Ewing Family of Tumors

Summary Type: Treatment
Summary Audience: Health professionals
Summary Language: English
Summary Description: Expert-reviewed information summary about the treatment of Ewing's family of tumors.

Ewing Family of Tumors

General Information About This PDQ Summary

This cancer treatment information summary provides an overview of the prognosis, diagnosis, classification, staging, and treatment of the Ewing family of tumors (EFT). In this review, the EFT includes bone primaries (classic Ewing sarcoma, primitive neuroectodermal tumor, and Askin tumor [chest wall]), which will be referred to as Ewing tumor of bone (ETB) and extraosseous primaries, which will be referred to as extraosseous Ewing sarcoma (EOE). General information about EFT will be presented in the General Information About Ewing Family of Tumors section of this summary. Information derived primarily from studies in which the vast majority of patients have bone primaries is presented in the ETB sections, and a separate section about EOE is also presented. Studies using immunohistochemical markers,¹ cytogenetics,^2,3 molecular genetics, and tissue culture ⁴ indicate that these tumors are all derived from the same primordial bone marrow-derived mesenchymal stem cell.

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. These summaries are updated regularly according to the latest published research findings by an Editorial Board of pediatric oncology specialists.

Cancer in children and adolescents is rare. 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 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.⁵ 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.

In recent decades, dramatic improvements in survival have been achieved for children and adolescents with cancer. 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 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.

General Information About Ewing Family of Tumors

The median age for patients with EFT is 15 years and more than 50% of patients are adolescents. 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 include lower extremity (41%); upper extremity (9%); chest wall (16%); pelvis (26.0%); spine (6%); and skull (2%). For EOE, the most common sites are trunk (32%), extremity (26%), head and neck (18%), retroperitoneum (16%), and other sites (9%).^6,

Prognostic factors for Ewing tumor of bone

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

Pretreatment factors

• Site: Patients with ETB in the distal extremities have the best prognosis. Patients with ETB in the proximal extremities have an intermediate prognosis, followed by patients with central or pelvic sites.^7,8,
• 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.^9,
• Age: Younger patients (<10 years of age) have a better prognosis than adolescents, young adults, or adults.^7,8,
• Gender: Girls with ETB have a better prognosis than boys.^8,
• Serum lactate dehydrogenase: Increased serum lactate dehydrogenase (LDH) levels prior to treatment are associated with inferior prognosis. However, increased LDH levels are correlated with large primary tumors and metastatic disease.^8,
• Metastases: Any metastatic disease defined by standard imaging techniques or bone marrow aspirate/biopsy by morphology is an adverse prognostic factor. Patients with metastatic disease confined to lung have a better prognosis than patients with extrapulmonary metastatic sites.^7,10,
• Histopathology: The degree of neural differentiation is not a prognostic factor in ETB.^11,12,
• Molecular pathology: The EWS-FL1 translocation associated with EFT can occur at several potential breakpoints in each of the genes which join to form the novel segment of DNA. Some variants of the novel gene created by the translocation have been associated with a more favorable prognosis.^13,
• Detectable fusion transcripts in morphologically normal marrow: Reverse transcription polymerase chain reaction (RT-PCR) 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.^14,
• Other biological factors: Overexpression of the p53 protein ¹⁵ and loss of 16q ¹⁶ may be adverse prognostic factors. Increased telomerase activity may carry an adverse prognostic significance.^17,

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.^18,19,20,21 For patients who receive pre- and post-induction chemotherapy positron emission tomography (PET) scans, decreased PET uptake following chemotherapy correlated with good histologic response.^22,

¹ Olsen SH, Thomas DG, Lucas DR: Cluster analysis of immunohistochemical profiles in synovial sarcoma, malignant peripheral nerve sheath tumor, and Ewing sarcoma. Mod Pathol 19 (5): 659-68, 2006.

² Delattre O, Zucman J, Melot T, et al.: The Ewing family of tumors--a subgroup of small-round-cell tumors defined by specific chimeric transcripts. N Engl J Med 331 (5): 294-9, 1994.

³ Dagher R, Pham TA, Sorbara L, et al.: Molecular confirmation of Ewing sarcoma. J Pediatr Hematol Oncol 23 (4): 221-4, 2001.

⁴ Llombart-Bosch A, Carda C, Peydro-Olaya A, et al.: Soft tissue Ewing's sarcoma. Characterization in established cultures and xenografts with evidence of a neuroectodermic phenotype. Cancer 66 (12): 2589-601, 1990.

⁵ Guidelines for the pediatric cancer center and role of such centers in diagnosis and treatment. American Academy of Pediatrics Section Statement Section on Hematology/Oncology. Pediatrics 99 (1): 139-41, 1997.

⁶ Raney RB, Asmar L, Newton WA Jr, et al.: Ewing's sarcoma of soft tissues in childhood: a report from the Intergroup Rhabdomyosarcoma Study, 1972 to 1991. J Clin Oncol 15 (2): 574-82, 1997.

⁷ Cotterill SJ, Ahrens S, Paulussen M, et al.: Prognostic factors in Ewing's tumor of bone: analysis of 975 patients from the European Intergroup Cooperative Ewing's Sarcoma Study Group. J Clin Oncol 18 (17): 3108-14, 2000.

⁸ Bacci G, Longhi A, Ferrari S, et al.: Prognostic factors in non-metastatic Ewing's sarcoma tumor of bone: an analysis of 579 patients treated at a single institution with adjuvant or neoadjuvant chemotherapy between 1972 and 1998. Acta Oncol 45 (4): 469-75, 2006.

⁹ Ahrens S, Hoffmann C, Jabar S, et al.: Evaluation of prognostic factors in a tumor volume-adapted treatment strategy for localized Ewing sarcoma of bone: the CESS 86 experience. Cooperative Ewing Sarcoma Study. Med Pediatr Oncol 32 (3): 186-95, 1999.

¹⁰ Miser JS, Krailo MD, Tarbell NJ, et al.: Treatment of metastatic Ewing's sarcoma or primitive neuroectodermal tumor of bone: evaluation of combination ifosfamide and etoposide--a Children's Cancer Group and Pediatric Oncology Group study. J Clin Oncol 22 (14): 2873-6, 2004.

¹¹ Parham DM, Hijazi Y, Steinberg SM, et al.: Neuroectodermal differentiation in Ewing's sarcoma family of tumors does not predict tumor behavior. Hum Pathol 30 (8): 911-8, 1999.

¹² Luksch R, Sampietro G, Collini P, et al.: Prognostic value of clinicopathologic characteristics including neuroectodermal differentiation in osseous Ewing's sarcoma family of tumors in children. Tumori 85 (2): 101-7, 1999 Mar-Apr.

¹³ de Alava E, Kawai A, Healey JH, et al.: EWS-FLI1 fusion transcript structure is an independent determinant of prognosis in Ewing's sarcoma. J Clin Oncol 16 (4): 1248-55, 1998.

¹⁴ Schleiermacher G, Peter M, Oberlin O, et al.: Increased risk of systemic relapses associated with bone marrow micrometastasis and circulating tumor cells in localized ewing tumor. J Clin Oncol 21 (1): 85-91, 2003.

¹⁵ Abudu A, Mangham DC, Reynolds GM, et al.: Overexpression of p53 protein in primary Ewing's sarcoma of bone: relationship to tumour stage, response and prognosis. Br J Cancer 79 (7-8): 1185-9, 1999.

¹⁶ Ozaki T, Paulussen M, Poremba C, et al.: Genetic imbalances revealed by comparative genomic hybridization in Ewing tumors. Genes Chromosomes Cancer 32 (2): 164-71, 2001.

¹⁷ Ohali A, Avigad S, Cohen IJ, et al.: Association between telomerase activity and outcome in patients with nonmetastatic Ewing family of tumors. J Clin Oncol 21 (20): 3836-43, 2003.

¹⁸ Paulussen M, Ahrens S, Dunst J, et al.: Localized Ewing tumor of bone: final results of the cooperative Ewing's Sarcoma Study CESS 86. J Clin Oncol 19 (6): 1818-29, 2001.

¹⁹ Rosito P, Mancini AF, Rondelli R, et al.: Italian Cooperative Study for the treatment of children and young adults with localized Ewing sarcoma of bone: a preliminary report of 6 years of experience. Cancer 86 (3): 421-8, 1999.

²⁰ Wunder JS, Paulian G, Huvos AG, et al.: The histological response to chemotherapy as a predictor of the oncological outcome of operative treatment of Ewing sarcoma. J Bone Joint Surg Am 80 (7): 1020-33, 1998.

²¹ Oberlin O, Deley MC, Bui BN, et al.: Prognostic factors in localized Ewing's tumours and peripheral neuroectodermal tumours: the third study of the French Society of Paediatric Oncology (EW88 study). Br J Cancer 85 (11): 1646-54, 2001.

²² Hawkins DS, Schuetze SM, Butrynski JE, et al.: [18F]Fluorodeoxyglucose positron emission tomography predicts outcome for Ewing sarcoma family of tumors. J Clin Oncol 23 (34): 8828-34, 2005.

Cellular Classification

Ewing family of tumors (EFT) 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 EFT 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 EFT, and positivity by immunochemistry is found in several other tumors including synovial sarcoma, non-Hodgkin lymphoma, and gastrointestinal stromal tumors. Concurrent positivity for membrane CD 99 and FL-1 strongly suggest the diagnosis of EFT.¹ The detection of a translocation involving the EWS gene on chromosomes 22 band q12 and any one of a number of partner chromosomes is the key feature in the diagnosis of EFT.^2,

The individual cells of EFT 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 (PAS) 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 Family of Tumors

Cytogenetic studies of the EFT 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 factors gene 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, ETV 1, located on chromosome 7, and E1AF, located on chromosome 17; this results 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 EFTs, 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. 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 EFT.^5,6 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.

¹ Parham DM, Hijazi Y, Steinberg SM, et al.: Neuroectodermal differentiation in Ewing's sarcoma family of tumors does not predict tumor behavior. Hum Pathol 30 (8): 911-8, 1999.

² Delattre O, Zucman J, Melot T, et al.: The Ewing family of tumors--a subgroup of small-round-cell tumors defined by specific chimeric transcripts. N Engl J Med 331 (5): 294-9, 1994.

³ Urano F, Umezawa A, Yabe H, et al.: Molecular analysis of Ewing's sarcoma: another fusion gene, EWS-E1AF, available for diagnosis. Jpn J Cancer Res 89 (7): 703-11, 1998.

⁴ Hattinger CM, Rumpler S, Strehl S, et al.: Prognostic impact of deletions at 1p36 and numerical aberrations in Ewing tumors. Genes Chromosomes Cancer 24 (3): 243-54, 1999.

⁵ Meier VS, Kühne T, Jundt G, et al.: Molecular diagnosis of Ewing tumors: improved detection of EWS-FLI-1 and EWS-ERG chimeric transcripts and rapid determination of exon combinations. Diagn Mol Pathol 7 (1): 29-35, 1998.

⁶ Dagher R, Pham TA, Sorbara L, et al.: Molecular confirmation of Ewing sarcoma. J Pediatr Hematol Oncol 23 (4): 221-4, 2001.

Stage Information

For patients with confirmed Ewing tumor of bone (ETB), 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. Staging modalities under evaluation but not required on current clinical trials include fluorodeoxyglucose positron emission tomography and molecular analysis of bone marrow for the presence of fusion transcript. In certain studies determination of pretreatment tumor volume is an important variable (Euro-Ewings 99).

For ETB, 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.

¹ Panicek DM, Gatsonis C, Rosenthal DI, et al.: CT and MR imaging in the local staging of primary malignant musculoskeletal neoplasms: Report of the Radiology Diagnostic Oncology Group. Radiology 202 (1): 237-46, 1997.

Treatment Option Overview

Patients should be evaluated by specialists from all disciplines (e.g., radiologist, chemotherapist, pathologist, surgeon or orthopedic oncologist, and radiation oncologist) as early as possible. Appropriate imaging studies of the site should be obtained prior to biopsy. The surgeon 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. 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 (e.g., tissue culture for cytogenetics, imprints, frozen tissue, as well as formalin-fixed tissue).

The successful treatment of patients with Ewing family of tumors (EFT) requires systemic chemotherapy ^{1,2,3,4,5,6,7} in conjunction with either surgery or radiation therapy or both modalities for local tumor control.^8,9,10,11,12 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, patients who receive radiation alone for local control are stratified by pretreatment tumor volume for post–radiation 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.^13,14,15,16 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 Tumor of Bone

Multidrug chemotherapy for EFT 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. Protocols in the United States generally alternate courses of vincristine, cyclophosphamide, and doxorubicin with courses of ifosfamide/etoposide,³ while European protocols generally combine vincristine, doxorubicin and an alkylating agent with or without etoposide in a single treatment cycle.⁷ Duration of primary chemotherapy ranges from 6 months to approximately 1 year.

Local Control for Ewing Tumor of Bone

Over the past two decades, the use of surgery as the primary modality of local control has increased. In an Italian study, 74% of patients with nonmetastatic Ewing tumor of bone (ETB) underwent surgery as part of local control (67.4%–surgery alone; 32.6%–surgery and radiation).¹² For patients receiving radiation therapy as the sole modality for local control, doses range from approximately 55 Gy to 60 Gy. Patients with inadequate surgical margins often receive reduced-dose radiation therapy (45 Gy) following surgery. One study suggests that the addition of 45 Gy postoperative radiation therapy does not improve outcome for patients with inadequate surgical margins.¹² There is a general consensus that surgery should be performed only when there is a high expectation of achieving adequate surgical margins. If there is a low likelihood of achieving adequate surgical margins, patients should receive full-dose radiation therapy for local control.

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.^{17,18,19,20,21,22,23,24} 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.²² 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 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,^25,26,27 femur,^28,29 humerus,³⁰ hand and foot,³¹ chest wall/rib,^32,33,34,35 head and neck,³⁶ and spine.^37,38,39,

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 ETB. Currently, patients with EOE are eligible for studies that include ETB.

From 1972 to 1991, 130 patients with EOE were treated on the Intergroup Rhabdomyosarcoma Studies (IRS) I, II, and III.⁴⁰ One hundred and sixteen patients had localized disease at diagnosis. Ten-year survival was 62%, 61%, and 77% for patients on IRS I, II, and III, respectively. Of interest, in a small cohort of patients with localized, gross, residual disease following initial surgery, there was no benefit from the addition of doxorubicin to VAC-type (vincristine, actinomycin-D, cyclophosphamide) therapy and radiation. However, the doxorubicin was not used in a dose-intensive manner. Gross total tumor resection was an important prognostic factor.

From 1987 to 2004, 111 patients with nonmetastatic EOE were enrolled on the RMS 88 and 96 protocols.⁴¹ 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 event-free survival (EFS) and overall survival (S) were 59% and 69%, respectively. In a multivariate analysis, independent adverse prognostic factors included axial primary, tumor size >10 cm, IRS Group III, and lack of radiation therapy. Nonrandomized patients treated on a rhabdomyosarcoma protocol showed inferior outcome compared with patients treated in the same timeframe to one designed for treating Ewing sarcoma alone; the major difference being the use of doxorubicin.^42,

Two hundred and thirty six patients with EOE were entered on studies of the German Pediatric Oncology Group.⁴³ The median age at diagnosis was 15 years and 133 patients were male. Primary tumor site was extremity (62) and central site (174). Sixty of 236 patients had metastases at diagnosis. Chemotherapy consisted of vincristine, doxorubicin, cyclophosphamide, and actinomycin (VACA), CEVAIE, or vincristine, ifosfamide, doxorubicin, etoposide (VIDE). The 5-year EFS and OS was 49% and 60%, respectively. Five-year survival was 70% for patients with localized disease and 33% for patients with metastases at diagnosis. Overall survival in patients with localized disease did not seem related to tumor site or size.

Second Malignant Neoplasms

Patients treated for EFTs 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 EFTs,^44,45,46,47 although some dose-intensive regimens appear to be associated with a higher risk of hematological malignancy.^48,49 Treatment-related AML and MDS arise most commonly at 2 to 5 years following diagnosis. Survivors of EFTs remain at increased risk of developing a second solid tumor throughout their lifetime. The risk of developing solid tumors appears to be greatest in patients treated with radiation therapy, and sarcomas usually occur within the prior radiation field.^47,50 The risk of developing a sarcoma following radiation therapy is dose-dependent, with higher doses associated with an increased risk of sarcoma development.^45,46 The cumulative risk of developing a secondary solid tumor at 15 to 20 years from diagnosis appears to be in the 5% to 10% range.^44,45,46 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.

The designations in PDQ that treatments are “standard” or “under clinical evaluation” are not to be used as a basis for reimbursement determinations.

¹ Craft A, Cotterill S, Malcolm A, et al.: Ifosfamide-containing chemotherapy in Ewing's sarcoma: The Second United Kingdom Children's Cancer Study Group and the Medical Research Council Ewing's Tumor Study. J Clin Oncol 16 (11): 3628-33, 1998.

² Shankar AG, Pinkerton CR, Atra A, et al.: Local therapy and other factors influencing site of relapse in patients with localised Ewing's sarcoma. United Kingdom Children's Cancer Study Group (UKCCSG). Eur J Cancer 35 (12): 1698-704, 1999.

³ Nilbert M, Saeter G, Elomaa I, et al.: Ewing's sarcoma treatment in Scandinavia 1984-1990--ten-year results of the Scandinavian Sarcoma Group Protocol SSGIV. Acta Oncol 37 (4): 375-8, 1998.

⁴ Ferrari S, Mercuri M, Rosito P, et al.: Ifosfamide and actinomycin-D, added in the induction phase to vincristine, cyclophosphamide and doxorubicin, improve histologic response and prognosis in patients with non metastatic Ewing's sarcoma of the extremity. J Chemother 10 (6): 484-91, 1998.

⁵ Grier HE, Krailo MD, Tarbell NJ, et al.: Addition of ifosfamide and etoposide to standard chemotherapy for Ewing's sarcoma and primitive neuroectodermal tumor of bone. N Engl J Med 348 (8): 694-701, 2003.

⁶ Thacker MM, Temple HT, Scully SP: Current treatment for Ewing's sarcoma. Expert Rev Anticancer Ther 5 (2): 319-31, 2005.

⁷ Juergens C, Weston C, Lewis I, et al.: Safety assessment of intensive induction with vincristine, ifosfamide, doxorubicin, and etoposide (VIDE) in the treatment of Ewing tumors in the EURO-E.W.I.N.G. 99 clinical trial. Pediatr Blood Cancer 47 (1): 22-9, 2006.

⁸ Dunst J, Schuck A: Role of radiotherapy in Ewing tumors. Pediatr Blood Cancer 42 (5): 465-70, 2004.

⁹ Donaldson SS: Ewing sarcoma: radiation dose and target volume. Pediatr Blood Cancer 42 (5): 471-6, 2004.

¹⁰ Bacci G, Ferrari S, Longhi A, et al.: Role of surgery in local treatment of Ewing's sarcoma of the extremities in patients undergoing adjuvant and neoadjuvant chemotherapy. Oncol Rep 11 (1): 111-20, 2004.

¹¹ Krasin MJ, Rodriguez-Galindo C, Davidoff AM, et al.: Efficacy of combined surgery and irradiation for localized Ewings sarcoma family of tumors. Pediatr Blood Cancer 43 (3): 229-36, 2004.

¹² Bacci G, Longhi A, Briccoli A, et al.: The role of surgical margins in treatment of Ewing's sarcoma family tumors: experience of a single institution with 512 patients treated with adjuvant and neoadjuvant chemotherapy. Int J Radiat Oncol Biol Phys 65 (3): 766-72, 2006.

¹³ Paulussen M, Ahrens S, Burdach S, et al.: Primary metastatic (stage IV) Ewing tumor: survival analysis of 171 patients from the EICESS studies. European Intergroup Cooperative Ewing Sarcoma Studies. Ann Oncol 9 (3): 275-81, 1998.

¹⁴ Pinkerton CR, Bataillard A, Guillo S, et al.: Treatment strategies for metastatic Ewing's sarcoma. Eur J Cancer 37 (11): 1338-44, 2001.

¹⁵ Miser JS, Krailo M, Meyers P, et al.: Metastatic Ewing's sarcoma(es) and primitive neuroectodermal tumor (PNET) of bone: failure of new regimens to improve outcome. [Abstract] Proceedings of the American Society of Clinical Oncology 15: A-1472, 467, 1996.

¹⁶ Bernstein ML, Devidas M, Lafreniere D, et al.: Intensive therapy with growth factor support for patients with Ewing tumor metastatic at diagnosis: Pediatric Oncology Group/Children's Cancer Group Phase II Study 9457--a report from the Children's Oncology Group. J Clin Oncol 24 (1): 152-9, 2006.

¹⁷ Kushner BH, Meyers PA: How effective is dose-intensive/myeloablative therapy against Ewing's sarcoma/primitive neuroectodermal tumor metastatic to bone or bone marrow? The Memorial Sloan-Kettering experience and a literature review. J Clin Oncol 19 (3): 870-80, 2001.

¹⁸ Marina N, Meyers PA: High-dose therapy and stem-cell rescue for Ewing's family of tumors in second remission. J Clin Oncol 23 (19): 4262-4, 2005.

¹⁹ Burdach S: Treatment of advanced Ewing tumors by combined radiochemotherapy and engineered cellular transplants. Pediatr Transplant 8 (Suppl 5): 67-82, 2004.

²⁰ McTiernan A, Driver D, Michelagnoli MP, et al.: High dose chemotherapy with bone marrow or peripheral stem cell rescue is an effective treatment option for patients with relapsed or progressive Ewing's sarcoma family of tumours. Ann Oncol 17 (8): 1301-5, 2006.

²¹ Burdach S, Meyer-Bahlburg A, Laws HJ, et al.: High-dose therapy for patients with primary multifocal and early relapsed Ewing's tumors: results of two consecutive regimens assessing the role of total-body irradiation. J Clin Oncol 21 (16): 3072-8, 2003.

²² Meyers PA, Krailo MD, Ladanyi M, et al.: High-dose melphalan, etoposide, total-body irradiation, and autologous stem-cell reconstitution as consolidation therapy for high-risk Ewing's sarcoma does not improve prognosis. J Clin Oncol 19 (11): 2812-20, 2001.

²³ Oberlin O, Rey A, Desfachelles AS, et al.: Impact of high-dose busulfan plus melphalan as consolidation in metastatic Ewing tumors: a study by the Société Française des Cancers de l'Enfant. J Clin Oncol 24 (24): 3997-4002, 2006.

²⁴ Hawkins D, Barnett T, Bensinger W, et al.: Busulfan, melphalan, and thiotepa with or without total marrow irradiation with hematopoietic stem cell rescue for poor-risk Ewing-Sarcoma-Family tumors. Med Pediatr Oncol 34 (5): 328-37, 2000.

²⁵ Hoffmann C, Ahrens S, Dunst J, et al.: Pelvic Ewing sarcoma: a retrospective analysis of 241 cases. Cancer 85 (4): 869-77, 1999.

²⁶ Sucato DJ, Rougraff B, McGrath BE, et al.: Ewing's sarcoma of the pelvis. Long-term survival and functional outcome. Clin Orthop (373): 193-201, 2000.

²⁷ Bacci G, Ferrari S, Mercuri M, et al.: Multimodal therapy for the treatment of nonmetastatic Ewing sarcoma of pelvis. J Pediatr Hematol Oncol 25 (2): 118-24, 2003.

²⁸ Bacci G, Ferrari S, Longhi A, et al.: Local and systemic control in Ewing's sarcoma of the femur treated with chemotherapy, and locally by radiotherapy and/or surgery. J Bone Joint Surg Br 85 (1): 107-14, 2003.

²⁹ Ozaki T, Hillmann A, Hoffmann C, et al.: Ewing's sarcoma of the femur. Prognosis in 69 patients treated by the CESS group. Acta Orthop Scand 68 (1): 20-4, 1997.

³⁰ Ayoub KS, Fiorenza F, Grimer RJ, et al.: Extensible endoprostheses of the humerus after resection of bone tumours. J Bone Joint Surg Br 81 (3): 495-500, 1999.

³¹ Casadei R, Magnani M, Biagini R, et al.: Prognostic factors in Ewing's sarcoma of the foot. Clin Orthop (420): 230-8, 2004.

³² Shamberger RC, Laquaglia MP, Krailo MD, et al.: Ewing sarcoma of the rib: results of an intergroup study with analysis of outcome by timing of resection. J Thorac Cardiovasc Surg 119 (6): 1154-61, 2000.

³³ Sirvent N, Kanold J, Levy C, et al.: Non-metastatic Ewing's sarcoma of the ribs: the French Society of Pediatric Oncology Experience. Eur J Cancer 38 (4): 561-7, 2002.

³⁴ Shamberger RC, LaQuaglia MP, Gebhardt MC, et al.: Ewing sarcoma/primitive neuroectodermal tumor of the chest wall: impact of initial versus delayed resection on tumor margins, survival, and use of radiation therapy. Ann Surg 238 (4): 563-7; discussion 567-8, 2003.

³⁵ Schuck A, Ahrens S, Konarzewska A, et al.: Hemithorax irradiation for Ewing tumors of the chest wall. Int J Radiat Oncol Biol Phys 54 (3): 830-8, 2002.

³⁶ Windfuhr JP: Primitive neuroectodermal tumor of the head and neck: incidence, diagnosis, and management. Ann Otol Rhinol Laryngol 113 (7): 533-43, 2004.

³⁷ Venkateswaran L, Rodriguez-Galindo C, Merchant TE, et al.: Primary Ewing tumor of the vertebrae: clinical characteristics, prognostic factors, and outcome. Med Pediatr Oncol 37 (1): 30-5, 2001.

³⁸ Marco RA, Gentry JB, Rhines LD, et al.: Ewing's sarcoma of the mobile spine. Spine 30 (7): 769-73, 2005.

³⁹ Schuck A, Ahrens S, von Schorlemer I, et al.: Radiotherapy in Ewing tumors of the vertebrae: treatment results and local relapse analysis of the CESS 81/86 and EICESS 92 trials. Int J Radiat Oncol Biol Phys 63 (5): 1562-7, 2005.

⁴⁰ Raney RB, Asmar L, Newton WA Jr, et al.: Ewing's sarcoma of soft tissues in childhood: a report from the Intergroup Rhabdomyosarcoma Study, 1972 to 1991. J Clin Oncol 15 (2): 574-82, 1997.

⁴¹ Spiller M, Bisogno G, Ferrari A, et al.: Prognostic factors in localized extraosseus Ewing family tumors. [Abstract] Pediatr Blood Cancer 46 (10) : A-PD.024, 434, 2006.

⁴² Castex MP, Rubie H, Stevens MC, et al.: Extraosseous localized ewing tumors: improved outcome with anthracyclines--the French society of pediatric oncology and international society of pediatric oncology. J Clin Oncol 25 (10): 1176-82, 2007.

⁴³ Ladenstein R, Pötschger U, Jürgens H, et al.: Comparison of treatment concepts for extraosseus Ewing tumors (EET) within consecutive trials of two GPOH Cooperative Study Groups. [Abstract] Pediatr Blood Cancer 45 (10) : A-P.C.004, 450, 2005.

⁴⁴ Paulussen M, Ahrens S, Lehnert M, et al.: Second malignancies after Ewing tumor treatment in 690 patients from a cooperative German/Austrian/Dutch study. Ann Oncol 12 (11): 1619-30, 2001.

⁴⁵ Fuchs B, Valenzuela RG, Petersen IA, et al.: Ewing's sarcoma and the development of secondary malignancies. Clin Orthop (415): 82-9, 2003.

⁴⁶ Dunst J, Ahrens S, Paulussen M, et al.: Second malignancies after treatment for Ewing's sarcoma: a report of the CESS-studies. Int J Radiat Oncol Biol Phys 42 (2): 379-84, 1998.

⁴⁷ Kuttesch JF Jr, Wexler LH, Marcus RB, et al.: Second malignancies after Ewing's sarcoma: radiation dose-dependency of secondary sarcomas. J Clin Oncol 14 (10): 2818-25, 1996.

⁴⁸ Bhatia S, Krailo MD, Chen Z, et al.: Therapy-related myelodysplasia and acute myeloid leukemia after Ewing sarcoma and primitive neuroectodermal tumor of bone: A report from the Children's Oncology Group. Blood 109 (1): 46-51, 2007.

⁴⁹ Kushner BH, Heller G, Cheung NK, et al.: High risk of leukemia after short-term dose-intensive chemotherapy in young patients with solid tumors. J Clin Oncol 16 (9): 3016-20, 1998.

⁵⁰ Hawkins MM, Wilson LM, Burton HS, et al.: Radiotherapy, alkylating agents, and risk of bone cancer after childhood cancer. J Natl Cancer Inst 88 (5): 270-8, 1996.

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 from diagnosis.⁹

Current standard chemotherapy in the United States includes vincristine, doxorubicin, and cyclophosphamide, also known as VAdriaC, alternating with ifosfamide and etoposide.⁹ The combination of ifosfamide and etoposide has shown activity in ETB, and a large randomized clinical trial and a nonrandomized trial demonstrated that outcome was improved when ifosfamide and etoposide 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 ifosfamide/etoposide had an 82% 4-year EFS.¹² However, in a trial of the former Children's Cancer Group (CCG), which compared a dose-intensified chemotherapy regimen of vincristine, doxorubicin, cyclophosphamide, ifosfamide, and etoposide with standard doses of the same regimen, however, no differences in outcome were observed.^13,.

Local control can be achieved by surgery and/or radiation. Surgery is generally the preferred approach if the lesion is resectable.^14,15 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.¹⁶ An Italian retrospective study showed that surgery only improved outcome 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 the French Ewing’s 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.¹⁶ Currently, European investigators are studying whether treatment intensification (i.e., high-dose chemotherapy with stem cell rescue [SCR]) 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. Biopsy should be from soft tissue as often as possible to avoid increasing the risk of fracture.^17,

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 the tumor with acceptable morbidity in most patients.^1,2,18 The radiation dose may be adjusted depending upon 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.¹⁷ When radiation therapy was utilized for local control, the presence of metastatic disease at initial presentation was associated with higher risk for local failure.¹⁹ 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 higher 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.^20,

The current recommendations of the Intergroup Ewing’s Sarcoma Study (IESS) for patients with gross residual disease is 45 Gy to original disease site plus a 10.8 Gy boost to gross residual disease. For those with microscopic residual disease, the recommendation is 45 Gy plus a 5.4 Gy boost. 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.^21,

Treatment Options Under Clinical Evaluation

The following is an example of a national and/or institutional clinical trial that is currently being conducted. For more information about clinical trials, please see the NCI Web site.

• A closed Children’s Oncology Group (COG) study randomly assigned patients with nonmetastatic disease to receive dose-intensive chemotherapy (i.e., alternating VAdriaC with ifosfamide and etoposide) with filgrastim (G-CSF) on a 21- or 14-day schedule to determine whether increasing the dose intensity of all drugs simultaneously through a reduction of the interval between chemotherapy cycles, known as interval compression, improves survival. The experimental interval compression arm is based on a nonrandomized pilot study that used hematopoietic growth factors to promote interval-dose compression to shorten courses of chemotherapy from 21 days to 14 days.^22,

¹ Dunst J, Jürgens H, Sauer R, et al.: Radiation therapy in Ewing's sarcoma: an update of the CESS 86 trial. Int J Radiat Oncol Biol Phys 32 (4): 919-30, 1995.

² Donaldson SS, Torrey M, Link MP, et al.: A multidisciplinary study investigating radiotherapy in Ewing's sarcoma: end results of POG #8346. Pediatric Oncology Group. Int J Radiat Oncol Biol Phys 42 (1): 125-35, 1998.

³ Craft A, Cotterill S, Malcolm A, et al.: Ifosfamide-containing chemotherapy in Ewing's sarcoma: The Second United Kingdom Children's Cancer Study Group and the Medical Research Council Ewing's Tumor Study. J Clin Oncol 16 (11): 3628-33, 1998.

⁴ Nilbert M, Saeter G, Elomaa I, et al.: Ewing's sarcoma treatment in Scandinavia 1984-1990--ten-year results of the Scandinavian Sarcoma Group Protocol SSGIV. Acta Oncol 37 (4): 375-8, 1998.

⁵ Krasin MJ, Davidoff AM, Rodriguez-Galindo C, et al.: Definitive surgery and multiagent systemic therapy for patients with localized Ewing sarcoma family of tumors: local outcome and prognostic factors. Cancer 104 (2): 367-73, 2005.

⁶ Bacci G, Forni C, Longhi A, et al.: Long-term outcome for patients with non-metastatic Ewing's sarcoma treated with adjuvant and neoadjuvant chemotherapies. 402 patients treated at Rizzoli between 1972 and 1992. Eur J Cancer 40 (1): 73-83, 2004.

⁷ Rosito P, Mancini AF, Rondelli R, et al.: Italian Cooperative Study for the treatment of children and young adults with localized Ewing sarcoma of bone: a preliminary report of 6 years of experience. Cancer 86 (3): 421-8, 1999.

⁸ Bacci G, Longhi A, Briccoli A, et al.: The role of surgical margins in treatment of Ewing's sarcoma family tumors: experience of a single institution with 512 patients treated with adjuvant and neoadjuvant chemotherapy. Int J Radiat Oncol Biol Phys 65 (3): 766-72, 2006.

⁹ Grier HE, Krailo MD, Tarbell NJ, et al.: Addition of ifosfamide and etoposide to standard chemotherapy for Ewing's sarcoma and primitive neuroectodermal tumor of bone. N Engl J Med 348 (8): 694-701, 2003.

¹⁰ Ferrari S, Mercuri M, Rosito P, et al.: Ifosfamide and actinomycin-D, added in the induction phase to vincristine, cyclophosphamide and doxorubicin, improve histologic response and prognosis in patients with non metastatic Ewing's sarcoma of the extremity. J Chemother 10 (6): 484-91, 1998.

¹¹ Smith MA, Ungerleider RS, Horowitz ME, et al.: Influence of doxorubicin dose intensity on response and outcome for patients with osteogenic sarcoma and Ewing's sarcoma. J Natl Cancer Inst 83 (20): 1460-70, 1991.

¹² Kolb EA, Kushner BH, Gorlick R, et al.: Long-term event-free survival after intensive chemotherapy for Ewing's family of tumors in children and young adults. J Clin Oncol 21 (18): 3423-30, 2003.

¹³ Granowetter L, Womer R, Devidas M, et al.: Comparison of dose intensified and standard dose chemotherapy for the treatment of non-metastatic Ewing's sarcoma (ES) and primitive neuroectodermal tumor (PNET) of bone and soft tissue: a Pediatric Oncology Group-Children's Cancer Group phase III trial. [Abstract] Med Pediatr Oncol 37: A-038, 172, 2001.

¹⁴ Hoffmann C, Ahrens S, Dunst J, et al.: Pelvic Ewing sarcoma: a retrospective analysis of 241 cases. Cancer 85 (4): 869-77, 1999.

¹⁵ Shamberger RC, Laquaglia MP, Krailo MD, et al.: Ewing sarcoma of the rib: results of an intergroup study with analysis of outcome by timing of resection. J Thorac Cardiovasc Surg 119 (6): 1154-61, 2000.

¹⁶ Oberlin O, Deley MC, Bui BN, et al.: Prognostic factors in localized Ewing's tumours and peripheral neuroectodermal tumours: the third study of the French Society of Paediatric Oncology (EW88 study). Br J Cancer 85 (11): 1646-54, 2001.

¹⁷ Fuchs B, Valenzuela RG, Sim FH: Pathologic fracture as a complication in the treatment of Ewing's sarcoma. Clin Orthop (415): 25-30, 2003.

¹⁸ Krasin MJ, Rodriguez-Galindo C, Billups CA, et al.: Definitive irradiation in multidisciplinary management of localized Ewing sarcoma family of tumors in pediatric patients: outcome and prognostic factors. Int J Radiat Oncol Biol Phys 60 (3): 830-8, 2004.

¹⁹ La TH, Meyers PA, Wexler LH, et al.: Radiation therapy for Ewing's sarcoma: results from Memorial Sloan-Kettering in the modern era. Int J Radiat Oncol Biol Phys 64 (2): 544-50, 2006.

²⁰ Schuck A, Ahrens S, Konarzewska A, et al.: Hemithorax irradiation for Ewing tumors of the chest wall. Int J Radiat Oncol Biol Phys 54 (3): 830-8, 2002.

²¹ Kuttesch JF Jr, Wexler LH, Marcus RB, et al.: Second malignancies after Ewing's sarcoma: radiation dose-dependency of secondary sarcomas. J Clin Oncol 14 (10): 2818-25, 1996.

²² Womer RB, Daller RT, Fenton JG, et al.: Granulocyte colony stimulating factor permits dose intensification by interval compression in the treatment of Ewing's sarcomas and soft tissue sarcomas in children. Eur J Cancer 36 (1): 87-94, 2000.

Ewing Tumor of Bone: Metastatic Tumors

Prognosis of patients with metastatic disease is poor.^1, Current therapies for patients who present with metastatic disease achieve 8-year event-free survival (EFS) of approximately 20% and overall survival (OS) of approximately 30%.^2,

Standard Treatment Options

Standard treatment for patients with metastatic Ewing tumor of bone (EBT) 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%.^1,2,3,4 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 for cyclophosphamide and ifosfamide did not improve outcome compared with regimens utilizing standard dose intensity.⁵ For patients with lung/pleural metastases only, cure rates are approximately 30%. Patients who did not receive lung radiation had a worse outcome than those receiving lung radiation.⁶ Patients with only bone/bone marrow metastases have an approximate 20% to 25% cure rate. Patients with combined lung and bone/bone marrow metastases have a less than 15% cure rate.^1,

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.^7,8,9 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 to 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.^1,10,11 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.^5,12,13 The impact of high-dose chemotherapy with peripheral blood stem cell support for patients with lung metastases is currently unknown.¹² 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 extra-pulmonary sites is an investigator choice in the Euro-Ewing study, limited to European investigators. 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.

Treatment Options Under Clinical Evaluation

The following is an example of an international clinical trial that is currently being conducted. For more information about clinical trials, please see the NCI Web site.

• 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.
• The COG is performing a clinical trial of low-dose antiangiogenic chemotherapy in combination with standard multiagent chemotherapy for patients with newly diagnosed metastatic Ewing sarcoma family of tumors. COG AEWS02P1 adds vinblastine and celecoxib to cyclophosphamide, doxorubicin, vincristine, ifosfamide, and etoposide.

¹ Paulussen M, Ahrens S, Burdach S, et al.: Primary metastatic (stage IV) Ewing tumor: survival analysis of 171 patients from the EICESS studies. European Intergroup Cooperative Ewing Sarcoma Studies. Ann Oncol 9 (3): 275-81, 1998.

² Miser JS, Krailo MD, Tarbell NJ, et al.: Treatment of metastatic Ewing's sarcoma or primitive neuroectodermal tumor of bone: evaluation of combination ifosfamide and etoposide--a Children's Cancer Group and Pediatric Oncology Group study. J Clin Oncol 22 (14): 2873-6, 2004.

³ Cangir A, Vietti TJ, Gehan EA, et al.: Ewing's sarcoma metastatic at diagnosis. Results and comparisons of two intergroup Ewing's sarcoma studies. Cancer 66 (5): 887-93, 1990.

⁴ Pinkerton CR, Bataillard A, Guillo S, et al.: Treatment strategies for metastatic Ewing's sarcoma. Eur J Cancer 37 (11): 1338-44, 2001.

⁵ Bernstein ML, Devidas M, Lafreniere D, et al.: Intensive therapy with growth factor support for patients with Ewing tumor metastatic at diagnosis: Pediatric Oncology Group/Children's Cancer Group Phase II Study 9457--a report from the Children's Oncology Group. J Clin Oncol 24 (1): 152-9, 2006.

⁶ Paulussen M, Ahrens S, Craft AW, et al.: Ewing's tumors with primary lung metastases: survival analysis of 114 (European Intergroup) Cooperative Ewing's Sarcoma Studies patients. J Clin Oncol 16 (9): 3044-52, 1998.

⁷ Arai Y, Kun LE, Brooks MT, et al.: Ewing's sarcoma: local tumor control and patterns of failure following limited-volume radiation therapy. Int J Radiat Oncol Biol Phys 21 (6): 1501-8, 1991.

⁸ Dunst J, Jürgens H, Sauer R, et al.: Radiation therapy in Ewing's sarcoma: an update of the CESS 86 trial. Int J Radiat Oncol Biol Phys 32 (4): 919-30, 1995.

⁹ Donaldson SS, Torrey M, Link MP, et al.: A multidisciplinary study investigating radiotherapy in Ewing's sarcoma: end results of POG #8346. Pediatric Oncology Group. Int J Radiat Oncol Biol Phys 42 (1): 125-35, 1998.

¹⁰ Madero L, Muñoz A, Sánchez de Toledo J, et al.: Megatherapy in children with high-risk Ewing's sarcoma in first complete remission. Bone Marrow Transplant 21 (8): 795-9, 1998.

¹¹ Spunt SL, McCarville MB, Kun LE, et al.: Selective use of whole-lung irradiation for patients with Ewing sarcoma family tumors and pulmonary metastases at the time of diagnosis. J Pediatr Hematol Oncol 23 (2): 93-8, 2001.

¹² Meyers PA, Krailo MD, Ladanyi M, et al.: High-dose melphalan, etoposide, total-body irradiation, and autologous stem-cell reconstitution as consolidation therapy for high-risk Ewing's sarcoma does not improve prognosis. J Clin Oncol 19 (11): 2812-20, 2001.

¹³ Burdach S, Meyer-Bahlburg A, Laws HJ, et al.: High-dose therapy for patients with primary multifocal and early relapsed Ewing's tumors: results of two consecutive regimens assessing the role of total-body irradiation. J Clin Oncol 21 (16): 3072-8, 2003.

Ewing Tumor of Bone: Recurrent Tumors

Standard Treatment Options

The prognosis for patients with recurrent or progressive Ewing tumor of bone (ETB) is poor, though the prognosis for patients relapsing more than two years following completion of primary therapy is better than for those patients who relapse while on their initial chemotherapy regimen or earlier than two years following completion of primary therapy.^1,2,3 Five-year event-free and overall survival following recurrence is less than 10%.^2,4 Patients with both local and distant recurrence have a worse outcome than those with either local or distant recurrence.¹ Patients who relapse 2 or more years after diagnosis and patients who have local recurrences that can be treated with radical surgery and intensive chemotherapy have the most favorable outcomes.¹ In one large series, the majority of relapses occurred within 5 years of diagnosis. Ten to 15% of relapses occurred after 5 years. Very few patients who relapsed later were salvaged.⁵ The selection of further treatment depends on many factors, including the site of recurrence and prior treatment, as well as individual patient considerations. Ifosfamide and etoposide are active in ETB and should be considered for patients who have not previously received these agents.⁶ The combination of cyclophosphamide plus topotecan has been active in patients with recurrent or refractory disease.^7,8 The combination of irinotecan and temozolomide has achieved objective responses in patients with recurrent ETB.⁹ Aggressive attempts to control the disease, including myeloablative regimens, may be warranted.¹⁰ A European survey 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.¹¹ Radiation therapy to bone lesions may provide palliation though radical resection may improve outcome.¹ Patients with pulmonary metastases should receive whole-lung irradiation.¹ Residual disease in the lung may be surgically removed.

Treatment Options Under Clinical Evaluation

Clinical trials investigating new agents and new combinations of agents are available and should be considered. Information about ongoing clinical trials is available from the NCI Web site.

¹ Rodriguez-Galindo C, Billups CA, Kun LE, et al.: Survival after recurrence of Ewing tumors: the St Jude Children's Research Hospital experience, 1979-1999. Cancer 94 (2): 561-9, 2002.

² Shankar AG, Ashley S, Craft AW, et al.: Outcome after relapse in an unselected cohort of children and adolescents with Ewing sarcoma. Med Pediatr Oncol 40 (3): 141-7, 2003.

³ Bacci G, Longhi A, Ferrari S, et al.: Pattern of relapse in 290 patients with nonmetastatic Ewing's sarcoma family tumors treated at a single institution with adjuvant and neoadjuvant chemotherapy between 1972 and 1999. Eur J Surg Oncol 32 (9): 974-9, 2006.

⁴ Bacci G, Longhi A, Ferrari S, et al.: Prognostic factors in non-metastatic Ewing's sarcoma tumor of bone: an analysis of 579 patients treated at a single institution with adjuvant or neoadjuvant chemotherapy between 1972 and 1998. Acta Oncol 45 (4): 469-75, 2006.

⁵ Bacci G, Forni C, Longhi A, et al.: Long-term outcome for patients with non-metastatic Ewing's sarcoma treated with adjuvant and neoadjuvant chemotherapies. 402 patients treated at Rizzoli between 1972 and 1992. Eur J Cancer 40 (1): 73-83, 2004.

⁶ Miser JS, Kinsella TJ, Triche TJ, et al.: Ifosfamide with mesna uroprotection and etoposide: an effective regimen in the treatment of recurrent sarcomas and other tumors of children and young adults. J Clin Oncol 5 (8): 1191-8, 1987.

⁷ Saylors RL 3rd, Stine KC, Sullivan J, et al.: Cyclophosphamide plus topotecan in children with recurrent or refractory solid tumors: a Pediatric Oncology Group phase II study. J Clin Oncol 19 (15): 3463-9, 2001.

⁸ McTiernan A, Driver D, Michelagnoli MP, et al.: High dose chemotherapy with bone marrow or peripheral stem cell rescue is an effective treatment option for patients with relapsed or progressive Ewing's sarcoma family of tumours. Ann Oncol 17 (8): 1301-5, 2006.

⁹ Wagner LM, McAllister N, Goldsby RE, et al.: Temozolomide and intravenous irinotecan for treatment of advanced Ewing sarcoma. Pediatr Blood Cancer 48 (2): 132-9, 2007.

¹⁰ Burdach S, Jürgens H, Peters C, et al.: Myeloablative radiochemotherapy and hematopoietic stem-cell rescue in poor-prognosis Ewing's sarcoma. J Clin Oncol 11 (8): 1482-8, 1993.

¹¹ Burdach S, van Kaick B, Laws HJ, et al.: Allogeneic and autologous stem-cell transplantation in advanced Ewing tumors. An update after long-term follow-up from two centers of the European Intergroup study EICESS. Stem-Cell Transplant Programs at Düsseldorf University Medical Center, Germany and St. Anna Kinderspital, Vienna, Austria. Ann Oncol 11 (11): 1451-62, 2000.

Changes to This Summary (06/14/2007)

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

This summary was extensively revised.

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