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Journal of Clinical Oncology, Vol 24, No 24 (August 20), 2006: pp. 3997-4002 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.05.7059 Impact of High-Dose Busulfan Plus Melphalan As Consolidation in Metastatic Ewing Tumors: A Study by the Société Française des Cancers de l'Enfant
From the Departments of Paediatric Oncology, Biostatistics, and Pathology, Institut Gustave Roussy, Villejuif; Department of Paediatric Oncology, Centre Oscar Lambret, Lille; Department of Paediatric Oncology, Centre Léon Bérard, Lyon, France; Department of Paediatric Oncology, Hôpital Michalon, Grenoble; Department of Paediatric Oncology, Hôpital d'enfants, Nancy; Department of Paediatric Oncology, Centre hospitalo-universitaire, Besançon; Department of Paediatric Oncology, Hôpital Clocheville, Tours; Department of Paediatric Oncology, Hôpital Purpan, Toulouse; and the Department of Paediatric Oncology, Institut Curie, Paris, France Address reprint requests to Odile Oberlin, MD, Department of Paediatric Oncology, Institut Gustave-Roussy, Rue Camille Desmoulins, 94805 Villejuif Cedex, France; e-mail: oberlin{at}igr.fr
PURPOSE: To improve the prognosis for patients with metastatic Ewing sarcoma/primitive neuroectodermal tumors (ES/PNET) using conventional chemotherapy and consolidation high-dose chemotherapy (HDCT) containing busulfan and melphalan. PATIENTS AND METHODS: Ninety-seven unselected patients with newly diagnosed metastatic ES/PNET received induction chemotherapy that included five cycles of cyclophosphamide 150 mg/m2/d for 7 days, doxorubicin 35 mg/m2/d once, followed by two cycles of ifosfamide 1.8 g/m2/d for 5 days, and etoposide 100 mg/m2/d for 5 days. Patients in complete or very good partial remission received HDCT with busulfan total dose 600 mg/m2 and melphalan 140 mg/m2 followed by autologous blood stem cells. Local therapy (surgery and/or radiation therapy) was performed before or after HDCT. RESULTS: Ninety-seven patients were enrolled from 1991 to 1999 (median age, 12.3 years; range, 0.2 to 25 years). Among them, 75 received HDCT. The 5-year event-free survival (EFS) rate for all 97 patients was 37% and the overall survival (OS) rate was 38%. The EFS after HDCT was 47%. The EFS for the 44 patients with lung-only metastases was 52%, whereas it was 36% for patients with bone metastases without bone marrow involvement. Among the 23 patients with bone marrow metastases, only one survived. The multivariate analysis for both EFS and for OS identified three independent prognostic factors: age, fever at diagnosis, and bone marrow involvement. CONCLUSION: Compared with conventional chemotherapy, HDCT may yield benefits for patients with lung-only metastases or bone metastases. These results warrant confirmation in a randomized trial and provide part of the background data for the ongoing Euro-Ewing study.
In contrast with the dramatic improvement in survival for localized Ewing sarcoma/primitive neuroectodermal tumors (ES/PNET) during the last 30 years, the prognosis of metastatic tumors treated with conventional chemotherapy, radiation therapy, and surgery remains poor. Most reports cite long-term survival rates below 35%.1-10 A number of small series and case reports suggested that consolidation with high-dose therapy and stem-cell rescue could improve the outcome for patients with high-risk ES/PNET. Extensive experience has been gained with high-dose single agents. Melphalan demonstrated activity against assessable disease.11-13 Single-agent busulfan, however, has not been assessed widely, probably because it is difficult to perform phase II trials with a notoriously toxic agent without a curative intent. Burdach et al14 reported response in two of three patients refractory to chemotherapy. In a monocentric study, eight patients with measurable disease received chemotherapy containing busulfan, cyclophosphamide, and/or melphalan. This treatment yielded encouraging results, with three complete responses, four partial responses, and one minor response,15 and prompted the inclusion of such a combination in the national French protocol. We present the results obtained.
Eligibility Criteria Patients were eligible for this study if they had untreated metastatic bone ES/PNET. Appearance of the sample under the light microscope consistent with ES or PNET of bone was required for enrollment. Representative slides were reviewed centrally but this review was not required for study enrollment. The protocol was reviewed and approved by the institutional review boards of participating institutions. Informed consent was obtained from the parents or guardian of each child or from adult patients according to the Declaration of Helsinki.
Pretreatment Evaluation
Chemotherapy Chemotherapy cycles 1 to 5 consisted of cyclophosphamide150 mg/m2/d for 7 days followed on day 8 by doxorubicin 35 mg/m2/d, with courses beginning on days 1, 15, 29, 50, and 71. Cycles 6 and 7 included etoposide 100 mg/m2/d and ifosfamide 1.8 g/m2/d associated with mesna (2-mercaptoethane sulfonate) on days 1 to 5. Primary tumor and metastases were re-evaluated after three and five courses. If the patient did not achieve at least partial response after three courses of cyclophosphamide and doxorubicin, the protocol stipulated that they should switch to the second-line chemotherapy. To proceed to the next phase of protocol treatment, patients had to have a good response of the primary tumor and all sites of metastatic disease. A good response was defined as either a complete response of all measurable disease or a very good partial response. Patients in whom all measurable disease had been eradicated with the exception of persistent abnormalities on radionuclide bone scan were assessed as having a very good partial response. A persistently abnormal radionuclide bone scan did not preclude the initiation of local therapy or HDCT/SCT. Autologous peripheral-blood stem cells after stimulation by granulocyte colony-stimulating factor were used as the preferred graft source. The recommended cell dose per transplantation was at least 3 x 106 CD34 cells/kg of body weight. HDCT consisted of oral busulfan 150 mg/m2/d on days –6, –5, –4, and –3 (total 600 mg/m2) and melphalan 140 mg/m2 on day –2 followed by stem-cell rescue on day 0.
Local Therapy The radiation dose was dependent on the quality of surgery and the histologic response to chemotherapy. If the primary tumor was treated with radiation therapy alone or if surgery was incomplete, 45 Gy was delivered to the entire tumor-bearing bone; one epiphyseal center was spared when possible. Boosts of 10 to 15 Gy leading to a total dose of 55 to 60 Gy were delivered to the bony tumor volume and the residual mass whenever possible, with a 2-cm safety margin. No radiation was delivered after complete resection of a tumor containing less than 5% of residual cells. For the other patients who had a complete resection but more than 5% of viable tumor cells in the specimen, the location of the tumor and the percentage of residual tumor cells were taken into account when the radiation dose was calculated, which was usually 40 Gy. Timing of local therapy depended on the location of the primary tumor and the extent of surgery. If the planned surgery was wide, leading to a prolonged healing period, or if radiation fields were planned to encompass bulky pelvic or abdominal disease, it was recommended that local therapy be postponed until after the HDCT/SCT. Lung irradiation was not delivered.
Statistical Analyses The statistical significance of prognostic variables was tested by the log-rank test.17 A multivariate analysis was then performed with the Cox proportional hazards model (SAS program; SAS Institute, Cary, NC). The multivariate analysis models were determined by the likelihood ratio test.
Patients From January 1991 to August 1999, 97 patients with newly diagnosed metastatic ES/PNET were entered onto the study. Patient characteristics are listed in Table 1. Forty-four patients had only lung metastases; 23 patients had bone marrow involvement, either isolated or with other metastases; 22 patients had bone metastases without bone marrow involvement; and eight patients had neither bone nor bone marrow involvement but pleural metastases (n = 4), node metastases (n = 2), epidural metastases (n = 1), or positive CSF (n = 1).
Induction Therapy All 97 patients received three cycles of cyclophosphamide plus doxorubicin. Twenty-five (26%) patients with an insufficient response after three courses were switched to etoposide plus ifosfamide courses after the first three cycles. Altogether, 441 cycles of cyclophosphamide plus doxorubicin were administered. Toxicity was mild and only 10 cycles resulted in infection. Two patients developed hematuria. A total of 166 courses of etoposide plus ifosfamide were administered. Only 25 cycles resulted in infection, and hospitalization was required after 19 cycles (11%). Three patients developed microscopic transient hematuria. No patients developed neurotoxicity.
HDCT There were three toxicity-related deaths. Two of them were due to acute respiratory distress syndrome and one to multiorgan system failure after veno-occlusive disease. These deaths occurred at 3, 3, and 4 months after transplantation, respectively. Nineteen patients developed veno-occlusive disease (25% of patients who underwent HDCT). Twenty-four patients recovered without sequelae. Severe mucositis occurred in three patients.
Local Therapy Seven patients did not undergo local therapy: two died early as a result of toxicity, three experienced relapse within a short period of time, and tumors in two patients were considered inoperable or impossible to irradiate. Histologic response was graded as good in 28 patients and as poor in 12 patients. It was not evaluated in four patients.
Second Malignancies
Outcome Recurrent disease occurred after a median interval of 14 months after the initial diagnosis (range, 7 to 75 months) and a median interval of 8 months after HDCT/SCT (range, 1 to 10 months). One patient was lost to follow-up 1 month after HDCT/SCT and 34 survivors were still alive with a median follow-up of 8.2 years (range, 3.4 to 11.9 years) after the diagnosis and 7.6 years (range, 2.8 to 11.6 years) after HDCT/SCT. The 5-year EFS of the 75 patients who received HDCT/SCT was 47% ± 11% and their 10-year EFS was 43% ± 12%.
Prognostic Factors
EFS and OS were strongly associated with age at diagnosis (5-year EFS of patients younger than 15 years was 46% v 21% for older patients [P < .001], and 5-year OS of patients younger than 15 years was 49% v 20% for older patients [P < .001]) and with the volume of the primary (5-year EFS for patients with a tumor smaller than 200 mL was 56% v 28% for larger tumors [P = .004], and 5-year OS for patients with a tumor smaller than 200 mL was 58% v 30% for larger tumors [P = .002]). Patients who had fever at diagnosis had lower EFS and OS rates compared with patients who did not (5-year EFS, 15% v 45%, respectively; P = .00007) and 5-year OS, 15% v 48%, respectively; P = .0004). There was no significant difference in EFS and OS according to sex or the primary tumor site. Clinical factors associated with EFS and OS were evaluated by multivariate analysis involving the prognostic factors identified in the univariate analysis (Table 3). This multivariate analysis identified three independent prognostic factors for EFS: age 15 years or older, fever at diagnosis, and bone marrow involvement at diagnosis. In addition to these three factors, the volume of the primary tumor (> 200 mL) had an impact on OS.
Successful treatment of patients with metastatic ES/PNET remains a challenge. This study used a conventional chemotherapy strategy for remission induction, followed by HDCT with subsequent autologous stem-cell reconstitution for patients who achieved a complete response or a very good partial response of metastatic disease. This series confirms the heterogeneity of patients with metastatic disease. Patients with lung-only metastases had a better prognosis than patients who had bone metastases at diagnosis (with or without lung metastases) without bone marrow involvement. The third group (patients with bone marrow involvement) had the worst prognosis. The large prognostic study performed by Cotterill et al18 showed a similar impact of bone/bone marrow disease. Five-year relapse-free survival was 29% for patients with lung-only metastases, 19% for those with bone metastases, and 8% for those with combined lung and bone metastases, confirming the data of the German Cooperative Ewing Sarcoma studies.19 Similarly unsatisfactory results appear in all reports of patients with ES/PNET metastatic to bone or bone marrow.4,19-24 Compared with results obtained by conventional chemotherapy, even though this was not a randomized study, our study might suggest that HDCT/SCT can improve the prognosis of patients with lung-only metastases. The 5-year EFS for these patients was 52% versus EFS ranging from 23% to 36% after conventional chemotherapy.7,8,25 Considering the high-risk group of patients with metastases, authors generally report on the global outcome of patients with bone or bone marrow metastases without emphasizing the dismal prognosis in patients with bone marrow involvement, this being the only metastatic site with an independent prognostic value in the multivariate analysis. This subgroup of patients had a 4% EFS at 5 years in our experience, compared with the 36% EFS for patients with bone metastases without bone marrow involvement. However, in the report on the Memorial Sloan-Kettering Cancer Center (New York, NY) experience in patients with metastases to bone or bone marrow, of 12 patients with bone marrow involvement at diagnosis, only one is a long-term survivor despite intensive induction chemotherapy (P6) followed by myeloablative therapy. The P6 protocol included cycles of cyclophosphamide (4.2 g/m2)/doxorubicin (75 mg/m2)/vincristine and included cycles of ifosfamide (9 g/m2)/etoposide (500 mg/m2). Patients in complete or very good partial remission after P6 received myeloablative therapy with either total-body irradiation/melphalan (180 mg/m2) or thiotepa (900 mg/m2)/carboplatin (1,500 mg/m2).4
The impact of age at diagnosis has often been debated in localized tumors. Few series are large enough to study this factor in patients with metastatic disease. In our experience, age older than 15 years had a negative impact on EFS in the multivariate analysis. In the high-risk protocol of the Meta-European Intergroup Cooperative Ewing Sarcoma studies, age Concepts for high-dose therapy in Ewing tumors are based on dose response and dose-intensity relationships, and alkylating agents have been chosen by many groups because of their moderate nonhematologic toxicity even when administered at high doses with stem-cell support. Besides the limited data on busulfan administered in phase II trials, the analysis of European Group for Blood and Marrow Transplantation (EBMT) registry data on patients grafted for Ewing tumors revealed that patients who received busulfan-containing regimens fared better (n = 46; 60%) versus patients who received regimens without busulfan (n = 120; 26%).22 The total duration of protocol chemotherapy was short (19 weeks of induction followed by HDCT/SCT) and the total duration of therapy was about 6 months. The cumulative dose of induction chemotherapy was low (cyclophosphamide 5,250 mg/m2, doxorubicin 175 mg/m2, ifosfamide 18 g/m2, etoposide 1 g/m2), which may seem less intensive than other published induction regimens.3,26 However, despite the use of such high-intensity regimens, the survival of patients with metastatic disease does not appear better than what we observed. None of the four patients treated with the VACIME combination (eight courses of vincristine 2 mg/m2 on day 0; doxorubicin 20 mg/m2/day on days 0-3; cyclophosphamide 360 mg/m2/day on days 0-4; ifosfamide 1,800 mg/m2/day on days 0-4; mesna 2,400 mg/m2/day; and etoposide 100 mg/m2/day on days 0-4) are alive.26 The 4-year EFS rate was 12% after the P6 protocol.3 Treatment failures in patients with lung-only metastases mainly were due to pulmonary/pleural relapses, either isolated or combined with local failure (12 of 13). This raises the question of the role of local therapy for the lungs and pleural space. The first Intergroup study demonstrated that prophylactic lung irradiation was effective in controlling microscopic lung metastases in patients who were not administered doxorubicin-containing chemotherapy.27 With the development of such chemotherapy, lung irradiation was abandoned or restricted. In St Jude's Hospital (Memphis, TN), it was only delivered to patients with lung metastases that did not respond completely to induction chemotherapy,25 whereas in the Cooperative Ewing Sarcoma studies, lung irradiation was an option for patients with lung metastases at diagnosis who achieved a complete clinical response to chemotherapy. In a multivariate analysis, lung irradiation was associated with improved survival.8 Within the French group, we considered that the potential lung toxicity of busulfan28 precludes combining lung irradiation with busulfan. In our experience, the majority of the patients with lung-only metastases who experienced relapse did so in the lungs. Bilateral lung irradiation with 15 to 20 Gy therefore could be an attractive alternative to busulfan-based HDCT. This issue currently is being addressed in a randomized trial within the EURO-EWING-99 study. Some of the high-dose regimens included total-body irradiation (TBI), however these experiences emphasized the toxicity of such approaches. Among a series of 36 patients treated with TBI containing regimens for bone metastases or early relapses, nine died as a result of treatment-related causes, three developed a second malignancy, and 18 experienced relapse, leading to a 21% EFS rate.14 The Children's Cancer Group has reported a 16% EFS rate at 2 years in 24 patients with skeletal metastases using melphalan, etoposide, and TBI as consolidation treatment, and concluded that this strategy did not improve the prognosis in this group of patients.24 Combining TBI with busulfan is not feasible because of the sensitizing effect of busulfan. The TBI concept has been modified for total marrow irradiation. Hawkins et al29 treated nine patients at relapse with busulfan 12 mg/kg, melphalan 100 mg/m2, and thiotepa 500 mg/m2 as conditioning chemotherapy before total marrow irradiation. Six patients were long-term disease-free survivors and one patient had multifocal disease at relapse. Conversely, there were no survivors among the seven patients treated with the same regimen without TBI for various reasons (dose-limiting prior radiation, low peripheral stem-cell yield, and progressive disease). In conclusion, our study demonstrated that consolidation HDCT containing busulfan plus melphalan was feasible on a national scale. Compared with conventional chemotherapy, it may provide benefits for patients with lung-only or bone metastases. These results warrant confirmation in a randomized trial and were one of the bases of the ongoing EURO-EWING study, which uses an intensive induction regimen (vincristine 1.5 mg/m2 day 1, and ifosfamide 3g/m2, doxorubicin 20 mg/m2, and etoposide 150 mg/m2 on days 1 to 3) followed by HDCT with busulfan plus melphalan for patients with metastatic disease. This protocol is a one-arm study for extrapulmonary metastases and is comparing in a randomized trial the same consolidation regimen with conventional chemotherapy combined with lung irradiation in lung-only metastases.
The authors indicated no potential conflicts of interest.
We thank Lorna Saint Ange for editing this manuscript.
Supported by Institut Gustave Roussy and by Société Française des Cancers de l'Enfant. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Craft A, Cotterill S, Malcolm A, et al: Ifosfamide-containing chemotherapy in Ewing's sarcoma: The Second United Kingdom Children's Cancer Study Group and the Medical Research Council Ewing's Tumor Study. J Clin Oncol 16:3628-3633, 1998[Abstract] 2. Craft AW, Cotterill SJ, Bullimore JA, et al: Long-term results from the first UKCCSG Ewing's Tumour Study (ET-1): United Kingdom Children's Cancer Study Group (UKCCSG) and the Medical Research Council Bone Sarcoma Working Party. Eur J Cancer 33:1061-1069, 1997[CrossRef][Medline] 3. Kolb EA, Kushner BH, Gorlick R, et al: Long-term event-free survival after intensive chemotherapy for Ewing's family of tumors in children and young adults. J Clin Oncol 21:3423-3430, 2003 4. 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 5. Marina NM, Pappo AS, Parham DM, et al: Chemotherapy dose-intensification for pediatric patients with Ewing's family of tumors and desmoplastic small round-cell tumors: A feasibility study at St. Jude Children's Research Hospital. J Clin Oncol 17:180-190, 1999 6. Meyer WH, Kun L, Marina N, et al: Ifosfamide plus etoposide in newly diagnosed Ewing's sarcoma of bone. J Clin Oncol 10:1737-1742, 1992 7. Miser JS, Krailo MD, Tarbell NJ, et al: Treatment of metastatic Ewing's sarcoma or 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 8. Paulussen M, Ahrens S, Craft AW, et al: Ewing's tumors with primary lung metastases: Survival analysis of 114 (European Intergroup) Cooperative Ewing's Sarcoma Studies patients. J Clin Oncol 16:3044-3052, 1998 9. Sandoval C, Meyer WH, Parham DM, et al: Outcome in 43 children presenting with metastatic Ewing sarcoma: The St. Jude Children's Research Hospital experience, 1962 to 1992. Med Pediatr Oncol 26:180-185, 1996[CrossRef][Medline] 10. Wexler LH, DeLaney TF, Tsokos M, et al: Ifosfamide and etoposide plus vincristine, doxorubicin, and cyclophosphamide for newly diagnosed Ewing's sarcoma family of tumors. Cancer 78:901-911, 1996[CrossRef][Medline] 11. Cornbleet MA, Corringham RE, Prentice HG, et al: Treatment of Ewing's sarcoma with high-dose melphalan and autologous bone marrow transplantation. Cancer Treat Rep 65:241-244, 1981[Medline] 12. Graham-Pole J, Lazarus HM, Herzig RH, et al: High-dose melphalan therapy for the treatment of children with refractory neuroblastoma and Ewing's sarcoma. Am J Pediatr Hematol Oncol 6:17-26, 1984[Medline] 13. Hartmann O: New strategies for the application of high-dose chemotherapy with haematopoietic support in paediatric solid tumours. Ann Oncol 4:13-16, 1995 (suppl 6) 14. 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 15. Hartmann O, Benhamou E, Beaujean F, et al: High-dose busulfan and cyclophosphamide with autologous bone marrow transplantation support in advanced malignancies in children: A phase II study. J Clin Oncol 4:1804-1810, 1986[Abstract] 16. Huvos AG, Rosen G, Marcove RC: Primary osteogenic sarcoma: Pathologic aspects in 20 patients after treatment with chemotherapy en bloc resection, and prosthetic bone replacement. Arch Pathol Lab Med 101:14-18, 1977[Medline] 17. Peto R, Pike MC, Armitage P, et al: Design and analysis of randomized clinical trials requiring prolonged observation of each patient: II. Analysis and examples. Br J Cancer 35:1-39, 1977[Medline] 18. Cotterill SJ, Ahrens S, Paulussen M, et al: Prognostic factors in Ewing's tumor of bone: Analysis of 975 patients from the European Intergroup Cooperative Ewing's Sarcoma Study Group. J Clin Oncol 18:3108-3114, 2000 19. Paulussen M, Ahrens S, Burdach S, et al: Primary metastatic (stage IV) Ewing tumor: Survival analysis of 171 patients from the EICESS studies—European Intergroup Cooperative Ewing Sarcoma Studies. Ann Oncol 9:275-281, 1998 20. Bernstein ML, Devidas M, Lafreniere D, et al: Intensive therapy with growth factor support for patients with Ewing tumor metastatic at diagnosis: Pediatric Oncology Group/Children's Cancer Group Phase II Study 9457—A report from the Children's Oncology Group. J Clin Oncol 24:152-159, 2006 21. Jenkin RD, Al Fawaz I, Al Shabanah M, et al: Localised Ewing sarcoma/PNET of bone: Prognostic factors and international data comparison. Med Pediatr Oncol 39:586-593, 2002[CrossRef][Medline] 22. Ladenstein R, Hartmann O, Pinkerton CR, et al: A multivariate and matched pair analysis on high-risk Ewing tumor (ET) patients treated by megatherapy (MGT) and stem cell reinfusion (SCR) in Europe. Proc Am Soc Clin Oncol 18:555a, 1999 (abstr 2144) 23. 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 [Erratum: Bone Marrow Transplant 18:675, 1996][Medline] 24. 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 25. Spunt SL, McCarville MB, Kun LE, et al: Selective use of whole-lung irradiation for patients with Ewing sarcoma family tumors and pulmonary metastases at the time of diagnosis. J Pediatr Hematol Oncol 23:93-98, 2001[CrossRef][Medline] 26. Felgenhauer J, Hawkins D, Pendergrass T, et al: Very intensive, short-term chemotherapy for children and adolescents with metastatic sarcomas. Med Pediatr Oncol 34:29-38, 2000[CrossRef][Medline] 27. Nesbit ME Jr, Gehan EA, Burgert EO Jr, et al: Multimodal therapy for the management of primary, nonmetastatic Ewing's sarcoma of bone: A long-term follow-up of the First Intergroup study. J Clin Oncol 8:1664-1674, 1990[Abstract] 28. Pearl M: Busulfan lung. Am J Dis Child 131:650-652, 1977 29. Hawkins D, Barnett T, Bensinger W, et al: Busulfan, melphalan, and thiotepa with or without total marrow irradiation with hematopoietic stem cell rescue for poor-risk Ewing-sarcoma family tumors. Med Pediatr Oncol 34:328-337, 2000[CrossRef][Medline] Submitted January 20, 2006; accepted June 23, 2006.
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
17 years at initial diagnosis (P < .005) was found to confer a significantly dismal outcome,
