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© 2003 American Society for Clinical Oncology High-Dose Therapy for Patients With Primary Multifocal and Early Relapsed Ewing’s Tumors: Results of Two Consecutive Regimens Assessing the Role of Total-Body Irradiation
From the Division of Pediatric Hematology and Oncology, Departments of Pediatric Surgery and Radiation Oncology, and Clinical Studies Coordination Center, University of Halle-Wittenberg, Halle; Departments of Pediatric Hematology/Oncology and Radiation Oncology, University of Düsseldorf, Düsseldorf; Department of Hematology/Oncology, City Hospital Oldenburg, Oldenburg; Department of Pediatric Oncology, University of Münster, Münster, Germany; and St Anna Kinderspital, Vienna, Austria. Address reprint requests to Stefan Burdach, MD, PhD, Martin-Luther-University Halle-Wittenberg, Children’s Cancer Research Center, and Division of Pediatric Hematology/Oncology, 06097 Halle, Germany; email: meta-eicess{at}medizin.uni-halle.de.
Purpose: Risk stratification of metastatic and relapsed Ewing’s tumors (ETs) has been a matter of debate during the last decade. Patients with bone or bone marrow metastases or early or multiple relapses constitute the worst risk group in ET and have a poorer prognosis than patients with primary lung metastases or late relapses. In this article, the results of the present Meta European Intergroup Cooperative Ewing Sarcoma Study (MetaEICESS) (tandem melphalan/etoposide [TandemME]) were compared with the result of the previous study (hyper melphalan/etoposide [HyperME]), both at 5 years, in a patient population within the same high-risk stratum to determine toxicity. Patients and Methods: Among 54 eligible patients, 26 were treated according to the HyperME protocol, and 28 were treated according to TandemME protocol. Patients received six cycles of the Cooperative Ewing Sarcoma Study treatment in HyperME and six cycles of the EICESS treatment in TandemME as induction chemotherapy. Patients also received involved-compartment irradiation for local intensification and myeloablative systemic intensification consolidation with hyperfractionated total-body irradiation (TBI) combined with melphalan/etoposide in HyperME or two times the melphalan/etoposide in TandemME followed by autologous stem-cell transplantation. Results: The event-free survival (EFS) rate ± SD in HyperME and TandemME was 22% ± 8% and 29% ± 9%, respectively. The dead of complication rate was 23% in HyperME and 4% in TandemME. Conclusion: TandemME offers a decent, albeit still not satisfactory, rate of long-term remissions in most advanced ETs (AETs), with short-term treatment and acceptable toxicity. TBI was not required to maintain EFS level in this setting but was associated with a high rate of toxic death. Future prospective studies in unselected patients are warranted to evaluate high-dose therapy in an unselected group of patients with AET.
CURE OF patients with Ewing’s tumors (ETs) has been improved by multimodal therapy, including surgery, radiotherapy, and chemotherapy. To date, patients with localized disease at primary diagnosis have a long-term event-free survival (EFS) of more than 50%.1 Patients with metastatic or relapsed disease carry a worse prognosis. Risk stratification of metastatic and relapsed ET has been a matter of debate during the last decade. Within the group of primary metastases, most1,2 but not all3 data show that patients with bone or bone marrow metastases have an even poorer prognosis than patients with primary lung metastases.1 In early studies, only few, if any, patients with bone or bone marrow metastases survived.4–6 For example, in the United Kingdom Children’s Cancer Study Group Ewing’s Tumor study, none of eight patients treated between 1978 and 1986 survived beyond 38 months from diagnosis after treatment according to the study’s protocol (without myeloablative therapy).7 In a retrospective analysis of 48 patients, the prognosis was also extremely poor (< 5%).5 In more recent studies, the prognosis seems to be somewhat better, ranging between 16%3 and 19%,1 even without high-dose therapy (HDT). In addition, early relapses have a worse prognosis than late relapses. Early relapses are defined as occurring earlier than 24 months after diagnoses. Patients who relapsed early had a 4% to 8.5% 5-year survival compared with a 23% to 35% 5-year survival in patients who relapsed late.1,8 These survival rates relate to patients who did not undergo HDT. Taken together, primary bone or bone marrow metastases and early, multiple, or multifocal relapse constitute the worst-risk group in ET. They encompass a group termed advanced ET (AET).9 Several myeloablative HDT regimens, followed by stem-cell transplantation as consolidation treatment, have been used in attempts to improve survival for this group of patients.9 Two consecutive studies of the Meta European Intergroup Cooperative Ewing Sarcoma Study Group (MetaEICESS) are reported here. In hyper melphalan/etoposide (HyperME), patients received six times the Cooperative Ewing Sarcoma Study (CESS) treatment or related induction chemotherapy, involved-compartment irradiation (ICI) for local intensification, and, finally, myeloablative systemic intensification consolidation with hyperfractionated total-body irradiation (TBI) combined with melphalan/etoposide followed by autologous stem-cell transplantation (autoSCT). In tandem melphalan/etoposide (TandemME), patients received six cycles of EICESS treatment or related induction chemotherapy and two times the melphalan/etoposide, with autoSCT for consolidation. As of January 2002, 26 patients have received the HyperME regimen, and 28 patients have received the TandemME regimen. Results are presented in this article.
Patient Characteristics For patients in the HyperME protocol, characteristics and chemotherapy regimens have been described in detail recently (Table 1  ).10 Briefly, between November 1986 and December 1994, 26 patients with high-risk AET received HyperME myeloablative chemotherapy with subsequent autoSCT preceded by induction chemotherapy and ICI ± surgery. In the TandemME study, 28 patients with AET received autoSCT after high-dose chemotherapy between May 1995 and May 2000. They received consolidation therapy with two times the high-dose melphalan/etoposide followed by autoSCT. Exclusion criterion for both protocols was nonresponse to previous chemotherapy. All patients or their guardians signed informed consent before therapy. Protocol treatment was applied after institutional review board approval according to the precepts established by the Helsinki Conference Declaration.
Stem-Cell Harvest Autologous CD34+ selected peripheral-blood stem cells were used as the preferred graft source. The recommended cell dose per transplantation was at least unselected 4 x 106 CD34+ cells per kg of body weight. In HyperME, three patients received autologous bone marrow as the stem-cell source. Autologous bone marrow and peripheral stem cells were harvested during induction chemotherapy after the third or fourth cycle of chemotherapy or after both cycles. For stem-cell harvesting, patients received 5 to 10 µg/kg/d or 250 µg/m2 granulocyte colony-stimulating factor for priming beginning 24 hours after completion of the last course of chemotherapy, and harvesting was started according to the CD34+ cell count.11
Myeloablative Therapy The median time between the event that made patients eligible for HDT and autoSCT was 6.5 months. The interval between the last course of induction chemotherapy and the beginning of the conditioning regimen was recommended to be at least 4 weeks and no longer than 6 weeks. Autologous stem-cell graft was reinfused on day 0. Patients received from 1.8 x 106 to 1.5 x 107 CD34+ cells/kg. For enhancement of myeloid reconstitution, granulocyte colony-stimulating factor 250 µg/m2 or 5 to 10 µg/kg body weight was administered beginning day +1 after autoSCT until the neutrophil count was more than 1,000/µL.
ICI and Other Local Therapy
Immunotherapy With Interleukin-2 (IL-2)
Statistical Analysis
Overall Outcome and Engraftment As of January 1, 2002, the EFS rate ± SD for all 54 patients was 23% ± 6%, and the OS rate was 25%, with a median follow-up after event that led to eligibility for transplantation of 105 months (range, 28 to 190 months; Fig 1 ). In HyperME, the median follow-up was 146 months (range, 98 to 190 months); for TandemME, the median follow-up was 68 months (range, 28 to 88 months). In HyperME and TandemME, all 54 patients were engrafted, which is defined as an absolute neutrophil count of more than 500/µL on 3 consecutive days, except one TandemME patient who died on day +5 after the first autoSCT. A detailed analysis focuses on the following risk factors.
Ablative Regimen Both consolidation protocols had a comparable outcome, with an EFS at 5 years of 22% in HyperME and 29% in TandemME and an OS of 22% in HyperME and 35% in TandemME (Fig 2A and Fig 2B). In HyperME, six of 26 patients survived in complete remission after autoSCT, 14 of 26 patients died of disease, and six of 26 patients died of complications. The EFS rate ± SD was 22% ± 8%, with a median survival of 18 months after the last event before autoSCT (range, 6 to 187 months). The six of 26 patients who are alive and in remission survived event-free with a median of 126 months (range, 90 to 187 months).
In TandemME, the EFS rate ± SD at 5 years was 29% ± 9%. The median EFS time was 22.6 months (range, 5 to 82 months) after the last event before autoSCT. Eleven of 28 patients are alive, and nine of them are in complete remission. The patients is complete remission are surviving event-free at a median of 59 months (range, 24 to 82 months) from the event that made them eligible for transplantation. One patient is alive 13 months after relapse, successful treatment of relapse, and second complete remission 53 months after transplantation, and one patient is alive with relapse 35 months after transplantation, yielding an OS rate ± SD of 35% ± 9%. Recurrence of disease occurred within 12 months in 15 of 26 patients in HyperME and in 16 of 28 patients in TandemME. Five of 26 patients in HyperME and three of 28 patients in TandemME had an event more than 12 months after completion of HDT.
Stage More encouraging, six of 13 patients in the HyperME study who underwent transplantation because of early relapse are alive with an EFS rate ± SD of 46% ± 13% (median EFS time, 126 months; range, 90 to 187 months). Five of 11 patients in TandemME who underwent transplantation because of early relapse are alive with an EFS rate ± SD of 45% ± 15% (median EFS time, 62 months; range, 24 to 82 months).
Toxicity Three additional patients developed secondary malignancies. Two patients had a secondary myelodysplastic syndrome. Both patients died of septicemia and multiorgan systemic failure, the first one during reinduction chemotherapy and the second patient after second transplantation on day +93. The third patient developed a liposarcoma of the right pelvis and underwent chemotherapy, but the treatment failed, and he finally died of his secondary malignant neoplasm. In TandemME, 57 cycles of HDT were assessable (one patient died on day +5 after the first autoSCT). Grade 4 hematologic toxicity was seen in all patients after both autoSCTs. Infection and fever was the most common complication, apart from hematologic toxicity; grade 1 occurred in three patients, grade 2 occurred in 14 patients, grade 3 occurred in 12 patients, and grade 4 occurred in two patients. Within the group of gut toxicity, mucositis was the most frequent symptom; grade 1 occurred in six patients, grade 2 occurred in six patients, grade 3 occurred in three patients, and grade 4 occurred in six patients. Enteritis occurred in four patients (grade 1, n =1; grade 2, n =1; grade 3, n =1; and grade 4, n =1). Moreover, two patients suffered from grade 1 skin toxicity. In one patient, grade 3 renal toxicity was seen, and in one patient, grade 1 heart toxicity was seen. Other complications observed included interstitial pneumonitis (n = 2) after lung irradiation, and single cases of atrioventricular node re-entry tachycardia, thrombosis of the internal jugular vein, radiogenic peritonitis, and persistent alopecia. No liver or neurologic symptoms were observed. Altogether, one patient died of septicemia, including acute respiratory distress syndrome, on day +5 after autoSCT. Secondary malignancies were not seen during observation time.
Age
Immunotherapy
Patients with primary metastases to bone or bone marrow or early, multiple, or multifocal relapse constitute the worst-risk group in the treatment of ET, termed AET.9 Fifty-four AET patients were treated in two consecutive studies with high-dose consolidation therapy using ME chemotherapy with or without 12 Gy of TBI. The EFS rate at 7 years was 23% for the total group with a secondary malignancy as the last event occurring at 5.5 years. In the first MetaEICESS study, patients with AET received for induction chemotherapy VAIA or EVAIA, ICI parallel to the last two courses of chemotherapy for local intensification, and hyperfractionated TBI combined with ME plus autoSCT (HyperME protocol) for systemic intensification. Twenty-six patients were treated according to this protocol as previously reported.6,10 Results updated in this article show an EFS rate ± SD of 22% ± 8% at 5 years after autoSCT. In the second MetaEICESS study, patients were treated with myeloablative therapy using TandemME followed by autoSCT. Twenty-eight patients were treated between May 1995 and May 2000, according to the TandemME protocol. After a median follow-up of 68 months, eleven of 28 patients are alive; nine of these 11 patients are in first complete remission after transplantation. One of 11 patients relapsed locally in the lung 4.3 years after transplantation and is in complete remission 2.5 years after local treatment of relapse. This relapse was registered as an event. Sixteen of 28 patients died of disease, and one patient died of complications. Another patient is alive with relapse. Thus, the EFS rate ± SD after 5 years for all patients in the TandemME study was 29% ± 9%, and the OS rate is 35%. Comparability of both studies is limited because of the long observation period and because of the variations described in therapy before HDT, diagnostic imaging, postconditioning immunotherapy, and additional variations in supportive care. However, because induction chemotherapy and local treatment were comparable and studies were limited to four institutions with quite strict definition of eligible stage and two HDT protocols, an analysis of evolution of results in both studies has been undertaken, yielding a similar outcome. Results of MetaEICESS studies for primary multifocal ET were 0% EFS in HyperME and 21% EFS in TandemME at 5 years. Results are similar to concurrent studies without HDT, which range from less than 5% to 19%.1,3,5 Results for early relapse were 46% EFS in HyperME and 45% EFS in TandemME compared with 4% to 8.5% without HDT. Clearly, neither this nor any other study so far has proven that AET benefits from HDT. The reason for this is that the present study, like most other HDT studies, addressed selected patients only. Meyers et al14 have assessed the role of HDT in a controlled retrospective nonrandomized study of unselected patients with primary multifocal ET. In their study, no advantage of HDT was demonstrated. In fact, the study showed that approximately 30% of patients, who were eligible for HDT at time of diagnosis, did not undergo HDT for various reasons. Results at 2 years were 24% for the selected group that underwent transplant and 20% for the unselected group. The difference in outcome between selected and unselected groups reported in this study may help to interpret other studies addressing only a selected group of patients who survive without events until the time of transplantation. In patients with early relapse, no studies have been published addressing the efficacy of HDT in an unselected patient group. Nevertheless, similar results of the two HDT regimens reported here, as well as in other studies, may be a result of the fact that neither regimen alters the course of metastatic ET. However, these reports can contribute to evaluation of toxicity of TBI-containing and no TBI-containing high-dose consolidation regimens. As a consequence of this observation, we agree with the recommendation of Meyers et al that HDT with autoSCT for patients with metastatic ET should be administered only as part of a prospective investigational trial. The same applies to patients with relapse. Given the study design–based difficulties of comparing MetaEICESS results with results without HDT, we focus this analysis on comparing the two MetaEICESS regimes mainly with regard to toxicity. The main difference between HyperME and TandemME reported here relates to the death of complication rate. After HyperME plus autoSCT, six (23%) of 26 patients died of complications (three patients died of secondary malignancies) compared with one (4%) of 28 patients in TandemME. This patient died of septicemia 5 days after autoSCT. In addition, two patients had persistence of compromised organ function, such as interstitial pneumonitis. Three patients had secondary malignancies 4.3, 4.7, and 5.5 years after HyperME. No secondary malignancies have been seen after TandemME so far. Irradiation has been reported to be the therapeutic modality with the highest risk of secondary malignancies.15 Actual incidence of secondary malignancies at 5, 10, and 15 years was 7.7%, 11.5%, and 11.5% for HyperME and 3.7%, 5.6%, and 5.6% for the total group, respectively. Analysis of the CESS 81 and CESS 86 studies shows a cumulative risk of secondary malignancies after treatment for ET of 0.7% after 5 years, 2.9% after 10 years, and 4.7% after 15 years without high-dose consolidation therapy.16 Because the observation time of TandemME protocol is not as long as the observation time of HyperME, long-term follow-up is warranted. To date, early and late toxicity is reduced with TandemME compared with HyperME. Thus, TBI may contribute to high toxicity without improving results in patients with AET.
In addition, duration and cumulative doses of myeloablative compared with conventional consolidation therapy should be considered. Patients treated with TandemME received a total of eight chemotherapy cycles (six conventional VIDE cycles and two HDT ME consolidation cycles, yielding a total therapy duration of Another difference between HyperME and TandemME may relate to age-dependent prognosis. In HyperME, prognosis for patients 17 years or younger was better than for older patients. For patients younger than or equal to 17 years old, the EFS rate ± SD was 32% ± 11%, whereas no patient older than 17 years of age survived (P = .001, log-rank; P = 0.003, Breslow). Using TandemME, the EFS rate for patients older than 17 years was not significantly different from the EFS rates for patients below 17 years (19% ± 11% compared with 40% ± 14%, respectively; P = .20, log-rank; P = .25, Breslow). Comparing both studies, survival of patients older than 17 years was not significantly different in the two chemotherapeutic regimens. Age at diagnosis as significant prognostic risk factor has been described by several authors.7,17–19 Therefore, older patients especially might possibly benefit from TandemME. We also assessed the role of high-dose exogenous IL-2 in AET. Given the lack of any benefit from IL-2 after HDT, further studies with this schedule of high-dose exogenous IL-2 in AET are not warranted. The present analysis of 54 patients with primary multifocal and early relapsed ET clearly does not demonstrate an advantage of the TBI-containing HyperME regimen compared with the TandemME regimen, the latter yielding an EFS rate ± SD of 29% ± 9% and an OS of 35% at a median follow-up of 68 months. The recent landmark article by Meyers et al discussed above has also addressed the role of TBI in HDT for treatment of ET metastatic to bone or bone marrow. Twenty-three selected patients who actually underwent high-dose consolidation with TBI had an EFS of 24% at 2 years. This study has clearly put in doubt not only the role of myeloablative therapy but also the role of TBI in the treatment of patients with ET with primary metastases to bone or bone marrow.14
Although the role of TBI has been challenged by the present and other studies,14,20,21 there is no question that radiation is efficacious in ET. However, the dose conventionally applied with TBI or total-marrow irradiation is insufficient for eradication of ET cells. The threshold for ET cells is considered to be approximately To date, an increment in EFS by HDT in a specific subset of ET has never been assessed in a prospective randomized study. Instead, during the last decade, the discussion about the use of HDT or megatherapy in ET has mainly focused on the question of whether TBI or busulfan is the superior high-dose regimen modality. This question has been addressed by Ladenstein et al20 and Hawkins et al,22 yielding variable results. These studies, however, addressed efficacy in a selected group of patients, as well as early but not late toxicity. Our results show that the emphasis on TBI versus busulfan in the present debate concerning HDT may have to be refocused. In fact, this study shows that neither TBI nor busulfan is necessary to obtain an OS rate of 35% at 5 years in AET patients who responded to chemotherapy and became eligible for transplantation. Nevertheless, similar results of the two HDT regimens reported here may be a result of the fact that neither regimen alters the course of metastatic ET. This may also apply to the other reports assessing TBI-containing and no TBI-containing high-dose consolidation regimens. In conclusion, myeloablative consolidation protocols avoiding TBI can limit the toxicity of HDT, including secondary malignancies. The TandemME protocol using short-term low cumulative treatment with appropriate ICI necessitating field-dependent stem-cell support followed by myeloablative tandem systemic consolidation offers a decent, albeit still not satisfactory, rate of long-term remissions with acceptable toxicity in most patients with AET. Thus, the potential of TandemME should be evaluated in a randomized study.
We thank Professor M. Bamberg for his essential contribution to the establishment of total-body irradiation in advanced Ewing’s tumors. We also thank the medical and nursing staffs of the participating institutions for their provision of excellent patient care.
This study was supported by grant No. KKS Halle 01GH0105 from the German Federal Ministry of Education and Research, a grant from the Elterninitiative Kinderkrebsklinik Düsseldorf e.V., grant No. 83 25 from AMGEN Ltd, and grant No. 85 18 from Nexell International.
1. 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
2. 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
3. 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 4. Huckels-Klasen MJ: Therapiemöglichkeiten für Patienten mit primär metastasiertem Ewing-Sarkom: Eine Analyse der nach der Kooperativen Ewing-Sarkom Studie CESS 81 behandelten Patienten. Dissertation, Duesseldorf, Germany, 1991 5. Wessalowski R, Jurgens H, Bodenstein H, et al: Results of treatment of primary metastatic Ewing sarcoma: A retrospective analysis of 48 patients. Klin Padiatr 200:253–260, 1988[Medline]
6. Burdach S, Jurgens H, Peters C, et al: Myeloablative radiochemotherapy and hematopoietic stem cell rescue in poor prognosis Ewing sarcoma. J Clin Oncol 11:1482–1488, 1993 7. Craft AW, Cotterill SJ, Bullimore JA, et al: Long-term results from the first UKCCSG Ewing’s Tumor Study (ET-1). Eur J Cancer 33:1061–1069, 1997[CrossRef][Medline] 8. 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] 9. Burdach S, Jurgens H: High-dose chemoradiotherapy (HDC) in the Ewing family of tumors (EFT). Crit Rev Oncol Hematol 41:169–189, 2002[Medline]
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. Engel BC, Laws HJ, Dirksen U, et al: Circulating CD34 + cell counts as predictive parameter for the efficacy of peripheral stem cell apheresis in Ewing tumor patients. Klin Padiatr 209:186–190, 1997[Medline] 12. Pape H, Laws HJ, Burdach S, et al: Radiotherapy and high-dose chemotherapy in advanced Ewing’s tumors. Strahlenther Onkol 175:484–487, 1999[CrossRef][Medline] 13. Atzpodien J, Gulati SC, Shimazaki C, et al: Ewing’s sarcoma: Ex vivo sensitivity towards natural and lymphokine-activated killing. Oncology 45:437–443, 1988[Medline]
14. 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 15. Tucker MA, D’Angio GJ, Boice JD Jr, et al: Bone sarcomas linked to radiotherapy and chemotherapy in children. N Engl J Med 317:588–593, 1987[Abstract] 16. Dunst J, Ahrens S, Paulussen M, et al: Second malignancies after treatment for Ewing’s sarcoma: A report of the CESS studies. Int J Radiat Oncol Biol Phys 42:379–384, 1998[CrossRef][Medline] 17. Stewart DA, Gyonyor E, Paterson AH, et al: High-dose melphalan +/- total body irradiation and autologous hematopoietic stem cell rescue for adult patients with Ewing’s sarcoma or peripheral neuroectodermal tumor. Bone Marrow Transplant 18:315–318, 1996[Medline] 18. Rosito P, Mancini AF, Rondelli R, et al: Italian Cooperative Study for the treatment of children and young adults with localized Ewing sarcoma of bone: A preliminary report of 6 years of experience. Cancer 86:421–428, 1999[CrossRef][Medline] 19. Delepine N, Delepine G, Cornille H, et al: Prognostic factors in patients with localized Ewing’s sarcoma: The effect on survival of actual received drug dose intensity and of histologic response to induction therapy. J Chemother 9:352–363, 1997[Medline] 20. 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 tumours registry. Bone Marrow Transplant 15:697–705, 1995[Medline] 21. Ladenstein R, Hartmann O, Pinkerton R, et al: A multivariate and matched pair analysis on high-risk Ewing tumor patients treated by megatherapy and stem cell reinfusion in Europe. Proc Am Soc Clin Oncol 18:555, 1999 (abstr) 22. Hawkins D, Barnett T, Bensinger W, et al: Busulphan, 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 December 6, 2002; accepted May 27, 2003.
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
17 years at time of diagnosis. In HyperME, six of 18 patients survived event-free (32% ± 11%) compared with six of 14 patients (40% ± 13%) in TandemME. Patients older than 17 years showed a trend toward better long-term outcome with TandemME. Three of 14 patients older than 17 years survived after Tandem ME (5-year EFS ± SD, 19% ± 11%) compared with none of eight patients after HyperME. 
21 weeks). Patients undergoing conventional, nonablative consolidation according to the EURO-Ewing protocol received a total of 14 chemotherapy cycles (six VIDE cycles and eight consolidation cycles of vincristine, actinomycin D, and etoposide, yielding a total therapy duration of 
