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Journal of Clinical Oncology, Vol 25, No 10 (April 1), 2007: pp. 1176-1182 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.05.0559 Extraosseous Localized Ewing Tumors: Improved Outcome With Anthracyclines—The French Society of Pediatric Oncology and International Society of Pediatric Oncology
From the Hematology Oncology and Orthopedic Surgery Units, Children's Hospital; Department of Pathology, Rangueil Hospital, Toulouse; Departments of Biostatistics and Pediatric Oncology, Institut Gustave Roussy, Villejuif; Department of Genetics and Molecular Biology of Tumors, Institut Curie, Paris, France; Hospital Miguel Servet, Zarragoza, Spain; and the Department of Paediatric Oncology, Royal Hospital, Bristol, United Kingdom Address reprint requests to Odile Oberlin, MD, Department of Pediatric Oncology, Institut Gustave Roussy, 39 rue C Desmoulins, 94805 Villejuif, France; e-mail: oberlin{at}igr.fr
Purpose To evaluate the outcome of children with an extraosseous Ewing tumor (EOE) according to treatment. Patients and Methods Children with EOE were treated either with the strategy used for malignant mesenchymal tumors (MMTs) by the International Society of Pediatric Oncology (SIOP) or with the French Society of Pediatric Oncology (SFOP) regimen used for osseous Ewing tumors (OET). The MMT strategy included vincristine/actinomycin for small and resected tumors or ifosfamide/vincristine/actinomycin for unfavorable sites or unresectable tumors. Surgical excision was to be attempted after four courses, followed by local irradiation in case of residue. Osseous Ewing (OE) protocol included three courses of cyclophosphamide/doxorubicin followed either by two similar courses in case of good response or two courses of ifosfamide/etoposide in case of no response. After resection of the primary, treatment included conventional chemotherapy in case of good histologic response and high-dose chemotherapy and radiotherapy for poor response. All diagnosis specimens were reviewed by the panel. Results Between 1989 and 1999, 63 patients were registered. Characteristics of patients treated by both protocols were similar. Five-year overall survival (OS) and event-free survival (EFS) of those treated with the OE protocol are 83% and 75%, respectively, which is significantly better than the OS and EFS of those treated with the MMT strategy (59% and 44%, respectively; P = .04 and .008, respectively). The size of the primary and the type of protocol influenced patients’ EFS. In multivariate analysis, only the regimen had an impact on OS and EFS. Conclusion Our study shows that patients with EOE should be treated with OE regimens, probably because of the use of anthracyclines.
Ewing tumor is the second most common primary bone malignancy in childhood and adolescence, with an estimated annual incidence of 0.6 per 1 million children and adolescents.1-3 Extraosseous Ewing tumor (EOE) is a type of small, round cell tumor of the soft tissues that has a dual identity.4 On the one hand, it can be considered within the group of malignant mesenchymal tumors (MMTs) because of its location in soft tissues and its similar clinical presentation.5,6 On the other hand, it may be classified within the Ewing tumor (ET) family because of similar cytologic and immunohistologic characteristics (evidence for neuroectodermal origin, features of neurodifferentiation, and CD99 expression in 98% of the tumors).7 Furthermore, these tumors share the same cytogenetic profile, with more than 95% of ET characterized by a rearrangement of chromosome 22, most frequently the translocation t(11;22) (q24;q12), resulting in EWS-FLi1 fusion.2,8-18 Depending on the classification used, EOEs account for approximately 5% of MMTs and 20% of ETs. The best treatment for this tumor is, however, still a matter of debate. Historically, EOEs have often been treated like rhabdomyosarcoma (RMS) using MMT regimens, although, from 1993, the French Society of Pediatric Oncology (SFOP) chose to include these children in the national protocol for the treatment of ET of bone (EW93). To determine the most appropriate treatment for EOE, we compared the outcome of patients treated in a protocol designed for MMT compared with that for ET of bone during the same period.
Patients This study includes all consecutive patients presenting with localized (nonmetastatic) EOE treated either with the International Society of Pediatric Oncology (SIOP) MMT89 protocol or the SFOP EW93 protocol. Only patients younger than 25 years were eligible for the EW93 protocol, and patients younger than 18 years for the MMT89 protocol. Informed consent was obtained from the parents or guardians of each child, or from adult patients, according to the research ethics requirements of each participating institution. This study was approved by Institut Gustave-Roussy board.
Histopathology Molecular testing was available for 10 patients, and found the classical translocation t(11,22) in eight of them.
Pretreatment Evaluation
Assessment of Response
MMT89 Protocol
EW93 Protocol For the EW93 protocol (Fig 2), induction chemotherapy consisted of three courses of cyclophosphamide (150 mg/m2/d) for 7 consecutive days (days 1 to 7) followed by doxorubicin (35 mg/m2) at day 8 (CPM-DXR). Each course was administered at 14-day intervals beginning on days 1, 15, and 29. Patients with a good clinical response (decrease of pain, tumor volume, inflammatory local reaction) received a further two courses at days 50 and 71. Poor responders (NR; increase of pain, tumor volume, inflammatory local reaction) received two courses of ifosfamide (1.8 g/m2/d days 1 to 5) and etoposide (100 mg/m2/d days 1 to 5; IFO-VP16).
Carcinologic surgical resection of the primary was strongly recommended at this point, if feasible. The resected specimen was examined by the local pathologist to determine the histologic response based on a grading system derived from Huvos’ description for osteosarcoma.14 Response was defined according to three groups: good response (no identifiable viable tumor or < 5% of identifiable residual tumor cells), intermediate response (5% to 30% of identifiable residual tumor cells), and bad response (more than 30% of identifiable residual tumor cells).
Further chemotherapy was stratified according to histologic response in patients who underwent surgery after preoperative chemotherapy or the size of the primary tumor in patients who had had complete resection at diagnosis. Patients who exhibited a good histologic response to chemotherapy or who underwent initial resection of a small primary tumor (< 5 cm) received six courses of vincristine (1.5 mg/m2) and actinomycin (VA; 1.5 mg/m2) every 2 weeks, followed by three more courses of CPM-DXR. Patients with a poor histologic response to chemotherapy or with unresectable tumors (patients in whom surgery could not be attempted, for example, because of their having a difficult site) received two courses of IFO-VP16 followed by high-dose chemotherapy with busulfan (150 mg/m2/d days 1 to 4) and melphalan (140 mg/m2 day 5; BU-MEL) and autologous stem-cell transplantation. Patients with an intermediate histologic response to chemotherapy and those with unresectable large tumors (
Statistical Analysis
Characteristics of Patients and Treatment Between January 1989 and December 1999, 63 consecutive patients were registered with nonmetastatic EOE (positivity of CD99). Their characteristics are described in Table 1. These characteristics were compared with those of the 503 patients with RMS treated in MMT89 and 215 patients with OET treated in EW93. The group of 63 patients with EOE was analyzed in two subgroups according to the protocol used for treatment. No significant differences were identified in patient characteristics between those treated in MMT89 and EW93 excepted a trend regarding age and primary site (Table 2).
Outcome according to primary treatment and chemotherapy is shown in Figure 3.
Carcinologic surgery (either at diagnosis in case of small accessible tumor or after preoperative chemotherapy) was performed in 86% of the patients, more often in those treated by the EW93 protocol (96%) than in those treated by the MMT89 protocol (75%). Radiation therapy (35 to 50 Gy) was administered to 60% of the patients but was also more frequently administered to those treated in the EW93 protocol (18 of 31 patients; 58%) compared with those treated in the MMT89 protocol (14 of 32 patients; 44%). Only one patient in EW93 received high-dose chemotherapy.
Survival
Relapse and Outcome Relapse or PD were observed in 26 patients at a median interval of 24 months after diagnosis (range, 4 months to 7 years). The first event in these patients was local relapse (n = 5), metastatic relapse (n = 13), or combined relapse (n = 1), or PD (n = 7). Median interval from diagnosis was 22 months for local relapse (range, 10 to 85 months) and 21 months for metastatic relapse (range, 4 to 47 months). All patients received salvage therapy with chemotherapy and some form of local treatment. This included high-dose chemotherapy with a busulfan-containing regimen followed by stem-cell rescue in six patients. All patients with PD died as a result of their disease 10 to 24 months after diagnosis. Among the five patients with local relapse, four remain in CR2 at a median follow-up of 5 years. Among the 13 patients with metastatic relapse, four are alive in CR2 at a median follow-up of 2 years, 6 months. Overall, eight of 19 relapsing patients are alive in CR2 at a median follow-up of 3 years after their first relapse. Metastatic relapses was observed in 13 patients: nine of 32 in MMT89 and four of 31 in EW93. This is different, but nonsignificant because of the small total number of patients.
Prognostic Factors
Multivariate analysis was performed for the same 57 patients (Table 4) and showed that OS rate was influenced only by treatment protocol (P = .03), although EFS was related both to the treatment and the size of the primary (P = .01 and .05, respectively).
In this study, the 63 patients with EOE showed characteristics (age, sex ratio, size, and location of the primary) that are similar to those from other published studies.2,23 Although most authors11,13,23 emphasize that both histologic and cytogenetic analyses are required to confirm the diagnosis of EOE, in this series, cytogenetic and molecular analysis were available in only a minority of patients. Nevertheless, tumor samples from all patients were submitted for central pathology review to confirm the diagnosis. The data from this study show that patients with EOE treated according to a protocol designed for OET have a better outcome than do those treated according to an MMT protocol. In fact, the protocol used was significant as a predictive factor in multivariate analysis both for OS and EFS. Furthermore, among patients treated on MMT89, OS and EFS were lower for those with EOE than for those with RMS. This appeared to be a result of a higher incidence of metastatic relapse in EOE and is an observation supported by other studies.2,8,24-27 Several very large trials have clearly indicated that for OET older age is an adverse prognostic factor. Because the patients treated on OET regimen were older than the patients treated on MMT protocol, that would confer a prognostic disadvantage to the cohort treated with the EOT regimen. Because the cohort treated with EOT regimen had a superior outcome, this further strengthens the conclusion that MMT protocols are not suitable for patients with EOE. Conversely, the results showed that the outcome of the patients with EOE and OET are similar provided that they are treated with OET-directed regimens. A report from St Jude's Children's Research Hospital (Memphis, TN)28 on a small series of 17 patients with localized EOE treated with chemotherapy combinations including ifosfamide and etoposide, like OET, showed 5-year OS and EFS rates of 77% and 62%, respectively; they concluded that patients with EOE should be treated with protocols designed for patients with OET. Another study reported a series of 44 patients with ET, of whom half had EOE, treated with OET regimen.29 In this study, patients with EOE fared significantly worse than did those with OET (5-year survival of 21% v 52%), but because this series included only patients older than 18 years, many of whom had metastatic disease at diagnosis, this does not provide a reasonable comparison. There were important differences in approach to local therapy between the two protocols used in this study, and it could be suggested that the difference observed in outcome was related to intensified local treatment (surgery and radiotherapy) in EW93 described herein. However, the higher rate of relapse seen in patients treated with the MMT89 strategy was mainly attributable to metastatic rather than local relapse. It is more likely that the improved survival of patients with EOE treated with OET regimens is related to the use of anthracyclines. Randomized trials have confirmed the value of doxorubicin (5-year disease-free survival, 24% with vinvristine, dactinomycin, and cyclophosphamide (VAC) v 60% with VAC-DXR) and the benefit of a pulsed, more intensive anthracycline-containing regimen.30-33 The addition of IFO-VP16 to OET regimens has also contributed to improved survival. The third North American study conducted from 1988 to 1992 (comparing VAC-DXR v VAC-DXR-IFO-VP16) confirmed a survival benefit for those receiving IFO-VP16, particularly for nonmetastatic patients.34 These observations now justify the inclusion of patients with EOE in the current European study Euro-Ewing 99 protocol, which also includes intensive pulses of chemotherapy with vincristine-IFO-DXR-VP16. To our knowledge, this unselected series of patients with localized EOE is the largest reported study in the literature. We conclude that protocols designed for the treatment of RMS are not suitable for these patients, particularly because of a high metastatic failure rate. Improved outlook seen with an OET regimen is supported by similar observations in the literature and most likely results from impact of the use of anthracyclines. Nevertheless, further improvements in outcome are required, and the achievement of this will involve better stratification of treatment against prognostic factors such as the size of the primary tumor, histologic response to primary chemotherapy, and, possibly, molecular evidence for subclinical metastatic disease at diagnosis.35 The impact of such an approach is being evaluated in the ongoing European collaborative study (Euro-Ewing 99 study).
The authors indicated no potential conflicts of interest.
Collection and assembly of data: Annie Rey Data analysis and interpretation: Annie Rey, Odile Oberlin Manuscript writing: Marie-Pierre Castex, Hervé Rubie, Michael C.G. Stevens, Carlota Calvo Escribano, Anne Gomez-Brouchet, Annie Rey, Olivier Delattre, Odile Oberlin Final approval of manuscript: Marie-Pierre Castex, Hervé Rubie, Michael C.G. Stevens, Jérôme Sales de Gauzy, Anne Gomez-Brouchet, Annie Rey, Odile Oberlin
Presented in part at the 40th Annual Meeting of the American Society of Clinical Oncology, June 5-8, 2004, New Orleans, LA, and the Annual Meeting of the Societe Francaise des Cancers de l'Enfant, June 6, 2003, Nantes, France. Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Delattre O, Zucman J, Melot T, et al: The Ewing family of tumors, a subgroup of small-round-cell tumors defined by specific chimeric transcripts. N Engl J Med 331:294-299, 1994 14. Zoubek A, Dockhorn-Dworniczak B, Christiansen H, et al: Does expression of different EWS chimeric transcripts define clinically distinct risk groups of Ewing tumor patients? J Clin Oncol 14:1245-1251, 1996 15. De Alava E, Kawai A, Healey JH, et al: EWS-FLI1 fusion transcript structure is an independent determinant of prognosis in Ewing's sarcoma. J Clin Oncol 16:1248-1255, 1998 16. Fletcher JA: Ewing's sarcoma oncogene structure: A novel prognostic marker? J Clin Oncol 16:1241-1243, 1998 17. Sahu K, Pai RR, Khadilkar UN: Fine needle aspiration cytology of the Ewing's sarcoma family of tumors. Acta Cytol 44:332-336, 2000[Medline] 18. Kretschmar CS, Ewing's sarcoma and the peanut tumors. N Engl J Med 331:325-326, 1994 19. Stevens C, Rey A, Bouvet N, et al: Treatment of nonmetastatic rhabdomyosarcoma in childhood and adolescence: Third study of the International Society of Paediatric Oncology-SIOP Malignant Mesenchymal Tumor 89. J Clin Oncol 23:2618-2628, 2005 20. Fleiss JI: Statistical Methods for Rates and Proportions (ed 2). New York, NY, Wiley, 1981 21. Peto R, Mc Pherson K: Design and analysis of clinical trials requiring prolonged observation of each patient. Br J Cancer 35:1-39, 1977[Medline] 22. Cox DR: The Analysis of Binary Data. London, United Kingdom, Chapman & Hall, 1977 23. Dehner LP: Primitive neuroectodermal tumor and Ewing's sarcoma. Am J Surg Pathol 17:1-13, 1993[Medline] 24. Raney RB, Asmar L, Newton WA, et al: Ewing's sarcoma of soft tissue in childhood: A report from the intergroup rhabdomyosarcoma study, 1972 to 1991. J Clin Oncol 15:574-582, 1997 25. Paoletti H, Colineau X, Acalet L, et al: Soft tissue Ewing's sarcoma: About 3 cases and literature analysis. [in French]. 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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
) Only for unfavorable sites.
5 cm), even when a good response had been achieved with chemotherapy, received six cycles of VA and six cycles of IFO-VP16. Radiotherapy (35 to 50 Gy) was administered to all patients with unresected tumors, to those with incomplete surgical resection, and to those with a poor histologic response to induction chemotherapy. 
2 tests corrected for heterogeneity or with Fisher's exact test.
