Ewing Sarcoma: Metastatic Tumors

Standard Treatment Options
Treatment Options Under Clinical Evaluation
Current Clinical Trials

Prognosis of patients with metastatic disease is poor.[1] Current therapies for patients who present with metastatic disease achieve 6-year event-free survival (EFS) of approximately 28% and overall survival (OS) of approximately 30%.[2] For patients with lung/pleural metastases only, 4-year EFS is approximately 40%. Patients with only bone/bone marrow metastases have a 4-year EFS of approximately 28% and patients with combined lung and bone/bone marrow metastases have a 4-year EFS of approximately 14%.[1] Patients who did not receive lung radiation had a worse outcome than those receiving lung radiation.[3]

Standard treatment for patients with metastatic Ewing tumor of bone (ETB) utilizing alternating vincristine, doxorubicin, cyclophosphamide, and ifosfamide/etoposide combined with adequate local control measures applied to both primary and metastatic sites often results in complete or partial responses; however, the overall cure rate is 20%.[1,2,4,5] In the Intergroup Ewing Sarcoma Study, patients with metastatic disease showed no benefit from the addition of ifosfamide and etoposide to a standard regimen of vincristine, doxorubicin, cyclophosphamide and actinomycin-D.[2] In another Intergroup study, increasing dose intensity of cyclophosphamide, ifosfamide, and doxorubicin did not improve outcome compared with regimens utilizing standard dose intensity.[2] This regimen increased toxicity and risk of second malignancy without improving EFS or OS.[2]

Radiation therapy should be delivered in a setting in which stringent planning techniques are applied by those experienced in the treatment of the ETB. Such an approach will result in local control of tumor with acceptable morbidity in most patients.[6-8] Radiation therapy to the primary tumor as well as to the sites of metastatic disease should be considered but may interfere with delivery of chemotherapy if too much bone marrow is included in the field. Metastatic sites of disease in bone and soft tissues should receive fractionated radiation therapy doses totaling between 45 Gy and 56 Gy. All patients with pulmonary metastases should undergo whole-lung radiation, even if complete resolution of overt pulmonary metastatic disease has been achieved with chemotherapy.[1,9,10] Radiation doses are modulated based on the amount of lung to be radiated and on pulmonary function. Doses between 12 Gy and 15 Gy are generally used if whole lungs are treated.

More intensive therapies, many of which incorporate high-dose chemotherapy with or without total-body irradiation in conjunction with stem cell support, have not shown improvement in EFS rates for patients with bone and/or bone marrow metastases.[2,11-19] The impact of high-dose chemotherapy with peripheral blood stem cell support for patients with lung metastases is unknown.[11] European investigators use high-dose chemotherapy and stem cell support for patients with extrapulmonary metastatic sites. Use of high-dose therapy and autologous stem cell reconstitution for patients with metastases at extrapulmonary sites is an investigator choice in the Euro-Ewing study (EURO-EWING-INTERGROUP-EE99 ¹ [COG-AEWS0331]). It is not being studied as a randomized prospective question, but the study will acquire data about the outcome of patients treated with this consolidation. Melphalan, at nonmyeloablative doses, has proved to be an active agent in an upfront window study for patients with metastatic disease at diagnosis, however, the cure rate remained extremely low.[20]

The following is an example of an international clinical trial that is currently being conducted. Information about ongoing clinical trials is available from the NCI Web site ².

• EURO-EWING-INTERGROUP-EE99 ¹ (COG-AEWS0331) (Combination Chemotherapy With or Without Peripheral Stem Cell Transplantation, Radiation Therapy, and/or Surgery in Treating Patients With Ewing Sarcoma): 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.

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with metastatic Ewing sarcoma/peripheral primitive neuroectodermal tumor ³. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site ².

References

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.  [PUBMED Abstract]
   
   
2. Miser JS, Goldsby RE, Chen Z, et al.: Treatment of metastatic Ewing sarcoma/primitive neuroectodermal tumor of bone: evaluation of increasing the dose intensity of chemotherapy--a report from the Children's Oncology Group. Pediatr Blood Cancer 49 (7): 894-900, 2007.  [PUBMED Abstract]
   
   
3. 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.  [PUBMED Abstract]
   
   
4. 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.  [PUBMED Abstract]
   
   
5. 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]
   
   
6. 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.  [PUBMED Abstract]
   
   
7. 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.  [PUBMED Abstract]
   
   
8. 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.  [PUBMED Abstract]
   
   
9. 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.  [PUBMED Abstract]
   
   
10. 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.  [PUBMED Abstract]
    
    
11. 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]
    
    
12. 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]
    
    
13. 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]
    
    
14. Ladenstein R, Pötschger U, Le Deley MC, et al.: Primary disseminated multifocal Ewing sarcoma: results of the Euro-EWING 99 trial. J Clin Oncol 28 (20): 3284-91, 2010.  [PUBMED Abstract]
    
    
15. Gilman AL, Oesterheld J: Myeloablative chemotherapy with autologous stem cell rescue for Ewing sarcoma. Bone Marrow Transplant 42 (11): 761; author reply 763, 2008.  [PUBMED Abstract]
    
    
16. 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]
    
    
17. Gardner SL, Carreras J, Boudreau C, et al.: Myeloablative therapy with autologous stem cell rescue for patients with Ewing sarcoma. Bone Marrow Transplant 41 (10): 867-72, 2008.  [PUBMED Abstract]
    
    
18. 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]
    
    
19. Fraser CJ, Weigel BJ, Perentesis JP, et al.: Autologous stem cell transplantation for high-risk Ewing's sarcoma and other pediatric solid tumors. Bone Marrow Transplant 37 (2): 175-81, 2006.  [PUBMED Abstract]
    
    
20. Luksch R, Grignani G, Fagioli F, et al.: Response to melphalan in up-front investigational window therapy for patients with metastatic Ewing's family tumours. Eur J Cancer 43 (5): 885-90, 2007.  [PUBMED Abstract]