Ewing Tumor of Bone: Metastatic Tumors
Prognosis of patients with metastatic disease is poor. 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%.
Standard Treatment Options
Standard treatment for patients with metastatic Ewing tumor of bone (ETB) utilizing alternating vincristine, doxorubicin, cyclophosphamide, and ifosfamide/etoposide combined with adequate local control measures applied to both primary and metastatic sites often results in complete or partial responses; however, the overall cure rate is 20%.[1,2,3,4] 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. In another Intergroup study, increasing dose intensity of cyclophosphamide, ifosfamide, and doxorubicin did not improve outcome compared with regimens utilizing standard dose intensity. This regimen increased toxicity and risk of second malignancy without improving EFS or OS. For patients with lung/pleural metastases only, cure rates are approximately 40%. Patients who did not receive lung radiation had a worse outcome than those receiving lung radiation. 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 cure rate of less than 15%.
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 (POG-8346).[6,7,8] Radiation therapy to the primary tumor as well as to the sites of metastatic disease should be considered but may interfere with delivery of chemotherapy if too much bone marrow is included in the field. Metastatic sites of disease in bone and soft tissues should receive fractionated radiation therapy doses totaling between 45 Gy and 56 Gy. All patients with pulmonary metastases should undergo whole-lung radiation, even if complete resolution of overt pulmonary metastatic disease has been achieved with chemotherapy.[1,9,10] Radiation doses are modulated based on the amount of lung to be radiated and on pulmonary function. Doses between 12 Gy and 15 Gy are generally used if whole lungs are treated.
More intensive therapies, many of which incorporate high-dose chemotherapy with or without total-body irradiation in conjunction with stem cell support, have not shown improvement in EFS rates for patients with bone and/or bone marrow metastases.[2,11,12] The impact of high-dose chemotherapy with peripheral blood stem cell support for patients with lung metastases is currently unknown. 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). 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.