Teaching pack: Rhabdomyosarcoma

Rhabdomyosarcoma (RMS) has two main types: embryonal (~70%, younger children, RAS-pathway mutations, favourable) and alveolar (~25%, adolescents, PAX3- or PAX7-FOXO1 fusion in ~80%, unfavourable). Fusion status has replaced histology in risk stratification since fusion-negative alveolar RMS behaves like embryonal. Sites range from orbit and parameningeal head and neck to genitourinary and extremity; risk groups combine site, size, nodal status, metastases, age and fusion status.

Therapy is VAC (vincristine, actinomycin D, cyclophosphamide) in North America or IVA (ifosfamide) in Europe, with local control by surgery and/or radiotherapy at week ~13. Key trial results: adding irinotecan (VAC/VI, ARST0531) did not improve outcomes but reduced cyclophosphamide exposure; maintenance vinorelbine-cyclophosphamide after standard therapy improved survival in high-risk localised disease (EpSSG RMS 2005, Lancet Oncol 2019); temsirolimus added to chemotherapy improved event-free survival in intermediate-risk disease (ARST1431, reported 2024). Metastatic disease (especially bone/marrow, age >10) has survival under 30% and is the target of the FaR-RMS international trial. Relapse is usually fatal outside low-risk cases.

• Fusion status has replaced histology in risk stratification in both COG and European protocols.
• Maintenance chemotherapy (EpSSG RMS 2005) is the first survival gain in decades for high-risk localised disease.
• Temsirolimus is the first targeted agent to improve event-free survival in a randomised RMS trial (ARST1431).
• Metastatic disease remains the unsolved problem; international FaR-RMS trial pools patients across continents.

1. 1972Intergroup Rhabdomyosarcoma Study (IRS-I) begins
2. 1993PAX3-FOXO1 fusion identified (Galili, Barr)
3. 2010Fusion-negative alveolar RMS behaves like embryonal (Williamson, JCO)
4. 2019EpSSG RMS 2005: maintenance vinorelbine-cyclophosphamide improves survival (Lancet Oncol)
5. 2019ARST0531: irinotecan does not improve outcome but spares cyclophosphamide
6. 2024ARST1431: temsirolimus + chemotherapy improves EFS in intermediate risk

• Temsirolimus (treatment)
• Vinorelbine (treatment)
• CAR-T cell therapy (technology)
• B7-H3 (target)
• Cobolimab (treatment)

• Childhood Cancer Survivor Study (CCSS) (observational study, n=50,000): 15-year cumulative all-cause mortality by treatment era: 12.4% vs 6%
• MASCT-I Combined With Doxorubicin and Ifosfamide for First-line Treatment of Advanced Soft Tissue Sarcoma (phase 2, n=148): result not yet recorded
• Study Of Palbociclib Combined With Chemotherapy In Pediatric Patients With Recurrent/Refractory Solid Tumors (phase 2, n=128): result not yet recorded

• Metastatic alveolar RMS: survival <30% for 30 years.
• PAX3-FOXO1 is an undrugged fusion transcription factor.
• Local-control morbidity in young children (orbit, bladder, prostate).
• Relapse after intermediate-risk therapy is rarely curable.

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.

• NCI PDQ: childhood rhabdomyosarcoma: https://www.cancer.gov/types/soft-tissue-sarcoma/patient/rhabdomyosarcoma-treatment-pdq
• EpSSG RMS 2005 maintenance (Lancet Oncol 2019): https://doi.org/10.1016/S1470-2045(19)30617-5
• FaR-RMS trial: https://clinicaltrials.gov/study/NCT04625907
• Wikipedia: https://en.wikipedia.org/wiki/Rhabdomyosarcoma
• Guideline: https://doi.org/10.1016/S1470-2045(19)30617-5