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Trends in diagnostic biopsy sample collection approaches for primary bone sarcomas have shifted in the past 2 decades. Although open/incisional biopsies used to be the predominant approach to obtain diagnostic material for Ewing sarcoma and osteosarcoma, image-guided core needle biopsies have increased in frequency and are safe for patients. These procedures are less invasive and reduce recovery times but have potential limitations. The quantity and quality of tissue obtained through these procedures vary between institutions. Acquired viable tissue volumes can be low, limiting the conduct of downstream expanded clinical workup, molecular analyses, and research. Patients with advanced Ewing sarcoma and osteosarcoma continue to have overall poor outcomes despite dose-intensive cytotoxic chemotherapy. The biology of treatment resistance is not currently well understood, partly due to limited availability of relevant tissue to study. There is a need for access to quality tumor specimens for molecular and other analyses to identify high-risk tumor subsets and drive discovery to improve patient outcomes. Given broad variability in bone tumor tissue procurement and processing across member institutions, the Children's Oncology Group Bone Tumor Committee convened a multidisciplinary group of experts to outline the current and near-future tissue needs for optimal clinical care and access to research platforms. The goal of this working group was to provide high-level guidance on biopsy practices that safely meet these evolving needs. Harmonizing tissue collection practices is paramount to improving the care of children, adolescents, and young adults diagnosed with Ewing sarcoma and osteosarcoma.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned coprimary or secondary analyses are not yet available. Clinical trial updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. Long-term outcomes from Children's Oncology Group study AEWS0031 were assessed to determine whether the survival advantage of interval-compressed chemotherapy (ICC) was maintained over 10 years in patients with localized Ewing sarcoma (ES). AEWS0031 enrolled 568 eligible patients. Patients were randomly assigned to receive vincristine-doxorubicin-cyclophosphamide and ifosfamide-etoposide alternating once every 3 weeks (standard timing chemotherapy [STC]) versus once every 2 weeks (ICC). For this updated report, one patient was excluded because of uncertainty of original diagnosis. The 10-year event-free survival (EFS) was 70% with ICC compared with 61% with STC ( P = .03), and 10-year overall survival (OS) was 76% with ICC compared with 69% with STC ( P = .04). There was no difference in the 10-year cumulative incidence of second malignant neoplasms (SMNs; P C [see Data Supplement, online only] = .5). A test for interaction demonstrated that ICC provided greater risk reduction for patients with tumor volume ≥200 mL than for patients with tumors <200 mL, but no evidence for a significant interaction in other subgroups defined by age, primary site, and histologic response. With longer-term follow-up, ICC for localized ES is associated with superior EFS and OS without an increased risk for SMN compared with STC. ICC is associated with improved outcomes even in adverse-risk patient groups.

Purpose: To identify potential clinical prognostic factors associated with a higher risk of local recurrence in patients with localized pelvic Ewing sarcoma treated with radiation therapy., Methods and Materials: Data for 101 patients treated with definitive radiation therapy (RT) or both surgery and radiation (S + RT) to primary pelvic tumors on INT-0091, INT-0154, and AEWS0031 were analyzed. Imaging data for patients who did not receive radiation were not available for central review; therefore, patients with surgery alone were not included. Cumulative incidence rates for local failure at 5 years from time of local control were calculated accounting for competing risks., Results: The most common pelvic subsite was sacrum (44.6%). RT was used in 68% of patients and S + RT in 32%. The local failure rate was 25.0% for RT and 6.3% for S + RT (P = .046). There was no statistically significant difference in local control modality by tumor characteristics. Tumors originating in the ischiopubic-acetabulum region were associated with the highest local failure incidence, 37.5% (P = .02, vs sacrum and iliac/buttock tumors), particularly those treated with RT (50.0%, P = .06). A higher incidence of local failure was seen with each additional 100 mL of tumor at diagnosis (P = .04). Multivariable analysis demonstrated RT alone (hazard ratio [HR], 5.1; P = .04), tumor subsite (particularly ischiopubic-acetabulum tumors; HR 4.6; P = .02), and increasing volume per 100 mL (HR, 1.2; P = .01) were associated with a higher incidence of local recurrence., Conclusions: Combination surgery and RT is associated with improved local control in patients with pelvic Ewing sarcoma compared with definitive RT. Tumors involving the ischiopubic-acetabulum region and increasing tumor volume at diagnosis are associated with inferior local control. Tumor characteristics did not correlate with choice of local therapy modality suggesting an opportunity to develop best local therapy practices guidelines for future studies based on tumor features., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Purpose: The primary aim of this phase III randomized trial was to test whether the addition of vincristine, topotecan, and cyclophosphamide (VTC) to interval compressed chemotherapy improved survival outcomes for patients with previously untreated nonmetastatic Ewing sarcoma., Methods: Patients were randomly assigned to receive standard five-drug interval compressed chemotherapy (regimen A) for 17 cycles or experimental therapy with five cycles of VTC within the 17 cycles (regimen B). Patients were stratified by age at diagnosis (< 18 years and ≥18 years) and tumor site (pelvic bone, nonpelvic bone, and extraosseous). Tumor volume at diagnosis was categorized as < 200 mL or ≥ 200 mL. Local control occurred following six cycles. Histologic response was categorized as no viable or any viable tumor. Event-free survival (EFS) and overall survival (OS) were compared between randomized groups with stratified log-rank tests., Results: Of 642 enrolled patients, 309 eligible patients received standard and 320 received experimental therapy. The 5-year EFS and OS were 78% and 87%, respectively. There was no difference in survival outcomes between randomized groups (5-year EFS regimen A v regimen B, 78% v 79%; P = .192; 5-year OS 86% v 88%; P = .159). Age and primary site did not affect the risk of an EFS event. However, age ≥ 18 years was associated with an increased risk of death at 5 years (hazard ratio 1.84; 95% CI, 1.15 to 2.96; P = .009). The 5-year EFS rates for patients with pelvic, nonpelvic bone, and extraosseous primary tumors were 75%, 78%, and 85%, respectively. Tumor volume ≥ 200 mL was significantly associated with lower EFS., Conclusion: While VTC added to five-drug interval compressed chemotherapy did not improve survival, these outcomes represent the best survival estimates to date for patients with previously untreated nonmetastatic Ewing sarcoma., Competing Interests: Patrick J. LeaveyResearch Funding: Eleison Pharmaceuticals Nadia N. LaackResearch Funding: Bristol Myers Squib Mark D. KrailoConsulting or Advisory Role: Merck Sharp & DohmeTravel, Accommodations, Expenses: Merck Sharp & Dohme R. Lor RandallHonoraria: Daiichi Sankyo, Onkos Surgical, OncliveTravel, Accommodations, Expenses: Biomet, Daiichi Sankyo/Lilly Steven G. DuBoisResearch Funding: Merck (Inst), Roche/Genentech (Inst), Lilly (Inst), Curis (Inst), Loxo (Inst), BMS (Inst), Eisai (Inst), Pfizer (Inst), Turning Point Therapeutics (Inst), Bayer (Inst), Salarius Pharmaceuticals (Inst)Travel, Accommodations, Expenses: Roche/Genentech, Salarius PharmaceuticalsUncompensated Relationships: Y-mAbs Therapeutics Inc Damon R. ReedConsulting or Advisory Role: Eisai, PfizerTravel, Accommodations, Expenses: Salarius Pharmaceuticals Douglas S. HawkinsResearch Funding: Loxo (Inst), Bristol Myers Squibb (Inst), Merck Sharp & Dohme (Inst), Bayer (Inst), Lilly (Inst), Eisai (Inst), Amgen (Inst), Seattle Genetics (Inst), Incyte (Inst), Jazz Pharmaceuticals (Inst), Pfizer (Inst)Travel, Accommodations, Expenses: Bayer, AstraZeneca Helen NadelConsulting or Advisory Role: ICON Clinical Research G. Douglas LetsonEmployment: StrykerConsulting or Advisory Role: StrykerTravel, Accommodations, Expenses: Stryker Mark BernsteinResearch Funding: Merck Paul ChubaEmployment: Radiation Oncology Specialists Neyssa MarinaEmployment: Five Prime Therapeutics, Genentech/Roche (I), Synthorx, Sanofi PasteurStock and Other Ownership Interests: Five Prime Therapeutics, Genentech/Roche (I), Synthorx, Sanofi PasteurTravel, Accommodations, Expenses: Five Prime Therapeutics, SynthorxUncompensated Relationships: Stanford University School of MedicineOpen Payments Link: https://openpaymentsdata.cms.gov/physician/1210881 Richard GorlickResearch Funding: Eisai Katherine A. JanewayHonoraria: Foundation MedicineConsulting or Advisory Role: Bayer, IpsenTravel, Accommodations, Expenses: Bayer Leo MascarenhasConsulting or Advisory Role: BayerResearch Funding: AstraZeneca/MedImmune, Lilly, Bayer, Salarius Pharmaceuticals, Turning Point Therapeutics, Pfizer, Incyte, Amgen, E.R. Squibb Sons, LLC, Jazz Pharmaceuticals, MerckTravel, Accommodations, Expenses: Bayer, Lilly, Thermo Fisher Scientific, Salarius PharmaceuticalsUncompensated Relationships: Children's Oncology Group Foundation, The Pablove Foundation, American Society of Pediatric Hematology/OncologyNo other potential conflicts of interest were reported.

The incidence of bone marrow metastasis (BMM) in newly diagnosed Ewing sarcoma (ES) is variable across studies. An optimal staging strategy for detecting BMM is not defined. While bone marrow (BM) biopsy and/or aspirate (BMBA) have been the gold standard, [F-18]fluorodeoxyglucose positron emission tomography (FDG-PET) to detect BMM may decrease reliance on BMBA. We conducted a systematic review to assess incidence of BMM and the role of FDG-PET. We observed a pooled incidence of BMM by BMBA of 4.8% in all newly diagnosed ES patients and 17.5% among patients with metastatic disease. Only 1.2% of patients had BMM as their sole metastatic site. FDG-PET detection of BMM compared to BMBA demonstrated pooled 100% sensitivity and 96% specificity, positive predictive value of 75%, and negative predictive value of 100%. In the era of FDG-PET imaging, omission of BMBA may be considered in patients with otherwise localized disease after initial staging studies., (© 2020 Wiley Periodicals LLC.)

Purpose: The R2Pulm trial was conducted to evaluate the effect of busulfan-melphalan high-dose chemotherapy with autologous stem-cell rescue (BuMel) without whole-lung irradiation (WLI) on event-free survival (main end point) and overall survival, compared with standard chemotherapy with WLI in Ewing sarcoma (ES) presenting with pulmonary and/or pleural metastases., Methods: From 2000 to 2015, we enrolled patients younger than 50 years of age with newly diagnosed ES and with only pulmonary or pleural metastases. Patients received chemotherapy with six courses of vincristine, ifosfamide, doxorubicin, and etoposide (VIDE) and one course of vincristine, dactinomycin, and ifosfamide (VAI) before either BuMel or seven courses of VAI and WLI (VAI plus WLI) by randomized assignment. The analysis was conducted as intention to treat. The estimates of the hazard ratio (HR), 95% CI, and P value were corrected for the three previous interim analyses by the inverse normal method., Results: Of 543 potentially eligible patients, 287 were randomly assigned to VAI plus WLI (n = 143) or BuMel (n = 144). Selected patients requiring radiotherapy to an axial primary site were excluded from randomization to avoid excess organ toxicity from interaction between radiotherapy and busulfan. Median follow-up was 8.1 years. We did not observe any significant difference in survival outcomes between treatment groups. Event-free survival was 50.6% versus 56.6% at 3 years and 43.1% versus 52.9% at 8 years, for VAI plus WLI and BuMel patients, respectively, resulting in an HR of 0.79 (95% CI, 0.56 to 1.10; P = .16). For overall survival, the HR was 1.00 (95% CI, 0.70 to 1.44; P = .99). Four patients died as a result of BuMel-related toxicity, and none died after VAI plus WLI. Significantly more patients in the BuMel arm experienced severe acute toxicities than in the VAI plus WLI arm., Conclusion: In ES with pulmonary or pleural metastases, there is no clear benefit from BuMel compared with conventional VAI plus WLI.

Purpose: To identify clinical and treatment variables associated with a higher risk of local failure in Ewing sarcoma patients treated on recent Children's Oncology Group protocols., Methods and Materials: Data for 956 patients treated with ifosfamide and etoposide-based chemotherapy on INT-0091, INT-0154, and AEWS0031 were analyzed. Local treatment modalities were defined as surgery, definitive radiation therapy (RT), or surgery plus radiation (S+RT). Five-year cumulative incidence of local failure was determined., Results: The local failure rate for the entire cohort was 7.3%, with a 3.9% rate for surgery, 15.3% for RT (P<.01), and 6.6% for S+RT (P=.12). The local failure incidence was 5.4% for extremity tumors, 13.2% for pelvis tumors (P<.01), 5.3% for axial non-spine tumors (P=.90), 9.1% for extraskeletal tumors (P=.08), and 3.6% for spine tumors (P=.49). The incidence of local failure was 14.8% for extremity tumors and 22.4% for pelvis tumors treated with RT, compared with 3.7% for extremity tumors and 3.9% for pelvis tumors treated with surgery (P≤.01). There was no difference in local failure incidence by local treatment modality for axial non-spine, spine, and extraskeletal tumors. The local failure incidence was 11.9% in patients aged ≥18 years versus 6.7% in patients aged <18 years (P=.02). Age ≥18 years (hazard ratio 1.9, P=.04) and treatment with RT (hazard ratio 2.40, P<.01) remained independent prognostic factors for higher local failure incidence on multivariate analysis. Tumor size (

Background: The prognostic significance of having extraskeletal (EES) versus skeletal Ewing sarcoma (ES) in the setting of modern chemotherapy protocols is unknown. The purpose of this study was to compare the clinical characteristics, biologic features, and outcomes for patients with EES and skeletal ES., Methods: Patients had localized ES and were treated on two consecutive protocols using five-drug chemotherapy (INT-0154 and AEWS0031). Patients were analyzed based on having an extraskeletal (n = 213) or skeletal (n = 826) site of tumor origin. Event-free survival (EFS) was estimated using the Kaplan-Meier method, compared using the log-rank test, and modeled using Cox multivariate regression., Results: Patients with extraskeletal ES (EES) were more likely to have axial tumors (72% vs. 55%; P < 0.001), less likely to have tumors >8 cm (9% vs. 17%; P < 0.01), and less likely to be white (81% vs. 87%; P < 0.001) compared to patients with skeletal ES. There was no difference in key genomic features (type of EWSR1 translocation, TP53 mutation, CDKN2A mutation/loss) between groups. After controlling for age, race, and primary site, EES was associated with superior EFS (hazard ratio = 0.69; 95% confidence interval: 0.50-0.95; P = 0.02). Among patients with EES, age ≥18, nonwhite race, and elevated baseline erythrocyte sedimentation rate were independently associated with inferior EFS., Conclusion: Clinical characteristics, but not key tumor genomic features, differ between EES and skeletal ES. Extraskeletal origin is a favorable prognostic factor, independent of age, race, and primary site., Competing Interests: Statement None of the authors have any conflicts of interest related to this work or its publication. Author S.L.L. has a leadership role and stock/ownership interest in Salarius Pharmaceuticals, however, again, this is not a conflict for this study., (© 2016 Wiley Periodicals, Inc.)

Background: The choice of a local control (LC) modality for Ewing sarcoma (EWS) of the femur is controversial. This study aimed to determine the effect of LC modality on tumor LC and patient outcomes., Methods: The study reviewed the treatment and outcomes for 115 patients who had EWS of the femur treated with similar chemotherapy in three cooperative group trials. Patient outcomes were analyzed according to the LC modality using the log-rank test and the cumulative incidence of local or distant failure using competing risks regression., Results: The median age of the patients was 13 years. The most common tumor location was the proximal femur followed by the mid femur. For 55 patients with available data, the tumor was larger than 8 cm in 29 patients and 8 cm or smaller in 26 patients. For 84 patients (73 %), surgery only was performed, whereas 17 patients (15 %) had surgery plus radiation, and 14 patients (12 %) had radiation only. The 5-year event-free survival (EFS) rate was 65 % (95 % confidence interval [CI], 55-73 %), and the 5-year overall survival (OS) rate was 70 % (95 % CI, 61-78 %). Patient outcomes did not differ significantly according to tumor location within the femur (proximal, mid or distal) or tumor size (<8 vs ≥8 cm). The findings showed no statistically significant differences in EFS, OS, cumulative incidence of local failure, or cumulative incidence of distant failure according to LC modality (surgery, surgery plus radiation, or radiation)., Conclusions: The LC modality did not significantly affect disease outcome for EWS of the femur. Further study of treatment complications and functional outcome may help to define the optimal LC modality., Competing Interests: There are no conflicts of interest.

Purpose: Flow cytometry and RT-PCR can detect occult Ewing sarcoma cells in the blood and bone marrow. These techniques were used to evaluate the prognostic significance of micrometastatic disease in Ewing sarcoma., Experimental Design: Newly diagnosed patients with Ewing sarcoma were enrolled on two prospective multicenter studies. In the flow cytometry cohort, patients were defined as "positive" for bone marrow micrometastatic disease if their CD99(+)/CD45(-) values were above the upper limit in 22 control patients. In the PCR cohort, RT-PCR on blood or bone marrow samples classified the patients as "positive" or "negative" for EWSR1/FLI1 translocations. The association between micrometastatic disease burden with clinical features and outcome was assessed. Coexpression of insulin-like growth factor-1 receptor (IGF-1R) on detected tumor cells was performed in a subset of flow cytometry samples., Results: The median total bone marrow CD99(+)CD45(-) percent was 0.0012% (range 0%-1.10%) in the flow cytometry cohort, with 14 of 109 (12.8%) of Ewing sarcoma patients defined as "positive." In the PCR cohort, 19.6% (44/225) patients were "positive" for any EWSR1/FLI1 translocation in blood or bone marrow. There were no differences in baseline clinical features or event-free or overall survival between patients classified as "positive" versus "negative" by either method. CD99(+)CD45(-) cells had significantly higher IGF-1R expression compared with CD45(+) hematopoietic cells (mean geometric mean fluorescence intensity 982.7 vs. 190.9; P < 0.001)., Conclusions: The detection of micrometastatic disease at initial diagnosis by flow cytometry or RT-PCR is not associated with outcome in newly diagnosed patients with Ewing sarcoma. Flow cytometry provides a tool to characterize occult micrometastatic tumor cells for proteins of interest. Clin Cancer Res; 22(14); 3643-50. ©2016 AACR., (©2016 American Association for Cancer Research.)

Background: Although multiple prognostic variables have been proposed for Ewing sarcoma (EWS), little work has been done to further categorize these variables into prognostic groups for risk classification., Procedure: We derived initial prognostic groups from 2,124 patients with EWS in the SEER database. We constructed a multivariable recursive partitioning model of overall survival using the following covariates: age; stage; race/ethnicity; sex; axial primary; pelvic primary; and bone or soft tissue primary. Based on this model, we identified risk groups and estimated 5-year overall survival for each group using Kaplan-Meier methods. We then applied these groups to 1,680 patients enrolled on COG clinical trials., Results: A multivariable model identified five prognostic groups with significantly different overall survival: (i) localized, age <18 years, non-pelvic primary; (ii) localized, age <18, pelvic primary or localized, age ≥18, white, non-Hispanic; (iii) localized, age ≥18, all races/ethnicities other than white, non-Hispanic; (iv) metastatic, age <18; and (v) metastatic, age ≥18. These five groups were applied to the COG dataset and showed significantly different overall and event-free survival based upon this classification system (P < 0.0001). A sub-analysis of COG patients treated with ifosfamide and etoposide as a component of therapy evaluated these findings in patients receiving contemporary therapy., Conclusions: Recursive partitioning analysis yields discrete prognostic groups in EWS that provide valuable information for patients and clinicians in determining an individual patient's risk of death. These groups may enable future clinical trials to adjust EWS treatment according to individualized risk., (© 2015 Wiley Periodicals, Inc.)

Background: Patients with Ewing sarcoma require local primary tumor control with surgery, radiation, or both. The optimal choice of local control for overall and local disease control remains unclear., Methods: Patients with localized Ewing sarcoma of bone who were treated on 3 consecutive protocols with standard-dose, 5-drug chemotherapy every 3 weeks were included (n=465). Propensity scores were used to control for differences between local control groups by constructing multivariate models to assess the impact of local control type on clinical endpoints (event-free survival [EFS], overall survival, local failure, and distant failure) independent of differences in their propensity to receive each local control type., Results: Patients who underwent surgery were younger (P=.02) and had more appendicular tumors (P<.001). Compared with surgery, radiation had higher unadjusted risks of any event (hazard ratio [HR], 1.70; 95% confidence interval [CI], 1.18-2.44), death (HR, 1.84; 95% CI, 1.18-2.85), and local failure (HR, 2.57; 95% CI, 1.37-4.83). On multivariate analysis, compared with surgery, radiation had a higher risk of local failure (HR, 2.41; 95% CI, 1.24-4.68), although there were no significant differences in EFS (HR, 1.42; 95% CI, 0.94-2.14), overall survival (HR, 1.37; 95% CI, 0.83-2.26), or distant failure (HR, 1.13; 95% CI, 0.70-1.84) between local control groups., Conclusions: In this large group of similarly treated patients, choice of the mode of local control was not related significantly to EFS, overall survival, or distant failure, although the risk of local failure was greater for radiation compared with surgery. These data support surgical resection when appropriate, whereas radiotherapy remains a reasonable alternative in selected patients., (© 2014 American Cancer Society.)

Purpose: Chemotherapy with alternating vincristine-doxorubicin-cyclophosphamide and ifosfamide-etoposide cycles and primary tumor treatment with surgery and/or radiation therapy constitute the usual approach to localized Ewing sarcoma in North America. We tested whether chemotherapy intensification through interval compression could improve outcome., Patients and Methods: This was a prospective, randomized controlled trial for patients younger than 50 years old with newly diagnosed localized extradural Ewing sarcoma. Patients assigned to standard and intensified treatment were to begin chemotherapy cycles every 21 and 14 days, respectively, provided an absolute neutrophil count greater than 750×10(6)/L and a platelet count greater than 75×10(9)/L. Patients received vincristine (2 mg/m2), doxorubicin (75 mg/m2), and cyclophosphamide (1.2 g/m2) alternating with ifosfamide (9 g/m2) and etoposide (500 mg/m2) for 14 cycles, with filgrastim (5 mg/kg per day; maximum, 300 mg) between cycles. Primary tumor treatment (surgery, radiation, or both) was to begin at week 13 (after four cycles in the standard arm and six cycles in the intensified arm). The primary end point was event-free survival (EFS). The study is registered at ClinicalTrials.gov (identifier: NCT00006734)., Results: Five hundred eighty-seven patients were enrolled and randomly assigned, and 568 patients were eligible, with 284 patients in each regimen. For all cycles, the median cycle interval for standard treatment was 21 days (mean, 22.45 days); for intensified treatment, the median interval was 15 days (mean, 17.29 days). EFS at a median of 5 years was 65% in the standard arm and 73% in the intensified arm (P=.048). The toxicity of the regimens was similar., Conclusion: For localized Ewing sarcoma, chemotherapy administered every 2 weeks is more effective than chemotherapy administered every 3 weeks, with no increase in toxicity.

Purpose: The Ewing sarcoma family of tumors (ESFT) is a group of malignant tumors of soft tissue and bone sharing a chromosomal translocation affecting the EWS locus. The Intergroup INT-0091 demonstrated the superiority of a regimen of vincristine, cyclophosphamide, doxorubicin (VDC), and dactinomycin alternating with ifosfamide and etoposide (IE) over VDC for patients with nonmetastatic ESFT of bone. The goal of this study was to determine whether a dose-intensified regimen of VDC alternating with IE would further improve the outcome for patients with nonmetastatic ESFT of bone or soft tissue., Methods: Patients with previously untreated, nonmetastatic ESFT of bone or soft tissue were eligible. They were randomly assigned to receive standard doses of VDC/IE over 48 weeks or a dose-intensified regimen of VDC/IE over 30 weeks., Results: Four hundred seventy-eight patients met eligibility requirements: 231 patients received the standard regimen; 247 patients received the intensified regimen. The 5-year event-free survival (EFS) and overall survival rates for all eligible patients were 71.1% (95% CI, 67.7% to 75.0%) and 78.6% (95% CI, 74.6% to 82.1%), respectively. There was no significant difference (P = .57) in EFS between patients treated with the standard (5-year EFS, 72.1%; 95% CI, 65.8% to 77.5%) or intensified regimen (5-year EFS, 70.1%; 63.9% to 75%). Patients with soft tissue tumors accounted for 20% of the study population; there was no difference in outcome between patients with soft tissue and bone primary sites., Conclusion: Dose escalation of alkylating agents as tested in this trial did not improve the outcome for patients with nonmetastatic ESFT of bone or soft tissue.

The EICESS-92 Trial compared the efficacy of cyclophosphamide and ifosfamide in patients with Ewing sarcoma. Subgroup analysis suggested that patients with large, localized tumors benefited from the addition of etoposide, whereas patients with metastases did not.

Background: Patients with relapsed or refractory Ewing sarcoma have a poor outcome with conventional therapies. Cytarabine decreases EWS/FLI1 protein levels in Ewing sarcoma cells and has demonstrated preclinical activity against Ewing sarcoma in vitro and in vivo. The purpose of this phase II clinical trial was to estimate the response rate of intermediate-dose cytarabine in patients with relapsed or refractory Ewing sarcoma., Procedure: Patients with a histologic diagnosis of Ewing sarcoma were eligible if they were <30 years of age, had relapsed or refractory measurable disease, and met standard organ function requirements. Patients received cytarabine 500 mg/m(2)/dose intravenously over 2 hr every 12 hr for 10 doses with cycles repeated every 21 days. Response was assessed according to RECIST criteria., Results: Ten patients (median age 20 years; 7 males) were treated. Only five patients had documented EWS/FLI1 translocated tumors. No objective responses were seen. One patient had stable disease for 5 cycles before developing progressive disease. All patients evaluable for hematologic toxicity developed grade 4 neutropenia and thrombocytopenia during protocol therapy. Patients were not able to receive therapy according to the planned 21-day cycles, with a median interval of 26.5 days., Conclusions: Cytarabine at the dose and schedule utilized in this trial resulted in hematologic toxicity that limited delivery of this therapy. This regimen also had minimal activity in this patient population.

Background: The prognosis for patients with recurrent Ewing sarcoma (EWS) is very poor with 5-year survival of 13%., Methods: To evaluate prognostic factors for these patients we studied patients initially treated on the multi-institutional study INT0091., Results: Two hundred sixty-two patients experienced disease recurrence. The median time to first recurrence was 1.3 years (0-7.4 years), 1.4 years (0-7.4 years) for patients with initially localized disease and 1 year (0-6 years) for patients with initially metastatic disease. Time to first recurrence from date of initial diagnosis was a predictor of post-recurrence survival (P < 0.0001). Twenty-one percent of patients, with recurrent or progressive disease >or=2 years from initial diagnosis, had an estimated 5-year survival of 30% (vs. 7% estimated 5-year survival with an earlier recurrence). No statistical difference was detected between patients whose disease recurred <1 year and between 1 and 2 years from initial diagnosis. A stepwise relative risk model and backwards stepwise regression was used to explore factors significantly associated with risk for post-recurrence death. Significant risk factors for death after recurrence included recurrence at combined local and distant sites, elevated LDH at initial diagnosis and initial recurrence less than 2 years after diagnosis. Isolated pulmonary recurrence was not predictive of survival after recurrence., Conclusion: Patients with a longer disease control interval represent the subset of patients most likely to survive following recurrence of EWS. All patients with recurrence would benefit from collaborative trials to investigate new therapeutic options., ((c) 2008 Wiley-Liss, Inc.)

Ewing sarcoma is the second most common type of malignant bone tumor in children and young adults. We report 2 patients with a history of Ewing sarcoma who were diagnosed with recurrent tumor during or immediately after pregnancy. To determine whether the hormonal milieu of pregnancy might have contributed to recurrence, we performed immunohistochemistry for estrogen and progesterone receptors on available tumor tissue. These receptors were not detected by immunohistochemistry. Increased medical surveillance during pregnancy may have resulted in ascertainment of recurrence in these 2 patients.

The Children's Oncology Group (COG) is a multi-institutional cooperative group dedicated to childhood cancer research that has helped to increase the survival of children with cancer through clinical trials. These clinical trials include a standardized regimen of imaging examinations performed prior to, during, and following therapy. This article presents imaging guidelines developed by a multidisciplinary group from the COG Bone Tumor Committee. These guidelines provide both required and recommended studies. Recommended examinations may become required in the future. These guidelines should be considered a work in progress that will evolve with advances in imaging and childhood cancer research.

Background: The outcome for patients with Ewing sarcoma family of tumors (ESFTs) of bone with metastases at diagnosis remains poor despite new approaches to treatment. We evaluated whether a dose-intensity chemotherapy regimen improved survival for patients with ESFTs of bone with metastases at diagnosis., Methods: We entered 60 patients with metastatic ESFTs of bone onto a single arm trial of a new intensive therapy. Treatment consisted of 51-weeks of chemotherapy and local control of the primary with radiation, surgery, or both. The chemotherapeutic protocol included two alternating blocks: one with vincristine (2 mg/m(2)), doxorubicin (90 mg/m(2)), and cyclophosphamide (2,200 mg/m(2)); and the second with ifosfamide (2,800 mg/m(2)/day x 5 days) and etoposide (100 mg/m(2)/day x 5 days)., Results: Of the 60 patients with metastatic ESFTs of bone enrolled onto this single arm trial, 12 had metastasis to lung only, 7 to bone marrow or bone only, 38 to multiple sites, 2 in other sites and 3 not specified. There were three toxic deaths. Six patients (6-year cumulative incidence: 9%) developed second malignant neoplasms and died. The 6-year overall event-free survival (EFS) was 28% (standard error (SE) 6%) and survival (S) was 29% (SE 6%)., Conclusion: An intensified treatment regimen using higher doses of cyclophosphamide, ifosfamide, and doxorubicin increased toxicity and risk of second malignancy without improving EFS and S., (2007 Wiley-Liss, Inc)

This study describes the magnitude of risk of therapy-related myelodysplasia and acute myeloid leukemia (t-MDS/AML) in 578 individuals diagnosed with Ewing sarcoma and enrolled on Children's Oncology Group therapeutic protocol, INT-0091. Between 1988 and 1992, patients with or without metastatic disease were randomized to receive doxorubicin, vincristine, cyclophosphamide, and dactinomycin (regimen A) or these 4 drugs alternating with etoposide and ifosfamide (regimen B). Between 1992 and 1994, patients with metastatic disease were nonrandomly assigned to receive high-intensity therapy (regimen C: regimen B therapy with higher doses of doxorubicin, cyclophosphamide, and ifosfamide). Median age at diagnosis of Ewing sarcoma was 12 years, and median length of follow-up, 8 years. Eleven patients developed t-MDS/AML, resulting in a cumulative incidence of 2% at 5 years. While patients treated on regimens A and B were at a low risk for development of t-MDS/AML (cumulative incidence: 0.4% and 0.9% at 5 years, respectively), patients treated on regimen C were at a 16-fold increased risk of developing t-MDS/AML (cumulative incidence: 11% at 5 years), when compared with those treated on regimen A. Increasing exposure to ifosfamide from 90 to 140 g/m2, cyclophosphamide from 9.6 to 17.6 g/m2, and doxorubicin from 375 to 450 mg/m2 increased the risk of t-MDS/AML significantly.

Purpose: The impact of the modality used for local control of Ewing sarcoma is uncertain. We investigated the relationship between the type of local control modality, surgery, radiation (RT) or both (S + RT), and subsequent risk for local failure (LF) in patients with nonmetastatic pelvic Ewing sarcoma treated on INT-0091., Patients and Methods: Patients < or = 30 years with Ewing sarcoma, primitive neuroectodermal tumor or primitive sarcoma of bone were randomly assigned to receive chemotherapy with doxorubicin, vincristine, cyclophosphamide, and dactinomycin, (VACA) or with these four drugs alternating with ifosfamide and etoposide (VACA-IE). The local control modality, surgery, RT or both was chosen by the treating physicians. The effect of local control modality was assessed after adjusting for the size of tumor (< 8 cm, > or = 8 cm) and chemotherapy type., Results: Seventy-five patients with pelvic tumors and a median follow-up of 4.4 years (0.6 to 11.4 years) comprised the study population. Twelve underwent surgery, 44 received RT, and 19 received both. The 5-year event-free survival (EFS) and cumulative incidence of LF was 49% and 21% (16%, LF only; 5%, LF and distant failure). There was no significant difference in EFS or LF by tumor size (< 8 cm, > or = 8 cm), local control (LC) modality, or chemotherapy. However, VACA-IE seems to confer an LC benefit (11% v 30%; P = .06)., Conclusion: There was no significant effect of local control modality (surgery, RT or S + RT) selected by the treating physicians on rates of local failure or EFS. However, VACA-IE improves LC (11%) compared with previously published results for pelvic Ewing sarcoma.

Purpose: Prognosis is poor for Ewing sarcoma patients with metastasis at diagnosis. We intensified a five-drug therapy (ifosfamide, etoposide alternated with vincristine, doxorubicin, and cyclophosphamide) using filgrastim but not stem-cell support. We studied topotecan alone and combined with cyclophosphamide in therapeutic windows before the five-drug therapy. A randomly assigned proportion of patients received amifostine as a cytoprotective agent., Patients and Methods: Eligible patients were < or = 30 years old and had histologically proven Ewing sarcoma or primitive neuroectodermal tumor (PNET) and metastasis at diagnosis. Chemotherapeutic cycles began every 21 days, after recovery from toxicities., Results: One hundred ten of the 117 patients enrolled were eligible. Thirty-six patients received initial topotecan. Three had partial responses (PRs), and 17 had progressive disease (PD). Thirty-seven patients were administered topotecan and cyclophosphamide; 21 of these patients achieved PR, and one patient had PD. In a randomly assigned group of 69 patients, amifostine did not provide myeloprotection, which was measured by absolute neutrophil count, platelet count, or cycle intervals. The best responses to the overall therapy included 45 complete responses, 41 PRs, stable disease in 14 patients, and PD in five patients. For all patients, the 2-year event-free survival (EFS) rate was 24% (+/- 4%), and the overall survival rate was 46% (+/- 5%). For the 39 patients with isolated pulmonary metastases, the 2-year EFS rate was 31% (+/- 7%) compared with 20% (+/- 5%) for patients with more widespread disease., Conclusion: Topotecan had limited activity in patients with Ewing sarcoma or PNET metastatic at diagnosis. The topotecan-cyclophosphamide combination was active. Amifostine was not myeloprotective. Overall results showed no improvement compared with previous studies.

Purpose: One hundred twenty patients with metastatic Ewing's sarcoma or primitive neuroectodermal tumor (PNET) of bone were entered onto a randomized trial evaluating whether the addition of ifosfamide and etoposide to vincristine, doxorubicin, cyclophosphamide, and dactinomycin improved outcomes., Methods: Thirty-two patients had metastases to lungs only, 12 patients had metastases to bone marrow or bones only, 64 patients had metastases in multiple sites, and five patients had metastases in other sites; seven patients could not be assessed precisely. Treatment comprised 9 weeks of chemotherapy before local control and 42 weeks of chemotherapy; thereafter, regimen A consisted of vincristine 2 mg/m(2), cyclophosphamide 1,200 mg/m(2), and either doxorubicin 75 mg/m(2) or dactinomycin 1.25 mg/m(2). Regimen B consisted of regimen A alternating every 3 weeks with ifosfamide 1,800 mg/m(2)/d for 5 days and etoposide 100 mg/m(2)/d for 5 days., Results: Patients treated on regimen B did not have significantly better survival than those treated on regimen A. The event-free survival (EFS) and survival (S) at 8 years were 20% (SE, 5%) and 32% (SE, 6%), respectively, for those treated on regimen A and 20% (SE, 6%) and 29% (SE, 6%), respectively, for those treated on regimen B. Patients who had only lung metastases had EFS and S of 32% (SE, 8%) and 41% (SE, 9%), respectively, at 8 years. There were six toxic deaths (5%), four from cardiac toxicity and two from sepsis (four treated on regimen B and two treated on regimen A). Two had second malignant neoplasms., Conclusion: Adding ifosfamide and etoposide to standard therapy does not improve outcomes of patients with Ewing's sarcoma or PNET of bone with metastases at diagnosis.

Objective: To establish outcome and optimal timing of local control for patients with nonmetastatic Ewing sarcoma/primitive neuroectodermal tumor (ES/PNET) of the chest wall., Methods: Patients < or =30 years of age with ES/PNET of the chest wall were entered in 2 consecutive protocols. Therapy included multiagent chemotherapy; local control was achieved by resection, radiotherapy, or both. We compared completeness of resection and disease-free survival in patients undergoing initial surgical resection versus those treated with neoadjuvant chemotherapy followed by resection, radiotherapy, or both. Patients with a positive surgical margin received radiotherapy., Results: Ninety-eight (11.3%) of 869 patients had primary tumors of the chest wall. Median follow-up was 3.47 years and 5-year event-free survival was 56% for the chest wall lesions. Ten of 20 (50%) initial resections resulted in negative margins compared with 41 of 53 (77%) negative margins with delayed resections after chemotherapy (P = 0.043). Event-free survival did not differ by timing of surgery (P = 0.69) or type of local control (P = 0.17). Initial chemotherapy decreased the percentage of patients needing radiation therapy. Seventeen of 24 patients (70.8%) with initial surgery received radiotherapy compared with 34 of 71 patients (47.9%) who started with chemotherapy (P = 0.061). If a delayed operation was performed, excluding those patients who received only radiotherapy for local control, only 25 of 62 patients needed radiotherapy (40.3%; P = 0.016)., Conclusion: The likelihood of complete tumor resection with a negative microscopic margin and consequent avoidance of external beam radiation and its potential complications is increased with neoadjuvant chemotherapy and delayed resection of chest wall ES/PNET.

Background: Ewing's sarcoma and primitive neuroectodermal tumor of bone are closely related, highly malignant tumors of children, adolescents, and young adults. A new drug combination, ifosfamide and etoposide, was highly effective in patients with Ewing's sarcoma or primitive neuroectodermal tumor of bone who had a relapse after standard therapy. We designed a study to test whether the addition of these drugs to a standard regimen would improve the survival of patients with newly diagnosed disease., Methods: Patients 30 years old or younger with Ewing's sarcoma, primitive neuroectodermal tumor of bone, or primitive sarcoma of bone were eligible. The patients were randomly assigned to receive 49 weeks of standard chemotherapy with doxorubicin, vincristine, cyclophosphamide, and dactinomycin or experimental therapy with these four drugs alternating with courses of ifosfamide and etoposide., Results: A total of 518 patients met the eligibility requirements. Of 120 patients with metastatic disease, 62 were randomly assigned to the standard-therapy group and 58 to the experimental-therapy group. There was no significant difference in five-year event-free survival between the treatment groups (P=0.81). Among the 398 patients with nonmetastatic disease, the mean (+/-SE) five-year event-free survival among the 198 patients in the experimental-therapy group was 69+/-3 percent, as compared with 54+/-4 percent among the 200 patients in the standard-therapy group (P=0.005). Overall survival was also significantly better among patients in the experimental-therapy group (72+/-3.4 percent vs. 61+/-3.6 percent in the standard-therapy group, P=0.01)., Conclusions: The addition of ifosfamide and etoposide to a standard regimen does not affect the outcome for patients with metastatic disease, but it significantly improves the outcome for patients with nonmetastatic Ewing's sarcoma, primitive neuroectodermal tumor of bone, or primitive sarcoma of bone., (Copyright 2003 Massachusetts Medical Society)

Ewing's sarcoma/primitive neuroectodermal tumor is the most common tumor of the chest wall in children and adolescents. It is extremely malignant with a high frequency of both metastatic spread and of local recurrence. Cure requires intensive therapy to control both distant and local disease. Surgery and high-dose radiotherapy can achieve equivalent local control; however, radiation is associated with the additional morbidities of second malignancy and a significant adverse impact on both cardiac and pulmonary function. The optimal therapeutic sequence is initial biopsy followed by induction chemotherapy with subsequent resection of the primary tumor. This approach will achieve the lowest incidence of tumor present at the margins of resection and, hence, need for postoperative radiotherapy. The chest wall is a rare site for tumors in children and adolescents. In a series reported from St Jude's Children's Research Hospital, chest wall tumors constituted only 1.8% of the solid childhood tumors. They are primarily mesenchymal in origin and the Ewing's sarcoma/primitive neuroectodermal tumors (PNET) predominate. This report concentrates on the later tumors. They are recognized to be extremely malignant, and cure in those who present with metastatic disease is very difficult to achieve. Recent advances in our understanding of their cytogenetic basis and optimal treatment are presented., (Copyright 2001 by W.B. Saunders Company)

Objective: We sought to establish the outcome and optimal therapeutic sequence for patients with nonmetastatic Ewing sarcoma/primitive neuroectodermal tumor of the chest wall., Methods: Patients 30 years of age or younger with nonmetastatic Ewing sarcoma/primitive neuroectodermal tumor of the bone were randomly assigned to receive vincristine, doxorubicin, cyclophosphamide, and dactinomycin or those drugs alternating with ifosfamide and etoposide. Local control was obtained with an operation, radiotherapy, or both., Results: Fifty-three (13.4%) of 393 patients had primary tumors of the chest wall (all rib). Event-free survival at 5 years was 57% for the chest wall compared with 61% for other sites (P >.2). Ifosfamide and etoposide improved outcome in the overall group (5-year event-free survival, 68% vs 54%; P =.002), and a similar trend occurred in chest wall lesions (5-year event-free survival, 64% vs 51%). Patients with chest wall lesions had more attempts at initial surgical resection (30%) than those with other primary tumor sites (8%, P <.01). The attempt at initial resection for chest wall lesions did not correlate with size. Initial resections at other sites were restricted to smaller tumors. Initial resection resulted in negative pathologic margins in 6 of 16 patients, whereas the delayed resection resulted in negative margins in 17 of 24 patients (P =.05). Although there was no difference in survival by timing of the operation in rib lesions, a higher percentage of patients with initial surgical resection received radiation than those with resection after initial chemotherapy (P =. 13)., Conclusions: Although rib primary tumors are significantly larger than tumors found in other sites, their outcome is similar. We favor delayed resection whenever possible to minimize the number of patients requiring radiation therapy.

The outcome for 82 pediatric patients with Ewing sarcoma (ES) and primitive neuroectodermal tumor (PNET) of bone is reported; the patients were treated at the Dana-Farber Cancer Institute (DFCI) and Children's Hospital (CH) in Boston, MA (USA) from 1971-1988. The charts of all patients with ES/PNET of bone treated during this period were reviewed for disease status, therapy, sites of relapse, information on second malignancies, and survival status. Eighty-two patients with ES/PNET of bone treated at DFCI/CH were identified. The 10-year event-free survival (EFS) rates were 12% (95% confidence interval [CI] 0, 27%) and 38% (95% CI 26, 51%) for patients with and without metastases, respectively (P = 0.002); the overall survival (OS) rates were 17% (95% CI 1, 33%) and 48% (95% CI 35, 61%) for patients with and without metastases (P = 0.001). Median follow-up for surviving patients is 10.2 years. Primary site in the pelvis also was associated with a poor outcome for patients with no metastatic disease (P = 0.006 OS, P = 0.03 EFS). Thirty-one patients survived in first remission at least 5 years from diagnosis, and of these, five experienced relapse of original disease, and five experienced secondary malignancies. Pediatric patients treated for ES/PNET of bone remain at risk for life-threatening events into the second decade of follow-up. After 5 years, the risk of second malignant neoplasm is at least as high as the risk of late relapse. Prolonged follow-up of patients with ES and PNET of bone is indicated.

Ewing sarcoma (ES) is the second most common primary malignant tumor of bone in children and young adolescents. Most ES contain a pathognomonic translocation t(11;22)(q24;q12) that is likely a pivotal event in the tumorigenesis of these neoplasms. Many ES also contain nonrandom, numerical chromosomal aberrations, the most common of which are trisomies 8 and 12. In this study we evaluated the hypothesis that these trisomies might occur during neoplastic progression and might be associated with differences in biologic behavior. We tested this hypothesis using a combined cytogenetic and dual color fluorescence in situ hybridization approach to determine chromosome 8 and 12 copy number in 52 ES. Relative gains, primarily trisomies, of chromosomes 8 and 12 were found in 24 (46%) and 17 (33%) cases, respectively. Trisomy 8 and trisomy 12 were independent events acquired in a flexible order during ES genetic progression. Our preliminary findings also suggest a higher frequency of trisomies 8 and 12 in relapses than in primary tumors. Prospective studies will be required to determine whether either trisomy is prognostic in newly-diagnosed ES.

There has been an explosion of new knowledge regarding the Ewing family of tumors over the past 5 to 10 years. Classical Ewing's sarcoma and PNET are now known to be the same tumor with variable differentiation, defined by a translocation between the EWS gene on chromosome 22 with one of three ETS-like genes, especially the FLI-1 gene on chromosome 11. Molecular techniques used to identify this translocation along with the knowledge that the protein product of the MIC2 gene is highly expressed on the cell surface have greatly improved our diagnostic abilities in this family of tumors. Controversy still exists as to whether surgery improves event-free survival when compared with radiotherapy in Ewing's sarcoma. The high second tumor rate, if nothing else, has started moving many physicians to preferentially use surgery when the functional results are predicted to be reasonable. The addition of ifosfamide and etoposide to standard therapy in Ewing's sarcoma has improved survival for patients without metastases at presentation. However, outcome for patients with metastases or who develop metastases while on therapy or shortly thereafter remains poor. Preliminary reports of better outcome with megatherapy are interesting but not yet definitive. The decades ahead will probably see marked changes in therapy for Ewing's sarcoma. The unique translocation seen in virtually all of these tumors is a potential target for a "magic bullet" therapy, because the protein product of this translocation is present only in the malignant cells. Hopefully either immune modulation against this unique protein or further knowledge of how to use antisense genes will move us toward exquisitely targeted therapy in the Ewing family of tumors.

Purpose: To determine the feasibility of detecting Ewing's sarcoma (ES) or peripheral primitive neuroectodermal tumor (PNET) through a reverse-transcriptase polymerase chain reaction (RT-PCR) of the t(11;22)(q24;q12) fusion transcript in blood and bone marrow samples from patients with these neoplasms., Patients and Methods: Peripheral-blood (PB) and/or bone marrow aspirate (BM) samples were obtained from 28 patients with ES or PNET at initial presentation or at relapse. Patients were divided into two groups: newly diagnosed patients with nonmetastatic disease and those with metastatic/relapsed disease. RNA was extracted from fractionated BM and PB samples, and RT-PCR was performed for the EWS/HumFLI1 fusion mRNA was transcribed across the t(11;22) breakpoint., Results: Among the 16 patients with nonmetastatic disease, three of 16 were RT-PCR positive for EWS/HumFLI1 RNA in BM and three of 10 were positive in PB. The total number of nonmetastatic patients who were positive in either PB or BM was four of 16 (25%). Among patients with metastatic/relapsed disease, two of six were positive in BM and five of 10 were positive in PB. The total fraction of patients with metastatic/relapsed disease that was positive in either BM or PB was six of 12 (50%)., Conclusion: In this study, we show that it is possible to amplify the EWS/HumFLI1 RNA by RT-PCR from the BM and PB of a subset of patients with both nonmetastatic and metastatic ES or PNET, which implies that occult tumor cells are present at these sites. The true biologic and clinical meaning of this information is unknown. However, it does suggest a possible application of RT-PCR for the monitoring of residual disease in patients who are undergoing therapy for ES or PNET. This approach may permit early identification of patients who may benefit from alternative therapy or who may be spared possible overtreatment.

Ewing's sarcoma and peripheral neuroectodermal tumor (PNET) are small blue cell tumors with no reliable positive diagnostic markers. However, Ewing's sarcoma and PNET recently have been shown to strongly express an antigen determined by the MIC2 gene, whereas other blue cell tumors of childhood for the most part do not. MIC2 analysis therefore offers a distinctive addition to the panel of immunohistochemical stains used to differentiate among small blue cell tumors of childhood, since it represents the first positive marker for Ewing's sarcoma and PNET. This study addresses the reliability of MIC2 analysis using the monoclonal antibody 12E7 on tumors registered in the current Intergroup Ewing's Sarcoma protocol. Of 244 tumors, 221 (91%) showed a diffuse strong membranous pattern. The antibody appears to withstand all the fixation variables inherent in a multi-institutional study. We conclude that MIC2 expression is highly reliable as a positive marker for the Ewing's sarcoma/PNET family of tumors when the results are interpreted in the total context with clinical and pathologic parameters.

From 1976 to 1989 the authors treated 21 infants and children with malignant tumors of the chest wall. Fifteen were classified as Askin's tumors or Ewing's sarcoma, which we now consider as a single entity of primitive neuroectodermal origin. They are infrequent but highly aggressive tumors that involve the chest wall in children. Five patients presented with metastatic disease; despite chemotherapy and radiotherapy, all succumbed to progressive disease. Ten patients with localized disease received combined modality therapy including surgical resection (three after initial chemotherapy), radiotherapy, and chemotherapy. Surgery involved resection of the mass and up to three ribs, with prosthetic mesh reconstruction in one patient. Six of the 10 patients with localized disease are continuously disease-free 3.5 to 9 years (median, 5 years) following diagnosis. No patient had local recurrence. Of the four whose treatment failed, one died (free of disease) from complications after resection of an extensive primary tumor. In the second patient, acute monocytic leukemia developed shortly after relapse in a distant bone site. The patient died during induction for the leukemia. In the other two patients, hilar and carinal lymph node relapse occurred 68 and 80 months after initial treatment. One of the patients is considered in second remission (now 105 months later) after further chemotherapy (Adria-VAC) and radiation; the other succumbed to secondary relapse 17 months after second remission was achieved through chemotherapy, radiation, and surgery. Initial percutaneous needle biopsy of the large lesions has provided adequate material for histological, immunohistochemical, cytogenetic and ultrastructural diagnosis, and permitted initial chemotherapy before proceeding to surgical resection.(ABSTRACT TRUNCATED AT 250 WORDS)

Ewing's sarcoma and the related primitive neuroectodermal tumor (PNET) share a unique and specific t(11;22)(q24;q12) chromosomal translocation. The breakpoints have recently been cloned and shown to involve the EWS gene on chromosome 22 and the FLI-1 gene on chromosome 11. Translocation results in the fusion of these genes on the der(22) chromosome, resulting in the production of a novel chimeric EWS/FLI-1 message. Using oligonucleotide primers derived from EWS and FLI-1 complementary DNAs, we were able to amplify a specific fusion transcript from 18 of 18 cases containing t(11;22) and 10 of 14 cases of Ewing's sarcoma/PNET that had unsuccessful cytogenetics. No EWS/FLI-1 fusion transcripts were detected in five cell lines derived from cases of pediatric sarcomas having a histological diagnosis other than Ewing's sarcoma/PNET. The sensitivity and specificity of this PCR analysis demonstrates the usefulness of this approach for the primary diagnosis of t(11;22)-containing Ewing's sarcoma/PNET and for the detection of metastatic or residual disease.