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Originally published as JCO Early Release 10.1200/JCO.2005.12.915 on March 21 2005 © 2005 American Society of Clinical Oncology.
High-Dose Therapy and Stem-Cell Rescue for Ewing's Family of Tumors in Second Remission
1 Stanford University School of Medicine, Palo Alto, CA 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 al5 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 dose-response 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-to-treat 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 Sloan-Kettering 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 al5 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. What factors might contribute to a lack of efficacy of HDT in ESFT? One possibility is that the stem-cell or marrow product is contaminated with tumor cells. This remains controversial because some investigators have found a large number of patients with tumor-cell contamination,2,14,15 but this has not been confirmed by all groups.15,16 Tumor-cell contamination seems to play a role in recurrent disease for patients with metastatic neuroblastoma and acute myeloid leukemia17 and, therefore, remains a considerable concern for ESFT. Another potential impediment to the success of this strategy is the possibility that residual resistant disease remains even after administration of HDT. Overcoming drug resistance would be one way to address this particular issue. The role of HDT in relapsed ESFT also remains controversial and is even more difficult to evaluate because there are fewer patients available for evaluation in contrast to newly diagnosed patients. Interestingly, the European Bone Marrow Transplant Registry reported similar outcomes for patients with ESFT receiving HDT in first or subsequent remission, suggesting that HDT might be beneficial for a small number of patients with recurrent ESFT.18 However, because the use of this modality is limited to patients with responsive disease, evaluating its impact on outcome is difficult, and most reported series are biased by including only patients with responsive disease. Although Barker et al5 performed a multivariate analysis controlling for RFI and response to therapy, the only way to evaluate adequately the role of HDT in any setting would be with a controlled randomized trial. Short of that trial, statistical analyses might minimize the bias but are unlikely to eliminate it. There are a number of other biases that could also influence these results. Most importantly, patients in the trial by Barker et al5 were treated over a 17-year period and received different chemotherapy treatments both at diagnosis and relapse. This makes it difficult to evaluate adequately the impact of chemotherapy and changes in supportive care on outcome. It is evident that the prognosis for relapsed patients with ESFT has evolved over time. Hayes et al19 reported that 60% of patients with recurrent ESFT could achieve long-term survival at a time when ifosfamide and etoposide were not routinely used as upfront treatment. Our most recent experience with ESFT would suggest that patients who received this doublet as part of their initial therapy are more difficult to treat, as evidenced by a much lower response rate to retrieval therapy.20 Barker et al5 did not analyze the correlation of front-line chemotherapy with the survival of patients after HDT, so we cannot analyze the relative contribution of this treatment to their observed outcomes. They do report that response to salvage therapy was the single most important factor correlating with outcome after HDT. Ultimately, our goal remains to improve the outcome for pediatric patients with malignancies. Our challenge is to attempt to define the group of patients most likely to benefit from HDT and to continue to evaluate novel drugs or biologic agents with a different mechanism of action for the group of patients with highly resistant disease. Although it is unlikely that novel agents will improve the outcome of patients with recurrent disease, evaluation of new agents will eventually lead to the identification of new drugs, and this will be essential to continue to improve the outcome for patients with metastatic disease, patients with large pelvic tumors, and patients who develop disease recurrence. Authors' Disclosures of Potential Conflicts of Interest The authors indicated no potential conflicts of interest. REFERENCES
1. 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 348:694-701, 2003
2. Miser JS, Krailo MD, Tarbell NJ, et al: Treatment of metastatic Ewing's sarcoma/primitive neuroectodermal tumor of bone: Evaluation of combination ifosfamide and etoposide—A Children's Cancer Group and Pediatric Oncology Group Study. J Clin Oncol 22:2873-2876, 2004
3. 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 19:2812-2820, 2001 4. Rodriguez-Galindo C, Billups CA, Kun LE, et al: Survival after recurrence of Ewing tumors: The St Jude Children's Research Hospital experience, 1979-1999. Cancer 94:561-569, 2002[CrossRef][Medline]
5. Barker LM, Pendergrass TW, Sanders JE, et al: Survival after recurrence of Ewing's sarcoma family of tumors. J Clin Oncol 23:4354-4362, 2005
6. Matthay KK, Villablanca JG, Seeger RC, et al: Treatment of high-risk neuroblastoma with intensive chemotherapy, radiotherapy, autologous bone marrow transplantation, and 13-cis-retinoic acid: Children's Cancer Group. N Engl J Med 341:1165-1173, 1999 7. Armitage JO: High-dose chemotherapy and autologous hematopoietic stem cell transplantation: The Lymphoma experience and its potential relevance to solid tumors. Oncology 58:198-206, 2000[CrossRef][Medline] 8. Jacobsen AB, Wist EA, Solheim OP: Treatment of Ewing's sarcoma with high-dose melphalan and autologous bone marrow rescue. Monogr Ser Eur Organ Res Treat Cancer 14:157-160, 1984
9. Burdach S, Jurgens H, Peters C, et al: Myeloablative radiochemotherapy and hematopoietic stem-cell rescue in poor-prognosis Ewing's sarcoma. J Clin Oncol 11:1482-1488, 1993
10. Burdach S, van Kaick B, Laws HJ, et al: Allogeneic and autologous stem-cell transplantation in advanced Ewing tumors: An update after long-term follow-up from two centers of the European Intergroup study EICESS—Stem-Cell Transplant Programs at Dusseldorf University Medical Center, Germany and St Anna Kinderspital, Vienna, Austria. Ann Oncol 11:1451-1462, 2000
11. Horowitz ME, Kinsella TJ, Wexler LH, et al: Total-body irradiation and autologous bone marrow transplant in the treatment of high-risk Ewing's sarcoma and rhabdomyosarcoma. J Clin Oncol 11:1911-1918, 1993 12. Atra AWJ, Calvagna V, Shankar AG, et al: High-dose busulphan/melphalan with autologous stem cell rescue in Ewing's sarcoma. Bone Marrow Transplant 20:843-846, 1997[CrossRef][Medline]
13. 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 19:870-880, 2001 14. Leung W, Chen AR, Klann RC, et al: Frequent detection of tumor cells in hematopoietic grafts in neuroblastoma and Ewing's sarcoma. Bone Marrow Transplant 22:971-979, 1998[CrossRef][Medline] 15. Fischmeister G, Zoubek A, Jugovic D, et al: Low incidence of molecular evidence for tumour in PBPC harvests from patients with high risk Ewing tumours. Bone Marrow Transplant 24:405-409, 1999[CrossRef][Medline] 16. Thomson B, Hawkins D, Felgenhauer J, et al: RT-PCR evaluation of peripheral blood, bone marrow and peripheral blood stem cells in children and adolescents undergoing VACIME chemotherapy for Ewing's sarcoma and alveolar rhabdomyosarcoma. Bone Marrow Transplant 24:527-533, 1999[CrossRef][Medline] 17. Brenner MK, Rill DR, Moen RC, et al: Gene marking and autologous bone marrow transplantation. Ann N Y Acad Sci 716:204-214, 1994[Medline] 18. Ladenstein R, Lasset C, Pinkerton R, et al: Impact of megatherapy in children with high-risk Ewing's tumours in complete remission: A report from the EBMT Solid Tumour Registry. Bone Marrow Transplant 15:697-705, 1995[Medline] 19. Hayes FA, Thompson EI, Kumar M, et al: Long-term survival in patients with Ewing's sarcoma relapsing after completing therapy. Med Pediatr Oncol 15:254-256, 1987[Medline]
20. Saylors RL 3rd, Stine KC, Sullivan J, et al: Cyclophosphamide plus topotecan in children with recurrent or refractory solid tumors: A Pediatric Oncology Group phase II study. J Clin Oncol 19:3463-3469, 2001
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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