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© 2001 American Society for Clinical Oncology Localized Ewing Tumor of Bone: Final Results of the Cooperative Ewing’s Sarcoma Study CESS 86From the Departments of Pediatric Hematology/Oncology and Orthopedic Surgery, and Gerhard Domagk Institute of Pathology, University of Münster, Münster; Department of Radiotherapy, University of Halle, Halle; Institute of Paidopathology, University of Kiel, Kiel; Department of Pediatric Hematology/Oncology, Schwabing Children’s Hospital, Munich Technical University, Munich; Departments of Pediatric Hematology/Oncology, University of Hannover, Hannover, University of Frankfurt, Frankfurt, University of Hamburg, Hamburg, and University of Düsseldorf, Düsseldorf; and Olga Children’s Hospital, Stuttgart, Germany; Department of Orthopedic Surgery, University of Zürich, Zurich, Switzerland; Departments of Orthopedic Surgery and Pathology, University of Vienna, and St Anna Children’s Hospital, Vienna, Austria; and Department of Pediatric Hematology/Oncology, Emma Children’s Hospital, University of Amsterdam, the Netherlands. Address reprint requests to Michael Paulussen, MD, Department of Pediatric Hematology/Oncology, Albert-Schweitzer Str 33, D-48129, University of Münster, Germany; email; michael.paulussen{at}uni- muenster.de.
PURPOSE: Cooperative Ewing’s Sarcoma Study (CESS) 86 aimed at improving event-free survival (EFS) in patients with high-risk localized Ewing tumor of bone.
PATIENTS AND METHODS: We analyzed 301 patients recruited from January 1986 to July 1991 (60% male; median age 15 years). Tumors of volume >100 mL and/or at central-axis sites qualified patients for "high risk" (HR, n = 241), and small extremity lesions for "standard risk" (SR, n = 52). Standard-risk patients received 12 courses of vincristine, cyclophosphamide, and doxorubicin alternating with actinomycin D (VACA); HR patients received ifosfamide instead of cyclophosphamide (VAIA). Tumor sites were pelvis (27%), other central axis (28%), femur (19%), or other extremity (26%). The initial tumor volume was <100 mL in 33% of cases and RESULTS: On May 1, 1999 (median time under study, 133 months), the 10-year EFS was 0.52. Event-free survival did not differ between SR-VACA (0.52) and HR-VAIA (0.51, P = .92). Tumor volume of >200 mL (EFS, 0.36 v 0.63 for smaller tumors; P = .0001) and poor histologic response (EFS, 0.38 v 0.64 for good responders; P = .0007) had negative impacts on EFS. In multivariate analyses, small tumor volumes of <200 mL, good histologic response, and VAIA chemotherapy augured for fair outcome. Six of 301 patients (2%) died under treatment, and four patients (1.3%) developed second malignancies. CONCLUSION: Fifty-two percent of CESS 86 patients survived after risk-adapted therapy. High-risk patients seem to have benefited from intensified treatment that incorporated ifosfamide.
IT WAS NOT UNTIL the introduction of a combined-modality approach, which added systemic cytostatic drug therapy to local therapy, that long-term survival of Ewing tumor (ET) patients has been reported.1,2 While response rates were impressive, the long term outcomes in ET patients were compromised by substantial relapse rates of more than 50%. In a previous study, CESS 81, as well as in other trials, large and/or central-axis tumors presented special problems: local control was difficult to achieve and local or distant relapses occurred in large proportions of patients.3-8 The multicenter Cooperative Ewing’s Sarcoma Study (CESS) 86 of the German/Austrian Society of Pediatric Oncology and Hematology (GPOH) aimed at improving high-risk ET patients’ cure rates with risk-adapted cytostatic drug treatment, including the introduction of ifosfamide (IFO) for larger and/or central-axis tumors. Moreover, a local treatment advisory board of orthopedic surgeons and radiotherapists was established that offered assistance in planning central radiotherapy and surgery as well as in performing surgical procedures.9 The long-term results of 301 patients with localized ET of bone from the CESS-86 study will be presented, with consideration of event-free survival (EFS), relapse rates and relapse characteristics, risk factors predictive for treatment failure, and late sequelae.
Patient Population From January 1986 to July 1991, 407 patients with localized ET of bone were enrolled in CESS 86. The study was open for patients with histologically proven, localized primary ET of bone. According to the study criteria, patients were deemed ineligible for further analyses if they fulfilled one or more of the following exclusion criteria: distant metastases, diagnosis other than ET, or previous treatment with cytostatic drugs (n = 106); such patients will not be further discussed here. Three hundred one patients met the inclusion criteria and were included in the analyses presented here. One hundred eighty of 301 patients (60%) were male. The median age at diagnosis was 15 years (range, 8.5 months to 47 years). Patients were treated in 92 institutions in Germany, Austria, the Netherlands, and Switzerland. Informed consent was obtained from all patients and/or guardians. The study was approved by the appropriate ethics committees.
Diagnostic Work-Up and Staging Procedures Metastases were excluded by chest computed-tomography scan, bone marrow aspirates from two or more sites distant from the tumor, and whole-body technetium bone scan. Tumor volumes were calculated based on pretherapeutic maximum perpendicular diameters as measured by plain radiography and computed tomography scans, including soft tissue involvement, as described elsewhere.3 Histologic response towards preoperative chemotherapy was determined according to the method of Salzer-Kuntschick,11 in which 10% or fewer viable tumor cells in the surgical specimen were classified as "good response"; otherwise, response was regarded as "poor." Heart, liver, and kidney function were monitored at regular intervals before treatment, under therapy, and during follow-up. Staging procedures in case of suspected relapse were identical to those described above.
Tumor Site, Tumor Volume, Risk Group Allocation Patients were allocated to two risk groups and treated accordingly: Patients with small (<100 mL) extremity tumors were classified as "standard risk" patients (SR; n = 52); patients with tumor volumes of 100 mL or more (n = 177) and/or central-axis tumors (skull, shoulder, chest, spine, pelvic bones; n = 164) were classified as "high risk" patients (HR; n = 241). Eight of 301 patients could not be allocated to any risk group owing to missing information concerning tumor size or site. Figure 1 shows tumor sites; Table 1 details tumor sites, tumor volumes, and risk grouping.
Treatment Plan Following biopsy, four blocks of cytostatic drug therapy were given. Each block was to last 9 weeks and consisted of three courses of treatment each, administered at 3-week intervals. Standard-risk patients received four VACA chemotherapy blocks, each block consisting of vincristine at 1.5 mg/m2/d (days 1, 8, 15, 22), cyclophosphamide at 1,200 mg/m2/d (days 1, 43) or 400 mg/m2/d (days 22, 23, 24) both with Mesna as appropriate, Adriamycin (doxorubicin, Pharmacia SA, Milan, Italy) at 30 mg/m2/d (days 1, 2, 43, 44), and actinomycin D at 0.5 mg/m2/d x 3 (days 22, 23, 24). High-risk patients received four VAIA chemotherapy blocks, with IFO at 3,000 mg/m2/d (days 1, 2, 22, 23, 43, 44) and Mesna as appropriate, instead of cyclophosphamide; otherwise, VAIA was identical to VACA. Cumulative drug doses scheduled were doxorubicin 480 mg/m2, actinomycin D 6 mg/m2, vincristine 24 mg/m2, and cyclophosphamide 14,400 mg/m2 or IFO 72,000 mg/m2, respectively. Figure 2 outlines the treatment plan.
Local therapy was scheduled to be given before the second block; ie, at week 9. Local therapy was individually planned for each patient after discussions between the local investigators, the study center, the local and reference surgeons, and the radiotherapists. Tumor site, tumor size and resectability, the patient’s age, and individual preference were considered. A panel of orthopedic surgeons experienced in the surgical treatment of ET was available for planning and performing surgery. Central radiotherapy planning through reference radiotherapists was also made available for all patients. Complete surgery was desired, wherever feasible. Otherwise, 60 Gy of irradiation was delivered to the tumor bulk; the tumor-bearing compartment was to receive at least 44.8 Gy. In case of incomplete surgery, or poor histologic response, 44.8 Gy of postoperative radiotherapy were prescribed. Radiotherapy dose and technique details were reported elsewhere.4,12
Statistical Methods
On May 1, 1999, 7 years and 4 months after closure of the study, the median time under study was 133 months (range, 88-222). The median time to last follow-up or death was 77 months (range, 2-157). One hundred sixty of 301 patients (53%) have remained event free. Event-free survival 10 years after diagnosis was 0.52 (95% confidence interval [CI], 0.46-0.57), and OAS was 0.57 (95% CI, 0.51-0.63; see Fig 3). In the following paragraphs, several aspects of the study treatment will be described, and their potential impacts on outcomes will be analyzed both by univariate and multivariate procedures.
Local Therapy Local therapy was surgery in 68 patients (23%), surgery and radiotherapy in 146 patients (49%), or radiotherapy alone in 82 patients (28%). Local therapy was delivered at a median of 12 weeks after diagnosis, five patients had primary resection, and five patients had local therapy after the end of chemotherapy; ie, the range was 0 to 45 weeks. Eighty percent of patients received local therapy between weeks 9 and 20 of therapy.
Chemotherapy According to Risk Groups
Histologic Response to Preoperative Chemotherapy Histologic response in the surgical specimen was determined in 160 patients. Histologic response was good (ie,  10% viable tumor cells) in 17 (74%) of 23 VACA patients and in 78 (57%) of 137 VAIA patients, respectively ( 2 P = .125).
Univariate Analyses of Outcome and Risk Factors
Multivariate Analyses of Outcome and Risk Factors Cox proportional hazard models were applied for multivariate analyses of potentially predictive factors, including the variables looked at in the univariate analyses outlined above. Not all of the variables from the univariate analyses could be included in one global, multivariate test, as some of the variables were mutually exclusive; eg, histologic response was only available in patients undergoing surgery. Hence, the following models were analyzed: Model 1, which included the pretherapeutic variables sex (male v female), age (<15 years v  15 years), tumor size (<200 mL v 200 mL), tumor site (axial v extremity), and histologic subtype (Ewing’s sarcoma v PNET); Model 2, which included variables that were of prognostic impact in univariate analyses and were available in the majority of patients, namely, tumor site and tumor size together with the chemotherapy regimen applied (VACA v VAIA); and Model 3, which also included tumor site and size together with histologic response to chemotherapy (good v poor). Results are given in Table 4. Among pretherapeutic variables, only tumor size of 200 mL or greater retained its predictive impact, whereas all other variables in Model 1 did not seem to be of influence. In Model 2, tumor volume of 200 mL or greater, and VACA chemotherapy as opposed to VAIA chemotherapy was correlated to poor outcome. When histologic response was analyzed together with tumor size and site (as in Model 3), response remained as the sole significant risk factor. Several other multivariate models that test multiple combinations of variables failed to identify further significant predictive factors.
Relapse Pattern Out of the total of 301 patients, 160 patients (53%) remained event free, 16 patients (5%) experienced nonrelapse events (see below), and 125 patients (42%) relapsed. Twenty-two relapses (7% of patients) were local at the initial tumor site, 92 relapses (31% of patients) were metastatic, and 11 relapses (4% of patients) were both local and metastatic. In 103 patients with metastatic plus or minus local relapses, pulmonary and/or pleural metastases occurred in 50 patients (49% of metastatic relapses), bone and/or bone marrow metastases were seen in 29 patients (28% of metastatic relapses), metastases to both the skeleton and the lungs were diagnosed in 21 patients (20% of metastatic relapses), and three patients (3% of metastatic relapses) developed metastases to the brain, meningi, or lymph nodes. Figure 7 shows the relapse patterns in the total group and according to tumor site, modality of local therapy, surgical margins, response to chemotherapy, risk group allocation (SR v HR), and actual chemotherapy regimen (VACA v VAIA). In all subgroups, metastatic relapse was by far the most common type of relapse, ranging from 24% to 52%. Patients with poor histologic response to chemotherapy had the highest rate (52%) of metastatic relapse. Whereas local or local plus metastatic relapses were generally less common (range, 1% to 20%) in patients eligible for surgery with or without the need for postoperative irradiation, a trend towards better local control was seen (local relapse, 4.2%; local + metastatic relapse, 2.3%; total local failures, 6.5%) when compared with those patients who underwent radiotherapy as the only mode of local control because of suspected inaccessibility to surgery (local relapse, 13%; local + metastatic relapse, 7%; total local failures, 20%; 2 P = .001). Sufficient surgical margins contributed to local tumor control (3.5% local +/- metastatic failures v 12.7% without sufficient margins; 2 P = .015). The pelvic region presented as the tumor site where local control proved most difficult (local relapse, 14%; local + metastatic relapse, 4%; total local failures 18%), whereas in other central-axis lesions, local control was relatively better (local relapse, 5%; local + metastatic relapse, 7%; local failures total, 12%), and in extremity tumors local control was fair (local +/- metastatic failures, 5% to 9%).
Non-Relapse Events Three patients (1%) showed progression of disease under therapy, and one patient progressed after treatment had been stopped 4 weeks into therapy on his parents’ decision, despite good clinical response. One patient died in a traffic accident, and one patient committed suicide during therapy. Six patients (2%) developed fatal complications during or immediately after therapy: Three patients died from septic episodes during chemotherapy; one patient died from cerebral ischemia (stroke) during therapy; one patient suffered a fatal intestinal perforation 1 year after pelvic irradiation; and the sixth patient had cardiac arrest of unknown cause 1 month after the end of treatment (cardiac function was normal on all tests during therapy; no autopsy was done). Four patients (1.3% of all 301 patients; 2.2% of 179 survivors) developed second cancers, and three of these four died. Two patients developed acute myeloic leukemia: one patient was diagnosed with acute myeloic leukemia (FAB-type not specified) 2 years after the end of VACA therapy and died within 6 months; and 8 months after the end of VAIA therapy another patient presented with hyperleukocytosis of more than 1 x 1011/L. Acute myeloic leukemia (FAB M4) was diagnosed from her peripheral blood, and 1 day later she expired from respiratory insufficiency caused by pulmonary leukostasis. One patient with a scapula tumor developed a retroperitoneal embryonal rhabdomyosarcoma 6 years after the end of VAIA therapy. At the time of analysis she was in remission of both cancers. The fourth patient was successfully treated for a refractory anemia type myelodysplastic syndrome 8 years after VAIA therapy; at the time of analysis 4 years later, she was doing well and had recently become pregnant. The risk of developing a second malignancy 10 years after diagnosis of a ET in our study cohort was estimated to be 0.017 by competing risk analysis.
Survival After Relapse
Late Effects
This is a report of a large series of uniformly treated ET patients. Patients from CESS 86 received a four-drug, cytostatic regimen for 36 weeks, as well as local therapy, preferably as surgery. Overall survival and EFS, as well as several disease-related and treatment-related potential risk factors, were analyzed. The need for high-efficacy chemotherapy regimens is apparent from the observation that distant metastases were the most important type of treatment failure in ET patients according to this analysis and other studies.7,18-21 Among the subgroups analyzed here, patients with poor histologic response to chemotherapy had the highest rates of metastatic relapses (52%) and overall failures (61%). Moreover, in accord with other published reports,22-24 poor responders were found to have EFS rates significantly inferior (0.38) to those of patients with good responses (0.64, P = .0007). It is, however, not known whether or not modification of the treatment at the point in time when the specimen was obtained would have altered the outcome. As a consequence, a more intensive induction therapy has been introduced in the successive European Working Initiative of National Groups Ewing Tumor Study 1999 (EURO-EWING 99, performed by the European Organization for Research and Treatment of Cancer, French Society of Pediatric Oncology, GPOH, Swiss Institute for Applied Cancer Research, and United Kingdom Children’s Cancer Study Group). In EURO-EWING 99, induction for all patients consists of six courses of vincristine 1.5 mg/m2, IFO 9,000 mg/m2, doxorubicin 60 mg/m2, and etoposide 450 mg/m2. Moreover, for patients with poor histologic response to this preoperative chemotherapy, a randomized treatment intensification question is currently being raised about the comparison between standard dose consolidation therapy versus high-dose therapy with autologous stem cell support (http://medweb.uni-muenster.de/ institute/ paedonco/forschung/ewing/ewing99.html).
Large tumor volume and/or central-axis tumor site have been found to be correlated to an increased risk of treatment failure in a preceding study (CESS 81)3,25 and in reports of others.8,26-30 Given the promising results achieved with the incorporation of IFO in second-line protocols,31-34 CESS-86 HR patients (ie, patients with central axial tumors and patients with extremity lesions In CESS 86, the outcome in HR patients on VAIA was not inferior to the outcome in SR patients who received VACA. Moreover, only four of 15 SR patients who had VAIA instead of VACA (by violation of the protocol) relapsed (EFS, 0.71), as opposed to 14 of 29 patients who relapsed after regular VACA therapy (EFS, 0.51; P = .1682; results not shown). Multivariate analyses of 210 patients, in whom tumor site, tumor volume, and chemotherapy was documented, indicated a relative risk of 1.978 for patients on VACA compared with VAIA therapy (P = .0340), which was independent of both tumor site and volume. This may indicate that VAIA is a more effective chemotherapy regimen in ET than VACA. In CESS 86, larger tumors were observed more frequently than had been expected from the CESS-81 experience, most likely as a result of having more advanced imaging techniques. This trend toward registering larger tumor volumes more readily, along with the decision to apply the more intensive VAIA chemotherapy in all patients with tumor volumes above 100 mL, resulted in a new prognostic threshold of 200 mL; detailed analyses of this observation were published elsewhere.35 Larger tumor size will always represent a therapeutic challenge. It is quite possible that the upward shift in both the median tumor volume and the prognostic threshold observed in this study may just have been coincidental. Another explanation is that more efficacious therapeutic protocols may shift the prognostic threshold higher and, hence, may help to cure a greater numbers of patients. A successive trial, the European Intergroup Cooperative Ewing’s Sarcoma Study (EICESS 92), conducted by the German/Austrian GPOH and the British UKCCSG,36,37 asked a randomized question that compares VACA versus VAIA in SR patients. Final results of this study are pending. One important result of the CESS-86 analysis is the pattern of prognostic factors. In univariate analyses, tumor volume of 200 mL or more, poor histologic response, VACA chemotherapy (as compared with VAIA), central-axis tumor site, and insufficient margins were significant risk factors. In multivariate analyses, only tumor volume of 200 mL or more, poor response to chemotherapy, and VACA (compared with VAIA) chemotherapy retained their significance as risk factors. Several other potential risk factors were not found to influence outcome: adult age, histologic subtype, and modality of local therapy. Regarding the latter, it must, however, be stressed that surgery with or without radiotherapy was the advised and preferred modality to achieve local control and was applied in 72% of patients. This may have added to the impressively low local failure rates of 11% (local failures, 7%; combined local + metastatic relapses, 4%) in patients globally, 1% in patients with surgery, and merely 8% (local failures, 5%; and local + metastatic relapses, 3%) in patients for whom radiotherapy had to follow surgery because of insufficient margins or poor histologic response. Whereas local relapse was more common following radiotherapy (local relapse, 13%; local + metastatic relapses, 7% ; total relapse, 20%), metastatic relapse tended to occur more often after surgery. Perhaps the temporary presence of ET cells in the peripheral blood circulation during surgical maneuvers38 adds to the risk of metastatic spread, which, again, would support the need for even more intensive upfront systemic therapy. Given the preferred use of surgery for local control, a conclusive comparison between local treatment modalities in CESS 86 is not possible. With treatment according to the "pediatric" treatment protocol, the survival chances of adult ET patients in this study did not differ from younger patients’ cure rates, a finding which was recently confirmed by others.39,40 In contrast to some reports of others and ourselves,41,42 we were not able to demonstrate a difference in outcome between Ewing’s sarcoma patients and those with PNET in CESS 86. While it has been reported that patients with PNET present with metastatic disease more often than patients with classic Ewing’s sarcoma,43 the present report and other authors’ findings44 suggest that outcome is no different when a diagnosis is established at the localized stage of the disease. The CESS-86 treatment regimen was toxic, but major complications were uncommon. Treatment-related casualties occurred in 2% of patients. To date, second cancers have been observed in four patients (1.3% of all 301 patients; 2.2% of 179 ET survivors), and the risk of developing a second cancer after 10 years is 0.017. However, the period at risk for second cancers to occur is continuing, and other treatment-related late effects like cardiac problems may still occur. In recognition of this situation, the GPOH has recently introduced a nationwide Late Effects Surveillance System for the purpose of systematically following-up former pediatric cancer patients.45 In summary, small tumor size of less than 200 mL, good histologic response, and VAIA chemotherapy were positively correlated to EFS in univariate and multivariate analyses of 301 CESS-86 patients with localized ETs. It is noteworthy that sex, age at diagnosis, or histologic subtype (Ewing’s sarcoma v PNET) did not seem to have major impacts on outcome. The IFO-containing VAIA schedule in CESS 86 appeared to be superior to the conventionally dosed cyclophosphamide used in VACA. The results of a successive study that addresses this question in a randomized fashion are pending.
APPENDIX 1: Cooperative Ewing’s Sarcoma Study 86 Study Committee Members Radiotherapy: J.M.V. Burgers, Amsterdam; R. Hawliczek, Vienna; R. Kürfen, Düsseldorf; R. Sauer, Erlangen; M. Wannenmacher, Freiburg. Orthopedic Surgery, Surgery: A. Braun, Heidelberg; E. Müller, Düsseldorf; M. Salzer, Vienna, W. Winkelmann, Düsseldorf/Münster; Statistics : H.J. Jesdinsky, Düsseldorf; P. Kaatsch, Mainz, J. Michaelis, Mainz; Pediatric Oncology: J. Beck, Erlangen; W. Brandeis, Heidelberg; U. Göbel, Düsseldorf; V. Göbel, Heidelberg; G. Henze, Berlin; H. Jürgens, Düsseldorf/Münster; F. Lampert, Gießen; E. Niethammer, Tübingen; G. Prindull, Göttingen; H.J. Riehm, Hannover; J. Ritter, Münster; G. Schellong, Münster; J. Treuner, Stuttgart; P.A. Voûte, Amsterdam; W. Winkler, Hamburg; Medical Oncology: S. Seeber, Leverkusen; W. Schoppe, Düsseldorf.
APPENDIX 2: Participating Institutions and Principal Investigators
APPENDIX 2: (Cont’d)
Supported by Deutsche Krebshilfe grants no. DKH M33/87/Jü1, DKH M43/92/Jü2, and DKH 70-2551 Jü3, and EU BIOMED grants no. BMH1-CT92-1341 and BMH4-983956. We thank G. Braun-Munzinger, S. Jabar, B. Fröhlich, and A. Wagner for data processing, critical reading of the manuscript, and for running the study. We express our thanks to all participating institutions listed below. The results of CESS 86 could only have been achieved by the major efforts in treatment and documentation that were undertaken by the staffs of the participating institutions. This work is dedicated to professor emeritus Günther Schellong, former professor of Pediatric Hematology and Oncology of Münster University, on the occasion of his 75th birthday.
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Copyright © 2001 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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INTRODUCTION
