Treatment Option Overview
Patients should be evaluated by specialists from the appropriate disciplines (e.g., radiologist, chemotherapist, pathologist, surgical or orthopedic oncologist, and radiation oncologist) as early as possible. Appropriate imaging studies of the site should be obtained before biopsy. The surgical or orthopedic oncologist who will perform the definitive surgery should be involved before or during the biopsy so that the incision can be placed in an acceptable location. This is especially important if it is thought that the lesion can be totally excised or if a limb salvage procedure may be attempted. Biopsy should be from soft tissue as often as possible to avoid increasing the risk of fracture. The radiation oncologist and pathologist should be consulted before biopsy/surgery in order to be sure that the incision will not compromise the radiation port and so that multiple types of tissue samples are obtained. It is important to obtain fresh tissue, whenever possible, for cytogenetics and molecular pathology. A second option is to perform a needle biopsy as long as adequate tissue for molecular biology and cytogenetics is obtained.
The successful treatment of patients with Ewing sarcoma requires systemic chemotherapy [3-9] in conjunction with either surgery or radiation therapy or both modalities for local tumor control.[10-14] In general, patients receive preoperative chemotherapy before instituting local control measures. In patients who undergo surgery, surgical margins and histologic response are considered in planning postoperative therapy. Most patients with metastatic disease have a good initial response to preoperative chemotherapy; however, in most cases, the disease is only partially controlled or recurs.[15-18] Patients with lung as the sole metastatic site have a better prognosis than patients with metastases to bone and/or bone marrow. Adequate local control for metastatic sites, particularly bone metastases, may be an important issue.
Chemotherapy for Ewing Sarcoma
Multidrug chemotherapy for Ewing sarcoma always includes vincristine, doxorubicin, ifosfamide, and etoposide. Most protocols use cyclophosphamide as well. Certain protocols incorporate dactinomycin. The mode of administration and dose intensity of cyclophosphamide within courses differs markedly between protocols. A European Intergroup Cooperative Ewing Sarcoma Study (EICESS) trial suggested that 1.2 grams of cyclophosphamide produced a similar event-free survival (EFS) compared with 6 grams of ifosfamide in patients with lower-risk disease, and identified a trend toward better EFS for patients with localized Ewing sarcoma and higher-risk disease when treatment included etoposide (GER-GPOH-EICESS-92).[Level of evidence: 1iiA] Protocols in the United States generally alternate courses of vincristine, cyclophosphamide, and doxorubicin with courses of ifosfamide/etoposide, while European protocols generally combine vincristine, doxorubicin, and an alkylating agent with or without etoposide in a single treatment cycle.
The duration of primary chemotherapy ranges from 6 months to approximately 1 year. A randomized clinical trial (COG-AEWS0031 [NCT00006734]) from the Children’s Oncology Group showed that for patients presenting without metastases, the administration of cycles of cyclophosphamide, doxorubicin, and vincristine alternating with cycles of ifosfamide and etoposide at 2-week intervals achieved superior EFS (5-year EFS, 73%) than alternating cycles at 3-week intervals (5-year EFS, 65%).
Local control for Ewing sarcoma
Treatment approaches for Ewing sarcoma titrate therapeutic aggressiveness with the goal of maximizing local control while minimizing morbidity.
While surgery is effective and appropriate for patients who can undergo complete resection with acceptable morbidity, children who have unresectable tumors or who would suffer loss of function are treated with radiation therapy alone. Those who undergo gross resections with microscopic residual disease may benefit from adjuvant radiation therapy. Randomized trials that directly compare both modalities do not exist, and their relative roles remain controversial. Although retrospective institutional series suggest superior local control and survival with surgery rather than radiation therapy, most of these studies are compromised by selection bias. Data for patients with pelvic primary Ewing sarcoma from a North American intergroup trial showed no difference in local control or survival based on local-control modality—surgery alone, radiation therapy alone, or radiation plus surgery.
For patients who undergo gross total resection with microscopic residual disease, the value of adjuvant radiation therapy is controversial. Investigations addressing this issue are retrospective and nonrandomized, limiting their value. Investigators from St. Jude Children’s Research Hospital reported 39 patients with localized Ewing sarcoma who received both surgery and radiation. Local failure for patients with positive and negative margins was 17% and 5%, respectively, and overall survival (OS) was 71% and 94%, respectively. However, in a large retrospective Italian study, 45 Gy adjuvant radiation therapy for patients with inadequate margins did not appear to improve either local control or disease-free survival. It is not known whether higher doses of radiation therapy could improve outcome. These investigators concluded that patients who are anticipated to have suboptimal surgery should be considered for definitive radiation therapy.
Thus, surgery is chosen as definitive local therapy for suitable patients, but radiation therapy is appropriate for patients with unresectable disease or those who would experience functional compromise by definitive surgery. The possibility of impaired function needs to be measured against the possibility of second tumors in the radiation field (see below). Adjuvant radiation therapy should be considered for patients with residual microscopic disease, inadequate margins, or who have viable tumor in the resected specimen and close margins.
When preoperative assessment has suggested a high probability that surgical margins will be close or positive, preoperative radiation therapy has achieved tumor shrinkage and allowed surgical resection with clear margins.
High-Dose Therapy With Stem Cell Rescue for Ewing Sarcoma
For patients with a high risk of relapse with conventional treatments, certain investigators have utilized high-dose chemotherapy with hematopoietic stem cell transplant (HSCT) as consolidation treatment, in an effort to improve outcome.[23-34] In a prospective study, patients with bone and/or bone marrow metastases at diagnosis were treated with aggressive chemotherapy, surgery, and/or radiation and HSCT if a good initial response was achieved. The study showed no benefit for HSCT compared with historical controls. A retrospective review using international bone marrow transplant registries compared outcome after treatment with reduced-intensity conditioning to high-intensity conditioning followed by allogeneic stem cell transplant for patients with Ewing sarcoma at high risk for relapse.[Level of evidence: 3iiiA] There was no difference in outcome and the authors concluded that this suggested the absence of a clinically relevant graft-versus-tumor effect against Ewing sarcoma tumor cells with current approaches. Multiple small studies that report benefit for HSCT have been published but are difficult to interpret because only patients who have a good initial response to standard chemotherapy are considered for HSCT. The role of high-dose therapy followed by stem cell rescue is being investigated in a Euro-Ewing clinical trial (EURO-EWING-INTERGROUP-EE99) for patients that present with pulmonary metastases.
Ewing Sarcoma/Specific Sites
Separate journal articles have been written that discuss diagnostic findings, treatment, and outcome of patients with bone lesions at the following sites:
Extraosseous Ewing Sarcoma
Extraosseous Ewing sarcoma is biologically similar to Ewing sarcoma arising in bone. Until recently, most children and young adults with extraosseous Ewing sarcoma were treated on protocols designed for the treatment of rhabdomyosarcoma. This is important because many of the treatment regimens for rhabdomyosarcoma do not include an anthracycline, which is a critical component of current treatment regimens for Ewing sarcoma. Currently, patients with extraosseous Ewing sarcoma are eligible for studies that include Ewing sarcoma of bone.
From 1987 to 2004, 111 patients with nonmetastatic extraosseous Ewing sarcoma were enrolled on the RMS-88 and RMS-96 protocols. Patients with initial complete tumor resection received ifosfamide, vincristine, and actinomycin (IVA) while patients with residual tumor received IVA plus doxorubicin (VAIA) or IVA plus carboplatin, epirubicin, and etoposide (CEVAIE). Seventy-six percent of patients received radiation. The 5-year EFS and OS were 59% and 69%, respectively. In a multivariate analysis, independent adverse prognostic factors included axial primary, tumor size greater than 10 cm, Intergroup Rhabdomyosarcoma Studies Group III, and lack of radiation therapy.
Two hundred thirty-six patients with extraosseous Ewing sarcoma were entered on studies of the German Pediatric Oncology Group. The median age at diagnosis was 15 years and 133 patients were male. Primary tumor site was either extremity (n = 62) or central site (n = 174). Sixty of 236 patients had metastases at diagnosis. Chemotherapy consisted of vincristine, doxorubicin, cyclophosphamide, and actinomycin (VACA); CEVAIE; or vincristine, ifosfamide, doxorubicin, and etoposide (VIDE). The 5-year EFS and OS were 49% and 60%, respectively. Five-year survival was 70% for patients with localized disease and 33% for patients with metastasis at diagnosis. OS in patients with localized disease did not seem related to tumor site or size. In a retrospective French study, patients with extraosseous Ewing sarcoma were treated using a rhabdomyosarcoma regimen (no anthracyclines) or a Ewing sarcoma regimen (includes anthracyclines). Patients receiving the anthracycline-containing regimen had a significantly better EFS and OS compared with patients receiving no anthracyclines.[56,57]
Cutaneous Ewing sarcoma is a soft tissue tumor in the skin or subcutaneous tissue that seems to behave as a less-aggressive tumor than primary bone or soft tissue Ewing sarcoma. Tumors can form throughout the body, although the extremity is the most common site, and they are almost always localized. In a review of 78 reported cases, some lacking molecular confirmation, the OS was 91%. Adequate local control, defined as a complete resection with negative margins, radiation therapy, or a combination, significantly reduced the incidence of relapse. Standard chemotherapy for Ewing sarcoma should be used for these patients because there are no data to suggest which patients could be treated less aggressively.[58,59]
Patients treated for Ewing sarcoma have a significantly higher risk of developing subsequent neoplasms than patients in the general population.
Treatment-related acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) have generally been reported to occur in 1% to 2% of survivors of Ewing sarcoma,; [Level of evidence: 3iiiDi] although some dose-intensive regimens appear to be associated with a higher risk of hematological malignancy.[62,63]; [Level of evidence: 3ii] Treatment-related AML and MDS arise most commonly at 2 to 5 years after diagnosis.
Survivors of Ewing sarcoma remain at increased risk of developing a subsequent solid tumor throughout their lifetime. Sarcomas usually occur within the prior radiation field.[65,66] The risk of developing a sarcoma after radiation therapy is dose-dependent, with higher doses associated with an increased risk of sarcoma development.; [Level of evidence: 3iiiDi] The cumulative incidence of subsequent neoplasms in children treated for Ewing sarcoma between 1970 and 1986 at 25 years after diagnosis was 9.0% (confidence interval, 5.8–12.2). Most of these patients received radiation therapy; comparable long-term data do not yet exist for significant numbers of patients who did not receive radiation therapy.
(Refer to the PDQ summary on Late Effects of Treatment for Childhood Cancer for a full discussion of the late effects of cancer treatment in children and adolescents.)
- Fuchs B, Valenzuela RG, Sim FH: Pathologic fracture as a complication in the treatment of Ewing's sarcoma. Clin Orthop (415): 25-30, 2003. [PUBMED Abstract]
- Hoffer FA, Gianturco LE, Fletcher JA, et al.: Percutaneous biopsy of peripheral primitive neuroectodermal tumors and Ewing's sarcomas for cytogenetic analysis. AJR Am J Roentgenol 162 (5): 1141-2, 1994. [PUBMED Abstract]
- 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. [PUBMED Abstract]
- 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. [PUBMED Abstract]
- 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. [PUBMED Abstract]
- 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. [PUBMED Abstract]
- 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. [PUBMED Abstract]
- Thacker MM, Temple HT, Scully SP: Current treatment for Ewing's sarcoma. Expert Rev Anticancer Ther 5 (2): 319-31, 2005. [PUBMED Abstract]
- 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. [PUBMED Abstract]
- Dunst J, Schuck A: Role of radiotherapy in Ewing tumors. Pediatr Blood Cancer 42 (5): 465-70, 2004. [PUBMED Abstract]
- Donaldson SS: Ewing sarcoma: radiation dose and target volume. Pediatr Blood Cancer 42 (5): 471-6, 2004. [PUBMED Abstract]
- 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. [PUBMED Abstract]
- 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. [PUBMED Abstract]
- 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. [PUBMED Abstract]
- 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. [PUBMED Abstract]
- Pinkerton CR, Bataillard A, Guillo S, et al.: Treatment strategies for metastatic Ewing's sarcoma. Eur J Cancer 37 (11): 1338-44, 2001. [PUBMED Abstract]
- 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.
- 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. [PUBMED Abstract]
- Paulussen M, Craft AW, Lewis I, et al.: Results of the EICESS-92 Study: two randomized trials of Ewing's sarcoma treatment--cyclophosphamide compared with ifosfamide in standard-risk patients and assessment of benefit of etoposide added to standard treatment in high-risk patients. J Clin Oncol 26 (27): 4385-93, 2008. [PUBMED Abstract]
- Womer RB, West DC, Krailo MD, et al.: Randomized controlled trial of interval-compressed chemotherapy for the treatment of localized Ewing sarcoma: a report from the Children's Oncology Group. J Clin Oncol 30 (33): 4148-54, 2012. [PUBMED Abstract]
- Yock TI, Krailo M, Fryer CJ, et al.: Local control in pelvic Ewing sarcoma: analysis from INT-0091--a report from the Children's Oncology Group. J Clin Oncol 24 (24): 3838-43, 2006. [PUBMED Abstract]
- Wagner TD, Kobayashi W, Dean S, et al.: Combination short-course preoperative irradiation, surgical resection, and reduced-field high-dose postoperative irradiation in the treatment of tumors involving the bone. Int J Radiat Oncol Biol Phys 73 (1): 259-66, 2009. [PUBMED Abstract]
- 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. [PUBMED Abstract]
- 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. [PUBMED Abstract]
- Burdach S: Treatment of advanced Ewing tumors by combined radiochemotherapy and engineered cellular transplants. Pediatr Transplant 8 (Suppl 5): 67-82, 2004. [PUBMED Abstract]
- 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. [PUBMED Abstract]
- 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. [PUBMED Abstract]
- 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. [PUBMED Abstract]
- 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. [PUBMED Abstract]
- 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. [PUBMED Abstract]
- Rosenthal J, Bolotin E, Shakhnovits M, et al.: High-dose therapy with hematopoietic stem cell rescue in patients with poor prognosis Ewing family tumors. Bone Marrow Transplant 42 (5): 311-8, 2008. [PUBMED Abstract]
- Burdach S, Thiel U, Schöniger M, et al.: Total body MRI-governed involved compartment irradiation combined with high-dose chemotherapy and stem cell rescue improves long-term survival in Ewing tumor patients with multiple primary bone metastases. Bone Marrow Transplant 45 (3): 483-9, 2010. [PUBMED Abstract]
- Gaspar N, Rey A, Bérard PM, et al.: Risk adapted chemotherapy for localised Ewing's sarcoma of bone: the French EW93 study. Eur J Cancer 48 (9): 1376-85, 2012. [PUBMED Abstract]
- Drabko K, Raciborska A, Bilska K, et al.: Consolidation of first-line therapy with busulphan and melphalan, and autologous stem cell rescue in children with Ewing's sarcoma. Bone Marrow Transplant 47 (12): 1530-4, 2012. [PUBMED Abstract]
- Thiel U, Wawer A, Wolf P, et al.: No improvement of survival with reduced- versus high-intensity conditioning for allogeneic stem cell transplants in Ewing tumor patients. Ann Oncol 22 (7): 1614-21, 2011. [PUBMED Abstract]
- Hoffmann C, Ahrens S, Dunst J, et al.: Pelvic Ewing sarcoma: a retrospective analysis of 241 cases. Cancer 85 (4): 869-77, 1999. [PUBMED Abstract]
- 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. [PUBMED Abstract]
- 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. [PUBMED Abstract]
- 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. [PUBMED Abstract]
- 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. [PUBMED Abstract]
- 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. [PUBMED Abstract]
- Bacci G, Palmerini E, Staals EL, et al.: Ewing's sarcoma family tumors of the humerus: outcome of patients treated with radiotherapy, surgery or surgery and adjuvant radiotherapy. Radiother Oncol 93 (2): 383-7, 2009. [PUBMED Abstract]
- Casadei R, Magnani M, Biagini R, et al.: Prognostic factors in Ewing's sarcoma of the foot. Clin Orthop (420): 230-8, 2004. [PUBMED Abstract]
- Anakwenze OA, Parker WL, Wold LE, et al.: Ewing's sarcoma of the hand. J Hand Surg Eur Vol 34 (1): 35-9, 2009. [PUBMED Abstract]
- 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. [PUBMED Abstract]
- 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. [PUBMED Abstract]
- 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. [PUBMED Abstract]
- 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. [PUBMED Abstract]
- Windfuhr JP: Primitive neuroectodermal tumor of the head and neck: incidence, diagnosis, and management. Ann Otol Rhinol Laryngol 113 (7): 533-43, 2004. [PUBMED Abstract]
- 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. [PUBMED Abstract]
- Marco RA, Gentry JB, Rhines LD, et al.: Ewing's sarcoma of the mobile spine. Spine 30 (7): 769-73, 2005. [PUBMED Abstract]
- 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. [PUBMED Abstract]
- Bacci G, Boriani S, Balladelli A, et al.: Treatment of nonmetastatic Ewing's sarcoma family tumors of the spine and sacrum: the experience from a single institution. Eur Spine J 18 (8): 1091-5, 2009. [PUBMED Abstract]
- 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.
- 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.
- 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. [PUBMED Abstract]
- Dantonello TM, Int-Veen C, Harms D, et al.: Cooperative trial CWS-91 for localized soft tissue sarcoma in children, adolescents, and young adults. J Clin Oncol 27 (9): 1446-55, 2009. [PUBMED Abstract]
- Collier AB 3rd, Simpson L, Monteleone P: Cutaneous Ewing sarcoma: report of 2 cases and literature review of presentation, treatment, and outcome of 76 other reported cases. J Pediatr Hematol Oncol 33 (8): 631-4, 2011. [PUBMED Abstract]
- Terrier-Lacombe MJ, Guillou L, Chibon F, et al.: Superficial primitive Ewing's sarcoma: a clinicopathologic and molecular cytogenetic analysis of 14 cases. Mod Pathol 22 (1): 87-94, 2009. [PUBMED Abstract]
- Fuchs B, Valenzuela RG, Petersen IA, et al.: Ewing's sarcoma and the development of secondary malignancies. Clin Orthop (415): 82-9, 2003. [PUBMED Abstract]
- Goldsby R, Burke C, Nagarajan R, et al.: Second solid malignancies among children, adolescents, and young adults diagnosed with malignant bone tumors after 1976: follow-up of a Children's Oncology Group cohort. Cancer 113 (9): 2597-604, 2008. [PUBMED Abstract]
- 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. [PUBMED Abstract]
- 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. [PUBMED Abstract]
- Navid F, Billups C, Liu T, et al.: Second cancers in patients with the Ewing sarcoma family of tumours. Eur J Cancer 44 (7): 983-91, 2008. [PUBMED Abstract]
- 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. [PUBMED Abstract]
- 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. [PUBMED Abstract]
- Ginsberg JP, Goodman P, Leisenring W, et al.: Long-term survivors of childhood Ewing sarcoma: report from the childhood cancer survivor study. J Natl Cancer Inst 102 (16): 1272-83, 2010. [PUBMED Abstract]