Non-metastatic Ewing's Sarcoma Research Articles

Analysis of 41 cases of non-metastatic Ewing's sarcoma in children

To summarize the clinical characteristics, treatment outcomes, and prognostic factors of children with non-metastatic Ewing's sarcoma (ES). A retrospective analysis was conducted on the clinical data of 41 children with non-metastatic ES diagnosed and treated at the Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine from January 2010 to December 2018. All patients underwent chemotherapy based on the RMS-2009 protocol of the center, and local treatment such as surgery and/or radiotherapy was performed according to risk grouping. The Kaplan-Meier method was used to calculate the overall survival (OS) and event-free survival (EFS) rates. Univariate prognostic analysis was performed using the log-rank test, and multivariate analysis was conducted with Cox regression. Of the 41 children, 21 were male and 20 were female. The median age at diagnosis was 7.7 years (range: 1.2-14.6 years). The median follow-up time for patients with event-free survival was 68.1 months (range: 8.1-151.7 months). As of the last follow-up, 33 patients were in complete remission, and the overall 5-year EFS and OS rates were (78±6)% and (82±6)%, respectively. Univariate analysis by the log-rank test showed that a tumor diameter ≥8 cm, time from diagnosis to start of local treatment ≥16 weeks, and incomplete surgical resection were associated with poor prognosis (P<0.05). Multivariate Cox regression analysis indicated that incomplete surgical resection (HR=8.381, 95%CI: 1.681-41.801, P=0.010) was an independent risk factor for poor prognosis in children with ES. Secondary tumors occurred in 2 cases. A comprehensive treatment strategy incorporating chemotherapy, surgery, and radiotherapy can improve the prognosis of children with ES. Poor prognosis is associated with an initial tumor diameter ≥8 cm, while complete surgical resection and early initiation of local treatment can improve outcomes.

Disparities in incidence and survival for patients with Ewing sarcoma in Florida.

Ewing sarcoma (ES) is a malignant bone tumor most commonly affecting non-Hispanic White (NHW) adolescent males, though recognition among Hispanic individuals is rising. Prior population-based studies in the United States (US), utilizing Surveillance, Epidemiology, and End Results (SEER) have shown higher all-cause mortality among White Hispanics, Blacks, and those of low socioeconomic status (SES). Florida is not part of SEER but is home to unique Hispanic populations including Cubans, Puerto Ricans, South Americans that contrasts with the Mexican Hispanic majority in other US states. This study aimed to assess racial/ethnic disparities on incidence and survival outcomes among this diverse Florida patient population. Our study examined all patients diagnosed with osseous ES (2005-2018) in Florida (n = 411) based on the state's population-based cancer registry dataset. Florida Age-adjusted Incidence Rates (AAIRs) were computed by sex and race-ethnicity and compared to the equivalent populations in SEER. Cause-specific survival disparities among Florida patients were examined using Kaplan-Meier analysis. Univariable and multivariable analyses using Cox regression were performed for race/ethnicity, with adjustment for age, sex, year of diagnosis, site of disease, staging, SES, and insurance type. There was a significantly higher incidence of osseous ES in Florida Hispanic males (AAIR 2.6/1,000,000); (95% CI: 2.0-3.2 per 1,000,000; n = 84) compared to the SEER Hispanic males (AAIR 1.2/1,000,000;1.1-1.4 per 1,000,000; n = 382). Older age, distant metastasis, lack of chemotherapy or surgical resection were statistically significant determinants of poor survival while SES, insurance status and race-ethnicity were not. However, among nonmetastatic ES, Florida Hispanics had an increased risk of death compared to Florida NHW (adjusted Hazard Ratio 2.32; 95%CI: 1.20-4.46; p = 0.012). Florida Hispanic males have a higher-than-expected incidence of osseous ES compared to the US. Hispanics of both sexes show remarkably worse survival for nonmetastatic disease compared to NHW. This disparity is likely multifactorial and requires further in-depth studies.

Non-chemotherapy adjuvant agents in TP53 mutant Ewing sarcoma

Ewing sarcoma (EWS) is a malignant tumor arising in bone or soft tissue that occurs in adolescent and young adult patients as well as adults later in life. Although non-metastatic EWS is typically responsive to treatment when newly diagnosed, relapsed cases have an unmet need for which no standard treatment approach exists. Recent phase III clinical trials for EWS comparing 7 vs 5 chemotherapy drugs have failed to improve survival. To extend the durability of remission for EWS, we investigated 3 non-chemotherapy adjuvant therapy drug candidates to be combined with chemotherapy. The efficacy of these adjuvant drugs was investigated via anchorage-dependent growth assays, anchorage-independent soft-agar colony formation assays and EWS xenograft mouse models. Enoxacin and entinostat were the most effective adjuvant drug in both long-term in vitro and in vivo adjuvant studies. In the context that enoxacin is an FDA-approved antibiotic, and that entinostat is an investigational agent not yet FDA-approved, we propose enoxacin as an adjuvant drug for further preclinical and clinical investigation in EWS patients.

Effect of Radiotherapy Dose on Outcome in Nonmetastatic Ewing Sarcoma

Radiation therapy (RT) is an integral part of Ewing sarcoma (EwS) therapy. The Ewing 2008 protocol recommended RT doses ranging from 45 to 54 Gy. However, some patients received other doses of RT. We analyzed the effect of different RT doses on event-free survival (EFS) and overall survival (OS) in patients with EwS. The Ewing 2008 database included 528 RT-admitted patients with nonmetastatic EwS. Recommended multimodal therapy consisted of multiagent chemotherapy and local treatment consisting of surgery (S&RT group) and/or RT (RT group). EFS and OS were analyzed with uni- and multivariable Cox regression models including known prognostic factors such as age, sex, tumor volume, surgical margins, and histologic response. S&RT was performed in 332 patients (62.9%), and 145 patients (27.5%) received definitive RT. Standard dose ≤ 53 Gy (d1) was admitted in 57.8%, high dose of 54 to 58 Gy (d2) in 35.5%, and very high dose ≥ 59 Gy (d3) in 6.6% of patients. In the RT group, RT dose was d1 in 11.7%, d2 in 44.1%, and d3 in 44.1% of patients. Three-year EFS in the S&RT group was 76.6% for d1, 73.7% for d2, and 68.2% for d3 (P=.42) and in the RT group 52.9%, 62.5%, and 70.3% (P=.63), respectively. Multivariable Cox regression revealed age ≥ 15 years (hazard ratio [HR], 2.68; 95% confidence interval [CI], 1.63-4.38) and nonradical margins (HR, 1.76; 95% CI, 1.05-2.93) for the S&RT group (sex, P=.96; histologic response, P=.07; tumor volume, P=.50; dose, P=.10) and large tumor volume (HR, 2.20; 95% CI, 1.21-4.0) for the RT group as independent factors (dose, P=.15; age, P=.08; sex, P=.40). In the combined local therapy modality group, treatment with higher RT dose had an effect on EFS, whereas higher dose of radiation when treated with definitive RT was associated with an increased OS. Indications for selection biases for dosage were found. Upcoming trials will assess the value of different RT doses in a randomized manner to control for potential selection bias.

EWING'S SARCOMA IN THE PREMAXILLA OF A PEDIATRIC PATIENT: A CASE REPORT

In August 2019, a 5-year-old female pediatric patient was diagnosed with primary non-metastatic Ewing sarcoma. She began chemotherapy treatment in September 2019, ending in November 2019. Subsequently, she was referred to a head and neck specialist, where a tumor was observed in the upper anterior alveolar edge. A biopsy was performed which confirmed Ewing´s sarcoma and showed an infiltrate in the entire premaxilla without posterior or midface involvement. Surgery for tumor resection was performed in March 2020, with a conclusive biopsy of small and round cell malignant neoplasm, consistent with Ewing´s sarcoma, the surgical margins were compromised, thus requiring complementary radiotherapy treatment. The rehabilitation was performed with a polypropylene obturator prosthesis in the premaxilla region. The patient returned for a check-up, without complaints, and was able to express herself in an intelligible manner, with her stomatognathic functions in balance. In August 2019, a 5-year-old female pediatric patient was diagnosed with primary non-metastatic Ewing sarcoma. She began chemotherapy treatment in September 2019, ending in November 2019. Subsequently, she was referred to a head and neck specialist, where a tumor was observed in the upper anterior alveolar edge. A biopsy was performed which confirmed Ewing´s sarcoma and showed an infiltrate in the entire premaxilla without posterior or midface involvement. Surgery for tumor resection was performed in March 2020, with a conclusive biopsy of small and round cell malignant neoplasm, consistent with Ewing´s sarcoma, the surgical margins were compromised, thus requiring complementary radiotherapy treatment. The rehabilitation was performed with a polypropylene obturator prosthesis in the premaxilla region. The patient returned for a check-up, without complaints, and was able to express herself in an intelligible manner, with her stomatognathic functions in balance.

Health disparities among patients with Ewing sarcoma in Florida.

e18549 Background: Ewing sarcoma (ES) is the second most common malignant bone tumor in children and young adults. Although usually localized, subclinical metastatic disease is often present. Treatment includes multi-agent chemotherapy with surgery or radiation for local control. Though overall survival (OS) has improved to 70% for localized disease, mortality from recurrent or metastatic disease remains high. Although, ES is most common among Non-Hispanic White adolescent males, prior population-based ES studies utilizing Surveillance, Epidemiology, and End Results (SEER) have shown increased mortality among White Hispanics, Blacks, and those of low socioeconomic status (SES). Florida is not part of SEER but is home to a unique population with high proportions of immigrants and Hispanics of distinct backgrounds including Cubans, Puerto Ricans, and South Americans that contrasts to the Mexican Hispanic majority in other US states. As there are no prior population-based studies examining ES in Florida, the role of racial/ethnic disparities on outcomes among this diverse patient population remains unknown. By utilizing the Florida Cancer Data System (FCDS) for ES patients, this study will assess overall racial/ethnic disparities, evaluate the impact of racial/ethnic disparities on OS, and compare ES incidence rates in Florida with national SEER-21 rates to assess risk. Methods: This retrospective secondary analysis examined all patients diagnosed with ES (2005-2018) in Florida (n = 411) and SEER-21 (n = 1,513). Age-adjusted incidence (AAI) with 95% confidence interval (95%CI) was analyzed for the entire group and OS was estimated using Kaplan-Meier survival analysis. Univariable and multivariable analyses using Cox regression models were performed for variables of interest—race/ethnicity, age, sex, year of diagnosis, site of disease, staging, SES, and insurance type. Adjusted hazard ratio (aHR) with 95%CI were calculated. Results: Per the FCDS, there was a higher incidence of ES in Hispanic males (AAI 2.6; 95%CI: 2.0-3.2 per 1,000,000; n = 84) as compared to the SEER (1.2; 1.1-1.4; n = 250). Among non-metastatic ES, Hispanics had an increased risk for cancer-related mortality compared to Non-Hispanic Whites (aHR 2.9; 95%CI: 1.46-5.74; p =0.002), after adjusting for all other variables. In the full model (all cases regardless of stage at diagnosis), older age and distant metastasis were statistically significant factors for poor OS while SES and insurance status were not. Conclusions: Hispanics in Florida are of interest for ES with a higher-than-expected incidence compared to the US and remarkably worse survival for non-metastatic disease compared to Non-Hispanic Whites. Further in-depth studies are needed to examine why this disparity exists, but it is potentially multifactorial. This is the first known study for ES health disparities in Florida and provides updated national data for comparison.

Local Failure in Non-Metastatic Ewing Sarcoma Patients Treated with Definitive Radiation Therapy on AEWS1031: A Report from the Children's Oncology Group

<h3>Purpose/Objective(s)</h3> To evaluate clinical and treatment variables associated with local failure for Ewing sarcoma (ES) patients treated with definitive radiation therapy (RT) on AEWS1031. <h3>Materials/Methods</h3> AEWS1031 was a randomized phase 3 trial comparing two interval compressed chemotherapy regimens. Local control modality (surgery alone; RT; surgery + radiation) was at the discretion of the treating investigator. Local failure (LF) was defined as LF only or combined LF and distant failure. Standardized uptake values from PET obtained prior to (SUV1) and after neoadjuvant chemotherapy (SUV2) were used to define chemotherapy response. Good PET response was defined as tumor SUV2:1 ≤ 0.5. Event-free survival (EFS) and cumulative incidence of LF from local control in the cohort treated with RT only was estimated using the method of Fine and Gray. <h3>Results</h3> Patients in the cohort (n=159) had 60 pelvis (38%), 24 extremity (15%), 46 spine/chest wall/skull (29%), and 29 (12%) extraosseous tumors. 79% of patients were <18 years. Tumor volume was available in 148 patients with 105 tumors (71%) <200 mL at diagnosis. SUV2:1 ratio was available in 65 patients and 51 (78%) had a good PET response. Central RT plan review was conducted in 155 cases with 6 cases (3.8%) logged as a major protocol deviation. With a median follow up of 67 months after RT, five-year post-local control EFS was 81.8% (95% CI, 74.8–87.1%) and cumulative incidence of LF was 7.8% (95% CI, 4.5-13%). The cumulative incidence of combined local and distant relapse was 0.65% (95% CI, 0.09-4.5%). LF incidence by tumor site was 8.6% for pelvis, 12.5% for extremities, 6.7% for spine/chest wall/skull, and 3.6% for extraosseous tumors (p=0.61). LF incidence was higher for tumors ≥200 mL (14.3%) compared to tumors <200 mL (5.9%, p=0.04). There was no significant difference in LF for good PET responses vs. not (6% vs. 0%, p=0.30) and by patient age (12.9%, ≥18 years vs. 6.5%, <18 years; p=0.32). A major RT protocol deviation was associated with a higher LF incidence of 33.3% vs. 7% for none and/or minor deviations (p=0.03). <h3>Conclusion</h3> Local tumor control for patients treated with definitive RT on AEWS1031 (7.8% LF) was superior compared to prior COG ES studies (15.3% LF from combined INT0091, INT0154, and AEWS0031 analysis). In patients with unresectable primary tumors, PET response, tumor site, and patient age were not associated with LF. Tumor volume ≥200 mL at diagnosis and major RT protocol deviations were associated with higher LF. These data highlight the need for quality assurance when RT is the primary modality of local control.

New Approaches Promise to Improve Local Ewing Sarcoma Results.

The study by Whelan and colleagues showed that addition of busulfan and melphalan conditioning and autologous stem cell rescue to conventional EURO-E.W.I.N.G STUDY chemotherapy in local nonmetastatic Ewing sarcoma improves prognosis. However, almost 30% of these study patients will have relapsed before this stage of therapy is reached, and 78% of his patients were at high risk because of inadequate response to the initial chemotherapy given. Further improvement could be achieved by the integration of other novel advances with this approach. Ash and colleagues have shown that the separation of such cases into high- and low-risk groups by using CD56 negativity of the tumor cells is an improvement over current methods with a 100% 10-year progression-free survival in CD56- nonpelvic local isolated Ewing sarcoma patients. Their patients were treated on the SCMCIE 94 protocol, associated with no relapses before 30 months in 24 consecutive patients independent of the CD status. Integration of these novel approaches in diagnosis and treatment would allow truly high-risk patients, who would benefit from the procedure, to reach the busulfan and melphalan stage of therapy and delineate those patients who can be cured without such therapy. Details of the SCMCIE 94 protocol are given and the possible reasons for the different relapse patterns are discussed.

Construction and validation of nomograms for non-metastatic Ewing sarcoma: A prognostic factor analysis based on the SEER database.

Ewing sarcoma is the second most common osseous disease in children and adolescents. It presents with a poor prognosis due to the high degree of malignancy and distant metastasis. In order to predict the disease prognosis and investigate a suitable therapeutic strategy for Ewing sarcoma, the present study aimed to describe the clinical characteristics, and to construct and validate nomograms for patients with non-metastatic Ewing sarcoma. A total of 627 cases of non-metastatic Ewing sarcoma were retrospectively collected from the Surveillance, Epidemiology, and End Results database between 2005 and 2014. Survival analysis and a machine learning model were used to identify independent prognostic variables and establish nomograms to estimate overall survival (OS) and cause-specific survival (CSS). The nomograms were bootstrap internally validated and externally validated using non-metastatic Ewing sarcoma cases from the First Affiliated Hospital of Zhengzhou University. The accuracy was also assessed by comparing with current American Joint Committee on Cancer (AJCC) staging systems. The total series consisted of 627 patients with non-metastatic Ewing sarcoma with a mean age of 20.14 years. Age, tumor extension, sex, International Classification of Diseases for Oncology, 3rd Edition histology, surgery and chemotherapy were identified as independent risk factors for OS and CSS. The aforementioned outcomes were incorporated to construct the nomograms, and the concordance indices (C-indices) for internal validation of OS and CSS prediction were 0.791 and 0.813, which were higher than those for AJCC sixth edition (OS, 0.531; CSS, 0.534) and seventh edition (OS, 0.547; CSS, 0.561), while the C-indices for external validation of OS and CSS prediction were 0.834 and 0.825, respectively. In conclusion, age, sex, tumor extension and surgery were independent prognostic factors for both OS and CSS. In addition, with regard to OS, the Ewing sarcoma subtype was a poor factor and chemotherapy was a favorable one. Nomograms based on reduced Cox models attained a satisfactory accuracy in predicting the survival of patients with non-metastatic Ewing sarcoma and could assist clinicians in evaluating survival more accurately.

Adolescent-adult nonmetastatic Ewing sarcoma-Experience from a large developing country.

Outcome and toxicity data in adolescent-adult Ewing sarcoma (AA-ES) patients are sparse and merits exploration. Histopathologically confirmed, nonmetastatic AA-ES patients, who received standard institutional combination chemotherapy regimen (Ewing's family of tumors-2001 [EFT-2001]) comprising of ifosfamide plus etoposide and vincristine, doxorubicin plus cyclophosphamide, lasting a total of 12months between 2013 and 2018, were analyzed for treatment-related toxicities, event-free survival (EFS), and overall survival (OS). There were 235 patients (primary safety cohort [PSC]) with median age of 23 (15-61) years; 159 (67.7%) were males, 155 (65.9%) had skeletal primary and 114 (48.5%) had extremity tumors. One hundred ninety-six (83.4%) were treatment naïve (primary efficacy cohort [PEC]) and of these 119 (60.7%) had surgery. In PEC, at a median follow-up of 36.4 (interquartile range [IQR] 20-55) months, estimated 3-year EFS and OS were 67.3% (95% CI 60.3-75.1%) and 91.1% (95% CI 86.7-95.7%), respectively. Of these, 158 (80.6%) complying with intended treatment, at a median follow-up of 39 (IQR 26-57) months had an estimated 3-year EFS of 68.2% (95% CI 60.3-76.1%). In multivariable analysis, good prognostic factors included longer symptom(s) duration (HR 0.93, 95% CI 0.86-0.994), ≥99% necrosis (HR 0.30, 95% CI 0.11-0.77), and treatment completion (HR 0.32, 95% CI 0.14-0.74). Among PSC, grade 3-4 toxicities were febrile neutropenia (119, 50.6%), anemia (130, 55.3%), peripheral neuropathy (37, 15.7%), with three (1.3%) chemo-toxic deaths. The outcomes of AA nonmetastatic ES patients treated with EFT-2001 regimen were comparable to those reported by others, with acceptable toxicity. This regimen can be considered a standard of care in AA-ES.

Predictors of Recurrence and Patterns of Initial Failure in Localized Ewing Sarcoma: A Contemporary 20-Year Experience.

Background The majority of patients with localized Ewing sarcoma will remain disease-free long term, but for those who suffer recurrence, successful treatment remains a challenge. Identification of clinicopathologic factors predictive of recurrence could suggest areas for treatment optimization. We sought to describe our experience regarding predictors of recurrence and patterns of first failure in patients receiving modern systemic therapy for nonmetastatic Ewing sarcoma. Methods The medical records of pediatric and adult patients treated for localized Ewing sarcoma between 1999 and 2019 at Johns Hopkins Hospital were retrospectively analyzed. Local control was surgery, radiotherapy, or both. Recurrence-free survival (RFS) was calculated using the Kaplan–Meier method. Univariable and multivariable Cox proportional-hazards modeling was performed to obtain hazard ratios (HR) for recurrence. Results In 94 patients with initially localized disease, there were 21 recurrences: 4 local, 14 distant, and 3 combined. 5-year and 10-year RFS were 75.6% and 70.5%, respectively. On multivariable analysis including age at diagnosis and tumor size, <95% tumor necrosis following neoadjuvant chemotherapy (NAC; HR 14.3, p = 0.028) and radiological tumor size change during NAC (HR 1.04 per 1% decrease in size change, p = 0.032) were independent predictors of recurrence. Among patients experiencing distant recurrence, pulmonary metastases were present in 82% and were the only identifiable site of disease in 53%. Conclusions Poor pathologic or radiologic response to NAC is predictive of recurrence in patients with localized Ewing sarcoma. Suboptimal tumor size reduction following chemotherapy provides a means to risk-stratify patients who do not undergo definitive resection. Isolated pulmonary recurrence was a common event.

The impact of local control timing in Ewing sarcoma.

To assess the impact of delay in local control on survival outcomes of Ewing sarcoma (ES) patients. The cornerstone of therapy of localized ES includes chemotherapy and local control with surgery or radiotherapy. We sought to assess the impact of delay (>15 weeks) in timing of local control on survival outcomes of ES patients. Data of consecutive patients with primary non-metastatic ES of the extremities, treated at a single institution were collected. The impact of delay of timing for local control, demographics, and disease characteristics on overall survival (OS) was analyzed. A total of 43 patients with ES of the extremity were included. All patients received neoadjuvant chemotherapy. Local control was by surgery in 36 patients and definitive radiation in 7. A total of 16 patients had delay in local control. At a median follow of up of 48 months, patients with delay in local control had significantly inferior OS compared to those with optimal local control timing (5-year OS 56% vs. 80%, respectively, p = 0.044). Other factors that predicted inferior OS included definitive radiation as opposed to definitive surgery (5-year OS 25% vs. 79%, respectively, p = 0.041) and tumor necrosis <90% as opposed to ≥90% (5-year OS 55% vs. 90%, respectively, p = 0.01). Delay in definitive therapy, local control with radiation as opposed to surgery and poor post-chemotherapy tumor necrosis predict inferior OS in ES. Adopting strategies to minimize delay in local control could improve survival outcomes.

Integrated human organ-on-a-chip model for predictive studies of anti-tumor drug efficacy and cardiac safety.

Traditional drug screening models are often unable to faithfully recapitulate human physiology in health and disease, motivating the development of microfluidic organs-on-a-chip (OOC) platforms that can mimic many aspects of human physiology and in the process alleviate many of the discrepancies between preclinical studies and clinical trials outcomes. Linsitinib, a novel anti-cancer drug, showed promising results in pre-clinical models of Ewing Sarcoma (ES), where it suppressed tumor growth. However, a Phase II clinical trial in several European centers with patients showed relapsed and/or refractory ES. We report an integrated, open setting, imaging and sampling accessible, polysulfone-based platform, featuring minimal hydrophobic compound binding. Two bioengineered human tissues - bone ES tumor and heart muscle - were cultured either in isolation or in the integrated platform and subjected to a clinically used linsitinib dosage. The measured anti-tumor efficacy and cardiotoxicity were compared with the results observed in the clinical trial. Only the engineered tumor tissues, and not monolayers, recapitulated the bone microenvironment pathways targeted by linsitinib, and the clinically-relevant differences in drug responses between non-metastatic and metastatic ES tumors. The responses of non-metastatic ES tumor tissues and heart muscle to linsitinib were much closer to those observed in the clinical trial for tissues cultured in an integrated setting than for tissues cultured in isolation. Drug treatment of isolated tissues resulted in significant decreases in tumor viability and cardiac function. Meanwhile, drug treatment in an integrated setting showed poor tumor response and less cardiotoxicity, which matched the results of the clinical trial. Overall, the integration of engineered human tumor and cardiac tissues in the integrated platform improved the predictive accuracy for both the direct and off-target effects of linsitinib. The proposed approach could be readily extended to other drugs and tissue systems.

Outcomes following proton therapy for Ewing sarcoma of the cranium and skull base.

Despite the dosimetric advantages of proton therapy, little data exist on patients who receive proton therapy for Ewing sarcoma of the cranium and skull base. This study reports local disease control and toxicity in such patients. We reviewed 25 patients (≤21 years old) with nonmetastatic Ewing sarcoma of the cranium and skull base treated between 2008 and 2018. Treatment toxicity was graded per the Common Terminology Criteria for Adverse Events v4.0. The Kaplan-Meier product limit method provided estimates of disease control and survival. Median patient age was 5.9 years (range, 1-21.7). Tumor subsites included the skull base (48%), non-skull-base calvarial bones (28%), paranasal sinuses (20%), and nasal cavity (4%). All patients underwent multiagent alkylator- and anthracycline-based chemotherapy; 16% underwent gross total resection (GTR) before radiation. Clinical target volume (CTV) 1 received 45 GyRBE and CTV2 received 50.4 GyRBE following GTR or 54-55.8 GyRBE following biopsy or subtotal resection. Median follow-up was 3.7 years (range, 0.26-8.3); no patients were lost. The 4-year local control, disease-free survival, and overall survival rates were 96%, 86%, and 92%, respectively. Two patients experienced in-field recurrences. One patient experienced bilateral conductive hearing loss requiring aids, two patients developed intracranial vasculopathy, and 6 patients required hormone replacement therapy for neuroendocrine deficits. None developed a secondary malignancy. Proton therapy is associated with a favorable therapeutic ratio in children with large Ewing tumors of the cranium and skull base. Despite its high conformality, we observed excellent local control and no marginal recurrences. Treatment dosimetry predicts limited long-term neurocognitive and neuroendocrine side effects.

Radiation Treatment for Ewing Sarcoma Family of Tumors in Adult Patients: A Single Institution's Experience Over 40 Years.

To report prognostic factors and long-term outcomes in adults with Ewing sarcoma treated with definitive radiotherapy. We reviewed patients 18 years old and above with nonmetastatic Ewing sarcoma treated with radiotherapy +/- chemotherapy or surgery. Outcomes were stratified by age (30 and above vs. younger than 30 y), soft tissue extension, tumor size (≥8.5 vs. <8.5 cm), tumor location, resection (yes vs. no), and treatment era (1970-1992 vs. 1993-2012). Toxicities were scored using the RTOG criteria. Fifty-five patients (21 women) were treated with radiotherapy. Average age at diagnosis: 26.7 years (38 patients below 30 vs. 17 patients 30 y and above). A total of 43 had soft tissue extension (78%). Median tumor size: 8.5 cm. Most tumors were in the pelvis (40%), followed by the lower (27%) and upper (24%) extremities. All but 1 patient received chemotherapy; 13 underwent resection. Median dose: 55 Gy. Median follow-up: 3.6 years; 17.5 years for living patients. The 5-year overall (OS) and cause-specific survival (CSS) rates were both 46%. OS and CSS rates were unaffected by age (P=0.97), tumor size (P=0.12), or tumor location (P=0.99). Soft tissue extension portended a significantly poorer prognosis for 5-year OS and CSS: 37% vs. 82% (with and without, respectively; P=0.04). Patients who underwent resection had improved 5-year OS and CSS: 77% vs. 37%, respectively (P=0.01). Patients treated after 1993 had improved 5-year OS: 58% vs. 37% (P=0.0264). Adult patients with Ewing sarcoma experience similar treatment outcomes regardless of age at diagnosis. Soft tissue extension represents a poor prognostic factor. Aggressive trimodality therapy achieved the highest OS and CSS.

Non-metastatic Ewing's sarcoma family of tumors of bone in adolescents and adults: prognostic factors and clinical outcome-single institution results.

There is limited data regarding outcomes of Ewing's sarcoma family of tumors in adolescents and adults compared with the same tumors in childhood. The aim of the study was to analyze prognostic factors and treatment results in a cohort of adolescents and adults with non-metastatic skeletal Ewing's sarcoma family of tumors. From 1992-2008, 90 adolescents and adults with Ewing's sarcoma family of tumors of the bone were referred to our institution. Sixty-five (72%) non-metastatic patients with analyzable data and treated in our institution were retrospectively evaluated. All patients were treated with alternated chemotherapy regimens administered every 3 weeks. The local treatment modality was selected according to tumor and patient characteristics. The median age was 21 years (range, 13-50). Most patients (74%) were >17 years of age. Forty-six percent of the tumors were located in the extremities. Local therapy was surgery in 45 patients and radiotherapy alone in 19 patients. Twenty-one patients received preoperative and 13 patients postoperative radiotherapy. Median follow-up was 43 months (range, 7-167). The 5-year event-free and overall survival rates for all patients were 44% and 49%, respectively. On univariate survival analysis, event-free and overall survival were worse for patients >17 years of age, tumor size >8 cm in diameter, an axial location, positive surgical margins, and poor histopathological response (<90% necrosis). Age, tumor site and tumor size on event-free and overall survival remained significant on multivariate analysis. We identified age, tumor size, and tumor site as independent prognostic factors, in accord with the Western literature. These patients require novel treatment modalities.

Comparison of the effects of local treatment strategies in non-metastatic Ewing sarcoma of bone

ABSTRACTBackground: To investigate the optimal local treatment strategies for patients with non-metastatic Ewing sarcoma (ES) of bone.Methods: Patients with ES of bone were identified using the Surveillance Epidemiology and End Results database. Kaplan-Meier log-rank test and Cox regression models were performed to assess the effect of the types of local treatment strategies on cause-specific survival and overall survival.Results: 560 patients were included with a median age of 16 years. A total of 284, 162 and 114 patients received surgery alone, surgery and radiotherapy, and radiotherapy alone, respectively. The types of local treatment strategies had no effect on survival outcomes in multivariate analysis. In the subgroup analysis of patients with tumor diameter <8 cm, surgery ± radiotherapy had a significantly improved cause-specific survival (P = 0.039), and had potential to improve overall survival (P = 0.070) in multivariate analysis. The local treatment strategies had no effect on survival in patients with different tumor location.Conclusion: There is no local treatment of choice for non-metastatic ES of bone in terms of survival. More well-designed studies are needed to confirm our findings and investigate the role of various local treatment strategies in relation to primary tumor diameter.

Current treatment landscape and emerging management options for extremity sarcoma

Malignant tumors of extremity are mostly of mesenchymal origin and arise from bone or extraskeletal soft tissue. Combination chemotherapy has greatly increased the survival of non-metastatic localized osteosarcoma and Ewing's sarcoma; however, there is conflicting evidence regarding the role of neoadjuvant and adjuvant chemotherapy in soft tissue sarcoma due to the rarity and heterogeneous population. Despite intensive multimodal therapy and valiant efforts, most of the patients with relapsed and metastatic sarcoma will succumb to their disease. Molecular studies like next-generation sequencing have revealed various targetable biomarkers which can be further explored in the therapeutic landscape with specific targeted therapies. We reviewed all ongoing and completed clinical trials involving chemotherapy, targeted therapy, and immunotherapy valid for patients with extremity sarcoma. We present the current viable therapeutic options for such a cohort of patients in routine clinical practice.

What is the impact of local control in Ewing sarcoma: analysis of the first Brazilian collaborative study group \u2013 EWING1

BackgroundRelapse in localized Ewing sarcoma patients has been a matter of concern regarding poor prognosis. Therefore, we investigated the impact of local control modality (surgery, surgery plus radiotherapy, and radiotherapy) on clinical outcomes such as survival and recurrence in patients with non-metastatic Ewing sarcoma treated on the first Brazilian Collaborative Group Trial of the Ewing Family of Tumors (EWING1).MethodsSeventy-three patients with localized Ewing sarcoma of bone aged < 30 years were included. The treating physicians defined the modality of local control based on the recommendations of the coordinating center and the patient and tumor characteristics. Possible associations of local control modality with local failure (LF), disease-free survival (DFS), event-free survival (EFS), overall survival (OS), and clinical characteristics were analyzed.ResultsMean patient age was 12.8 years (range, 2 to 25 years) and median follow-up time was 4.5 years (range, 2.3 to 6.7 years). Forty-seven patients underwent surgery, 13 received radiotherapy, and 13 received both. The 5-year EFS, OS, and DFS for all patients was 62.1%, 63.3%, and 73.1%, respectively. The 5-year cumulative incidence (CI) of LF was 7.6% for surgery, 11.1% for radiotherapy, and 0% for postoperative radiotherapy (PORT) (p = 0.61). The 5-year EFS was 71.7% for surgery, 30.8% for radiotherapy, and 64.1% for PORT (p = 0.009).ConclusionsThere was a significant effect of local control modality on EFS and OS in the study. Surgery and PORT modalities yielded very close results. The group treated with radiotherapy alone had considerably worse outcomes. This may be confounded by greater risk factors in these patients. There was no significant effect of local control modality on the CI of LF and DFS.

Clinicopathological Features and Treatment Outcomes in Ewing's Sarcoma Patients: A 10-year experience of Alexandria Clinical Oncology Department.

Background:Ewing's sarcoma (ES) is an aggressive tumor, which is usually associated with micrometastases in the circulation. Thus, systemic chemotherapy in addition to local control modality is essential to improve outcomes. The aim of this study was to evaluate clinicopathological features and treatment outcomes in patients with ES.Materials and Methods:Medical files of 74 patients with nonmetastatic ES treated at our centers between 2004 and 2014 were retrospectively evaluated. The clinicopathological parameters were extracted and statistically correlated with event-free survival (EFS) and overall survival (OS).Results:The median age of patients was 13 years. The median follow-up duration was 63.8 months. About two-thirds (58.1%) of patients were male. Pain (74.3%) was the most common presenting symptom. Extremities (48.6%) were the frequently affected sites. Thirty-two patients (43.2%) presented by tumors larger than 8 cm. All patients were treated with chemotherapy. Local therapies were surgery and/or radiotherapy. The 5-year EFS and OS were 44% and 57%, respectively. On multivariate analysis, EFS and OS were significantly associated with age, tumor site, and tumor size.Conclusions:Despite limited resources in a developing country, the survival rates of ES are comparable to that in developed countries, and prognostic factors are age, tumor site, and tumor size.