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Teaching pack: Ewing sarcoma

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9 slides generated from the cancer page, with a quiz from the open benchmark and speaker notes that cite the sources. Arrow keys move between slides; Print gives one slide per page.

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  1. Teaching pack · Cancer · paediatric

    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.

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  2. What it is

    In two paragraphs

    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.

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  3. Standard of care

    What is given today, by setting

    SettingApproachGuideline
    LocalisedInterval-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
    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
    Metastatic (bone/marrow)Chemotherapy with palliative-intent local therapy; survival <20%; trials strongly preferred.not mapped
    RelapsedHigh-dose ifosfamide (rEECur), irinotecan-temozolomide, topotecan-cyclophosphamide, gemcitabine-docetaxel; local therapy; trials.NCCN Category 2A
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  4. State of the art

    Where the field stands

    • Interval compression (chemotherapy every 2 rather than 3 weeks) improved survival without new drugs (AEWS0031, Euro Ewing 2012).
    • 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.
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  5. History

    How we got here

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

    What is coming

    • Lurbinectedin (product)
    • Ifosfamide (product)
    • CAR-T cell therapy (technology)
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  7. Open problems

    What nobody has solved

    • 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.
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  8. Quiz

    Check understanding

    1. What is CAR-T and which cancers is it approved for?
      Answer
      A patient's T cells are engineered with a synthetic receptor, multiplied, and returned. Approved CD19 products treat B-cell lymphomas and leukaemias; BCMA products treat multiple myeloma; the first solid-tumour approval (Claudin 18.2, gastric) is in China.
    2. What is in vivo CAR-T and why is it exciting?
      Answer
      Targeted lipid nanoparticles or viral vectors deliver CAR-encoding mRNA or DNA to T cells inside the patient, avoiding manufacturing, lymphodepletion, and wait time and allowing redosing; first-in-human data in 2025-26 show B-cell depletion. AbbVie bought Capstan for up to $2.1B.
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  9. Sources

    Read the primary sources

    • NCCN Guidelines: Bone Cancer: https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1418
    • rEECur (Lancet 2024): https://doi.org/10.1016/S0140-6736(24)00248-9
    • NCI PDQ: Ewing sarcoma: https://www.cancer.gov/types/bone/patient/ewing-treatment-pdq
    • Wikipedia: https://en.wikipedia.org/wiki/Ewing_sarcoma
    • Guideline: https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1418
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