421 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 Pasquale Rosito, M.D.1 Antonia F. Mancini, M.D.1 Roberto Rondelli, M.D.1 Massimo E. Abate M.D.1 Andrea Pession, M.D.1 Lucia Bedei, M.D.1 Gaetano Bacci, M.D.2 Piero Picci, M.D.2 Mario Mercuri, M.D.2 Pietro Ruggieri, M.D.2 Giampiero Frezza, M.D.3 Mario Campanacci, M.D.2 Guido Paolucci, M.D.1 1 Department of Pediatrics, University of Bologna, Bologna, Italy. 2 Institute of Orthopedics, Rizzoli Hospital, Bologna, Italy. 3 Institute of Radiotherapy, University of Bologna, Bologna, Italy. Supported by the National Research Council (project 96.00632 PF 39). The following investigators participated in this study (by institution): Institute of Orthopedics, Rizzoli Hospital, Bologna: G. Bacci, P. Picci, M. Mercuri, P. Ruggieri, S. Ferrari, N. Baldini, C. Monti, A. Moio, and M. Campanacci; Institute of Radiotherapy, University of Bologna: G. Frezza and E. Barbieri; Department of Pediatrics, University of Bologna: P. Rosito, A. F. Mancini, R. Rondelli, M. E. Abate, A. Pession, L. Bedei, and G. Paolucci; Department of Pediatrics, University of Torino: A. Brach del Prever and E. Madon; Department of Pediatrics, University of Padova: M. Carli; Gaslini Institute, Genova: A. Dallorso; Department of Orthopaedic Oncology, University of Torino: A. Comandone; Department of Pediatrics, University of Firenze: G. Bernini; Department of Pediatrics, University of Trieste: P. Tamaro; Second Department of Pediatrics, Uni© 1999 American Cancer Society BACKGROUND. In 1991, the Italian Association for Pediatric Hematology-Oncology and the National Council of Research (CNR) initiated an Italian Cooperative Study (SE 91-CNR Protocol) with the main objective of improving the overall survival (SUR) and the event free survival (EFS) of children and young adults with localized Ewing sarcoma and primitive neuroectodermal tumors of bone compared with a previous study (IOR/Ew2 Protocol). METHODS. Between November 1991 and November 1997, 165 patients were enrolled in this study, 160 of whom were evaluable. The patients were treated with a multimodal approach characterized by intensified chemotherapy, hyperfractionated and accelerated radiation therapy, and the addition of ifosfamide and etoposide to standard chemotherapy with vincristine, actinomycin-D, doxorubicin, and cyclophosphamide. RESULTS. After a median follow-up of 37 months, 126 of the 160 evaluable patients remained free of disease recurrence. Thirty-one patients developed a disease recurrence (20 with disseminated disease). CONCLUSIONS. The 3-year SUR and EFS rates found in the current study (83.6% and 77.8%, respectively) may be considered satisfactory. Only age at diagnosis #14 years and a good histologic response appeared to affect the outcome of patients with localized Ewing sarcoma positively. These results appear to demonstrate the efficacy of the addition of ifosfamide in induction chemotherapy to four-drug standard combination chemotherapy, as confirmed by the improved outcome in terms of 3-year EFS reported in the SE 91-CNR Protocol compared with the IOR/Ew2 Protocol (77.8% vs. 60.7%). In addition, the better outcome also could be explained by the change in treatment strategy with a trend toward the use of more surgery than radiation therapy compared with the authors’ previous protocol. Cancer 1999;86:421–8. © 1999 American Cancer Society. KEYWORDS: Ewing sarcoma, childhood, adolescence, prognostic factors. E wing sarcoma of bone is the second most common malignant primary bone tumor of childhood. During past years, patient outcome has been improved significantly with the use of multimodal versity of Napoli: A. Fiorillo; Department of Pediatrics, University of Bari: S. Bagnulo; Oncologic Center, Ravenna: A. Tienghi; Division of Pediatrics, S. Giovanni Rotondo Hospital, Foggia: P. Paolucci; First Department of Pediatrics, University of Napoli: M. T. Di Tullio; and Oncologic Center of Verona: R. Balter. Address for reprints: Pasquale Rosito, M.D., Department of Pediatrics, University of Bologna, Via Massarenti 11, 40138 Bologna, Italy. Received July 29, 1998; revisions received December 21, 1998 and March 3, 1999; accepted March 3, 1999. 422 CANCER August 1, 1999 / Volume 86 / Number 3 therapy. In multi-institutional studies, 3–5 year survival rates of 50 – 60% have been reported.1–7 Despite these advances, several investigators have addressed their efforts to identify new strategies of treatment to improve long term survival rates for patients with Ewing sarcoma. The use of new drugs, such as ifosfamide and etoposide, the increase of dose intensity, and the selection of patients at low risk adopting clinical and biologic indicators as prognostic factors have been the main objects of such efforts. With the main objective of improving the overall survival (SUR) and the event free survival (EFS) rates of patients with localized Ewing sarcoma and primitive neuroectodermal tumors (PNET) of bone, a cooperative study (SE 91-National Council of Research [CNR] Protocol) was opened for recruitment of children and young adults patients in Italy. A further objective was to evaluate the prognostic significance of tumor site, patient age at diagnosis, tumor volume, and chemotherapy-induced tumor necrosis (patients who underwent surgery as primary local treatment). This report summarizes the results of this study after 6 years of experience. MATERIALS AND METHODS Eligibility Criteria Patients were eligible if they were age # 30 years at diagnosis, had not been treated previously, and had undergone a diagnostic biopsy of localized Ewing sarcoma within 1 month. Patients with evidence of positive pleural and/or ascitic fluid, positive cytology in the cerebrospinal fluid, or metastatic disease were considered ineligible. Informed consent was obtained from patients age $ 18 years and from parents of younger patients. Patients A total of 165 eligible patients from 15 Italian institutions were registered onto this study from November 1991 to June 1997. Five patients could not be analyzed, because the time for local control had not been reached. The evaluable population consisted of 160 patients: 106 males and 54 females (male to female ratio, 1.96). Their median age at the time of diagnosis was 15.6 years (range, 3–29 years), and 76 patients (47.5%) were age # 14 years at diagnosis. Primary tumor sites were bone segments of the extremities in 97 patients (51 patients; age # 14 years), 47 in proximal segments and 50 in distal segments; the pelvis, including the sacrum in 28 patients (11 patients age # 14 years); the trunk (thoracic and lumbar vertebrae, ribs, scapula, and clavicle) in 30 patients (11 patients age # 14 years); and the skull in 5 patients (3 patients age # 14 years). Response to induction chemotherapy was evaluated in 145 out of 160 patients, whereas in all patients response to local treatment by radiologic studies and clinical evaluation, toxicity, and compliance to protocol were determined. Tumor volume was evaluable in 108 of 160 patients. Ninety-nine of the 115 patients (87%) who underwent initial surgery for local control were evaluable for tumor necrosis. In this cohort of patients, the primary tumor sites treated by surgery initially were bone segments of the extremities in 74 patients, the scapula in 10 patients, the pelvis in 4 patients, the ribs in 10 patients, and the clavicle in 1 patient. Treatment Protocol SE-91 CNR, a multimodal protocol, consisted of multiagent chemotherapy combined with surgery and/or radiation therapy and was characterized by 1) high dose chemotherapy and hyperfractionated and accelerated radiation therapy; 2) addition of ifosfamide and etoposide to standard chemotherapy with vincristine, actinomycin-D, doxorubicin, and cyclophosphamide. During induction and Maintenance Phase 1, ifosfamide (I) was employed alternatively with cyclophosphamide (C) in addition to vincristine (V), doxorubicin (Adriamycin; Adr), and actinomycin-D (A). In Maintenance Phase 2 chemotherapy, ifosfamide was administered in association with etoposide (E) using the doses suggested by Miser et al.8 The SE-91 CNR Protocol treatment schema is outlined in Figure 1. Induction chemotherapy consisted of 3 courses every 3 weeks: two courses of VAdrC alternating with one course of VAI. Thereafter, maintenance chemotherapy was administered as follows: Phase 1 (including Phase 1a and Phase 1b), 5 courses every 3 weeks (3 courses of VAdrC alternating with 2 courses of VAI); Phase 2, 5 courses every 3 weeks (3 courses of E plus I alternating with 2 courses of VAC). Doxorubicin administration ended at the 24th week, for a total dose of 400 mg/m2. Local therapy was performed after 9 weeks of induction therapy. Surgery was considered when a lesion could be resected completely without functional morbidity. Patients who did not achieve a clinical complete response (CCR) with radiation therapy also underwent delayed surgery. Radiation therapy was given to patients with unresectable tumors and to patients with gross residual tumor or positive margins after surgery. A total dose of 6080 centigrays (cGy) in hyperfractionated and accelerated modality was given (160 cGy twice daily); 4480 cGy were given for the entire initial tumor volume Treatment of Localized Ewing Sarcoma/Rosito et al. 423 FIGURE 1. Outline of the Italian Association for Pediatric Hematology-Oncology SE 91 National Council of Research Protocol. Arrows indicate evaluations. A: actinomycin-D intravenous (IV) push 1.5 mg/m2 during induction and 1.25 mg/m2 during maintenance (maximum, 2 mg); (A): do not administrate actinomycin-D if important side effects of radiotherapy occur; Adr: doxorubicin (Adriamycin) 40 mg/m2 IV over 4 hours for 2 days; (Adr): do not administrate doxorubicin if the patient receives . 2000 centigrays (cGy) to any portion of the heart; C: cyclophosphamide 1200 mg/m2 IV over 30 minutes with Mesna; E: etoposide (VP-16) 100 mg/m2 IV over 1 hour for 5 days with Mesna; I: ifosfamide 1800 mg/m2 IV over 1 hour for 5 days; RT: radiation therapy; V: vincristine, 5 mg/m2 (maximum, 2 mg) IV push Days 1 and 8 of each cycle of induction. with a 5-cm margin with a 1600 cGy boost and a 2-cm margin around the initial bony disease. For patients with marginal surgery, a total dose of 4480 cGy was given. Tumor volume based on computed tomography scan was calculated according to the criteria of Gobel et al.9 The histopathologic grading of necrosis was determined according to the criteria of Picci et al.:10,11 Grade 1, macroscopic evidence of viable tumor; Grade 2, microscopic evidence of viable tumor; Grade 3, no evidence of viable tumor. The median treatment duration was 36 weeks. Response to therapy was evaluated after induction, after local therapy, and at the end of treatment according to the following criteria: A CCR was defined as a .90% decrease in the sum of the products of the maximum perpendicular greatest dimensions of all measurable soft tissue lesions and improvement in bone scan or bony architecture. A partial response (PR) was defined as a decrease .50% but ,90% in all measurable soft tissue lesions, whereas no response (NR) was defined as a decrease ,50% of the considered lesions. Statistical Analysis Patient data were collected using patient-oriented forms compiled by a physician in charge at each center. All information was stored, controlled, and analyzed by using VENUS, a facility-integrated software system running on an IBM mainframe computer at North-East Italian Interuniversity Computing Center (CINECA, Bologna, Italy). Follow-up was updated as of November 1997; therefore, and the potential follow-up ranged from a minimum of 5 months to a maximum of 69 months from diagnosis (median, 37 months). Survival (SUR) and event free survival (EFS) curves were estimated according to the method of Kaplan and Meier.12 The 95% confidence limits (CL) are reported for each SUR and EFS percentage estimate. For both curves, the starting point was the date of diagnosis. For EFS, no response to local treatment, local recurrence or distant relapse, and death due to any cause, whichever came first, were counted as failures. Death from any cause was considered a failure in SUR. For both analyses, time was censored at last follow-up date if no failure was observed. The log rank test was used to compare the outcomes of different groups.13 RESULTS After induction chemotherapy, 5 patients had a CCR, 127 patients had a PR, and 13 patients experienced an NR. Thus, 132 out of 160 evaluable patients (91%) achieved a positive response after 3 courses of induction chemotherapy. In 84 of 160 cases (53%), local treatment modality was represented by surgery alone (radical surgical resection with limb amputation in 6 patients; resection fibula in 3 patients; and resection calcaneus in 3 patients). Fifty-two patients (62%) were age , 14 years, whereas 32 patients (38%) were ages 424 CANCER August 1, 1999 / Volume 86 / Number 3 TABLE 1 Frequency of Local Recurrence, Metastases, and Death as First Evidence of Failure according to Local Treatment Local treatment First evidence of failure S (%) S 1 RT (%) RT (%) Total (%) No. of patients Local recurrence only Local recurrence and metastases Metastases only Death (no local recurrence or metastases) Total failures 84 2 (2) 4 (5) 9 (11) 31 1 (3) 1 (3) 2 (6) 45a 2 (4) 1 (2) 9 (20) 160 5 (3) 6 (4) 20 (13) 1 (1) 16 (19) — 4 (13) 2 (4) 14 (31) 3 (2) 34 (21) S: surgery; S 1 RT: surgery plus radiotherapy; RT: radiotherapy. Numbers in parentheses indicate the percentage of patients. a Ten patients underwent delayed surgery after RT. 15–30 years. Radiation therapy as the primary local treatment was used in 45 patients (28%). Thirty-five patients received radiation therapy alone, whereas 10 patients underwent delayed surgical resection. In such cases, resection followed radiation therapy either immediately or at completion of chemotherapy. Thirty-one patients (19%) received radiation therapy after marginal surgery. Regarding patients age , 14 years, 52 of 76 (68%) had surgery alone (with limb amputation in 4 patients, fibula in 1 patient, and calcaneus in 3 patients), 12 (16%) had radiation therapy as primary local treatment (2 patients underwent delayed surgical resection), and 12 (16%) received radiation therapy after surgery. Regarding the response rate after local treatment, all patients achieved a complete response (CR) after surgery or after surgery with radiation therapy, whereas only 32 of 45 patients (71%) achieved a CR after radiation therapy alone; 12 of 45 patients (27%) had a PR (10 underwent delayed surgery, and 1 died on therapy), and 1 patient had NR and died after local progression of disease. The outcomes of the 160 evaluable patients are shown in Figure 2 and are listed in Table 1. The overall SUR (CL) at 3–5 years was 83.6% (77–90%), whereas the EFS rates at 3 years and 5 years were 77.8% (70 – 85%) and 69.4% (59 – 80%), respectively. Thirty-one of 160 patients (19%; 9 patients age , 14 years) relapsed: 20 patients (11 died) with metastatic disease, 5 patients (1 died) had local recurrence, and 6 patients (5 died) had local recurrence with metastases. The median time to relapse was 15 months, ranging from 5 months to 63 months. Twenty patients died: 17 after relapse, 1 with a primary tumor in the pelvis who died after local progression of disease, 1 with a pelvic primary who died after radiation therapy because of typhlitis, and 1 who died on maintenance chemotherapy because of sepsis secondary to myelosuppression. No significant difference in the 3-year EFS rate was observed between the various local treatments. The group that underwent surgery with radiation therapy showed better results (87.1%; CL, 73–100) compared with the group that underwent surgery alone (76.8%; CL, 66 – 87) and the group that underwent radiation therapy as the primary local treatment (74.5%; CL, 61– 87). The 3-year EFS rate according to primary tumor site showed no statistically significant differences (extremities: 77.3%; CL, 67– 87; pelvis: 74.5%; CL, 58 –91; other sites: 81.1%; CL, 66 –96). Furthermore, no statistically significant difference was observed in terms of the 3-year EFS rate between proximal and distal extremities (proximal: 70.6%; CL, 57– 84; distal: 85.3%; CL, 74 –96). The 3-year EFS rate according to site of primary tumor and local treatment (Table 2) showed no statistically significant difference between alternative local treatments among all different sites. The 3-year EFS rate according to age at diagnosis (Fig. 3) showed a better outcome for patients age , 14 years (85.1%; CL, 76 –94) compared with patients age . 14 years (71.2%; CL, 60 – 82; P 5 0.008). The 3-year EFS rate by tumor volume did not show differences between patients with a tumor volume at diagnosis ,100 mL (83.4%; CL, 72–95) and patients with a tumor volume .100 mL (69.8%; CL, 56 – 84; P 5 0.18). No significant difference was detected in terms of EFS by considering a tumor volume cut-off at 200 mL. In only 99 patients out of 115 who underwent surgery after preoperative chemotherapy was it possible to compare EFS according to chemotherapy-induced necrosis. For this group of patients, the 3-year EFS rate (Fig. 4) showed a significant difference in Grade 1 compared with Grades 2 and 3: 49.0% (CL, 29 – 69) and 97.8% (CL, 94 –100), respectively (P 5 0.0001). One hundred patients were evaluable for treatment toxicity. The most common type of severe toxicity was Grade 4 neutropenia according to the World Health Organization classification.14 Considering the different phases of the protocol, the assessment of severe neutropenia varied from 17% to 26%, which occurred mainly during maintenance chemotherapy. The median duration of neutropenia was 6 days, ranging from 3 days to 9 days. Eleven patients experienced Grade 4 thrombocytopenia (3 patients during induction and 8 patients during maintenance chemotherapy), and 2 patients experienced Grade 4 anemia dur- Treatment of Localized Ewing Sarcoma/Rosito et al. 425 TABLE 2 Patient Distribution and 3-Years Event Free Survival according to Site of Primary Tumor and Local Treatment Local treatment S 1 RT S Site of primary tumor No. patients Proximal extremities Humerus Femur Distal extremities Tibia Fibula Tarsus Radius Metatarsus Metacarpus Pelvis Sacrum Ilium pubis ischium Other sites Rib Scapula Vertebra Skull Clavicle Total 35 6 29 35 16 9 4 2 2 2 3 0 3 11 7 2 0 1 1 84 % EFS (CL) 69.3 (53–85) 81.9 (67–96) 100b 81.8 (59–100) No. patients 2 1 1 9 0 6 1 1 1 0 3 2 1 17 6 8 0 3 0 31 % EFS (CL) 100a 88.9 (68–100) 100c 75.5 (54–96) RT No. patients 10 7 3 6 4 1 1 0 0 0 22 7 15 7 1 0 5 1 0 45d % EFS (CL) 70.0 (42–98) 100 68.2 (49–88) 85.7 (60–100) Total no. of patients 47 14 33 50 20 16 6 3 3 2 28 9 19 35 14 10 5 5 1 160 S: surgery; RT: radiotherapy; EFS: event free survival; 95% CL: 95% confidence limits. a Two patients were event free at 131 months and 361 months. b Three patients were event free at 48: months, 641 months, and 731 months. c Three patients were event free at 531 months, 631 months, and 781 months. d Ten patients underwent delayed surgery after RT (1 patient, femur; 2 patients, tibia; 3 patients, pelvis; 2 patients, vertebrae; 1 patient, skull; 1 patient, rib). ing maintenance. Among those with nonhematologic toxicity, only 1 patient experienced liver toxicity (Grade 4 elevation of alanine aminotransferase) during induction. Two patients experienced Grade 4 stomatitis: one during induction and the other during maintenance chemotherapy. One patient experienced a fatal sepsis with bone marrow aplasia during maintenance chemotherapy. The major complications of surgery, alone or combined with radiation therapy, were evaluated in 94 of 115 patients. Delay of wound healing was been observed in 6 patients who underwent surgery of the fibula (3 patients), tibia (2 patients), and femur (1 patient). This last patient required an amputation (with hip disarticulation) because of persistent infections after resection of the femur and reconstruction. These surgical complications delayed restarting chemotherapy for a mean of 26 days (range, 10 – 60 days) without affecting the outcome of disease (only 1 patient experienced a relapsed). Further complications after surgery were nerve paralysis (7 patients) and leg length discrepancy (9 patients; mean age, 14 years). The major local treatment complication after radiation therapy alone (evaluable in 29 of 45 patients) resulted in death in one patient during pelvic irradiation due to typhlitis. Other complications were transient esophageal ulcers after radiation therapy to the eighth dorsal vertebra in 1 patient, cutaneus ulcer of the leg after irradiation to the fibula in 1 patient, and radiation dermatitis in 6 patients. There was no delay in restarting chemotherapy in these latter patients. At present, long term sequelae resulted in the anchylosis (elbow and hip) in 2 patients after irradiation of the humerus and pelvis, and amenorrhea in 3 patients persisting for 8 months, 1 year, and 5 years after irradiation to the pelvis. The incidence of long term sequelae may be underestimated because of short follow-up. DISCUSSION Despite the short follow-up in the current study, the 3-year SUR and EFS rates can be considered satisfactory, revealing a better outcome compared with our previous IOR/Ew2 protocol.15 In this study, the overall 426 CANCER August 1, 1999 / Volume 86 / Number 3 FIGURE 2. The Italian Association for Pediatric Hematology-Oncology SE 91 National Council of Research Protocol. Overall survival (SUR) and event free survival (EFS) are indicated. Numbers in parentheses indicate the 95% confidence limits (CL). FIGURE 3. The Italian Association for Pediatric Hematology-Oncology SE 91 National Council of Research Protocol: Event free survival by patient age at diagnosis. Numbers in parentheses indicate the 95% confidence limits (CL). disease free survival (DFS) rate after 3 years was 60.7%, and the DFS rate for patients with a primary tumor in the axial bones was 48.6%. In the IOR/Ew2 study, ifosfamide and etoposide (4 cycles) were used only during maintenance therapy alternating with vincristine plus actinomicyn-D (4 cycles) and vincristine plus doxorubicin (4 cycles). The results of our study are not different from those of an earlier CCG/POG study16 of patients with nonmetastatic Ewing sarcoma and PNET. In that study, randomized treatment with ifosfamide, etoposide, and VAdCA resulted in an EFS rate of 65% at 4 years that was significantly higher compared with the VAdCA alone arm (EFS, 51%). Conversely, no benefit from ifosfamide instead of cyclophosphamide (IVAIVAd regimen instead of VAC-Vad) was demonstrated in the second French Society of Pediatric Oncology FIGURE 4. The Italian Association for Pediatric Hematology-Oncology SE 91 National Council of Research Protocol: Event free survival by grading of chemotherapy-induced necrosis is shown. Numbers in parentheses indicate the 95% confidence limits (CL). (SFOP) study in which the 5-year relapse free survival (RFS) rates were 52% and 51% respectively.17 In the current study, 78% of patients underwent surgery, 53% without radiation therapy. Of more concern was the restricted indication for radiation therapy, especially in pediatric patients, in whom surgery alone was performed in 68%. Surgery alone did not alter overall patient outcome. The 3-year EFS rates were similar for the different local treatments: surgery, 76.8%; surgery followed by radiation therapy, 87.1%; radiation therapy, 74.5%. The main cause of treatment failure was the development of distant metastases (16% of patients). The frequency of distant metastases was 15% after surgery, 22% after radiation therapy, and 10% after surgery with radiation therapy. Local recurrences were observed in 7% of patients; the frequency of recurrence was similar after surgery (7%), after radiation therapy (7%) and after surgery with radiation therapy (6%) (Table 1). However, the fact that most patients underwent surgery and radiation therapy at the same specialized center may have contributed to the good results. In our previous protocol,15 53.6% of patients underwent surgery with or without radiation therapy, 24.2% underwent surgery alone, and 46.4% underwent radiation therapy alone. In this study, the DFS rate at 3 years was significantly different for patients who underwent surgery with or without radiation therapy (DFS, 66.6%) compared with patients who underwent radiation therapy alone (DFS, 42.3%). Patients who underwent radiation therapy alone had a high incidence of local relapse (15.3% vs. 1.6%). In an SFOP study,17 59% of patients underwent surgery alone or with radiation therapy. The incidence Treatment of Localized Ewing Sarcoma/Rosito et al. of metastasis was not different in those treated with radiation therapy alone, but the incidence of local relapse was much greater (30% vs. 10%). In the CESS 86 study,18 75% of patients underwent surgery (53% with radiation therapy), whereas 25% of patients underwent radiation therapy alone. The overall frequency of relapse was 31% and was not influenced by the type of local treatment. The frequency of distant metastases was greater after surgery alone (26% of patients) compared with radiation therapy alone (16% of patients), and the frequency of local failure was greater after irradiation (14% of patients) than after surgery. Taking the prognostic factors into consideration, in the current study, we did not observe any differences in EFS according to site of primary tumor. The 3-year EFS rate by tumor site did not show a statistically significant difference between pelvis versus extremities versus other sites. The good results for patients with tumors at a pelvic site were remarkable: Of 28 patients, 20 (71%) remained disease free at a median follow-up of 42 months. In our previous protocol,15 we did not find any significant difference in terms of DFS between patients with primary tumor localized to extremities and patients with primary tumors that were localized to the axial skeleton. Also, in French studies,17–20 tumor site was not a prognostic factor. In our study, the EFS rate for patients age , 15 years was significantly higher (P 5 0.008) than that for young adults (Fig. 3). The GPHO/CESS and UKCCSG/ MRC studies19 demonstrated better results for patients age # 15 years compared with patients age . 15 years (RFS at 5 years: 59.9% vs. 48.4%), with confirmation of the prognostic significance of age in a multivariate analysis. The Delepine study20 demonstrated a significantly positive prognostic role in univariate analysis for patients age # 18 years compared with patients age . 18 years, but this finding was not confirmed by a multivariate analysis. In the current study, tumor volume was not a significant prognostic factor (volume #100 mL vs. .100 mL; volume #200 mL vs. .200 mL). In a German study (CESS 81), the DFS rate at 3 years was significantly different for patients who had a tumor volume #100 mL (DFS, 80%) compared with patients who had a tumor volume .100 mL (DFS, 31%).3 In a successive study (CESS 86), intensification of chemotherapy with the addition of ifosfamide and etoposide eliminated these difference in DFS rate.21 Also, in the Delepine study,20 the differences in EFS rate according to tumor volume was not demonstrated. In our study, we found a significant difference in terms of EFS in patients who had Grade 1 necrosis 427 after chemotherapy compared with patients who had Grade 2 and Grade 3 necrosis (P 5 0.0001). No difference was found between patients with Grade 2 necrosis and those with Grade 3 necrosis. A study by Picci et al.11 demonstrated the prognostic value of tumor necrosis in Ewing sarcoma of the extremities (5-year DFS rates: 34% with Grade 1 necrosis; 68% with Grade 2; 95% with Grade 3). In the SFOP study,17 a histologic good response (with ,50% viable residual cells) was observed in 71% of patients, and the RFS rate was 81%. All poor responders relapsed. In the European Intergroup Cooperative Ewing’s Sarcoma study,22 the preliminary results concerning the histologic response to induction chemotherapy showed a good response, with ,10% viable tumor, in 70% of patients. It is necessary to standardize the criteria for defining patients as good or poor responders. In conclusion, we could argue that the association of the two chemotherapeutic agents, ifosfamide and etoposide, used in addition to the standard chemotherapy with vincristine, actinomycin-D, doxorubicin, and cyclophosphamide, can improve the prognosis of patients with Ewing sarcoma. 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