Chemotherapy for Ewing Tumor of Bone
        Local control for Ewing tumor of bone
High-Dose Therapy with Stem Cell Rescue for Ewing Tumor of Bone
Ewing Tumor of Bone/Specific Sites
Extraosseous Ewing Sarcoma
Second Malignant Neoplasms

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 including fresh tissue for cytogenetics and flow cytometry, frozen tissue, and formalin-fixed tissue.

The successful treatment of patients with Ewing family of tumors (EFT) requires systemic chemotherapy [1-7] in conjunction with either surgery or radiation therapy or both modalities for local tumor control.[8-12] 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 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.[13-16] 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.

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,[5] 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.

Treatment approaches for EFT 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 EFT 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.[11] 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.[12] 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.

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.[17-24] 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.

Separate journal articles have been written that discuss diagnostic findings, treatment, and outcome of patients with bone lesions at the following sites: pelvis,[25-27] femur,[28,29] humerus,[30] hand and foot,[31] chest wall/rib,[32-35] head and neck,[36] and spine.[37-39]

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 1972 to 1991, 130 patients with EOE (determined by light microscopy only) were treated on the Intergroup Rhabdomyosarcoma Studies (IRS) I, II, and III.[40] One hundred sixteen patients had localized disease at diagnosis. Ten-year survival was 62%, 61%, and 77% for patients on IRS I, II, and III, respectively.

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 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.[42] The median age at diagnosis was 15 years and 133 patients were male. Primary tumor site was either extremity (62) or 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, 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.[43]

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,[44-47] 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 after diagnosis appears to be in the 5% to 10% range.[44-46] 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.

References

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.  [PUBMED Abstract]
   
   
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.  [PUBMED Abstract]
   
   
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.  [PUBMED Abstract]
   
   
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.  [PUBMED Abstract]
   
   
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.  [PUBMED Abstract]
   
   
6. Thacker MM, Temple HT, Scully SP: Current treatment for Ewing's sarcoma. Expert Rev Anticancer Ther 5 (2): 319-31, 2005.  [PUBMED Abstract]
   
   
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.  [PUBMED Abstract]
   
   
8. Dunst J, Schuck A: Role of radiotherapy in Ewing tumors. Pediatr Blood Cancer 42 (5): 465-70, 2004.  [PUBMED Abstract]
   
   
9. Donaldson SS: Ewing sarcoma: radiation dose and target volume. Pediatr Blood Cancer 42 (5): 471-6, 2004.  [PUBMED Abstract]
   
   
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.  [PUBMED Abstract]
    
    
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.  [PUBMED Abstract]
    
    
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.  [PUBMED Abstract]
    
    
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.  [PUBMED Abstract]
    
    
14. 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]
    
    
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.  [PUBMED Abstract]
    
    
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.  [PUBMED Abstract]
    
    
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.  [PUBMED Abstract]
    
    
19. Burdach S: Treatment of advanced Ewing tumors by combined radiochemotherapy and engineered cellular transplants. Pediatr Transplant 8 (Suppl 5): 67-82, 2004.  [PUBMED Abstract]
    
    
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.  [PUBMED Abstract]
    
    
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.  [PUBMED Abstract]
    
    
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.  [PUBMED Abstract]
    
    
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.  [PUBMED Abstract]
    
    
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.  [PUBMED Abstract]
    
    
25. 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]
    
    
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.  [PUBMED Abstract]
    
    
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.  [PUBMED Abstract]
    
    
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.  [PUBMED Abstract]
    
    
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.  [PUBMED Abstract]
    
    
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.  [PUBMED Abstract]
    
    
31. 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]
    
    
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.  [PUBMED Abstract]
    
    
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.  [PUBMED Abstract]
    
    
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.  [PUBMED Abstract]
    
    
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.  [PUBMED Abstract]
    
    
36. 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]
    
    
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.  [PUBMED Abstract]
    
    
38. Marco RA, Gentry JB, Rhines LD, et al.: Ewing's sarcoma of the mobile spine. Spine 30 (7): 769-73, 2005.  [PUBMED Abstract]
    
    
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.  [PUBMED Abstract]
    
    
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.  [PUBMED Abstract]
    
    
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. 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. 
    
    
43. 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]
    
    
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.  [PUBMED Abstract]
    
    
45. 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]
    
    
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.  [PUBMED Abstract]
    
    
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.  [PUBMED Abstract]
    
    
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.  [PUBMED Abstract]
    
    
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.  [PUBMED Abstract]
    
    
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.  [PUBMED Abstract]
    
    

Back to Top

< Previous Section  |  Next Section >