Overview

Highly aggressive sarcoma of bone and soft tissue in children/adolescents. EWS-FLI1 or related fusion oncogenes. Peak age 10-20 years. Most common in long bones, pelvis, chest wall. Multimodal treatment essential: neoadjuvant chemotherapy (VDC/IE: vincristine, doxorubicin, cyclophosphamide alternating with ifosfamide, etoposide), surgery and/or radiation for local control, adjuvant chemotherapy. 5-year survival 70-80% localized, 20-30% metastatic. High-dose chemotherapy with SCT for relapse.

Clinical Management: Treatment individualized based on stage, histology, molecular profile, and patient factors. Multidisciplinary tumor board review recommended. Refer to NCCN guidelines and FDA package inserts for complete dosing and administration.

Epidemiology & Impact

Ewing sarcoma is the second most common primary bone malignancy in children and adolescents, with approximately 200 new cases diagnosed annually in the United States. The disease primarily affects young people aged 10-20, with a median age of 15, and demonstrates a striking racial predilection for individuals of European descent. Males are affected 1.5 times more often. While most commonly arising in bone (pelvis, femur, chest wall), 20-30% present as extraosseous soft tissue tumors. Five-year survival for localized disease is approximately 70% but drops to 30% or less for the 25% who present with metastatic disease.

Molecular Biology & Biomarkers

Ewing sarcoma is defined by chromosomal translocations involving EWSR1 and ETS family transcription factors. The most common fusion, EWSR1-FLI1 (approximately 85% of cases), functions as an aberrant transcription factor driving the oncogenic program. The tumor has remarkably few additional mutations, with TP53 and STAG2 alterations being the most common secondary events conferring worse prognosis. The low mutational burden and limited immune infiltration contribute to poor response to checkpoint immunotherapy.

Evolving Treatment Landscape

Standard treatment combines multiagent chemotherapy (VDC/IE: vincristine, doxorubicin, cyclophosphamide alternating with ifosfamide and etoposide) with local control via surgery and/or radiation. For relapsed disease, irinotecan-temozolomide and cyclophosphamide-topotecan have activity. Lurbinectedin has shown encouraging results based on targeting EWS-FLI1 transcriptional dependency. Novel approaches under investigation include CDK4/6 inhibitors, PARP inhibitors, and LSD1 inhibitors targeting epigenetic machinery co-opted by the fusion protein.

Approved Ewing Sarcoma Therapies

Note: There are no FDA-approved targeted or novel therapies specifically for Ewing sarcoma. Standard of care consists of multi-agent chemotherapy (VDC/IE alternating regimen: vincristine, doxorubicin, cyclophosphamide alternating with ifosfamide and etoposide) combined with surgery and/or radiation. All component drugs have general FDA approval but are used in combination off-label for this specific indication.