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Ewing sarcoma

Ewing sarcoma is a bone and soft-tissue cancer of teenagers driven by a single fusion gene, EWSR1-FLI1. Intensive chemotherapy with surgery or radiation cures most localised cases; spread disease and relapse remain very hard, and the fusion protein itself has resisted drug design.

Ewing sarcoma is defined by FET-ETS fusions, EWSR1-FLI1 in ~85% and EWSR1-ERG in ~10%, which act as aberrant transcription factors at GGAA microsatellites; the genome is otherwise quiet (STAG2, CDKN2A, TP53 alterations carry poor prognosis). It arises in bone (pelvis, femur, chest wall) or soft tissue in adolescents and young adults.

Treatment is multimodal: interval-compressed VDC/IE (vincristine, doxorubicin, cyclophosphamide alternating with ifosfamide, etoposide) every 2 weeks (AEWS0031), which Euro Ewing 2012 showed superior to VIDE; local control by surgery, radiotherapy or both; and metastatic disease treated with the same backbone plus whole-lung irradiation, with high-dose busulfan-melphalan benefiting selected high-risk patients (Euro-EWING 99 R2). Relapse is treated with irinotecan-temozolomide, high-dose ifosfamide or topotecan-cyclophosphamide, ranked by the rEECur adaptive trial (high-dose ifosfamide best). Targeted attempts (IGF-1R antibodies, TK216 against EWS-FLI1, PARP inhibitors) have not succeeded; lurbinectedin and combinations are in trials.

State of the art today

  • rEECur is the first randomised trial in relapsed Ewing sarcoma and ranked four regimens with high-dose ifosfamide on top.
  • EWSR1-FLI1 is an 'undruggable' transcription factor; degraders, LSD1 inhibitors and menin/EWS-FLI1 interactome drugs are the research directions.
  • International cooperation (COG, Euro Ewing) is the only way trials complete.
Show survival figures (1)

Averages across everyone diagnosed, often years ago. Your stage, subtype, age, fitness and the treatment you receive matter more than the average, and the numbers are improving quickly.

  • Interval compression (chemotherapy every 2 rather than 3 weeks) improved survival without new drugs (AEWS0031, Euro Ewing 2012).
Who it affects
Show survival figures (1)

Averages across everyone diagnosed, often years ago. Your stage, subtype, age, fitness and the treatment you receive matter more than the average, and the numbers are improving quickly.

  • Ewing sarcoma is the second most common bone cancer in children and young adults; ~200-250 cases per year in the US, rare in people of African or East Asian ancestry; survival ~75% localised, ~30% metastatic.

Where the cases are

Cases by country · GLOBOCAN 2022
All countries →

No country-level case numbers. This cancer is not mapped to a GLOBOCAN site.

Standard of care

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Localised

Interval-compressed VDC/IE ×14 cycles (AEWS0031 / Euro Ewing 2012) with surgery ± radiotherapy (or definitive RT 55.8 Gy) after 6 induction cycles.

NCCN · Category 1
VincristineDoxorubicinCyclophosphamideIfosfamideEtoposideIMRT / IGRT (modern external beam)Limb-salvage surgery and endoprosthetic reconstruction
Metastatic (lung only)

Same chemotherapy plus whole-lung irradiation; busulfan-melphalan high-dose therapy in selected patients (Euro-EWING 99 R2pulm equivocal).

NCCN · Category 2A
VincristineDoxorubicinCyclophosphamideIfosfamideEtoposideAutologous stem cell transplant (high-dose therapy)
Metastatic (bone/marrow)

Chemotherapy with palliative-intent local therapy; survival <20%; trials strongly preferred.

VincristineDoxorubicinCyclophosphamide
Relapsed

High-dose ifosfamide (rEECur), irinotecan-temozolomide, topotecan-cyclophosphamide, gemcitabine-docetaxel; local therapy; trials.

NCCN · Category 2A
IfosfamideIrinotecan (and liposomal irinotecan)TemozolomideTopotecanCyclophosphamide

Subtypes & biomarkers

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Subtypes
Biomarkers clinicians test

Target prevalence in this cancer

Target / alterationPrevalenceSource
EWSR1-FLI1 fusion
85%
doi.org

How common each drug target or alteration is in this cancer. Population-level and approximate; see the target page for detail. Full matrix.

History

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  1. 1921James Ewing describes 'diffuse endothelioma of bone'
  2. 1974IESS-I: adjuvant VAC + doxorubicin raises survival from ~10% to ~60%
    VincristineDoxorubicinCyclophosphamide
  3. 1992EWSR1-FLI1 fusion cloned (Delattre, Nature)
  4. 2003INT-0091: adding ifosfamide-etoposide improves survival (Grier, NEJM)
    IfosfamideEtoposide
  5. 2012AEWS0031: interval compression improves EFS (Womer, JCO)
  6. 2018Euro-EWING 99 R2: busulfan-melphalan benefit in high-risk localised disease
    Autologous stem cell transplant (high-dose therapy)
  7. 2022Euro Ewing 2012: VDC/IE superior to VIDE (Lancet)
  8. 2022rEECur: high-dose ifosfamide best of four relapse regimens
    Ifosfamide

Pipeline

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ApprovedCytotoxic (transcription inhibitor)
Lurbinectedin · Zepzelca
ApprovedCytotoxic chemotherapy (alkylating agent)
Ifosfamide · Ifex
CAR-T cell therapy

Open problems

  • Metastatic-to-bone and relapsed disease: survival under 20-30%.
  • EWSR1-FLI1 remains undrugged after 30 years.
  • Late effects: cardiotoxicity, infertility, secondary leukaemia (etoposide, alkylators), radiation-induced sarcoma.
  • Ancestry-linked incidence differences (GGAA microsatellite polymorphism) unexplained.

Trials

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Recruiting now (live from ClinicalTrials.gov)

Recruiting trials near you · live from ClinicalTrials.gov
Ewing sarcoma
condition: Ewing sarcoma
Open on ClinicalTrials.gov →

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Expert centres

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Where the expertise is

Centres linked to this cancer in OnCo

Seeking a second opinion: ask your oncologist for a referral to a high-volume centre; most accept records and pathology by mail or telehealth. In the US, use the NCI's Find a Cancer Center tool or the nonprofit Cancer Commons, which navigates options for advanced cancers at no cost.

Questions to ask

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Bring to your appointment

Questions to ask your oncologist about Ewing sarcoma

Generated from this cancer's standard of care, biomarkers, and pipeline · 17 questions

Newly diagnosed

  1. What is my exact diagnosis, stage, and grade, and which tests established them?
    Why: Everything else follows from an accurate stage and subtype.
  2. Which biomarkers have been tested on my tumour (for example EWSR1-FLI1 / EWSR1-ERG fusion, CD99 membranous staining, NKX2-2, Metastatic status, Histologic response to induction, STAG2 loss, TP53 mutation, CDKN2A deletion), and what were the results?
    Why: These results decide eligibility for targeted therapy, immunotherapy, and trials.
  3. Which subtype is my cancer, and does that change the recommended treatment?
    Why: Recognised subtypes for this cancer include Skeletal Ewing sarcoma, Extraosseous Ewing sarcoma, EWSR1-FLI1 vs EWSR1-ERG fusion.
  4. Is germline (inherited) genetic testing recommended for me or my family?
    Why: Inherited variants can change treatment and matter for relatives.

Localised

  1. For my situation (localised), which of the standard options do you recommend and why?
    Why: Guideline options include: Interval-compressed VDC/IE ×14 cycles (AEWS0031 / Euro Ewing 2012) with surgery ± radiotherapy (or definitive RT 55.8 Gy) after 6 induction cycles.
  2. Am I a candidate for Vincristine, Doxorubicin, Cyclophosphamide or related drugs, and what side effects should I expect?
    Why: Knowing the expected toxicities helps you plan work, family, and supportive care.

Metastatic (lung only)

  1. For my situation (metastatic (lung only)), which of the standard options do you recommend and why?
    Why: Guideline options include: Same chemotherapy plus whole-lung irradiation; busulfan-melphalan high-dose therapy in selected patients (Euro-EWING 99 R2pulm equivocal).
  2. Am I a candidate for Vincristine, Doxorubicin, Cyclophosphamide or related drugs, and what side effects should I expect?
    Why: Knowing the expected toxicities helps you plan work, family, and supportive care.

Metastatic (bone/marrow)

  1. For my situation (metastatic (bone/marrow)), which of the standard options do you recommend and why?
    Why: Guideline options include: Chemotherapy with palliative-intent local therapy; survival <20%; trials strongly preferred.
  2. Am I a candidate for Vincristine, Doxorubicin, Cyclophosphamide, and what side effects should I expect?
    Why: Knowing the expected toxicities helps you plan work, family, and supportive care.

Relapsed

  1. For my situation (relapsed), which of the standard options do you recommend and why?
    Why: Guideline options include: High-dose ifosfamide (rEECur), irinotecan-temozolomide, topotecan-cyclophosphamide, gemcitabine-docetaxel; local therapy; trials.
  2. Am I a candidate for Ifosfamide, Irinotecan (and liposomal irinotecan), Temozolomide or related drugs, and what side effects should I expect?
    Why: Knowing the expected toxicities helps you plan work, family, and supportive care.

Any stage

  1. Are there clinical trials I could join, for example of Lurbinectedin, Ifosfamide, CAR-T cell therapy?
    Why: Trials are how the next standard of care is set; asking early keeps options open.
  2. Would a second opinion at a high-volume centre change anything, and can you help arrange it?
    Why: Rare or high-stakes decisions benefit from a centre that treats many similar patients.
  3. What supportive care (symptom control, nutrition, exercise, mental health, financial help) is available from the start?
    Why: Supportive care improves quality of life and helps patients complete treatment.
  4. I read that “Metastatic-to-bone and relapsed disease: survival under 20-30%”. How does that affect my plan?
    Why: Open problems are where trials and second opinions matter most.
  5. I read that “EWSR1-FLI1 remains undrugged after 30 years”. How does that affect my plan?
    Why: Open problems are where trials and second opinions matter most.

Print this page for your appointment (your browser's print command). These prompts are for discussion; your clinical team knows your case.

Everything relevant

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Direct links plus the targets, companies, and technologies of this cancer's products.

technologies

11
Allogeneic stem cell transplantationAutologous stem cell transplant (high-dose therapy)CAR-T cell therapyCardio-oncologyCytotoxic chemotherapyIMRT / IGRT (modern external beam)Isolated limb perfusion and infusionLimb-salvage surgery and endoprosthetic reconstructionPROTACs & molecular glues (targeted protein degradation)Proton therapyTopoisomerase-I inhibitors (and ADC payloads)

targets

4
EWSR1-FLI1 fusionKMT2A (MLL) rearrangementPARPTP53

drugs

11
Not mapped hereAlkylating agent (oxazaphosphorine prodrug)
Cyclophosphamide · Cytoxan / Endoxan
Not mapped hereActinomycin antibiotic (transcription inhibitor)
Dactinomycin (actinomycin D) · Cosmegen
ApprovedCytotoxic chemotherapy (taxane)
Docetaxel · Taxotere (generic)
ApprovedCytotoxic chemotherapy (anthracycline)
Doxorubicin · Adriamycin
Not mapped hereTopoisomerase II inhibitor (podophyllotoxin derivative)
Etoposide · VePesid / Etopophos / Toposar
ApprovedCytotoxic chemotherapy (alkylating agent)
Ifosfamide · Ifex
Not mapped hereTopoisomerase I inhibitor (camptothecin prodrug)
Irinotecan (and liposomal irinotecan) · Camptosar / Onivyde
ApprovedCytotoxic (transcription inhibitor)
Lurbinectedin · Zepzelca
Not mapped hereOral alkylating chemotherapy
Temozolomide · Temodar
ApprovedCytotoxic (topoisomerase-I inhibitor)
Topotecan · Hycamtin
Not mapped hereVinca alkaloid (microtubule inhibitor)
Vincristine · Oncovin / Marqibo

companies

5
IpsenJazz PharmaceuticalsPfizer (incl. Seagen)PharmaMarSanofi

institutions

2
Children's Oncology Group (COG)Nationwide Children's Hospital

pathways

2
p53 / RB / cell-cycle checkpointTranscriptional machinery & addiction

terms

2
Adolescent and young adult (AYA) oncologyGene fusion

collections

2
Alex's Lemonade Stand Foundation (ALSF)St. Baldrick's Foundation

Latest papers

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Latest papers · live from Europe PMC
Open in Europe PMC

Query for this cancer: (TITLE:"Ewing sarcoma" OR ABSTRACT:"Ewing sarcoma") AND (treatment OR therapy OR trial OR survival OR diagnosis). Results are unfiltered search hits about Ewing sarcoma, not a curated reading list.

Connected

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Pages like this

not linked directly; found by shared links

technologies

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Autologous stem cell transplant (high-dose therapy)CAR-T cell therapyCytotoxic chemotherapyIMRT / IGRT (modern external beam)Limb-salvage surgery and endoprosthetic reconstructionPROTACs & molecular glues (targeted protein degradation)Proton therapy

targets

3
EWSR1-FLI1 fusionPARPTP53

drugs

11
Not mapped hereAlkylating agent (oxazaphosphorine prodrug)
Cyclophosphamide · Cytoxan / Endoxan
Not mapped hereActinomycin antibiotic (transcription inhibitor)
Dactinomycin (actinomycin D) · Cosmegen
ApprovedCytotoxic chemotherapy (taxane)
Docetaxel · Taxotere (generic)
ApprovedCytotoxic chemotherapy (anthracycline)
Doxorubicin · Adriamycin
Not mapped hereTopoisomerase II inhibitor (podophyllotoxin derivative)
Etoposide · VePesid / Etopophos / Toposar
ApprovedCytotoxic chemotherapy (alkylating agent)
Ifosfamide · Ifex
Not mapped hereTopoisomerase I inhibitor (camptothecin prodrug)
Irinotecan (and liposomal irinotecan) · Camptosar / Onivyde
ApprovedCytotoxic (transcription inhibitor)
Lurbinectedin · Zepzelca
Not mapped hereOral alkylating chemotherapy
Temozolomide · Temodar
ApprovedCytotoxic (topoisomerase-I inhibitor)
Topotecan · Hycamtin
Not mapped hereVinca alkaloid (microtubule inhibitor)
Vincristine · Oncovin / Marqibo

companies

2
Jazz PharmaceuticalsPharmaMar

institutions

2
Children's Oncology Group (COG)Nationwide Children's Hospital

pathways

2
p53 / RB / cell-cycle checkpointTranscriptional machinery & addiction

terms

2
Adolescent and young adult (AYA) oncologyGene fusion

collections

2
Alex's Lemonade Stand Foundation (ALSF)St. Baldrick's Foundation