High-Dose Therapy and Stem-Cell Rescue for Ewing's Family of Tumors in Second Remission

The use of adjuvant multiagent chemotherapy and improved local control with surgery, with or without radiotherapy, has significantly improved the outcome for patients with Ewing’s sarcoma family of tumors (ESFT). The prognosis for patients who present with detectable metastatic disease or who recur remains poor. 1-3 Some of the patients in both of these poor prognosis groups are cured by conventional therapy. What is it that makes these patients different? The answer to that question remains elusive, and attempts to identify factors predictive of survival have been challenging. A recent analysis from St Jude Children’s Research Hospital correlated improved survival with a prolonged initial relapse-free interval (RFI), which was defined as more than 24 months. 4 In this issue, Barker et al 5 report on intensive chemotherapy followed by autologous stem-cell reconstitution (high-dose therapy [HDT]) as consolidation therapy for patients with ESFT in second remission. They conclude that HDT is a potentially efficacious therapeutic modality, at least in a subset of patients. Determining the setting in which HDT is most effective remains controversial because most HDT strategies reserve transplantation for patients who achieve either a partial or complete response. The authors attempt to adjust for this bias by performing a multivariate analysis that controls for RFI and response to therapy. They report that patients with a prolonged RFI and responsive disease and those patients receiving HDT have an improved progression-free and overall survival. These results are provocative, but they still raise the following question: what is the role of HDT in patients with ESFT? Because patients with ESFT have tumors responsive to alkylator-based therapy and these agents are presumed to have a steep dose-response curve, investigators have been intrigued by the possible role for HDT in these tumors. However, unequivocal demonstration of a steep doseresponse curve for alkylating agents in Ewing’s sarcoma is lacking. Review of the available data, however, reveals that HDT followed by autologous stem-cell reconstitution has only been successful for pediatric patients with metastatic neuroblastoma and relapsed lymphoma. 6,7 Although HDT has been used for patients with high-risk ESFT in first remission and for patients at relapse, critical review of the literature is complicated by small sample sizes in predominantly retrospective reviews, the use of different inclusion criteria, and the use of different preparative regimens. 8-12 The Children’s Cancer Group prospectively evaluated the use of HDT for patients with ESFT metastatic to bone and bone marrow. In this subset of patients, using an intent-totreat analysis, the authors did not find a benefit to the use of this modality, with an event-free survival rate of 17%. 3 Further evaluation of the use of HDT at Memorial SloanKettering Cancer Center also concluded that HDT did not improve the outcome for patients with metastatic ESFT. 13 Definite conclusions regarding the role of HDT in ESFT will only be possible from the results of a randomized controlled trial; the EURO-Ewing’s 99 study, which is currently ongoing, is evaluating the role of HDT for patients with ESFT and high-risk disease or lung metastases. This group of patients in high-risk first remission is different from the group of patients reported by Barker et al 5 who were in second remission, but demonstration of efficacy in a prospective randomized trial would certainly lend support to the use of HDT in that group as well.