Correspondence

Musculoskeletal Tumors of Childhood

N Engl J Med 1999; 341:1701-1702November 25, 1999

Article

To the Editor:

The review by Arndt and Crist (July 29 issue)1 underplays the role of stem-cell transplantation in the treatment of Ewing's sarcoma. Our group has worked on stem-cell transplantation in Ewing's sarcoma since the early 1980s and has published data demonstrating a two-year survival rate of approximately 70 percent among patients presenting with metastasis, large lesions (those more than 8 cm), or both, at diagnosis.2 Follow-up data since 1990 show 60 percent survival at 1 to 11 years among 40 such high-risk patients. These results should be considered promising.

Several developments, however, suggest that stem-cell transplantation may become an even better option in the future. These include improved methods to reduce the amount of tumor-cell contamination in autologous cells at the time of reinfusion, a known risk factor for relapse after transplantation.3 One such method is the use of peripheral-blood stem cells rather than marrow stem cells, a standard practice in most transplantation centers already.

Another is the detection of residual disease through sensitive immunocytochemical techniques, which allows the transplantation to be performed after all tumor cells have been eradicated and permits the exclusion of patients who still have tumor cells despite treatment. Such detection is now possible through an assay developed at several centers, including our own, that can detect as few as 1 Ewing's sarcoma cell per million cells.4

A third development is the use of CD34+ selection techniques to purge Ewing's sarcoma cells. In four of our recently treated patients, stem-cell harvests in which this technique was used contained no tumor-cell contamination; three of these four underwent stem-cell transplantation and have been in complete, continuous remission for 76 to 553 days. These three patients are also receiving post-transplantation therapy with interleukin-2, thalidomide, or both as antiangiogenesis therapy. It is not yet known whether these remissions will be sustained and whether they can be replicated in large patient populations.

Paulette Mehta, M.D.
John R. Wingard, M.D.
University of Florida College of Medicine, Gainesville, FL 32610-0296

4 References

1
Arndt CAS, Crist WM. Common musculoskeletal tumors of childhood and adolescence. N Engl J Med 1999;341:342-352
Full Text | Web of Science | Medline

2
Marcus RB Jr, Graham-Pole JR, Springfield DS, et al. High-risk Ewing's sarcoma: end-intensification using autologous bone marrow transplantation. Int J Radiat Oncol Biol Phys 1988;15:53-59
CrossRef | Web of Science | Medline

3
Rill DR, Santana VM, Roberts WM, et al. Direct demonstration that autologous bone marrow transplantation for solid tumors can return a multiplicity of tumorigenic cells. Blood 1994;84:380-383
Web of Science | Medline

4
Weinthal J, Moss T, Chen A, et al. A quantitative immunocytologic (ICC) assay for detecting Ewing's sarcoma cells in marrow and stem cell products. Prog Proc Am Soc Clin Oncol 1999;18:561a-561a abstract.

Author/Editor Response

The authors reply:

To the Editor: Drs. Mehta and Wingard cite a paper by Marcus et al.1 that reports 70 percent two-year disease-free survival among “standard-risk patients” without metastatic disease, a result that is expected for similar patients treated conventionally.2 In fact, only 3 of 10 patients treated on their third high-risk protocol had metastases at presentation. The two patients with lung metastases remained disease-free, and the one with bone metastases had already had no response. Furthermore, only 8 of these 10 “high-risk” patients completed the transplantation portion of the protocol. Cardiotoxicity developed in two before transplantation, and thus they could not undergo the procedure. The two-year follow-up time was too short to permit solid conclusions regarding curative potential, and the small and clinically heterogeneous patient population further complicated the interpretation of the results. Our comments referred to patients with metastatic disease at diagnosis.

Other reports of the potential value of high-dose chemotherapy with stem-cell support have the same limitations. The patient populations evaluated are small and clinically heterogeneous. The European Bone Marrow Transplant Group reported a five-year event-free survival of 32 percent among patients who underwent transplantation during a second complete remission, as compared with 21 percent for those with metastatic disease at presentation who underwent transplantation during a first complete remission.3 Thus, despite the use of very intensive therapy with stem-cell support, the outcome was not better than that expected with the use of contemporary multimodal therapy.2,4 In 1997, Atra and colleagues5 described early results in 18 patients with poor-risk Ewing's sarcoma (including 11 with metastatic disease at presentation) who were treated with high-dose busulfan and melphalan and stem-cell rescue. Six patients with initial metastatic disease survived, with a median follow-up of two years. The small number of patients in this series and the short duration of follow-up limit the conclusions that can be drawn.

We agree with Drs. Mehta and Wingard that tumor-cell contamination of stem-cell products is a potential risk factor for relapse, that new methods of purging tumor cells from autologous stem cells are of interest, and that immune modulation may eventually have a role in the improvement of treatment for patients with high-risk Ewing's sarcoma. Clearly, better therapy for such patients is urgently needed. Our expression of disappointment in the results of recent clinical trials in which high-dose therapy with stem-cell support was used for patients with metastatic Ewing's sarcoma was not intended to discourage such efforts.

Carola A.S. Arndt, M.D.
William M. Crist, M.D.
Mayo Clinic, Rochester, MN 55905

5 References

1
Marcus RB Jr, Graham-Pole JR, Springfield DS, et al. High-risk Ewing's sarcoma: end-intensification using autologous bone marrow transplantation. Int J Radiat Oncol Biol Phys 1988;15:53-59
CrossRef | Web of Science | Medline

2
Arndt CAS, Crist WM. Common musculoskeletal tumors of childhood and adolescence. N Engl J Med 1999;341:342-352
Full Text | Web of Science | Medline

3
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 1995;15:697-705[Erratum, Bone Marrow Transplant 1996;18:675.]
Web of Science | Medline

4
Miser JS, Krailo M, Meyers P, et al. Metastatic Ewing's sarcoma and primitive neuroectodermal tumor of bone: failure of new regimens to improve outcome. Prog Proc Am Soc Clin Oncol 1996;15:467-467 abstract.

5
Atra A, Whelan JS, Calvagna V, et al. High-dose busulphan/melphalan with autologous stem cell rescue in Ewing's sarcoma. Bone Marrow Transplant 1997;20:843-846
CrossRef | Web of Science | Medline

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