Evaluation of Outcome and Prognostic Factors in Extraosseous Ewing Sarcoma

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1 Pediatr Blood Cancer 2014;61: Evaluation of Outcome and Prognostic Factors in Extraosseous Ewing Sarcoma Bivas Biswas, MD, 1 N.K. Shukla, MD, 2 S.V.S. Deo, MD, 2 Sandeep Agarwala, MD, 3 D.N. Sharma, MD, 4 Sreenivas Vishnubhatla, PhD, 5 and Sameer Bakhshi, MD 1 * Background. Data on extraosseous Ewing sarcoma (EES) with uniform chemotherapy protocol are minimal. We aimed to examine this aspect in our patients, identify prognostic factors and compare the same with osseous Ewing sarcoma. Procedures. A single institutional data review of patients with EES treated between June 2003 and November 2011 with uniform chemotherapy and evaluated on intent-to-treat analysis was done. Results. Of 374 patients with Ewing sarcoma, 60 (16%) were EES with median age 16 years; 20 (33%) had metastases. After median follow-up of 25 months (range: ), 5-year event free survival (EFS), OS, and local-control-rate were %, %, and %, respectively for entire EES cohort. In multivariate analysis, hemoglobin 10 g/dl (P ¼ 0.03), and white blood cell count (WBC) > /L (P ¼ 0.009) predicted inferior EFS for the entire EES cohort. Low hemoglobin (P ¼ 0.05) and high LDH (P ¼ 0.01) predicted inferior OS for the entire EES cohort on multivariate analysis. As compared to the cohort of skeletal primary (n ¼ 314), higher proportion of patients underwent surgery in the cohort of EES (P ¼ 0.003); EFS (P ¼ 0.004) and OS (P ¼ 0.08) were superior for patients with EES than patients with skeletal Ewing sarcoma. Conclusion. These data of EES suggests that low hemoglobin and high WBC count adversely affect EFS. Overall outcome was significantly better for EES than skeletal primary tumors. Pediatr Blood Cancer 2014;61: # 2014 Wiley Periodicals, Inc. Key words: chemotherapy; outcome; primitive neuroectodermal tumor; prognostic factors; soft tissue INTRODUCTION Ewing sarcoma can arise from bone or soft tissue. Extraosseous Ewing sarcoma (EES) is rare and incidence varies from 6% to 47% of all Ewing sarcoma [1 5]. Historically they had been included in rhabdomyosarcoma protocols [6]. As the incidence is low, chemotherapy protocol has been extrapolated from that of skeletal Ewing sarcoma. There are few studies that evaluated prognostic factors in EES, and the majority of the studies have included patients treated over long-span of time with small sample size, heterogeneous chemotherapy protocol, lack of prognostication and conflicting results of outcome [4,6 24]. Here, we have analyzed the baseline clinicopathological characteristics, outcome and prognostic factors of 60 cases of EES treated at our institute over 8 years with uniform chemotherapy protocol, and compared the same with skeletal Ewing sarcoma. MATERIALS AND METHODS Patients This study involves data review of all patients with a proven diagnosis of Ewing sarcoma that were treated in our department from June 2003 to November Data of patients treated between January 2011 and November 2011 was collected prospectively. Specifically, Ewing sarcoma of soft tissue origin (without any cortical bone involvement) was selected for this analysis. Ewing sarcoma arising from brain was excluded from this analysis. Patient s baseline clinic-pathological features, metastatic work up, treatment modality, and outcome data were collected. Ethical clearance was taken from institutional ethical and review committee. Informed consent was taken from patient or guardian (in case of minor) in patients enrolled prospectively. Diagnostic Work Up All patients underwent biopsy (trucut or incisional) of primary lesion with immunohistochemistry (IHC). Diagnosis of Ewing sarcoma required presence of small blue round cell tumor and C 2014 Wiley Periodicals, Inc. DOI /pbc Published online 17 August 2014 in Wiley Online Library (wileyonlinelibrary.com). positivity for CD99 (MIC 2), and/or synaptophysin or chromogranin. Other round cell tumors were ruled out by performing IHC with leucocyte common antigen, desmin, and myogenin. Evaluation for translocation [t(11;22)(q24;q )] was not performed in this cohort as it was not available routinely in our institute. Diagnosis of Ewing sarcoma was made after review of pathology slides with IHC panel. Extent of lesion was determined by computed tomography (CT) or magnetic resonance imaging of the local site. All patients underwent metastatic work up including bone scan, CT chest, and bone marrow biopsy. Treatment and Response Evaluation Treatment protocol consisted of three phases: neoadjuvant chemotherapy for 9 12 weeks, local therapy, which was then followed with adjuvant chemotherapy. Chemotherapy was given alternating 3-weekly cycle of VAC (vincristine at 1.4 mg/m 2, 1 Department of Medical Oncology, Dr. B. R. A. Institute Rotary Cancer 2 Department of Surgical Oncology, Dr. B. R. A. Institute Rotary Cancer 3 Department of Pediatric Surgery, Dr. B. R. A. Institute Rotary Cancer 4 Department of Radiotherapy, Dr. B. R. A. Institute Rotary Cancer 5 Department of Biostatistics, Dr. B. R. A. Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, India Conflict of interest: Nothing to declare. Additional supporting information may be found in the online version of this article at the publisher s web-site. Presentations: This was presented as an oral paper in 45th Annual SIOP Meeting at Hong Kong in Sept Correspondence to: Sameer Bakhshi, Department of Medical Oncology, Dr. B. R. Ambedkar Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi , India. sambakh@hotmail.com Received 25 February 2014; Accepted 21 April 2014

2 1926 Biswas et al. max ¼ 2 mg; doxorubicin at 75 mg/m 2 or actinomycin D at 1.25 mg/m 2 and cyclophosphamide at 1.2 gm/m 2 with MESNA) with IE (ifosfamide at 9 gm/m 2 with MESNA and etoposide at 500 mg/m 2 ) [25] for total 48 weeks. Local therapy was radiotherapy or surgery with or without post-operative radiotherapy. The choice of local therapy was made on an individual basis depending on primary tumor site and resectability of tumor after neoadjuvant chemotherapy with care to avoid long term morbidity and disfigurement. Surgery was preferred wherever wide local excision was possible with clear surgical margin and without a mutilating surgery. The decision for surgical resection was taken by the treating surgeon. In general, patients with pathological CR were not subjected to adjuvant radiotherapy although decisions for adjuvant radiotherapy were taken on an individual case to case basis after discussion in the multidisciplinary clinic. After local therapy all patients were subjected to receive adjuvant chemotherapy up to planned total 48 weeks. Disease response was assessed by radiology after neoadjuvant chemotherapy and after completion of local therapy. Complete remission (CR), partial response (PR), stable disease (SD), and progressive disease (PD) were defined as per RECIST criteria [26] wherever applicable. All patients without metastases underwent local therapy if they were in CR/PR/SD post neoadjuvant chemotherapy while all patients with metastases received local therapy if they were in CR/PR at both primary and/or site(s) of metastases. Statistical Analysis Descriptive statistics were used for demographics and clinical characteristics. Chi-square test was used to detect association between categorical variables. Student t-test test were applied to compare continuous variables between groups. Survival was estimated by the Kaplan Meier method and compared using logrank test. Data were censored on June 30, Univariate Cox proportional hazard model followed by stepwise multivariate Cox regression analysis was done to identify the predictors of outcome. Factors with significance (P value) of up to 0.1 in univariate analysis were taken into multivariate analysis. Event free survival (EFS) was calculated from date of diagnosis to date of disease relapse or progression, death from any cause. Overall survival (OS) was calculated from date of diagnosis to date of death from any cause. Combined local and distant site failure was taken as local failure for analysis of local control rate (LCR). Patients who were lost to follow-up (LFU) or had treatment abandonment were also included for EFS and OS analysis and outcome in these patients was confirmed by telephonic contact. Treatment abandonment was included for survival analysis in the present study as it has been proposed that non-compliant and treatment abandonment patients should be included in survival analysis for studies from developing nations to provide a true picture of outcome from these countries [27]. STATA/SE 9.0 (StataCorp LP, College Station, TX) was used for statistical analysis. RESULTS Clinicopathological Profile The clinical findings are summarized in Supplemental Table SI. During the study period, 403 patients with Ewing sarcoma were registered at our centre, and as per our intention-to-treat analysis 374 patients were evaluable for survival analysis. Of the 403 patients with Ewing sarcoma, 65 (16%) had EES. Five patients did not take therapy and so here we have analyzed baseline characteristics and survival of 60/374 (16%) patients. Median age was 16 years (range: ) with median symptom duration was 3.5 months (range: months). Median tumor diameter was 9.8 cm (range: 2 24 cm) and tumor size >8 cm was observed in 28 (53%) patients. Most common primary regions of disease included abdomen in 16 (27%), extremity in 14 (23%), head and neck in 11 (18%), and thorax in 12 (11%) patients. Diagnostic work up revealed metastases in 20 (33%) patients. Patients with EES had shorter symptom duration (P ¼ 0.01) and higher prevalence in the axial region (P ¼ 0.001) as compared to skeletal primary; further, higher proportion of patients with EES underwent surgical resection (P ¼ 0.003) as compared to skeletal primary (Table I). Treatment All 60 patients were subjected to neoadjuvant chemotherapy and a median of six cycles (range: 4 7) of neoadjuvant chemotherapy was administered to all patients. Nine patients discontinued neoadjuvant chemotherapy (PR-5, SD-1 and not evaluated-3); six patients had PD while receiving neoadjuvant chemotherapy. Thus, 45 patients (75%) received local therapy: surgery was done in 30 (67%) patients of which 18 received adjuvant radiotherapy; definitive radiotherapy alone was administered in 15 (33%) patients. Out of the 30 patients who underwent surgical resection, R0 resection was achieved in 26 patients. Radiotherapy was given at a median dose of 50 Gy (range: Gy) in Gy/day, 5-days a week and over 5 6 weeks. Seven patients were LFU (PR-3, CR-2, TABLE I. Comparison of Baseline Patients and Tumor Characteristics Between Skeletal and EES Variables Skeletal (n ¼ 314) Soft tissue (n ¼ 60) P Mean age (years) Sex Male 228 (73) 42 (70) Female 86 (27) 18 (30) 0.68 Systemic symptoms No 216 (69) 48 (80) Yes 98 (31) 12 (20) 0.08 Mean symptom duration (months) Mean tumor diameter (cm) Tumor site Axial 170 (54) 46 (77) Appendicular 144 (46) 14 (23) Mean hemoglobin (g/dl) Mean WBC (/ml) 9,613 9, Mean albumin (g/dl) Mean SAP (IU/L) Mean LDH (U/L) Metastatic No 184 (59) 40 (67) Yes 130 (41) 20 (33) 0.24 Local treatment type Surgery 48 (23) 12 (26) Surgery þ radiotherapy 41 (20) 18 (41) Radiotherapy 119 (57) 15 (33) LDH, lactate dehydrogenase; SAP, serum alkaline phosphatase; WBC, white blood cell count.

3 Extraosseous Ewing sarcoma 1927 not evaluable-2) during or after receiving local treatment. Thus, remaining 38 patients received adjuvant chemotherapy (Fig. 1). Response to Neoadjuvant Chemotherapy and Local Therapy Out of 60 patients, re-evaluation after neoadjuvant chemotherapy was performed in 57 patients (discontinued therapy-3) and response was as follows: CR-14, PR-34, SD-3, and PD-6 with overall response rate (ORR) of 84% (n ¼ 48/57). Of the 45 patients who underwent either surgery and/or radiotherapy, post local therapy response was CR-31, PR-12, and not evaluated-2 with ORR of 100% (n ¼ 43/43). Treatment Failure and Outcome Treatment failure was observed in 16 (27%) patients: recurrences after achieving CR in six patients and PD during or post therapy in 10 patients (post neoadjuvant chemotherapy PD-6, and during/post adjuvant chemotherapy PD 4). Site of failure was local site alone in eight patients, distant metastasis in five patients, and combined failure in three patients. Median time to local failure was 12.1 months (range: ). Seventeen (28%) patients died during or after treatment (PD 7, toxic deaths 4, and six patients died at home, the cause of which could not be ascertained). After a median follow-up of 25 months (range: ), 5-year EFS, OS and LCR were %, %, and %, respectively for the entire cohort of EES. The 5-year LCR in surgery group, surgery plus radiotherapy group, and definitive radiotherapy group was 43.6%, 87.5%, and 77.9%, respectively. Comparison of Outcome of EES With Skeletal Ewing Sarcoma EES patients had significantly higher EFS (5-year estimate of 48.5% vs. 22.4%, P ¼ 0.004) and a trend towards higher OS (61.5% vs. 36%, P ¼ 0.08) when compared with skeletal Ewing sarcoma cohort (Figs. 2A and B). The findings were similar for EFS (5-year EFS of 62% vs. 31.7%, P ¼ 0.01), but not for OS (5-year OS of 68.3% vs. 48.2%, P ¼ 0.29) when localized cohort (extraosseous vs. skeletal) was compared (Figs. 2C and D). EES With Metastasis Twenty (33%) patients had metastatic disease at baseline. All patients received neoadjuvant chemotherapy and achieved ORR of 75% (CR-3, PR-12), while only 11 patients received local therapy (radiotherapy only 6, Surgery with or without radiotherapy 5). Fig. 1. Flow diagram showing treatment and outcome of study patients. CR, complete response; LFU, lost to follow up; N, number; PD, progressive disease; PR, partial response.

4 1928 Biswas et al. Fig. 2. Five-year EFS was 48.5% for EES (n ¼ 60) versus 22.4% for skeletal primary (n ¼ 314) (A). Five year OS was 61.5% for EES (n ¼ 60) versus 36% for skeletal primary (n ¼ 314) (B). Five-year EFS was 62% for EES (n ¼ 40) versus 31.7% for skeletal primary (localized cohort, n ¼ 184) (C). Five-year OS was 68.3% for EES (localized cohort, n ¼ 40) versus 48.2% for skeletal primary (localized cohort, n ¼ 184) (D). There was no difference in baseline clinical and tumor-related factors between localized and metastatic disease. After median follow up 16.6 months (range: ), the 3-year EFS, OS and LCR rates were %, %, and %, respectively. Prognostic Factors Univariate analysis. Univariate analysis showed primary of spine, abdomen and pelvis (P ¼ 0.02), hemoglobin 10 g/dl (P ¼ 0.004), white blood cell (WBC) count > /L (P ¼ 0.001), lactate dehydrogenase (LDH) >2 N U/L (P ¼ 0.002), and metastases (P ¼ 0.008) adversely predicted EFS (Table II). Primary of spine, abdomen and pelvis (P ¼ 0.04), tumor size >8 cm (P ¼ 0.02), hemoglobin 10 g/dl (P ¼ 0.003), WBC count > /L (P ¼ 0.04), and LDH >2 NU/L(P¼0.03) were found to have adverse outcome for OS. (Table II). Age 15 years (P ¼ 0.09), WBC count > /L (P ¼ 0.07), and LDH >2 N U/L had a trend towards inferior LCR (Supplemental Table SII). Multivariate analysis. Multivariate analysis showed hemoglobin 10 g/dl (P ¼ 0.03) and WBC count > /L (P ¼ 0.009) to predict inferior EFS (Table III) (Figs. 3A and B). For OS, hemoglobin 10 g/dl (P ¼ 0.006) and LDH >2 N U/L (P ¼ 0.03) independently predicted inferior outcome (Table III) (Figs. 3C and D). DISCUSSION EES constituted 16% of all Ewing sarcoma. This is consistent with previous published literature wherein EES comprised 6 47% of total Ewing sarcoma cohort [1 5]. In the above cohort, most common site of EES was abdomen which is also in consistence with previous published data [6,9,11,19]. Pelvic location of EES was 19.8% in report by Applebaum et al. [28] as compared to only 7% in our cohort, whereas axial location was 72.9% in previous report which is similar to our observation of 77%. One-third of our patients had metastatic disease; this may have been due to referral bias. Our analysis revealed low hemoglobin and high WBC count to adversely affect EFS, whereas low hemoglobin and raised LDH adversely affected OS on multivariate analysis. High serum LDH may reflect a high tumor burden and has been shown to be a poor prognostic factor in previous reports of EES [9,11]. However, the observation of low hemoglobin and high WBC count to affect outcome was unique. High WBC count may reflect systemic nature of the disease with possible micrometastatic pathology without over metastasis, or may be a paraneoplastic phenomenon. Patients of EES presenting with low hemoglobin had higher number of patients with systemic symptoms (42% vs. 10%, P ¼ 0.01), higher axial primary (585% vs. 29%, P ¼ 0.06), lower serum albumin level (3.7 gm% vs. 4.5 gm%, P ¼ ); this may explain the poorer prognosis in this subgroup of patients with EES.

5 Extraosseous Ewing sarcoma 1929 TABLE II. Univariate Analysis for Event Free Survival (EFS) and Overall Survival (OS) in Entire EES Cohort (n ¼ 60) EFS OS Variables Category 5-year EFS estimate (%) HR P 5-year OS estimate (%) HR P Age (years) 15 (n ¼ 29) >15 (n ¼ 31) Sex Male (n ¼ 42) Female (n ¼ 18) Systemic symptoms No (n ¼ 48) Yes (n ¼ 12) Symptom duration 4 months (n ¼ 38) >4 months (n ¼ 22) Tumor site HN, chest, limb (n ¼ 37) Spine & pelvis, abdomen (n ¼ 23) Tumor location Axial (n ¼ 46) Appendicular (n ¼ 14) Tumor diameter 8cm (n¼ 25) >8cm (n¼ 28) Hemoglobin (g/dl) 10 (n ¼ 12) >10 (n ¼ 41) WBC (/ml) 11,000 (n ¼ 36) >11,000 (n ¼ 16) LDH (U/L) 2 N(n¼25) >2 N(n¼18) Albumin (g/dl) 3.4 (n ¼ 6) >3.4 (n ¼ 40) Metastasis a No (n ¼ 40) Yes (n ¼ 20) Local treatment Sx þ RT (n ¼ 30) RT only (n ¼ 15) HR, hazard ratio; LDH, lactate dehydrogenase; RT, radiotherapy; Sx, surgery; WBC, white blood cell. a 3-year estimated value. There was a higher proportion of patients who underwent surgical resection as primary local therapy (77% vs. 43%, P ¼ 0.003) in comparison with the patients of skeletal Ewing sarcoma. Post neoadjuvant chemotherapy response was slightly higher in EES as compared to skeletal primary (ORR of 84.5% vs. 73%, P ¼ 0.07). This is similar to the observation of Applebaum et al. [28] who also observed the same finding when analyzing EES from the SEER data. It is difficult to explain this finding because there was no difference in baseline tumor size between the two groups. EES had significantly higher EFS and better OS when compared with that of skeletal primary in our cohort. This was in contrast to the observation in various published studies [10,16,18,19,21,29], where there was no difference in outcome between skeletal Ewing sarcoma and EES. Two recently published studies reported improved survival of EES in comparison to TABLE III. Multivariate Analysis Variables Category Entire group Entire cohort (n ¼ 60) After excluding patients whose status unknown for OS (n ¼ 38) HR P HR P A. Event free survival Hb (g/dl) 10 1 > WBC count (/ml) 11,000 1 >11, C. Overall survival (OS) Hb (g/dl) > LDH (U/L) 2 N 1 1 >2 N Hb, hemoglobin; HR, hazard ratio; LDH, lactate dehydrogenase; WBC, white blood cell.

6 1930 Biswas et al. Fig. 3. Five-year EFS was 13.7% for patients with hemoglobin 10 g/dl versus 59% for patients with hemoglobin >10 g/dl (n ¼ 60) (A). Five-year EFS in was 63.1% for patients with WBC /L versus 18.2% for patients with WBC > /L (n ¼ 60) (B). Five-year OS in was 14.6% for patients with hemoglobin 10 g/dl versus 73% for patients with hemoglobin >10 g/dl (n ¼ 60) (C). Five-year OS was 73.5% for patients with LDH 2 N U/L versus 45.9% for patients with LDH >2 N U/L (n ¼ 60) (D). skeletal Ewing sarcoma [13,28], as was seen in our cohort. For initial 18 months after diagnosis, the hazard ratio for event for patients with EES was 0.72 (95% CI , P ¼ 0.17) as compared to patients with skeletal primary tumors. After 18 months from initial diagnosis, hazard ratio for event for patients with EES was 0.34 (95% CI , P ¼ 0.02) as compared to patients with skeletal primary tumors. This result indicates that extraosseous origin of Ewing sarcoma has a greater chance of having an event in the initial period after diagnosis (first 18 months) than after 18 months of diagnosis as compared to skeletal Ewing sarcoma; this was also observed in the study of EES by Applebaum et al. [28]. The EES group had short mean symptom duration (4.3 days vs. 6.5 days, P ¼ 0.01), higher tumors of pelvic/spinal region (38% vs. 23.9%, P ¼ 0.02), higher number of axial tumors (76.7% vs. 54%, P ¼ 0.001), and higher number of surgical resection as local treatment (67.4% vs. 42.5%, P ¼ 0.002) as compared to skeletal primary group. Other clinic-pathological characteristics did not differ between the two groups. Though the group with EES had higher axial or pelvic/spinal tumor location, it is possible that the disease biology of these tumors may be more favourable as compared to the group with skeletal Ewing sarcoma; alternatively, the higher surgical resection rate in the group with EES as compared to the group with skeletal Ewing sarcoma may explain the superior survival rate in EES. The limitations of our study include the lack of translocation (EWS-FLI) analysis in our patients at diagnosis. Further approximately 23% (n ¼ 14) of our patients stopped therapy prematurely for whom the final survival status could be not ascertained. Further since the above is not a randomized study, it was not designed to detect the difference between surgery and radical radiotherapy as local treatment modality in EES. The strength of our study is that it included all patients with intention-to-treat analysis and received a uniform chemotherapy protocol. Hemoglobin and serum LDH adversely affected OS in entire EES cohort and continued to be independent prognostic factors for OS even after exclusion of patients whose final survival status for OS could not be ascertained. Low hemoglobin and high WBC count were associated with adverse EFS. In comparison to the cohort with skeletal primary tumors, the outcome was superior in the cohort with EES, and most events tend to occur early in the course of disease in the cohort with EES as compared to the cohort with skeletal Ewing sarcoma. REFERENCES 1. Siegal GP, Oliver WR, Reinus WR, et al. Primary Ewing s sarcoma involving the bones of the head and neck. Cancer 1987;60: Sinkovics JG, Plager C, Ayala AG, et al. Ewing sarcoma: Its course and treatment in 50 adult patients. Oncology 1980;37:

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