General Information

The National Cancer Institute provides the PDQ pediatric cancer treatment information summaries as a public service to increase the availability of evidence-based cancer information to health professionals, patients, and the public.

Fortunately, cancer in children and adolescents is rare, although the overall incidence of childhood cancer has been slowly increasing since 1975.[1] Children and adolescents with cancer should be referred to medical centers that have a multidisciplinary team of cancer specialists with experience treating the cancers that occur during childhood and adolescence. This multidisciplinary team approach incorporates the skills of the primary care physician, pediatric surgical subspecialists, radiation oncologists, pediatric oncologists/hematologists, rehabilitation specialists, pediatric nurse specialists, social workers, and others to ensure that children receive treatment, supportive care, and rehabilitation that will achieve optimal survival and quality of life. Refer to the PDQ Supportive and Palliative Care summaries for specific information about supportive care for children and adolescents with cancer.

Guidelines for pediatric cancer centers and their role in the treatment of pediatric patients with cancer have been outlined by the American Academy of Pediatrics.[2] At these pediatric cancer centers, clinical trials are available for most types of cancer that occur in children and adolescents, and the opportunity to participate in these trials is offered to most patients/families. Clinical trials for children and adolescents with cancer are generally designed to compare potentially better therapy with therapy that is currently accepted as standard. Most of the progress made in identifying curative therapies for childhood cancers has been achieved through clinical trials. Information about ongoing clinical trials is available from the NCI Web site.

Dramatic improvements in survival have been achieved for children and adolescents with cancer.[1] Between 1975 and 2002, childhood cancer mortality has decreased by more than 50%. For Ewing sarcoma, the 5-year survival rate has increased over the same time from 59% to 76% for children younger than 15 years and from 20% to 49% for adolescents aged 15 to 19 years.[1] Childhood and adolescent cancer survivors require close follow-up because cancer therapy side effects may persist or develop months or years after treatment. Refer to the PDQ summary on Late Effects of Treatment for Childhood Cancer for specific information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors.

Origin and Incidence of Ewing Sarcoma Family of Tumors

Studies using immunohistochemical markers,[3] cytogenetics,[4,5] molecular genetics, and tissue culture [6] indicate that classic Ewing sarcoma, primitive neuroectodermal tumor, and Askin tumor (chest wall), as well as extraosseous Ewing sarcoma (EOE) are all derived from the same primordial bone marrow-derived mesenchymal stem cell.[7,8] The incidence of Ewing sarcoma family of tumors (ESFTs) is approximately three per 1,000,000 per year and remained unchanged for 30 years.[9] Data from the Surveillance, Epidemiology, and End Results (SEER) registries reports an overall incidence of ESFT of one per 1,000,000 in the U.S. population. The incidence in patients aged 10 to 19 years is between nine and ten per 1,000,000. The same analysis suggests that the incidence of Ewing sarcoma is nine times greater in U.S. Caucasians than African Americans.[10]

The median age of patients with ESFT is 15 years, and more than 50% of patients are adolescents. Well-characterized cases of ESFT in neonates and infants have been described.[11,12] Based on data from 1,426 patients entered on European Intergroup Cooperative Ewing Sarcoma Studies (EI-CESS), 59% of patients are male and 41% are female. Primary sites of bone disease include the following:

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

For EOE, the most common primary sites of disease are the following:

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

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

Prognostic Factors for Ewing Sarcoma

There are two major types of prognostic factors for patients with Ewing sarcoma: pretreatment factors and treatment response factors.

Pretreatment factors

• Site: Patients with Ewing sarcoma in the distal extremities have the best prognosis. Patients with Ewing sarcoma in the proximal extremities have an intermediate prognosis, followed by patients with central or pelvic sites.[14,15,16] Patients with tumors of the sacrum have a very poor prognosis.[17]
• Size: Tumor volume has been shown to be an important prognostic factor in most studies. Cutoffs of either 100 mL or 200 mL are used to define larger tumors. Larger tumors tend to occur in unfavorable sites.[16,18]
• Age: Infants and younger patients (<15 years) have a better prognosis than adolescents aged 15 years or older, young adults, or adults.[12,14,15,16]
• Gender: Girls with Ewing sarcoma have a better prognosis than boys.[10,15]
• Serum lactate dehydrogenase: Increased serum lactate dehydrogenase (LDH) levels prior to treatment are associated with inferior prognosis. Increased LDH levels are also correlated with large primary tumors and metastatic disease.[15]
• Metastases: Any metastatic disease defined by standard imaging techniques or bone marrow aspirate/biopsy by morphology is an adverse prognostic factor. The presence or absence of metastatic disease is the single most powerful predictor of outcome. Patients with metastatic disease confined to lung have a better prognosis than patients with extrapulmonary metastatic sites.[14,16,19] 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.[20] Patients with metastasis to bone only seem to have a better outcome than patients with metastases to both bone and lung.[21] Positron emission tomography (PET) scans using fluorine-18-fluorodeoxyglucose (FDG) are under investigation as a staging tool that may provide additional information and alter therapy planning.[22] Whole body MRI may provide additional information which could potentially alter therapy planning.[23]
• Standard cytogenetics: Complex karyotype (defined as the presence of 5 or more independent chromosome abnormalities at diagnosis) and modal chromosome numbers lower than 50 appear to have adverse prognostic significance.[24]
• Detectable fusion transcripts in morphologically normal marrow: Reverse transcription polymerase chain reaction can be used to detect fusion transcripts in bone marrow. In a single retrospective study utilizing patients with normal marrow morphology and no other metastatic site, fusion transcript detection in marrow was associated with an increased risk of relapse.[25]
• Other biological factors: Overexpression of the p53 protein, Ki67 expression, and loss of 16q may be adverse prognostic factors.[26,27,28] High expression of microsomal glutathione S-transferase, an enzyme associated with resistance to doxorubicin, is associated with inferior outcome for Ewing sarcoma.[29]

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

• Pathologic fracture: Pathologic fractures do not appear to be a prognostic factor for ETB.[30]
• Histopathology: The degree of neural differentiation is not a prognostic factor in Ewing sarcoma.[31,32]
• Molecular pathology: The EWS-FL1 translocation associated with ESFT can occur at several potential breakpoints in each of the genes which join to form the novel segment of DNA. Once thought to be significant,[33] two large series have shown the EWS-FL1 translocation is not an adverse prognostic factor.[34,35]

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.[20,36,37,38] Female gender and younger age predict a good histologic response to preoperative therapy.[39] Patients with poor response to presurgical chemotherapy have an increased risk for local recurrence.[40] For patients who receive preinduction and postinduction chemotherapy PET scans, decreased PET uptake following chemotherapy correlated with good histologic response.[41,42]

References:

Cellular Classification

Ewing sarcoma family of tumors (ESFT) belong to the group of neoplasms commonly referred to as small, round, blue-cell tumors of childhood. The MIC2 gene product, CD99, is a surface membrane protein that is expressed in most cases of ESFT and is useful in suggesting diagnosis of these tumors when the results are interpreted in the context of clinical and pathologic parameters.[1]MIC2 positivity is not unique to ESFT, and positivity by immunochemistry is found in several other tumors including synovial sarcoma, non-Hodgkin lymphoma, and gastrointestinal stromal tumors. Concurrent positivity for membrane CD99 and FL-1 strongly suggest the diagnosis of ESFT.[1] The detection of a translocation involving the EWS gene on chromosome 22 band q12 and any one of a number of partner chromosomes is the key feature in the diagnosis of ESFT.[2]

The individual cells of ESFT 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.

Cytogenetic Changes in the Ewing Sarcoma Family of Tumors

Cytogenetic studies of the ESFT have identified a consistent alteration of the EWS locus on chromosome 22 band q12 that may involve other chromosomes, including 11 or 21.[3] Characteristically, the amino terminus of the EWS 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 EWS gene in order of frequency are ERG, located on chromosome 21; ETV1, located on chromosome 7; and E1AF, located on chromosome 17; these result in the following translocations: t(21;22),[4] t(7;22), and t(17;22), respectively. Besides these consistent aberrations involving the EWS gene at 22q12, additional numerical and structural aberrations have been observed in ESFTs, 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.[5] A molecular test (i.e., reverse transcription polymerase chain reaction [RT-PCR] and restriction analysis of PCR products), currently available on a research basis only, now offers the opportunity of markedly simplifying the definition of the ESFT.[6,7] 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.

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Stage Information

For patients with confirmed Ewing sarcoma, pretreatment staging studies should include magnetic resonance imaging (MRI) and/or computed tomography (CT) scan of the primary site, depending on the 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] Additional pretreatment staging studies should include bone scan, CT scan of the chest, and bone marrow aspiration and biopsy. Positron emission tomography using fluorine-18-fluorodeoxyglucose is an optional staging modality.[2,3] 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.

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.

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Treatment Option Overview

Patients should be evaluated by specialists from all disciplines (e.g., radiologist, chemotherapist, pathologist, surgical or orthopedic oncologist, and radiation oncologist) as early as possible. Appropriate imaging studies of the site should be obtained prior to biopsy. The surgical or orthopedic oncologist who will perform the definitive surgery should be involved prior to or during the biopsy so that the incision can be placed in an acceptable location. This is especially important if it is thought that the lesion can be totally excised or if a limb salvage procedure may be attempted. Biopsy should be from soft tissue as often as possible to avoid increasing the risk of fracture.[1] The radiation oncologist and pathologist should be consulted prior to biopsy/surgery in order to be sure that the incision will not compromise the radiation port and so that multiple types of tissue samples are obtained. It is important to obtain fresh tissue, whenever possible, for cytogenetics and molecular pathology.

The successful treatment of patients with Ewing sarcoma family of tumors (ESFT) requires systemic chemotherapy [2,3,4,5,6,7,8] in conjunction with either surgery or radiation therapy or both modalities for local tumor control.[9,10,11,12,13] In general, patients receive preoperative chemotherapy prior to instituting local control measures. In patients who undergo surgery, surgical margins and histologic response are considered in planning postoperative therapy. In the Euro-Ewing study (EURO-EWING-INTERGROUP-EE99), patients who receive radiation alone for local control are stratified by pretreatment tumor volume for postradiation 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.[14,15,16,17] 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 ESFT 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 (EICES) trial suggested that 1.2 grams of cyclophosphamide produced a similar event-free survival (EFS) compared with 6 grams of ifosfamide, and identified a trend toward better EFS for patients with localized Ewing sarcoma when treatment included etoposide (GER-GPOH-EICESS-92).[18][Level of evidence: 1iiA] Protocols in the United States generally alternate courses of vincristine, cyclophosphamide, and doxorubicin with courses of ifosfamide/etoposide,[6] while European protocols generally combine vincristine, doxorubicin, and an alkylating agent with or without etoposide in a single treatment cycle.[8] Duration of primary chemotherapy ranges from 6 months to approximately 1 year.

Local control for Ewing tumor of bone

Treatment approaches for ESFT 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.

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 ESFT 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.[12] 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.[13] 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. 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.[19]

High-Dose Therapy with Stem Cell Rescue for Ewing Tumor of Bone

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.[20,21,22,23,24,25,26,27,28,29] 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.[25] 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 Tumor of Bone/Specific Sites

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

• Pelvis.[30,31,32]
• Femur.[33,34]
• Humerus.[35,36]
• Hand and foot.[37,38]
• Chest wall/rib.[39,40,41,42]
• Head and neck.[43]
• Spine/sacrum.[44,45,46,47]

Extraosseous Ewing Sarcoma

Extraosseous Ewing sarcoma (EOE) is biologically similar to Ewing sarcoma arising in bone. Until recently, most children and young adults with EOE 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 tumor of bone (ETB). Currently, patients with EOE are eligible for studies that include ETB.

From 1987 to 2004, 111 patients with nonmetastatic EOE were enrolled on the RMS-88 and RMS-96 protocols.[48] 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, IRS Group III, and lack of radiation therapy.

Two hundred thirty-six patients with EOE were entered on studies of the German Pediatric Oncology Group.[49] 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 metastases at diagnosis. OS in patients with localized disease did not seem related to tumor site or size. In a retrospective French study, patients with EOE were treated using a rhabdomyosarcoma regimen (no anthracyclines) or an ETB regimen (includes anthracyclines). Patients receiving the anthracycline-containing regimen had a significantly better EFS and OS compared with patients receiving no anthracyclines.[50,51]

Superficial Ewing sarcoma is a soft tissue tumor in the skin or subcutaneous tissue.[52] Two small series suggested that superficial Ewing sarcoma had a better prognosis than tumors arising in other sites, but not all cases had molecular confirmation of diagnosis.[53,54] A larger series of molecularly confirmed cases reported that patients with superficial Ewing sarcoma did well when treated with local control and systemic therapy similar to the therapy used for all other Ewing sarcoma patients.[55]

Second Malignant Neoplasms

Patients treated for ESFT have a significantly higher risk of developing second malignancies 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 ESFT,[56,57]; [58][Level of evidence: 3iiiDi] although some dose-intensive regimens appear to be associated with a higher risk of hematological malignancy.[59,60]; [61][Level of evidence: 3ii] Treatment-related AML and MDS arise most commonly at 2 to 5 years following diagnosis. Survivors of ESFTs remain at increased risk of developing a second solid tumor throughout their lifetime. Sarcomas usually occur within the prior radiation field.[62,63] The risk of developing a sarcoma following radiation therapy is dose-dependent, with higher doses associated with an increased risk of sarcoma development.[57]; [58][Level of evidence: 3iiiDi] The cumulative risk of developing a secondary solid tumor at 10 years after diagnosis appears to be about 1.8%, although this may be higher with longer follow-up.[56,57]; [58][Level of evidence: 3iiiDi] (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.)

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Ewing Tumor of Bone: Localized Tumors

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 tumor of bone (ETB) achieve event-free survival (EFS) and overall survival (OS) of approximately 70% at 5 years after diagnosis.[9]

Current standard chemotherapy in the United States includes vincristine, doxorubicin, and cyclophosphamide, also known as VAdriaC or VDC, alternating with ifosfamide and etoposide (IE).[9] The combination of IE has shown activity in ETB, 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 doxorubicin dose intensity during the initial months of therapy was associated with an improved outcome.[11] The use of high-dose VAdriaC has shown promising results in small numbers of patients.[11] Forty-four patients treated with high-dose VAdriaC and IE had an 82% 4-year EFS.[12] However, in a trial of the former 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.[13] This trial did not maintain the dose intensity of alkylating agents for the duration of treatment and did not recapitulate the previously published experience.[12]

In a completed Children's Oncology Group (COG) trial (COG-AEWS0031), 568 patients with newly diagnosed localized extradural Ewing sarcoma family of tumors (ESFT) 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 3-year EFS (76% vs. 65%, P = .028). There was no increase in toxicity observed with the every 2-week schedule.[14]

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.[17] An Italian retrospective study showed that surgery improved outcome only in extremity tumors, although the number of patients with central axis ETB who achieve adequate margins is small.[8] In a series of 39 patients treated at St. Jude Children's Research Hospital, who received both surgery and radiation, the 8-year local failure rate was 5% for patients with negative surgical margins and 17% for those with positive margins.[5] If a very young child has an ETB, 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 compared with 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.[17] European investigators are studying whether treatment intensification (i.e., high-dose chemotherapy with stem cell rescue) will improve outcome for patients with a poor histologic response. Radiation therapy 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.[18]

Radiation therapy should be delivered in a setting in which stringent planning techniques are applied by those experienced in the treatment of ETB. Such an approach will result in local control of the tumor with acceptable morbidity in most patients.[1,2,19] 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 ETB using 55.8 Gy to the prechemotherapy tumor extent with a 2 cm margin compared with the same total-tumor dose following 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]

Higher rates of local failure are seen in patients older than 14 years who have tumors more than 8 cm in length.[20] When radiation therapy was utilized for local control, the presence of metastatic disease at initial presentation was associated with higher risk for local failure.[21] A retrospective analysis of patients with ETB 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.[22]

For patients with residual disease following attempt at surgical resection, the Intergroup Ewing Sarcoma Study (INT-0091 [POG-8850]) 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.[23]

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.

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

Current Clinical Trials

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

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

References:

Ewing Sarcoma: Metastatic Tumors

Prognosis of patients with metastatic disease is poor.[1] 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] For patients with lung/pleural metastases only, 4-year EFS is approximately 40%. Patients with only 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%.[1] Patients who did not receive lung radiation had a worse outcome than those receiving lung radiation.[3]

Standard Treatment Options

Standard treatment for patients with metastatic Ewing tumor of bone (ETB) 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%.[1,2,4,5] 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.[2] In another Intergroup study, increasing dose intensity of cyclophosphamide, ifosfamide, and doxorubicin did not improve outcome compared with regimens utilizing standard dose intensity.[2] This regimen increased toxicity and risk of second malignancy without improving EFS or OS.[2]

Radiation therapy should be delivered in a setting in which stringent planning techniques are applied by those experienced in the treatment of the ETB. Such an approach will result in local control of tumor with acceptable morbidity in most patients.[6,7,8] Radiation therapy to the primary tumor as well as to the sites of metastatic disease should be considered but may interfere with delivery of chemotherapy if too much bone marrow is included in the field. 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.[1,9,10] 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.[2,11,12,13,14,15,16,17,18,19] The impact of high-dose chemotherapy with peripheral blood stem cell support for patients with lung metastases is unknown.[11] European investigators 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 study (EURO-EWING-INTERGROUP-EE99 [COG-AEWS0331]). 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.[20]

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.

• EURO-EWING-INTERGROUP-EE99 (COG-AEWS0331): A randomized study for patients with pulmonary metastases only, which is evaluating standard chemotherapy and peripheral blood stem cell transplant versus standard chemotherapy and bilateral lung radiation, is being conducted in Europe and certain cancer centers in the United States. The Children's Oncology Group (COG) member institutions are participating in a limited way in the Euro-Ewing study. Specifically, the study is open through the COG for patients who present with metastases limited to the lung. They will be enrolled in the Euro-Ewing study and will be randomly assigned to receive chemotherapy or high-dose therapy with autologous stem cell reconstitution following induction chemotherapy and local control.

Current Clinical Trials

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

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

References:

Ewing Sarcoma: Recurrent Tumors

Standard Treatment Options

Recurrence of Ewing tumor of bone (ETB) is most common within 2 years of initial diagnosis (approximately 80%).[1] However, late relapses occurring more than 5 years from initial diagnosis are more common in ETB (13%; 95% confidence interval, 9.4–16.5) than in other pediatric solid tumors.[2] The overall prognosis for patients with recurrent Ewing sarcoma is poor; 5-year survival following recurrence is approximately 10% to 15%.[3,4,5]; [1][Level of evidence: 3iiA] Time to recurrence is the most important prognostic factor. Patients who recurred greater than 2 years from initial diagnosis had a 5-year survival of 30% versus 7% for patients who recurred within 2 years.[1][Level of evidence: 3iiA] Patients with both local recurrence and distant metastases have a worse outcome than patients with either isolated local recurrence or metastatic recurrence alone.[3]; [1][Level of evidence: 3iiA] Isolated pulmonary recurrence was not an important prognostic factor.[1][Level of evidence: 3iiA]

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, are active in recurrent Ewing sarcoma family of tumors and can be considered for these patients.[6,7,8,9,10] In one series, 20 patients received temozolomide and irinotecan following recurrence. Five patients achieved a complete response and seven achieved a partial response.[10] The combination of gemcitabine and docetaxel has achieved objective responses in relapsed Ewing sarcoma.[11][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).[12][Level of evidence: 3iiiDiv] Ifosfamide and etoposide may be active in patients who have not previously received these therapies.[13]

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.[14,15]; [16][Level of evidence: 3iiiDiii] Surveys of patients undergoing allogeneic stem cell transplantation for recurrent ETB did not show improved event-free survival when compared with autologous stem cell transplantation and was associated with a higher complication rate.[14,17,18]

Radiation therapy to bone lesions may provide palliation, though radical resection may improve outcome.[3] Patients with pulmonary metastases who have not received radiation therapy to the lungs should be considered for whole-lung irradiation.[3] Residual disease in the lung may be surgically removed.

Treatment Options Under Clinical Evaluation

The following is an example of a national or international clinical trial that is currently being conducted. Information about ongoing clinical trials is available from the NCI Web site

• COG-ADVL0918: A phase I trial combining temsirolimus with irinotecan and temozolomide in children, adolescents, and young adults with relapsed or refractory solid tumors.

Current Clinical Trials

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

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

References:

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Changes to This Summary (08 / 11 / 2011)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

General Information

Revised text about other biological pretreatment factors to state that overexpression of the p53 protein, Ki67 expression, and loss of 16q may be adverse prognostic factors (cited López-Guerrero et al. as reference 27).

Added Denecke et al. as reference 42.

Ewing Sarcoma: Metastatic Tumors

Added Ladenstein et al., Gilman et al., Rosenthal et al., Gardner et al., McTiernan et al., and Fraser et al. as references 14, 15, 16, 17, 18, and 19, respectively.

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About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of childhood Ewing sarcoma family of tumors. 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. Board members review recently published articles each month to determine whether an article should:

• be discussed at a meeting,
• be cited with text, or
• replace or update an existing article that is already cited.

Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

The lead reviewers for Ewing Sarcoma Family of Tumors Treatment are:

• Paul A. Meyers, MD (Memorial Sloan-Kettering Cancer Center)
• Thomas A. Olson, MD (AFLAC Cancer Center and Blood Disorders Service of Children's Healthcare of Atlanta - Egleston Campus)
• Nita Louise Seibel, MD (National Cancer Institute)

Any comments or questions about the summary content should be submitted to Cancer.gov through the Web site's Contact Form. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

Levels of Evidence

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Pediatric Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

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The preferred citation for this PDQ summary is:

National Cancer Institute: PDQ® Ewing Sarcoma Family of Tumors 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: 2011-08-11