, and lack of radiation therapy.
Two hundred thirty-six patients with extraosseous Ewing sarcoma were entered on studies of the German Pediatric Oncology Group. The median age at diagnosis was 15 years and 133 patients were male. Primary tumor site was either extremity (n = 62) or central site (n = 174). Sixty of 236 patients had metastases at diagnosis. Chemotherapy consisted of vincristine, doxorubicin, cyclophosphamide, and actinomycin (VACA); CEVAIE; or vincristine, ifosfamide, doxorubicin, and etoposide (VIDE). The 5-year EFS and OS were 49% and 60%, respectively. Five-year survival was 70% for patients with localized disease and 33% for patients with metastasis at diagnosis. OS in patients with localized disease did not seem related to tumor site or size. In a retrospective French study, patients with extraosseous Ewing sarcoma were treated using a rhabdomyosarcoma regimen (no anthracyclines) or a Ewing sarcoma regimen (includes anthracyclines). Patients receiving the anthracycline-containing regimen had a significantly better EFS and OS compared with patients receiving no anthracyclines.[56,57]
Cutaneous Ewing sarcoma is a soft tissue tumor in the skin or subcutaneous tissue that seems to behave as a less-aggressive tumor than primary bone or soft tissue Ewing sarcoma. Tumors can form throughout the body, although the extremity is the most common site, and they are almost always localized. In a review of 78 reported cases, some lacking molecular confirmation, the OS was 91%. Adequate local control, defined as a complete resection with negative margins, radiation therapy, or a combination, significantly reduced the incidence of relapse. Standard chemotherapy for Ewing sarcoma should be used for these patients because there are no data to suggest which patients could be treated less aggressively.[58,59]
Patients treated for Ewing sarcoma have a significantly higher risk of developing subsequent neoplasms than patients in the general population.
Treatment-related acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) have generally been reported to occur in 1% to 2% of survivors of Ewing sarcoma,; [Level of evidence: 3iiiDi] although some dose-intensive regimens appear to be associated with a higher risk of hematological malignancy.[62,63]; [Level of evidence: 3ii] Treatment-related AML and MDS arise most commonly at 2 to 5 years after diagnosis.
Survivors of Ewing sarcoma remain at increased risk of developing a subsequent solid tumor throughout their lifetime. Sarcomas usually occur within the prior radiation field.[65,66] The risk of developing a sarcoma after radiation therapy is dose-dependent, with higher doses associated with an increased risk of sarcoma development.; [Level of evidence: 3iiiDi] The cumulative incidence of subsequent neoplasms in children treated for Ewing sarcoma between 1970 and 1986 at 25 years after diagnosis was 9.0% (confidence interval, 5.8–12.2). Most of these patients received radiation therapy; comparable long-term data do not yet exist for significant numbers of patients who did not receive radiation therapy.
(Refer to the PDQ summary on Late Effects of Treatment for Childhood Cancer for a full discussion of the late effects of cancer treatment in children and adolescents.)
Standard Treatment Options
Because most patients with apparently localized disease at diagnosis have occult metastatic disease, multidrug chemotherapy as well as local disease control with surgery and/or radiation 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, also known as VAdriaC or VDC, alternating with ifosfamide and etoposide (IE). The combination of IE has shown activity in Ewing sarcoma, and a large randomized clinical trial and a nonrandomized trial demonstrated that outcome was improved when IE was alternated with VAdriaC.[2,9,10] Dactinomycin is no longer used in the United States but continues to be used in the Euro-Ewing studies. Increased dose intensity of doxorubicin during the initial months of therapy was associated with an improved outcome in a meta-analysis performed before the standard use of ifosfamide and etoposide. The use of high-dose VAdriaC has shown promising results in small numbers of patients. A single institution study of 44 patients treated with high-dose VAdriaC and IE had an 82% 4-year EFS. However, in an intergroup trial of the Pediatric Oncology Group and the Children's Cancer Group, which compared a dose-intensified chemotherapy regimen of vincristine, doxorubicin, cyclophosphamide, ifosfamide, and etoposide (VDC/IE) with standard doses of the same regimen, no differences in outcome were observed. Unlike the single institution trial, this trial did not maintain the dose intensity of alkylating agents for the duration of treatment.
In a completed Children's Oncology Group (COG) trial (COG-AEWS0031), 568 patients with newly diagnosed localized extradural Ewing sarcoma were randomly assigned to receive chemotherapy (VAdriaC alternating with IE) given every 2 weeks (interval compression) versus 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. 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. In past studies, smaller more peripheral tumors were more likely to be treated by surgery, and larger, more central tumors were more likely to be treated by radiation therapy. An Italian retrospective study showed that surgery improved outcome only in extremity tumors, although the number of patients with central axis Ewing sarcoma who achieve adequate margins is small. In a series of 39 patients treated at St. Jude Children's Research Hospital, who received both surgery and radiation, the 8-year local failure rate was 5% for patients with negative surgical margins and 17% for those with positive margins. Data for patients with pelvic primary Ewing sarcoma from a North American intergroup trial showed no difference in local control or survival based on local-control modality—surgery alone, radiation therapy alone, or radiation plus surgery.
If a very young child has Ewing sarcoma, surgery may be a less morbid therapy than radiation therapy because of the retardation of bone growth caused by radiation. Another potential benefit for surgical resection of the primary tumor is information concerning the amount of necrosis in the resected tumor. Patients with residual viable tumor in the resected specimen have a worse outcome than those with complete necrosis. In a French Ewing study (EW88), EFS for patients with less than 5% viable tumor, 5% to 30% viable tumor, and more than 30% viable tumor was 75%, 48%, and 20%, respectively. European investigators are studying whether treatment intensification (i.e., high-dose chemotherapy with stem cell rescue) will improve outcome for patients with a poor histologic response. Radiation therapy should be employed for patients who do not have a surgical option that preserves function and should be used for patients whose tumors have been excised but with inadequate margins. Pathologic fracture at the time of diagnosis does not preclude surgical resection and is not associated with adverse outcome.
Radiation therapy should be delivered in a setting in which stringent planning techniques are applied by those experienced in the treatment of Ewing sarcoma. Such an approach will result in local control of the tumor with acceptable morbidity in most patients.[1,2,20] The radiation dose may be adjusted depending on the extent of residual disease after the initial surgical procedure. Radiation therapy is generally administered in fractionated doses totaling approximately 55.8 Gy to the prechemotherapy tumor volume. A randomized study of 40 patients with Ewing sarcoma using 55.8 Gy to the prechemotherapy tumor extent with a 2 cm margin compared with the same total-tumor dose after 39.6 Gy to the entire bone showed no difference in local control or EFS. Hyperfractionated radiation therapy has not been associated with improved local control or decreased morbidity.
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 if 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 if 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 is 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.
For patients with residual disease after an attempt at surgical resection, the Intergroup Ewing Sarcoma Study (INT-0091) recommends 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 is recommended for those who have no evidence of microscopic residual disease following surgical resection.
Radiation therapy is associated with the development of second malignant neoplasms. A retrospective study noted that those 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.
Treatment Options Under Clinical Evaluation
The following is an example of an international clinical trial that is currently being conducted. Information about ongoing clinical trials is available from the NCI Web site.
Current Clinical Trials
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with localized Ewing sarcoma/peripheral primitive neuroectodermal tumor. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.
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] Factors such as age older than 14 years, a primary tumor volume of more than 200 mL, more than one bone metastatic site, bone marrow metastases, and additional lung metastases independently predict a poor outcome in patients presenting with metastatic disease.
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] In the Intergroup Ewing Sarcoma Study, patients with metastatic disease showed no benefit from the addition of ifosfamide and etoposide to a standard regimen of vincristine, doxorubicin, cyclophosphamide, and actinomycin-D. In another Intergroup study, increasing dose intensity of cyclophosphamide, ifosfamide, and doxorubicin did not improve outcome compared with regimens utilizing standard-dose intensity. This regimen increased toxicity and risk of second malignancy without improving EFS or OS.
Systematic use of radiation therapy and surgery for metastatic sites may improve overall outcome in patients with extrapulmonary metastases. In a retrospective data analysis of 120 patients with multifocal metastatic Ewing sarcoma, patients receiving local treatment of both primary tumor and metastases had a better outcome than patients receiving local treatment of primary tumor only or with no local treatment (3-year EFS, 39% vs. 17% and 14%, P < .001). A similar trend for better outcome with irradiation of all sites of metastatic disease was seen in two retrospective analyses of smaller groups of patients receiving radiation therapy to all tumor sites.[9,10] 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 of all sites of clinically detectable metastatic disease had better responses to systemic therapy and fewer sites of metastasis than patients who did not undergo similar therapy of metastatic sites.
Radiation therapy should be 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 tumor with acceptable morbidity in most patients. Metastatic sites of disease in bone and soft tissues should receive fractionated radiation therapy doses totaling between 45 Gy and 56 Gy. All patients with pulmonary metastases should undergo whole-lung radiation, even if complete resolution of overt pulmonary metastatic disease has been achieved with chemotherapy.[4,5,12] Radiation doses are modulated based on the amount of lung to be radiated and on pulmonary function. Doses between 12 Gy and 15 Gy are generally used if whole lungs are treated.
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.[2,3,9,13,14,15] The impact of high-dose chemotherapy with peripheral blood stem cell support for patients with lung metastases is unknown and is being studied in the EURO-EWING-INTERGROUP-EE99 trial. European investigators frequently use high-dose chemotherapy and stem cell support for patients with extrapulmonary metastatic sites; use of high-dose therapy and autologous stem cell reconstitution for patients with metastases at extrapulmonary sites is an investigator choice in the EURO-EWING-INTERGROUP-EE99 (COG-AEWS0331) study. It is not being studied as a randomized prospective question, but the study will acquire data about the outcome of patients treated with this consolidation. Melphalan, at nonmyeloablative doses, has proved to be an active agent in an upfront window study for patients with metastatic disease at diagnosis; however, the cure rate remained extremely low.
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with metastatic Ewing sarcoma/peripheral primitive neuroectodermal tumor. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
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. The overall prognosis for patients with recurrent Ewing sarcoma is poor; 5-year survival after recurrence is approximately 10% to 15%.[2,4,5]; [Level of evidence: 3iiA] Time to recurrence is the most important prognostic factor. Patients who recurred more than 2 years from initial diagnosis had a 5-year survival of 30% versus 7% for patients who recurred within 2 years.[1,2] Patients with both local recurrence and distant metastases have a worse outcome than patients with either isolated local recurrence or metastatic recurrence alone.[1,2] Isolated pulmonary recurrence was not an important prognostic factor.
The selection of treatment for patients with recurrent disease depends on many factors, including the site of recurrence and prior treatment, as well as individual patient considerations. 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.[6,7,8,9,10,11] There is no standardized second-line treatment for relapsed or refractory Ewing sarcoma. One phase II study of topotecan and cyclophosphamide showed a response in 6 of 17 patients with Ewing sarcoma; 16 of 49 patients had a clinical response in a similar trial from Germany.[6,8] In one retrospective series, 20 patients received temozolomide and irinotecan after recurrence. Five patients achieved a complete response and seven patients achieved a partial response. The combination of gemcitabine and docetaxel has achieved objective responses in relapsed Ewing sarcoma.[Level of evidence: 3iiA]; [Level of evidence: 3iiiDiv] High-dose ifosfamide (3 g/m2 /day for 5 days = 15 g/m2) has shown activity in patients who recurred after therapy which included standard ifosfamide (1.8 g/m2 /day for 5 days = 9 g/m2).[Level of evidence: 3iiiDiv]
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.[15,16]; [Level of evidence: 3iiiDiii] Surveys of patients undergoing allogeneic stem cell transplantation for recurrent Ewing sarcoma did not show improved event-free survival when compared with autologous stem cell transplantation and was associated with a higher complication rate.[15,18,19]
Monoclonal antibodies against the insulin-like growth factor 1 receptor (IGF1R) are reported to produce objective responses in metastatic recurrent Ewing sarcoma in roughly 10% of cases.[20,21,22,23][Level of evidence: 3iiDiv] In these studies, it was suggested that time-to-progression was prolonged compared with historical controls. A phase I trial of IGF1R antibodies combined with the mTOR inhibitor temsirolimus achieved two complete responses and three minor responses among 17 patients with metastatic recurrent Ewing sarcoma. Further studies are needed to identify patients who are likely to benefit from IGF1R therapy.
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.
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with recurrent Ewing sarcoma/peripheral primitive neuroectodermal tumor. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
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.
Revised text to state that between 1975 and 2010, childhood cancer mortality decreased by more than 50%. Also added that 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 (added Smith et al. as reference 3).
Added De Ioris et al. as reference 23.
Added text to state that in one institutional study, FDG-PET had a very high correlation with bone scan; the investigators suggested that it could replace bone scan for the initial extent of disease evaluation. Also added text to state that this finding was confirmed in a single-institution retrospective review (cited Newman et al. as reference 3 and Ulaner et al. as reference 4).
Treatment Option Overview
Added Drabko et al. as reference 34.
Ewing Sarcoma: Recurrent Tumors
Revised text to state that 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 (cited Raciborska et al. as reference 11).
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 Web site's Contact Form. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.
Levels of Evidence
Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Pediatric Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.
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The preferred citation for this PDQ summary is:
National Cancer Institute: PDQ® Ewing Sarcoma Treatment. Bethesda, MD: National Cancer Institute. Date last modified <MM/DD/YYYY>. Available at: http://cancer.gov/cancertopics/pdq/treatment/ewings/HealthProfessional. Accessed <MM/DD/YYYY>.
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Last Revised: 2014-08-15
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