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 sarcoma achieve event-free survival (EFS) and overall survival (OS) of approximately 70% at 5 years after diagnosis.
Current standard chemotherapy in the United States includes vincristine, doxorubicin, and cyclophosphamide, also known as VAdriaC or VDC, alternating with ifosfamide and etoposide (IE). The combination of IE has shown activity in Ewing sarcoma, and a large randomized clinical trial and a nonrandomized trial demonstrated that outcome was improved when IE 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 dose intensity of doxorubicin during the initial months of therapy was associated with an improved outcome in a meta-analysis done prior to the standard use of ifosfamide and etoposide. The use of high-dose VAdriaC has shown promising results in small numbers of patients. A single institution study of 44 patients treated with high-dose VAdriaC and IE had an 82% 4-year EFS. However, in an intergroup trial of the Pediatric Oncology Group and the Children's Cancer Group, which compared a dose-intensified chemotherapy regimen of vincristine, doxorubicin, cyclophosphamide, ifosfamide, and etoposide (VDC/IE) with standard doses of the same regimen, no differences in outcome were observed. Unlike the single institution trial, this trial did not maintain the dose intensity of alkylating agents for the duration of treatment.
In a completed Children's Oncology Group (COG) trial (COG-AEWS0031), 568 patients with newly diagnosed localized extradural Ewing sarcoma were randomly assigned to receive chemotherapy (VAdriaC alternating with IE) given every 2 weeks (interval compression) versus every 3 weeks (standard). Patients randomly assigned to the every 2-week interval of treatment had an improved 5-year EFS (73% vs. 65%, P = .048). There was no increase in toxicity observed with the every 2-week schedule.