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Journal of Clinical Oncology, Vol 26, No 27 (September 20), 2008: pp. 4385-4393 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2008.16.5720 Results of the EICESS-92 Study: Two Randomized Trials of Ewing's Sarcoma Treatment—Cyclophosphamide Compared With Ifosfamide in Standard-Risk Patients and Assessment of Benefit of Etoposide Added to Standard Treatment in High-Risk Patients
From the Department of Paediatric Haematology/Oncology, University Children's Hospital Münster; Departments of Radiotherapy and Orthopedic Surgery, and Gerhard Domagk Institute of Pathology, University of Münster; Department of Radiotherapy, University of Schleswig-Holstein, Lübeck; Institute of Pathology, University of Düsseldorf; Department of Paediatric Haematology and Oncology, University Hospital Giessen, Giessen, Germany; The Royal Victoria Infirmary, Institute of Child Health, Newcastle upon Tyne; Regional Paediatric Oncology Unit, St James University Hospital, Leeds; Cancer Research United Kingdom and University College London Cancer Trials Centre, University College London; Department of Oncology, University College Hospital, London; Children's Cancer and Leukaemia Group Data Centre, Cancer Studies and Molecular Medicine, University of Leicester; Queen Elizabeth II Hospital; and The Royal Orthopaedic Hospital, Birmingham, United Kingdom; St Anna Children's Hospital, Vienna, Austria; Department of Paediatric Oncology, Emma Children's Hospital Academisch Medisch Centrum, University of Amsterdam, Amsterdam, the Netherlands; and Department of Paediatric Oncology/Haematology, University Children's Hospital Universitäts-Kinderspital Beider Basel, Switzerland Corresponding author: Michael Paulussen, MD, Department of Paediatric Oncology/Haematology, University Children's Hospital (UKBB) Basel, Römergasse 8, CH-4005 Basel, Switzerland; e-mail: michael.paulussen{at}ukbb.ch
Purpose The European Intergroup Cooperative Ewing's Sarcoma Study investigated whether cyclophosphamide has a similar efficacy as ifosfamide in standard-risk (SR) patients and whether the addition of etoposide improves survival in high-risk (HR) patients.
Patients and Methods SR patients (localized tumors, volume <100 mL) were randomly assigned to receive four courses of vincristine, dactinomycin, ifosfamide, and doxorubicin (VAIA) induction therapy followed by 10 courses of either VAIA or vincristine, dactinomycin, cyclophosphamide, and doxorubicin (VACA; cyclophosphamide replacing ifosfamide). HR patients (volume Results A total of 647 patients were randomly assigned: 79 SR patients were assigned to VAIA, 76 SR patients were assigned to VACA, 240 HR were assigned to VAIA, and 252 HR patients were assigned to EVAIA. The median follow-up was 8.5 years. In the SR group, the hazard ratios (VACA v VAIA) for EFS and OS were 0.91 (95% CI, 0.55 to 1.53) and 1.08 (95% CI, 0.58 to 2.03), respectively. There was a higher incidence of hematologic toxicities in the VACA arm. In the HR group, the EFS and OS hazard ratios (EVAIA v VAIA) indicated a 17% reduction in the risk of an event (95% CI, –35% to 5%; P = .12) and 15% reduction in dying (95% CI, –34% to 10%), respectively. The effect seemed greater among patients without metastases (hazard ratio = 0.79; P = .16) than among those with metastases (hazard ratio = 0.96; P = .84). Conclusion Cyclophosphamide seemed to have a similar effect on EFS and OS as ifosfamide in SR patients but was associated with increased toxicity. In HR patients, the addition of etoposide seemed to be beneficial.
Ewing's sarcoma family of tumors (ESFT), including Ewing's sarcoma and malignant peripheral neuroectodermal tumors,1,2 are rare, with an incidence of 0.6 to 3 per million population.3 Historically, outcome has been extremely poor. Improvements in prognosis followed the introduction of effective systemic chemotherapy. Early studies used combinations of vincristine, cyclophosphamide, dactinomycin, and doxorubicin, which resulted in survival approaching 50%.4-6 Subsequently, ifosfamide was also shown to be effective, although the evidence mainly came from nonrandomized, single-arm studies.7-10 Two multi-institutional groups, the German/Dutch/Austrian/Swiss Cooperative Ewing's Sarcoma Studies (CESS; from the Gesellschaft für Pädiatrische Onkologie und Hämatologie, [GPOH]) and United Kingdom Children's Cancer Study Group (UKCCSG), had independently evolved similar chemotherapy regimens and overall treatment philosophies for the treatment of primary osseous ESFT. Both groups used an ifosfamide-based neoadjuvant induction therapy, local treatment with surgery, and/or radiotherapy, followed by ifosfamide-based maintenance therapy with a total treatment length between 9 and 12 months.8,10 These approaches had resulted in similar survival outcomes. Because neither group had enough patients to address chemotherapy questions in the context of a randomized, controlled trial, the groups agreed to a collaborative approach under the banner of the European Intergroup Cooperative Ewing's Sarcoma Studies (EICESS-92) to develop and promote randomized trials. Previous studies had identified a number of prognostic factors. Patients with metastases had a worse outcome than those without. In nonmetastatic disease, patients with small tumors (< 100 mL) had a better outcome than those with larger tumors.5,8,10,11 The EICESS-92 collaboration used these observations to develop two parallel risk-stratified randomized trials. A four-drug regimen of vincristine, dactinomycin, ifosfamide, and doxorubicin (VAIA) was common to both trials. In patients classified as having standard-risk (SR) disease, the primary aim of the trial was to determine whether consolidation chemotherapy with cyclophosphamide could be used instead of ifosfamide, because of a perceived reduction in toxicity, without any reduction in survival. In patients classified as having high-risk (HR) disease, the primary aim of the trial was to evaluate whether the addition of etoposide would be beneficial. Although etoposide in combination with ifosfamide had been found to improve survival compared with standard cyclophosphamide-based regimens,12-14 the high-risk study of EICESS-92 has been the first and only trial investigating the potential benefit of adding etoposide to a regimen already containing ifosfamide.
Study Design We conducted two separate prospective randomized trials according to patient risk groups, as defined by stage and tumor volume. Patients with localized tumors of less than 100 mL were placed in the SR group and patients with large localized tumors (  100 mL) or metastatic disease were placed in the HR group. SR patients were randomly assigned to receive four courses of VAIA followed by 10 courses of either VAIA or vincristine, dactinomycin, cyclophosphamide, and doxorubicin (VACA; cyclophosphamide replacing ifosfamide; Fig 1). HR patients were randomly assigned to receive 14 courses of either VAIA or VAIA plus etoposide (EVAIA). All treatment allocations were made before the start of chemotherapy.
Study Population EICESS-92 was originally open for patients with histologically proven localized primary ESFT of bone in all participating institutions of UKCCSG and CESS. Exclusion criteria included prior cytostatic drug therapy, any condition incompatible with the proposed treatment, age more than 35 years, delay of more than 3 weeks between biopsy and treatment, and refusal of consent. An amendment 6 months after the start of the study allowed inclusion of patients with metastatic disease at diagnosis, because at that time there was no other treatment regimen available for these patients. EICESS-92 was approved by the appropriate ethics committees and institutional review boards. Informed consent was obtained from all patients or guardians. All patients were randomly assigned within 3 weeks from diagnostic biopsy and before treatment started. UKCCSG patients were randomly assigned, by telephone, via the central office in Leicester, United Kingdom. GPOH patients were randomly assigned via the central office in Münster, Germany, using pre-prepared numbered envelopes. Random assignment was stratified by center. The database was frozen in March 2007. Tissue biopsies were performed in all patients. Histologic investigations and immunohistochemistry studies were performed by local and reference pathologists.
Extent and stage of disease were evaluated before therapy by tumor imaging, chest computed tomography, bone marrow aspirates and biopsies from uninvolved sites, and technetium bone scan. Tumor volumes were calculated based on pretherapeutic maximum perpendicular diameters, as determined in computed tomography or magnetic resonance imaging, including soft tissue components.15 Peritumoral edema was not regarded as tumor. The trial office was available for guidance and film review. Histologic response of primary tumor to neoadjuvant chemotherapy was classified as good (
Treatment Plan
Study Outcomes
Statistical Analysis
Survival was analyzed using standard methods20 based on an intention-to-treat analysis. Cox's regression was used to estimate hazard ratios after allowing for other factors, and the proportional hazards assumption was checked by examining Schoenfeld residuals. Toxicity was analyzed using the
Patient Population The patient flow through screening, enrollment, random assignment, and analysis of EICESS-92 is shown in Figure 2. Between July 1992 and December 1999, 647 patients were randomly assigned: 210 patients from the UKCCSG and 437 patients from GPOH. There were 79, 76, 240, and 252 patients in the SR-VACA, SR-VAIA, HR-VAIA, and HR-EVAIA arms, respectively. Patient characteristics are listed in Table 1. Three and six patients were allocated incorrectly to HR and SR groups, respectively. The median length of follow-up among all randomly assigned patients (censoring those who had died) was 8.5 years (25th to 75th centile, 6.8 to 10.5 years), similar between the treatment arms: 8.3, 8.2, 8.9, and 8.5 years, respectively.
Most patients received surgery or radiotherapy, with 45% receiving both (Table 1). Table 2 demonstrates that chemotherapy treatment compliance was broadly similar between treatment arms. The percentage of patients who received granulocyte colony-stimulating factor at least once was 40%, 37%, 45%, and 60% in the SR-VACA, SR-VAIA, HR-VAIA, and HR-EVAIA arms, respectively.
Treatment Efficacy There were 324 first events: 15 deaths owing to tumor progression, four treatment-related deaths (three from infectious complications and one death from unspecified treatment complications), four deaths from unknown causes, 214 distant metastases, 42 local relapses, 34 local and metastatic relapses, four relapses at unspecified sites, and seven second malignancies (one SR-VACA, one SR-VAIA, three HR-VAIA, and two HR-EVAIA). In total, there were 273 deaths. The distribution of first events and deaths by treatment arm is shown in the Appendix Table A1 (online only). SR. The 3-year EFS rates were 73% and 74% in the SR-VACA and SR-VAIA arms, respectively, which is close to the estimate of 70% used in the sample size calculations. The hazard ratios for EFS and OS were 0.91 (95% CI, 0.55 to 1.53) and 1.08 (95% CI, 0.58 to 2.03), respectively. Summary results, including 5-year rates and Kaplan-Meier curves, are given in Table 3 and Figure 3A.
HR. The 3-year EFS rates were 52% in the HR-EVAIA arm and 47% in the HR-VAIA arm, lower than the estimate of 55% used in the sample size calculation, probably because the initial assumptions were based on localized disease only. The hazard ratio (0.83) indicated a 17% reduction in event rate when using etoposide, and the upper limit (1.05) was just greater than 1.0. When we allowed for prognostic risk factors that may not be considered to be sufficiently balanced between the treatment arms (any difference > 5% in Table 1), namely age at diagnosis, metastatic status, and site of metastases, the EFS hazard ratio did not change much (0.86 instead of 0.83). After further allowing for subsequent local treatment, the hazard ratio became 0.77. Because the HR group consisted of patients with and without metastases, we examined EFS and OS in each subgroup. Although a formal test for interaction was not statistically significant (P = .47 for EFS and P = .34 for OS), there was some evidence that a treatment effect was greater in patients without metastases (EFS hazard ratio = 0.80; 95% CI, 0.58 to 1.09; P = .18) than in those with metastases (hazard ratio = 0.96; 95% CI, 0.67 to 1.39; P = .84). The corresponding hazard ratios for OS were 0.80 (95% CI, 0.57 to 1.13; P = .21) among patients without metastases and 1.02 (95% CI, 0.69 to 1.50; P = .91) among those with metastases. Figure 3B shows the Kaplan-Meier curves in these subgroups.
Toxicity
The SR-study of EICESS-92 is the first randomized trial to compare cyclophosphamide (1.2 g/m2/course) and ifosfamide (6g/m2/course) in ESFT. At the time the study commenced, the chosen doses of cyclophosphamide and ifosfamide were thought to be of equivalent safety in a multidrug combination, but it was unclear whether either of the drugs might be more effective. This study was conducted to provide some clarification. The results indicated similar efficacy for SR patients when these agents were used at the chosen doses. Despite extending the trial length by 2 years, accrual to the SR arms (n = 155) remained below expectation, most likely because of improvements in staging methods, which may have increased the proportion of larger tumors diagnosed.21 The 95% CI for the difference in EFS at 3 years was within the specified maximum allowable difference of ±15 percentage points, and the observed hazard ratios for both EFS and OS were so close to 1.0 that it is unlikely that they would have been materially different if the target sample size of 200 patients had been reached. Given these results, there is evidence that the two regimens have a similar effect. However, the SR trial was designed to allow a relatively large difference in 3-year EFS of 15 percentage points, and given the CI of 0.55 to 1.53 for the hazard ratio, a sample size of 155 or 200 patients would be underpowered, and we cannot reliably exclude the possibility of a smaller treatment difference. With hindsight, we should have used a lower maximum allowable difference of 10 percentage points or less, though this would have required a much larger number of patients ( 440 patients). To achieve such higher patient numbers within a reasonable time frame, a broader cooperation between international study groups has meanwhile been established, EURO-EWING99,22,23 which also includes randomization of good-risk disease to consolidation chemotherapy containing either cyclophosphamide or ifosfamide. The EICESS-92 HR trial is the first and only randomized study in ESFT to examine the effect on survival by adding etoposide to a regimen already containing ifosfamide. In HR patients, the observed difference in EFS between EVAIA and VAIA just missed the conventional level for statistical significance, but the upper limit of the CI for the EFS hazard ratio (1.05) was close to 1, being suggestive of a benefit of etoposide. The observed difference of 6.8 percentage points in 3-year EFS was smaller than the expected estimate of 15 percentage points, so it is likely that a sample size of 492 patients was underpowered to detect a smaller difference. With EFS hazard ratios of 0.80 for localized and 0.96 for metastatic disease, respectively, it is likely that the addition of etoposide had a more pronounced effect in localized disease. Our study was not powered in each of these subgroups, and subgroup analyses may produce false significant results.24 However, the observation that there seems to be no benefit of adding etoposide in patients with metastatic disease is consistent with data from the National Cancer Institute/Intergroup Ewing Tumor Group trial INT-0091, where the addition of both ifosfamide and etoposide to standard VACA significantly improved outcome in localized but not in metastatic disease.14 Among patients with localized disease in INT-0091, the greatest benefit of ifosfamide and etoposide was detected in patients with large and/or pelvic primary tumors14 (ie, those usually regarded as HR15,21,25). The survival benefit observed in the ifosfamide-etoposide augmented cohort, however, might have been mainly attributable to ifosfamide, which was absent from the standard arm. In EICESS-92, all HR patients received ifosfamide, the only difference between randomly assigned arms being the addition of etoposide in the experimental arm. This might explain the smaller effect observed compared with INT-0091, confirming that both ifosfamide and etoposide contribute to improved outcome in HR patients. We have demonstrated for the first time that the addition of etoposide to a regimen already containing ifosfamide may improve patient's outcome, although less markedly so as compared with adding both ifosfamide and etoposide to standard regimens. The external validity of these results is currently being explored in the ongoing Euro-EWING99 trial. A combination including etoposide and ifosfamide with vincristine and doxorubicin is applied as induction treatment, comparing standard consolidation versus high-dose therapy in patients with poor histologic response, in an attempt to rescue poor responders. In US studies, courses of vincristine, cyclophosphamide, and doxorubicin are alternated with ifosfamide and etoposide, whereas EVAIA in EICESS-92 applied all drugs (but cyclophosphamide) at the same time. In EICESS-92, 6 g/m2/course of ifosfamide were administered, whereas in the United States studies, ifosfamide-dose per (alternating) course is usually 9 g/m2. The outcome of patients with localized ESFT of any size in recent United States studies has been comparable to that of EICESS-92 patients with small tumors.14,15 Therefore, etoposide, ifosfamide, vincristine, and doxorubicin courses in Euro-EWING99 prescribe 9 g/m2 of ifosfamide. In EICESS-92, serious acute toxicities were rare, with only four toxic deaths occurring during the protocol treatment. Unexpectedly, the VACA arm in SR patients was associated with a higher incidence of acute grade 3 to 4 hematologic toxicities, mucositis, and infection. Cyclophosphamide (1.5 g/m2) was also associated with greater myelosuppression compared with ifosfamide (5 g/m2) in one other report.26 We detected no difference in acute renal glomerular toxicity between VACA and VAIA. Unfortunately, data on renal tubular toxicity were incomplete, so no final conclusions regarding overall renal toxicity could be drawn. To overcome this, the interstudy GPOH Late Effects Surveillance System was established. First short-term follow-up renal toxicity data have been published.27 In the HR group, the increase in the incidence of hematologic toxicities associated with adding etoposide was as expected and was manageable. There have been few randomized, risk-stratified trials in ESFT because of the rarity of this disease. EICESS-92 brought together two cooperative groups to successfully conduct two parallel randomized trials, though they took 7 years to complete. The results in the SR group suggest that cyclophosphamide resulted in a similar survival to ifosfamide, and in the HR group, the addition of etoposide seemed to increase survival. Both are unique observations never reported before. Despite the limitations of sample size in the SR group and of formal statistical significance in the HR group, these data add useful information to the limited published evidence from randomized trials in Ewing's sarcoma. Current treatment recommendations for patients with SR localized ESFT can incorporate either ifosfamide or cyclophosphamide applied in the doses and combinations used here. For HR localized ESFT, combinations including both ifosfamide and etoposide are warranted. In the future, we need multinational collaboration to undertake large enough studies in a timely fashion. New approaches tested in randomized controlled trials are needed to further improve outcome, particularly in patients with metastatic disease.
The author(s) indicated no potential conflicts of interest.
Conception and design: Alan W. Craft, Ian Lewis, Jürgen Dunst, Winfried Winkelmann, Herbert Jürgens Administrative support: Alan W. Craft, Ian Lewis, Herbert Jürgens Provision of study materials or patients: Michael Paulussen, Alan W. Craft, Ian Lewis, Jürgen Dunst, Andreas Schuck, Winfried Winkelmann, Gabriele Köhler, Christopher Poremba, Andreas Zoubek, Ruth Ladenstein, Henk van den Berg, Andrea Hunold, Anna Cassoni, David Spooner, Robert Grimer, Jeremy Whelan, Herbert Jürgens Collection and assembly of data: Michael Paulussen, Alan W. Craft, Ian Lewis, Carolyn Douglas, Andreas Schuck, Gabriele Köhler, Christopher Poremba, Andreas Zoubek, Ruth Ladenstein, Henk van den Berg, Andrea Hunold, Anna Cassoni, David Spooner, Robert Grimer, Jeremy Whelan, Herbert Jürgens Data analysis and interpretation: Michael Paulussen, Alan W. Craft, Ian Lewis, Allan Hackshaw, Carolyn Douglas, Andreas Zoubek, Ruth Ladenstein, Andrea Hunold, Jeremy Whelan, Anne McTiernan, Herbert Jürgens Manuscript writing: Michael Paulussen, Alan W. Craft, Ian Lewis, Allan Hackshaw, Jeremy Whelan, Anne McTiernan, Herbert Jürgens Final approval of manuscript: Michael Paulussen, Alan W. Craft, Ian Lewis, Allan Hackshaw, Carolyn Douglas, Jürgen Dunst, Andreas Schuck, Winfried Winkelmann, Gabriele Köhler, Christopher Poremba, Andreas Zoubek, Ruth Ladenstein, Henk van den Berg, Andrea Hunold, Anna Cassoni, David Spooner, Robert Grimer, Jeremy Whelan, Anne McTiernan, Herbert Jürgens
We thank all patients, parents, and investigators and the staff of the Children's Cancer and Leukemia Group and the Münster Ewing trial center, especially Claire Weston, Susanne Ahrens, and Andreas Ranft. We thank Ivo Leuschner for additional pathology review and G.U. Exner for surgical review.
Supported by Deutsche Krebshilfe (Grants No. DKH M43/92/Jü2 and DKH 70-2551 Jü3), and European Union Biomedicine and Health Programme (Grants No. BMH1-CT92-1341 and BMH4-983956), and Cancer Research United Kingdom. Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article. Clinical trial information can be found for the following: NCT0000251.
1. Ewing J: Diffuse endothelioma of bone. Proc N Y Pathol Soc 21:17-24, 1921 2. Bernstein M, Kovar H, Paulussen M, et al: Ewing sarcoma family of tumors: Ewing sarcoma of bone and soft tissue and the peripheral primitive neuroectodermal tumors, in Pizzo PA, Poplack DG (eds): Principles and Practice of Pediatric Oncology (ed 5). Philadelphia, PA, Lippincott Williams & Wilkins, 2006, pp 1002-1032 3. Hense HW, Ahrens S, Paulussen M, et al: Descriptive epidemiology of Ewing's tumor: Analysis of German patients from (EI)CESS 1980-1997 [in German]. Klin Padiatr 211:271-275, 1999[Medline] 4. Rosen G, Caparros B, Mosende C, et al: Curability of Ewing's sarcoma and considerations for future therapeutic trials. Cancer 41:888-899, 1978[CrossRef][Medline] 5. Jürgens H, Exner U, Gadner H, et al: Multidisciplinary treatment of primary Ewing's sarcoma of bone: A 6-year experience of a European Cooperative Trial. Cancer 61:23-32, 1988[CrossRef][Medline] 6. Oberlin O, Patte C, Demeocq F, et al: The response to initial chemotherapy as a prognostic factor in localized Ewing's sarcoma. Eur J Cancer Clin Oncol 21:463-467, 1985[CrossRef][Medline] 7. 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] 8. 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] 9. Bacci G, Mercuri M, Longhi A, et al: Neoadjuvant chemotherapy for Ewing's tumour of bone: Recent experience at the Rizzoli Orthopaedic Institute. Eur J Cancer 38:2243-2251, 2002[CrossRef][Medline] 10. Paulussen M, Ahrens S, Dunst J, et al: Localized Ewing tumor of bone: Final results of the Cooperative Ewing's Sarcoma Study CESS 86. J Clin Oncol 19:1818-1829, 2001 11. 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] 12. 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 13. 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 14. 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 15. Göbel V, Jürgens H, Etspüler G, et al: Prognostic significance of tumor volume in localized Ewing's sarcoma of bone in children and adolescents. J Cancer Res Clin Oncol 113:187-191, 1987[CrossRef][Medline] 16. Salzer-Kuntschik M, Delling G, Beron G, et al: Morphological grades of regression in osteosarcoma after polychemotherapy-study COSS 80. J Cancer Res Clin Oncol 106:21-24, 1983 (suppl)[Medline] 17. Dunst J, Sauer R, Burgers JM, et al: Radiation therapy as local treatment in Ewing's sarcoma: Results of the Cooperative Ewing's Sarcoma Studies CESS 81 and CESS 86. Cancer 67:2818-2825, 1991[CrossRef][Medline] 18. Dunst J, Jürgens H, Sauer R, et al: Radiation therapy in Ewing's sarcoma: An update of the CESS 86 trial. Int J Radiat Oncol Biol Phys 32:919-930, 1995[CrossRef][Medline] 19. Paulussen M, Ahrens S, Craft AW, et al: Ewing tumors with primary lung metastases: Survival analysis of 114 (European Intergroup) Ewing Sarcoma Studies patients. J Clin Oncol 16:3044-3052, 1998 20. Collett D: Modelling Survival Data in Medical Research. London, United Kingdom, Chapman and Hall, 1994 21. Ahrens S, Hoffmann C, Jabar S, et al: Evaluation of prognostic factors in a tumor volume adapted treatment strategy for localized Ewing's sarcoma of bone: The CESS 86 experience. Med Pediatr Oncol 32:186-195, 1999[CrossRef][Medline] 22. Euro-E.W.I.N.G. Study Committee: EURO-E.W.I.N.G. 99 Study Manual: European Ewing Tumour Initiative of National Groups Ewing Tumour Studies 1999. http://euro-ewing.uni-muensterde/ 23. Juergens C, Weston C, Lewis I, et al: Safety assessment of intensive induction with vincristine, ifosfamide, doxorubicin, and etoposide (VIDE) in the treatment of Ewing tumors in the EURO-E.W.I.N.G. 99 Clinical Trial. Pediatr Blood Cancer 47:22-29, 2006[CrossRef][Medline] 24. Wang R, Lagakos SW, Ware JH, et al: Statistics in medicine: Reporting of subgroup analyses in clinical trials. N Engl J Med 357:2189-2194, 2007 25. 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] 26. Bramwell VH, Mouridsen HT, Santoro A, et al: Cyclophosphamide versus ifosfamide: Final report of a randomized phase II trial in adult soft tissue sarcomas. Eur J Cancer Clin Oncol 23:311-321, 1987[CrossRef][Medline] 27. Stöhr W, Paulides M, Bielack S, et al: Ifosfamide-induced nephrotoxicity in 593 sarcoma patients: A report from the Late Effects Surveillance System. Pediatr Blood Cancer 48:447-452, 2007[CrossRef][Medline] Submitted January 31, 2008; accepted May 27, 2008.
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
10% viable tumor cells) or poor (> 10% viable cells).
2 test for proportions. 
