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Supplemental Table 1. Association of clinical features with BM micrometastatic cell burden (CD99+CD45- percent) in flow cytometry cohort. Supplemental Table 2. Total CD99+CD45- percent burden in Ewing sarcoma patients with clinically evident BM metastasis (N=6).

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.

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.

Background Dexrazoxane protects from lower-cumulative-dose doxorubicin cardiotoxicity, but the effect of dexrazoxane in children with sarcoma treated with higher-cumulative-dose doxorubicin is unknown. Methods We evaluated children with osteosarcoma (OS) on two Children’s Oncology Group trials with higher dose doxorubicin (375–600 mg/m2) preceded by dexrazoxane (10:1 dexrazoxane:doxorubicin dosing). They were evaluated after the minimum expected treatment time (METT), defined as 28 weeks. Cardiotoxicity was identified by echocardiography and serum N-terminal pro-brain natriuretic peptide (NT-proBNP). Second malignant neoplasm (SMN) data was collected. Results All children had normal left ventricular (LV) systolic function as measured by LV fractional shortening and no heart failure. The end-diastolic septal thickness Z-scores (P Z-scores (P Z-scores were significantly smaller for girls (P P = 0.06). Girls had significantly smaller LV end-diastolic dimension Z-scores normalized to BSA (P Conclusions Dexrazoxane prevented LV dysfunction and heart failure in children with OS receiving higher dose doxorubicin. However, LV structural changes were not fully prevented, especially in girls. As a result, hearts become abnormally small for body size, resulting in higher LV stress. Dexrazoxane did not increase the risk of SMN. Dexrazoxane should be used in this population, particularly for girls, to mitigate anthracycline-induced cardiotoxicity. Trial registrations ClinicalTrials.gov: NCT00003937 (P9754) registered 1 Nov 1999, and NCT00023998 (AOST0121) registered 13 Sept 2001.

Pediatric histiocytic neoplasms are hematopoietic disorders frequently driven by the BRAF-V600E mutation. Here we identified two BRAF gene fusions (novel MTAP-BRAF and MS4A6A-BRAF) in two aggressive histiocytic neoplasms. In contrast to previously described BRAF fusions, MTAP-BRAF and MS4A6A-BRAF do not respond to the paradox breaker RAF inhibitor (RAFi) PLX8394 due to stable fusion dimerization mediated by the N-terminal fusion partners. This highlights a significant and clinically relevant shift from the current dogma that BRAF-fusions respond similarly to BRAF-inhibitors. As an alternative, we show suppression of fusion-driven oncogenic growth with the pan-RAFi LY3009120 and MEK inhibition.

Pediatric histiocytic neoplasms are hematopoietic disorders frequently driven by the BRAF-V600E mutation. Here, we identified two BRAF gene fusions (novel MTAP-BRAF and MS4A6A-BRAF) in two aggressive histiocytic neoplasms. In contrast to previously described BRAF fusions, MTAP-BRAF and MS4A6A-BRAF do not respond to the paradox breaker RAF inhibitor (RAFi) PLX8394 due to stable fusion dimerization mediated by the N-terminal fusion partners. This highlights a significant and clinically relevant shift from the current dogma that BRAF-fusions respond similarly to BRAF-inhibitors. As an alternative, we show suppression of fusion-driven oncogenic growth with the pan-RAFi LY3009120 and MEK inhibition.

Pediatric histiocytic neoplasms are clonal hematopoietic disorders driven by mutations activating the mitogen-activated protein kinase (MAPK) pathway, such as BRAF-V600E. In non-BRAFV600E cases, we investigated alternative MAPK mutations and found two novel BRAF gene fusions. We investigated the distinct responsiveness of novel BRAF fusions to RAFi therapies and explored the mechanistic basis of such differential responses compared to other BRAF fusions. Two histiocytic patient tumors were analyzed using the CHOP Comprehensive Next-Gen Sequencing Solid Tumor Panel and a targeted RNA-seq panel for 106 fusion partner genes. In the two M- and L-type histiocytic neoplasms assessed, we found novel and rare BRAF gene fusions, MTAP-BRAF and MS4A6A-BRAF, respectively. Both BRAF fusions activated the MAPK/ PI3K pathways and showed homo- and hetero-dimerization with BRAF and the respective N-terminal fusion partner. In contrast to common BRAF fusions, MTAP-BRAF and MS4A6A-BRAF did not respond to PLX8394 due to a lack of disruption of active fusion homo- and hetero-dimers, which was in turn due to the untargeted, stable dimerization mediated by the N-terminal fusion partners. Conversely, we observed robust suppression with LY3009120 that bound fusion dimers and kept them in an inactivate confirmation. MEKi were found to successfully suppress fusion driven signaling and oncogenic phenotypes. Our finding that PLX8394 does not disrupt MTAP-BRAF or MS4A6A-BRAF dimerization due to contribution of N-terminal partners defines a novel paradigm for the distinct mechanisms sought by BRAF fusions in response to RAFi therapy. Overall, this study highlights the unique and differential biology hijacked by BRAF fusions in response to RAFi and further warrants detailed mechanistic classification of BRAF fusions based on their responsiveness to targeted agents.

Background Patients with recurrent or refractory osteosarcoma have a poor prognosis with less than 30% surviving two years. Eribulin is a synthetic analog of halichondrin B, has a novel mechanism of action when compared with other microtubule inhibitors, and may have antitumor activity in osteosarcoma. Methods A prospective study was designed to assess the disease control success at four months and objective response rates in patients with recurrent or refractory osteosarcoma treated with eribulin. Eligible patients were between 12 and 50 years of age, had measurable tumor, and met standard organ function requirements. Patients were given eribulin 1.4 mg/m2 /dose on days 1 and 8 of each 3-week cycle for up to 24 months if there was no progressive disease. Response to therapy was assessed using RECIST 1.1 criteria after cycles 2 and 5 and every fourth cycle thereafter. Results Nineteen patients enrolled on the AOST1322 study. The median age of enrollment was 16 years (range, 12-25 years). Twelve patients were male and seven female. Eribulin was well tolerated, with neutropenia identified as the most common toxicity. The median progression-free survival was 38 days and no patients reached the four-month time point without progression. No objective responses were seen in any patient. Conclusion This study rapidly assessed the clinical activity of a novel agent in this patient population. Eribulin was well tolerated, but there were no patients who demonstrated objective response, and all patients had progression prior to four months.

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: 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.

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 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.

BackgroundThe 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.MethodsThe 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.ResultsThe 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 (

Introduction: Pediatric histiocytic neoplasms are clonal hematopoietic disorders driven by mutations activating the mitogen-activated protein kinase (MAPK) pathway, such as BRAF- V600E. In non-BRAFV600E cases, we investigated alternative MAPK mutations and found two novel BRAF gene fusions. We have previously shown effective targeting of BRAF fusions (KIAA1549-BRAF) in pediatric low-grade gliomas (PLGGs) with paradox breaker RAF inhibitor (RAFi), PLX8394 and MEK inhibitors (MEKi). Here, we investigate the distinct responsiveness of novel BRAF fusions to RAFi therapies and explore the mechanistic basis of such differential responses compared to other BRAF fusions. Method: Two histiocytic patient tumors were analyzed using the CHOP Comprehensive Next- Gen Sequencing Solid Tumor Panel and a targeted RNA-seq panel for 106 fusion partner genes. Novel BRAF fusions identified were sub-cloned to create heterologous cell models. Immunoblotting of serum starved cells measured MAPK and PI3K pathway activation and soft agar assay tested for oncogenic phenotypes driven by BRAF fusions, along with response to PLX8394, LY3009120 (pan-RAF dimer inhibitor), and MEKi. Co-immunoprecipitation assays using Myc- and Flag-tagged BRAF fusion constructs assessed dimerization profiles, with or without inhibitors. Result: In the two M- and L-type histiocytic neoplasms assessed, we found novel and rare BRAF gene fusions, MTAP-BRAF and MS4A6A-BRAF, respectively. Both BRAF fusions activated the MAPK/ PI3K pathways and showed homo- and hetero-dimerization with BRAF and the respective N-terminal fusion partner. Compared to common BRAF fusions, MTAP-BRAF and MS4A6A- BRAF did not respond to PLX8394 due to no disruption of active fusion homo- and hetero-dimers, which was in turn was due to the untargeted, stable dimerization mediated by the N-terminal fusion partners. Conversely, we observed robust suppression with LY3009120 that bound fusion dimers and kept them in an inactivate confirmation. MEKi selumetinib and trametinib also suppressed fusion driven signaling and oncogenic phenotypes. Conclusion: We show that novel MTAP-BRAF and MS4A6A-BRAF fusions, found in histiocytic tumors, do not respond to RAFi PLX8394 but are targeted by LY3009120 or MEKi. Our finding that PLX8394 does not disrupt MTAP-BRAF or MS4A6A-BRAF dimerization due to contribution of N-terminal partners defines a novel paradigm for the distinct mechanisms sought by BRAF fusions in response to RAFi therapy. We show potent suppression of these mechanistically distinct BRAF fusions with MEKi or LY3009120 which function independent of vulnerability to fusion dimerization. Overall, this study highlights the unique and differential biology hijacked by BRAF fusions in response to RAFi and further warrants detailed mechanistic classification of BRAF fusions based on their responsiveness to targeted agents. Citation Format: Payal Jain, Lea F. Surrey, Joshua Straka, Pierre Russo, Richard Womer, Marilyn Li, Phillip B. Storm, Angela J. Waanders, Michael Hogarty, Jennifer Picarsic, Adam C. Resnick. Novel BRAF gene fusions in pediatric histiocytic neoplasms respond differentially to RAF targeted therapies based on dimerization profiles [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 632.

Introduction: Pelvic sarcomas may present with vague symptoms. The aim of this study was to examine the characteristics and clinical presentations of different types of pelvic sarcoma in children. Methods: This is a retrospective cohort study of patients up to 21 years of age with the diagnosis of pelvic sarcoma between January 2000 and June 2013. Data on demographics, tumor type and location, and clinical presentation were collected from the medical records. Results: A total of 59 patients [37 males (62.7%) and 22 females (37.3%)] were examined in this study. Mean age at presentation was 11.3 ± 5 years (range 0.8–21 years). Thirty-six patients had Ewing sarcoma (61%), 9 osteosarcoma (6.8%), 4 undifferentiated sarcoma (6.8%), 2 (3.4%) rhabdomyosarcoma, 2 synovial cell sarcoma, and one (1.7%) of each fibrosarcoma, dermatofibrosarcoma, fibromyxoid sarcoma, chondrosarcoma, chordoma, and epithelioid sarcoma. Pain at presentation was reported in 41 patients, 13 mass, 8 limping, and 5 neurologic symptoms. Most of the bony tumors were painful (77%), while most of the soft tissue tumors were painless (70%). Nine patients presented with constitutional symptoms. Most patients presented within 4–12 months from symptoms beginning. Twenty-one patients (35.6%) presented with metastases (14 Ewing sarcoma, 6 osteosarcoma, and 1 synovial cell sarcoma). Pelvic radiographs showed lytic lesion in 11 patients, 4 sclerotic lesions, 6 mixed lesion, 6 had only soft tissue mass, 1 radiograph showed osteopenia, and 2 radiographs were reported normal. Conclusion: Ewing sarcoma was the most common pelvic sarcoma tumor in children. In most cases, pelvic sarcoma in children presented with pain mimicking other benign conditions. Some patients presented with metastatic disease with no prognostic clinical or radiographical signs or symptoms. Pelvic sarcoma should be considered a differential diagnosis as part of children work up.

Background The combination of topotecan and cyclophosphamide is active in relapsed Ewing sarcoma family of tumors (ESFT). The feasibility of adding these agents combined with vincristine (vincristine–topotecan–cyclophosphamide [VTc]) to standard five-drug chemotherapy with vincristine–doxorubicin–cyclophosphamide (VDC) and ifosfamide–etoposide (IE) administered in an interval-compressed (2-week instead of 3-week intervals) schedule was investigated. Procedure Newly diagnosed patients with localized ESFT < 31 years, with good performance status and adequate organ function were eligible. Seventeen alternating cycles of chemotherapy with VTc, VDC, and IE were administered at 2-week intervals. Local control (LC) of the primary tumor occurred following six cycles. Primary endpoints were the ability to deliver chemotherapy in an interval-compressed schedule, and the rate of grade 3 or greater nonhematologic toxicity and grade 4 hematologic toxicity, which delayed chemotherapy by ≥2 weeks. Secondary endpoints were event-free survival (EFS) and overall survival (OS). Results Thirty-five patients with a median age of 11 years were enrolled. The mean time to last dose of chemotherapy prior to LC was 12.6 ± 1.4 weeks and 45.5% of patients received intended chemotherapy without any delay prior to LC. There were no toxic deaths or unexpected toxicities. Five-year EFS was 79.6% (95% confidence interval [CI]: 61.8–89.7%) and 5-year OS was 88% (95% CI: 71.4–95.3%). Conclusions The addition of VTc to standard therapy was tolerable with sufficient interval compression compared to historical standard 3-week cycles.

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

Relapse of Ewing sarcoma (ES) can occur months or years after initial remission and salvage therapy for relapsed disease is usually ineffective. Thus, there is great need to develop biomarkers that can predict which patients are at risk for relapse so that therapy and post-therapy evaluation can be adjusted accordingly. For the current study we performed whole genome expression profiling on two independent cohorts of clinically annotated ES tumors in an effort to identify and validate prognostic gene signatures. ES specimens were obtained from the Children's Oncology Group (COG) and whole genome expression profiling performed using Affymetrix Human Exon 1.0 ST arrays. Lists of differentially expressed genes between survivors and non-survivors were used to identify prognostic gene signatures. An independent cohort of tumors from the Euro-Ewing cooperative group was similarly analyzed as a validation cohort. Unsupervised clustering of gene expression data failed to segregate tumors based on outcome. Supervised analysis of survivors vs. non-survivors revealed a small number of differentially expressed genes and several statistically significant gene signatures. Gene specific enrichment analysis (GSEA) demonstrated that integrin and chemokine genes were associated with survival in tumors where stromal contamination was present. Tumors that did not harbor stromal contamination showed no association of any genes or pathways with clinical outcome. Our results reflect the challenges of performing RNA-based assays on archived bone tumor specimens. In addition, they reveal a key role for tumor stroma in determining ES prognosis. Future biologic and clinical investigations should focus on elucidating the contribution of tumor:microenvironment interactions on ES progression and response to therapy. Key words: ES, gene expression profiling, prognostic signature.

Purpose. To associate baseline patient characteristics and relapse across consecutive COG studies.Methods. We analyzed risk factors for LESFT patients in three randomized COG trials. We evaluated age at enrollment, primary site, gender, tumor size, and treatment (as randomized). We estimated event-free survival (EFS, Kaplan-Meier) and compared risk across groups (log-rank test). Characteristics were assessed by proportional hazards regression with the characteristic of interest as the only component. Confidence intervals (CI) for RR were derived. Factors related to outcome at level 0.05 were included in a multivariate regression model.Results. Between 12/1988 and 8/2005, 1444 patients were enrolled and data current to 2001, 2004, or 2008 were used. Patients were with a median age of 12 years (0–45), 55% male and 88% Caucasian. The 5-year EFS was 68.3% ± 1.3%. In univariate analysis age, treatment, and tumor location were identified for inclusion in the multivariate model, and all remained significant (p< 0.01). Since tumor size was not collected in the last study, the other two were reanalyzed. This model identified age, treatment, tumor location, and tumor size as significant predictors.Conclusion. Age > 18 years, pelvic tumor, size > 8 cms, and chemotherapy without ifosfamide/etoposide significantly predict worse outcome. AEWS0031 isNCT00006734, INT0091 and INT0054 designed before 1993 (unregistered).

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.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.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 aged18 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 (/≥ 8 cm) was available in 40% of patients and did not correlate with local failure incidence.Local tumor control is excellent and similar between surgery and RT for axial non-spine, spine, and extraskeletal tumors. Age ≥18 years and use of RT, primarily for pelvis and extremity tumors, are associated with the highest risk of local failure. Further efforts should focus on improving outcomes for these patients.

Purpose: Pediatric head and neck malignancies are managed with intensive multimodality therapy. Proton beam therapy (PBT) may reduce toxicity by limiting exposure of normal tissue to radiation. In this study, we report acute toxicities and early outcomes following PBT for pediatric head and neck malignancies.Materials and methods: Between 2010 and 2016, pediatric patients with nonhematologic malignancies of the head and neck were treated with PBT. Clinical and dosimetric data were abstracted from the medical record and treatment planning system with institutional review board approval.Results: Sixty-nine consecutive pediatric patients were treated with proton-based radiotherapy for head and neck malignancies. Thirty-five were treated for rhabdomyosarcoma to a median dose of 50.4 Gy relative biological effectiveness [RBE]. Ten patients were treated for Ewing sarcoma to a median dose of 55.8 Gy[RBE]. Twenty-four patients were treated for other histologies to a median dose of 63.0 Gy[RBE]. Grade 3 oral mucositis, anorexia, and dysphagia were reported to be 4, 22, and 7%, respectively. Actuarial 1-year freedom from local recurrence was 92% (95% CI 80–97). Actuarial 1-year overall survival was 93% (95% CI 79–98) in the entire cohort. Oral cavity mucositis was significantly correlated with oral cavity dose (D80 and D50 [P Conclusions: In this study, we report low rates of acute toxicity in a cohort of pediatric patients with head and neck malignancies. PBT appears safe for this patient population, with local control rates similar to historical reports. Longer follow-up will be required to evaluate late toxicity and long-term disease control.

Background A growing collection of retrospective studies have suggested that TP53 mutations and/or CDKN2A deletions have prognostic significance in Ewing sarcoma. We sought to evaluate these variables in patients with localized disease treated prospectively on a single Children’s Oncology Group protocol.

Background Patients with Ewing sarcoma require local primary tumor control with surgery, radiation, or both. Optimal choice of local control for overall and local disease control remains unclear.

ObjectiveWe sought to determine how sex and dexrazoxane therapy influence cardiac remodelling in children with sarcoma receiving high-dose doxorubicin.MethodsIn a retrospective cohort of 85 children with sarcoma receiving high-dose doxorubicin, echocardiography measures prior to, early after (within 6 months of doxorubicin completion) and 1 – 2 years after doxorubicin completion were quantified. At each follow-up visit, multivariable, propensity-adjusted linear regression models evaluated dexrazoxane’s effects on changes in left ventricular (LV) shortening fraction (SF), structure, strain and wall stress for subgroups divided by sex. Likelihood ratio tests assessed the interaction between sex and dexrazoxane in determining these changes.ResultsEarly after doxorubicin completion, males not treated with dexrazoxane (n = 15) developed increased cavity size and diminished circumferential strain; females (n = 8) developed diminished SF and strain indices, and increased cavity size and wall stress. With dexrazoxane, males (n = 33) demonstrated less deterioration in circumferential strain by 3.4% (95% CI 0.01 to 6.8), and females (n = 29) demonstrated less reduction in SF by 5.7% (95% CI 2.1 to 9.3), and had mitigation of increases in cavity size and wall stress. In interaction analyses, females had greater protection with dexrazoxane with regard to SF (p = 0.019) and cavity size in diastole (p = 0.002) and systole (p ≤ 0.001). These findings largely persisted 1 – 2 years after doxorubicin therapy.ConclusionsEarly, sustained alterations in LV structure and function occur in children with sarcoma after high-dose doxorubicin, with adverse changes and protective effects of dexrazoxane more pronounced in females as compared with males. Dexrazoxane may have sex-specific cardioprotective effects.

Purpose To simplify the recommended staging evaluation by correlating tumor and clinical features with patterns of distant metastasis in newly diagnosed patients with embryonal rhabdomyosarcoma (ERMS) or alveolar rhabdomyosarcoma (ARMS). Patients and Methods Patient data from the Intergroup Rhabdomyosarcoma Study Group and the Children's Oncology Group over two periods were analyzed: 1991 to 1997 and 1999 to 2004. We used recursive partitioning analyses to identify factors (including histology, age, regional nodal and distant metastatic status, tumor size, local invasiveness, and primary site) that divided patients into subsets with the most different rates of metastatic disease. Results Of the 1,687 patients analyzed, 5.7% had lung metastases, 4.8% had bone involvement, and 6% had bone marrow (BM) involvement. Rhabdomyosarcoma (RMS) without local invasion (T1) had a low rate of metastasis for all distant sites, especially ERMS (0% bone, 0% BM). ARMS with local invasion (T2) had a higher rate of metastasis for all distant sites (13% lung, 18% bone, 23% BM). ERMS, T2 also had a higher rate of metastatic lung involvement (9%). The likelihood of bone or BM involvement increased in the presence of lung metastases (41% with, 6% without). Regional nodal metastases (N1) predicted a high rate of metastasis in all distant sites (14% lung, 14% bone, 18% BM). A staging algorithm was developed. Conclusion Staging studies in childhood RMS can be tailored to patients' presenting characteristics. Bone marrow aspirate and biopsy and bone scan are unnecessary in at least one third of patients with RMS.

Background To determine feasibility and safety of proactive enteral tube feeding (ETF) in pediatric oncology patients. Methods Pediatric patients with newly diagnosed brain tumors, myeloid leukemia or high-risk solid tumors were eligible. Subjects agreeing to start ETF before cycle 2 chemotherapy were considered proactive participants (PPs). Those who declined could enroll as chart collection receiving nutritional standard of care. Nutritional status was assessed using standard anthropometric measurements. Episodes of infection and toxicity related to ETF were documented from diagnosis to end of therapy. A descriptive comparison between PPs and controls was conducted. Results One hundred four eligible patients were identified; 69 enrolled (20 PPs and 49 controls). At diagnosis, 17% of all subjects were underweight and 26% overweight. Barriers to enrollment included physician, subject and/or family refusal, and inability to initiate ETF prior to cycle 2 of chemotherapy. Toxicity of ETF was minimal, but higher percentage of subjects in the proactive group had episodes of infection than controls. Thirty-nine percent of controls eventually started ETF and were twice as likely to receive parenteral nutrition. PPs experienced less weight loss at ETF initiation than controls receiving ETF and were the only group to demonstrate improved nutritional status at end of study. Conclusions Proactive ETF is feasible in children with cancer and results in improved nutritional status at end of therapy. Episodes of infection in this study are concerning; therefore, a larger randomized trial is required to further delineate infectious risks and toxicities that may be mitigated by improved nutritional status. Pediatr Blood Cancer 2014;61:281–285. © 2013 Wiley Periodicals, Inc.

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 × 106/L and a platelet count greater than 75 × 109/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 Ewing sarcoma family tumors (ESFTs) exhibit chromosomal translocations that lead to the creation of chimeric fusion oncogenes. Combinatorial diversity among chromosomal breakpoints produces varying fusions. The type 1 EWS-FLI1 transcript is created as a result of fusion between exons 7 of EWS and 6 of FLI1, and retrospective studies have reported that type 1 tumors are associated with an improved outcome. We have re-examined this association in a prospective cohort of patients with ESFT treated according to current Children's Oncology Group (COG) treatment protocols. Methods Frozen tumor tissue was prospectively obtained from patients diagnosed with ESFT, and reverse transcriptase polymerase chain reaction (RT-PCR) was used to determine translocation status. Analysis was confined to patients with localized tumors who were diagnosed after 1994 and treated according to COG protocols. Translocation status was correlated with disease characteristics, event-free survival (EFS), and overall survival (OS). Results RT-PCR identified chimeric fusion oncogenes in 119 of 132 ESFTs. Eighty-nine percent of identified transcripts were EWS-FLI1, and of these, 58.8% were type 1. Five-year EFS and OS rates for patients with type 1 and non–type 1 fusions diagnosed between 2001 and 2005 were equivalent (type 1: EFS, 63% ± 7%; OS, 83% ± 6%; non–type 1: EFS, 71% ± 9%; OS, 79% ± 8%). Conclusion Current intensive treatment protocols for localized ESFT have erased the clinical disadvantage that was formerly observed in patients with non–type 1 EWS-FLI1 fusions.

In the field of sarcoma molecular diagnosis, the "test" most frequently requested is for the gene fusions generated by the chromosomal translocations in Ewing family tumors (EFTs). Of note, this test is perhaps the most complicated of all of the molecular assays in the sarcoma diagnostic toolbox. Starting with the frequent 11;22 translocation involving the EWS gene on chromosome 22 and the FLI1 gene on chromosome 11, the chromosome breakpoints are spread among four introns in the EWS gene and six introns in the FLI1 gene to give a large number of possible EWS-FLI1 fusion products.1 The size of the fusion transcripts can vary over a 700-bp range, thereby necessitating cautious investigation of a large range of product sizes in diagnostic reverse transcription-polymerase chain reaction (RT-PCR) assays. To increase the complexity further, a relatively frequent variant 21;22 chromosomal translocation generates a fusion of EWS to ERG, which encodes an ETS domain-containing transcription factor highly related to FLI1 with a comparable distribution of chromosomal breakpoints.1 Next, as described in the article by Wang and associates in this issue of The Journal of Molecular Diagnostics,2 the complexity continues to rise as there are three additional translocations [t(2;22), t(7;22), and t(17;22)] that juxtapose EWS to genes, encoding three additional members of the ETS transcription factor family (FEV, ETV1, and E1AF, respectively) in small numbers of EFT cases. In addition to these rare variant fusions, there is also a second set of rare variants involving the FUS gene, which encodes an RNA-binding protein highly related to EWS. This second set includes a 16;21 translocation in which FUS is juxtaposed to ERG,3 which was found in a small group of cases and, as described by Ng and colleagues4 also in this issue of the JMD, a FUS-FEV fusion resulting from a novel 2;16 translocation found in a single case. Based on these collective findings, a definitive investigation of the gene fusions associated with EFT is, to put it simply, a daunting task.

Relapse of Ewing sarcoma (ES) can occur months or years after initial remission, and salvage therapy for relapsed disease is usually ineffective. Thus, there is great need to develop biomarkers that can predict which patients are at risk for relapse so that therapy and post‐therapy evaluation can be adjusted accordingly. For this study, we performed whole genome expression profiling on two independent cohorts of clinically annotated ES tumours in an effort to identify and validate prognostic gene signatures. ES specimens were obtained from the Children's Oncology Group and whole genome expression profiling performed using Affymetrix Human Exon 1.0 ST arrays. Lists of differentially expressed genes between survivors and non‐survivors were used to identify prognostic gene signatures. An independent cohort of tumours from the Euro‐Ewing cooperative group was similarly analysed as a validation cohort. Unsupervised clustering of gene expression data failed to segregate tumours based on outcome. Supervised analysis of survivors versus non‐survivors revealed a small number of differentially expressed genes and several statistically significant gene signatures. Gene‐specific enrichment analysis demonstrated that integrin and chemokine genes were associated with survival in tumours where stromal contamination was present. Tumours that did not harbour stromal contamination showed no association of any genes or pathways with clinical outcome. Our results reflect the challenges of performing RNA‐based assays on archived bone tumour specimens. In addition, they reveal a key role for tumour stroma in determining ES prognosis. Future biological and clinical investigations should focus on elucidating the contribution of tumour:micro‐environment interactions on ES progression and response to therapy.

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.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.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.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.

Author(s): Monument, Michael J; Johnson, Kirsten M; McIlvaine, Elizabeth; Abegglen, Lisa; Watkins, W Scott; Jorde, Lynn B; Womer, Richard B; Beeler, Natalie; Monovich, Laura; Lawlor, Elizabeth R; Bridge, Julia A; Schiffman, Joshua D; Krailo, Mark D; Randall, R Lor; Lessnick, Stephen L | Abstract: BackgroundThe genetics involved in Ewing sarcoma susceptibility and prognosis are poorly understood. EWS/FLI and related EWS/ETS chimeras upregulate numerous gene targets via promoter-based GGAA-microsatellite response elements. These microsatellites are highly polymorphic in humans, and preliminary evidence suggests EWS/FLI-mediated gene expression is highly dependent on the number of GGAA motifs within the microsatellite.ObjectivesHere we sought to examine the polymorphic spectrum of a GGAA-microsatellite within the NR0B1 promoter (a critical EWS/FLI target) in primary Ewing sarcoma tumors, and characterize how this polymorphism influences gene expression and clinical outcomes.ResultsA complex, bimodal pattern of EWS/FLI-mediated gene expression was observed across a wide range of GGAA motifs, with maximal expression observed in constructs containing 20-26 GGAA motifs. Relative to white European and African controls, the NR0B1 GGAA-microsatellite in tumor cells demonstrated a strong bias for haplotypes containing 21-25 GGAA motifs suggesting a relationship between microsatellite function and disease susceptibility. This selection bias was not a product of microsatellite instability in tumor samples, nor was there a correlation between NR0B1 GGAA-microsatellite polymorphisms and survival outcomes.ConclusionsThese data suggest that GGAA-microsatellite polymorphisms observed in human populations modulate EWS/FLI-mediated gene expression and may influence disease susceptibility in Ewing sarcoma.

BACKGROUND Rhabdomyosarcoma (RMS) of the parotid region is rare and to the authors' knowledge little information is available regarding the site of tumor origin, clinical presentation, and outcome in these patients. Therefore, the authors reviewed the files of all patients with RMS of the parotid region who were registered on the Intergroup Rhabdomyosarcoma Studies (IRS) I–IV. METHODS Patient charts and the Intergroup Rhabdomyosarcoma Study Group (IRSG) database were reviewed. RESULTS Sixty-two patients presenting with a mass in the parotid region were identified. None of the tumors was localized exclusively to the parotid gland, so the primary site was referred to as the “parotid region.” The tumor invaded a parameningeal site in 30 patients. These cases have been designated as parameningeal-parotid tumors to distinguish them from 32 cases that did not invade a parameningeal site and were designated as nonparameningeal-parotid tumors. The majority of patients had Group III tumors in both the nonparameningeal-parotid and parameningeal-parotid subgroups. However, although there were 16 patients with Group I or II tumors in the nonparameningeal-parotid subgroup, no patients with Group I or II tumors were found in the parameningeal-parotid subgroup (P = 0.001). Fifty-six of 62 patients (90%) received radiotherapy. The parameningeal primary site designation resulted in intensification of both chemotherapy and radiotherapy for patients with parameningeal-parotid RMS. The 5-year failure-free survival rate was 81% and the 5-year survival rate was 84%. There were no deaths reported among patients with Group I or II tumors. The 5-year failure-free survival did not appear to differ when comparing patients with parameningeal-parotid tumors with patients with nonparameningeal-parotid tumors (P = 0.21). CONCLUSIONS Treatment as defined by the IRS protocols has been reported to be highly effective for patients with RMS of the parotid region. Outcome for the more aggressively treated patients with parameningeal-parotid RMS appears similar to that for patients with nonparameningeal-parotid RMS. Cancer 2001;92:3135–46. © 2001 American Cancer Society.

A goal of the COG Ewing Sarcoma Biology Committee is enabling identification of reliable biomarkers that can predict treatment response and outcome through the use of prospectively collected tissues and correlative studies in concert with COG therapeutic studies. In this report, we aim to provide a concise review of the most well-characterized prognostic biomarkers in Ewing Sarcoma (ES), and to provide recommendations concerning design and implementation of future biomarker studies. Of particular interest and potentially high clinical relevance are studies of cell cycle proteins, sub-clinical disease, and copy number alterations. We discuss findings of particular interest from recent biomarker studies and examine factors important to the success of identifying and validating clinically relevant biomarkers in ES. A number of promising biomarkers have demonstrated prognostic significance in numerous retrospective studies and now need to be validated prospectively in larger cohorts of equivalently treated patients. The eventual goal of refining the discovery and use of clinically relevant biomarkers is the development of patient specific ES therapeutic modalities.

Multidisciplinary care and advances in chemotherapy have dramatically improved the prognosis of paediatric sarcoma patients, but much work remains. There are new techniques for molecular diagnosis of Ewing's sarcomas and alveolar rhabdomyosarcomas, with molecular techniques of staging and subclassification under development. Osteosarcoma is a clinically heterogeneous disease which continues to resist biologic diagnosis, classification, or staging. In chemotherapy, the roles of ifosfamide and doxorubicin in rhabdomyosarcoma treatment remain unclear. While many children with metastatic or recurrent sarcomas undergo massive therapy with peripheral stem cell or autologous marrow rescue, the efficacy of these manoeuvres is debatable. Osteosarcoma appears to respond best to regimens containing doxorubicin and cisplatin, while the roles of alkylating agents, high-dose methotrexate, and carboplatin remain unclear. Ewing's sarcoma treatment increasingly includes surgery because of the risk of secondary osteosarcoma after radiation. Most osteosarcoma patients now have limb-sparing excisions, though amputation may provide better function and cosmesis with less risk of complications in some patients. The role of multimodal treatment including chemotherapy for the miscellaneous soft tissue sarcomas remains uncertain.

BACKGROUND: The insulin-like growth factor-1 (IGF-1) signaling pathway plays an important role in the pathology of Ewing sarcoma (ES). Retrospective studies have suggested that levels of IGF-1 and IGF binding protein 3 (IGFBP-3) are correlated with the outcome of patients with ES. METHODS: The IGF-1 signaling pathway was investigated prospectively in 269 patients who had localized, previously untreated ES. Serum samples were obtained at diagnosis, and concentrations of IGF-1 and IGFBP-3 were determined by enzyme-linked immunosorbent assays. In addition, immunohistochemistry (IHC) was performed to assay for phosphorylated p70S6 kinase, protein kinase B (Akt), and forkhead box protein O1 (FOXO1) and to determine the presence of protein tyrosine phosphatase-L1 (PTPL1). IHC findings along with IGF-1 and IGFBP-3 concentrations were correlated with age, tumor location, sex, event-free survival, and overall survival. RESULTS: Patients aged >18 years tended to have higher levels of IGF-1 (P ¼ .10), lower levels of IGFBP-3 (P ¼ .16), and decreased IGFBP-3:IGF-1 ratios (P ¼ .01). No correlations were observed between sex, tumor location, or outcomes and concentrations of IGF-1 or IGFBP-3. Phosphorylation of p70S6 kinase, Akt, and FOXO1 was detected in the majority of patient tissues but was not associated with age, sex, or tumor location. PTPL1 was present in >80% of tumors and also was not correlated with age, sex, or tumor location. There was no difference in survival with respect to the presence of phosphorylated p70S6 kinase, phosphorylated FOXO1, phosphorylated Akt, or PTPL1. CONCLUSIONS: The baseline IGFBP-3:IGF-1 ratio was correlated with age but did not affect the outcomes of patients with ES. The authors concluded that additional investigation of the IGF-1 pathway is warranted in patients with ES, and especially in those who have received treatment with IGF-1 receptor antibody inhibitors. Cancer 2011;117:4966–76. V C 2011 American Cancer Society.

A retrospective analysis identified 29 children with nasopharyngeal malignancies who were evaluated at the Children's Hospital of Philadelphia from 1970 through 1989. Rhabdomyosarcoma (15) and carcinoma (9) were the most common tumor types, and there were distinct differences in the clinical presentations of these two malignancies. Patients with rhabdomyosarcoma were generally younger than those with carcinoma and enjoyed longer survival. Six (67%) of the children with carcinoma were black; all of the patients with rhabdomyosarcoma were white. Patients with carcinoma were also more likely to present with cervical metastases. The presentation, evaluation, and methods of treatment for pediatric nasopharyngeal malignancies are discussed.

The addition of liposomal muramyl tripeptide phosphatidylethanolamine (MTP-PE) to chemotherapy has been shown to improve overall survival in patients with nonmetastatic osteosarcoma (OS). The authors report the results of addition of liposomal MTP-PE to chemotherapy for patients with metastatic OS.Intergroup-0133 was a prospective randomized phase 3 trial for the treatment of newly diagnosed patients with OS. The authors compared 3-drug chemotherapy with cisplatin, doxorubicin, and high-dose methotrexate (Regimen A) to the same 3 drugs with the addition of ifosfamide (Regimen B). The addition of liposomal MTP-PE to chemotherapy was evaluated.Five-year event-free survival (EFS) for patients who received liposomal MTP-PE (n = 46) was 42% versus 26% for those who did not (n = 45) (relative risk for liposomal MTP-PE, 0.72; P = .23; 95% confidence interval [CI], 0.42-1.2). The 5-year overall survival for patients who received MTP-PE versus no MTP-PE was 53% and 40%, respectively (relative risk for liposomal MTP-PE, 0.72; P = 0.27; 95% CI, 0.40-1.3). The comparison of Regimen A with Regimen B did not suggest a difference for EFS (35% vs 34%, respectively; relative risk for Regimen B, 1.07; P = .79; 95% CI, 0.62-1.8) or overall survival (52% vs 43%, respectively; relative risk for Regimen B, 1.1, P = .75; 95% CI, 0.61-2.0).When the metastatic cohort was considered in isolation, the addition of liposomal MTP-PE to chemotherapy did not achieve a statistically significant improvement in outcome. However, the pattern of outcome is similar to the pattern in nonmetastatic patients.

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.

Background: The dose intensity of chemotherapy has been described as affecting the outcome of the treatment of a number of different types of tumors. A delay in the resumption of chemotherapy after definitive surgery for the treatment of osteosarcoma can decrease the overall dose intensity. The goal of this study was to assess the prognostic significance of the time to resumption of chemotherapy after definitive surgery in patients with localized osteosarcoma in an extremity. Methods: The relationships of the time between definitive surgery and resumption of chemotherapy with death and adverse events in 703 patients with a localized resectable osteosarcoma in an extremity (556 treated in the Children's Oncology Group [COG] Study [INT 0133] and 147 treated at five tertiary care cancer centers) were assessed with use of Cox proportional hazards models. Results: The twenty-fifth, fiftieth, and seventy-fifth percentiles of time from definitive surgery to resumption of chemotherapy were twelve, sixteen, and twenty-one days, respectively. Overall survival was poorer for patients who had had a delay of greater than twenty-one days before the resumption of chemotherapy compared with those who had had a shorter delay (hazard ratio = 1.57 [95% confidence interval = 1.04 to 2.36]; p = 0.03). Of seventy-one COG-study patients with postoperative complications, 32% (twenty-three) had a delay of more than twenty-one days before resumption of chemotherapy, but 20% (eighty-nine) of 444 patients with no complications had a similar delay. Conclusions: In this retrospective analysis, increased time from the definitive surgery to the resumption of chemotherapy was found to be associated with an increased risk of death of patients with localized osteosarcoma in an extremity. Within the limitations of a retrospective study, the data indicate that it is best to resume chemotherapy within twenty-one days after definitive surgery. Surgeons, oncologists, patients, and those responsible for scheduling need to work together to ensure timely resumption of chemotherapy after surgery. Level of Evidence: Prognostic Level II. See Instructions to Authors for a complete description of levels of evidence.

BACKGROUND High-dose cisplatin combined with etoposide and bleomycin (HDPEB) improves event-free survival (EFS) in advanced pediatric germ-cell tumors (PGCT), but has significant ototoxicity. Amifostine appears to protect against toxicity. The authors combined amifostine with HDPEB and evaluated the efficacy and toxicity, specifically whether ototoxicity deccreased. METHODS Eligibility criteria included age < 15 years and unresectable Stage III/IV extracranial, extragonadal PGCT. Patients received bleomycin 15 IU/m2 on Day 1, then etoposide 100 mg/m2 per day, amifostine 825 mg/m2 per day, and cisplatin 40 mg/m2per day on Days 1–5, intravenously. The cycles were repeated every 3–4 weeks with imaging evaluation after 4 cycles. Patients with residual radiographic abnormalities underwent resection. Patients with residual tumor received two additional HDPEB cycles. Hearing evaluations were required at diagnosis and after two and four cycles. Audiologic results were reviewed and compared with historical controls treated with HDPEB. RESULTS Twenty-five eligible patients were enrolled between April 2000 and April 2002. Their median age was 1.6 years (range, 0.64–13.9 years), 17 patients were female, 11 had metastases, and 24 had a yolk sac carcinoma component histologically. Primary sites included sacrococcygeal area/pelvis (n = 15), vagina (n = 5), and other (n = 5). Two-year EFS and overall survival were 83.5% ± 12.8% and 85.6% ± 12.3%, respectively. Eight patients were removed from the study (four had progressive disease/disease recurrence and four had ototoxicity). Grade 3/4 toxicities included neutropenia (n = 20), thrombocytopenia (n = 14), electrolyte imbalances (n = 14), and gastrointestinal toxicity (n = 12). Twenty-four of 25 patients received hearing evaluations, and 75% had significant hearing loss. CONCLUSIONS Amifostine did not protect against HDPEB-associated ototoxicity. Cancer 2005. © 2005 American Cancer Society.

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 ≤ 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.