What is it about?

Mesenchymal chondrosarcoma (MCS) is characterised by small round cell biology with frequent HEY1-NCOA2 fusion, early haematogenous spread, and greater sensitivity to systemic chemotherapy (CHT) than other chondrosarcoma subtypes. CHT is used in both the peri-operative (neoadjuvant and adjuvant) and metastatic settings. Recommended regimens are similar to those used in Ewing’s sarcoma and include vincristine, doxorubicin, and cyclophosphamide (VDC, sometimes abbreviated as VAdriaC/IE), ifosfamide and etoposide (IE). Gemcitabine–docetaxel (GD) is a later-line option in metastatic settings. We thoroughly reviewed retrospective and prospective studies (primarily on novel immunotherapies and targeted therapies) and case reports to evaluate treatment outcomes, including overall survival (OS) and progression-free survival (PFS), as well as the CHT regimens used. The strategies used in neoadjuvant, adjuvant and palliative CHT (first and subsequent lines) were discussed separately.

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Why is it important?

Mesenchymal chondrosarcoma (MCS) is characterised by small round cell biology, frequent HEY1-NCOA2 fusion, and high vascularity. These features plausibly lessen extracellular matrix barriers and confer relative chemosensitivity. We synthesised peri-operative (preoperative/neoadjuvant; postoperative/adjuvant) and palliative chemotherapy outcomes separately across multiple cohorts and case reports as well as the summarised the guidelines (ESMO/NCCN) In localised disease, integrating multi-agent Ewing-type chemotherapy with complete resection is associated with improved disease control. Contemporary 5-year overall survival (OS) typically spans ~55–73% across studies, while event-free survival (EFS) gains are demonstrated more consistently than OS gains in pooled analyses. In advanced MCS, first-line polychemotherapy yields modest, non-curative activity, with objective response rates (ORRs) of ~25–35% in adults, median progression-free survival (PFS) of ~4.7–6.7 months, and median OS of ~18 months. Activity may be higher in younger patients and for platinum–anthracycline combinations. We also discussed emerging therapies. Trabectedin demonstrates low disease control rate in translocation-related sarcomas, including few MCS cases. Anti-angiogenic tyrosine kinase inhibitors, such as apatinib and pazopanib, demonstrate activity in chondrosarcoma, but MCS-specific data are lacking. IDH1 inhibition benefits conventional subtypes rather than MCS. Early immunotherapy experience is limited, but pathway-directed strategies targeting BCL2 and PI3K-mTOR warrant evaluation. Keywords: mesenchymal chondrosarcoma; perioperative chemotherapy; anthracyclines; HEY1-NCOA2 fusion; neoadjuvant treatment; adjuvant therapy

Perspectives

MCS is characterised by small round cell biology, early haematogenous spread and relative chemosensitivity. Across contemporary series, 5-year OS typically spans ~55–73%, with the most consistent systemic-therapy signal being improved EFS/DFS rather than OS. In localised disease, peri-operative multi-agent Ewing-type CHT integrated with complete resection is associated with reduced relapse risk and longer disease control, e.g., EMSOS: HR for recurrence 0.482 (95% CI 0.213–0.996); HR for death 0.445 (95% CI 0.256–0.774) [12]. Radiographic tumour shrinkage with NAC is uncommon and stable disease predominates; nevertheless, NAC may confer advantages of early micrometastatic control and facilitate margin-negative resection in selected cases [11]. AC is expert-consensus recommended and guideline-endorsed; pooled and multi-institutional data suggest delayed relapse and longer EFS, while OS gains remain less certain given ultra-rare disease constraints and retrospective designs. In advanced MCS, first-line polychemotherapy produces modest, non-curative activity (ORR ~25–35% in adults; median PFS ~4.7–6.7 months), with higher activity reported in paediatric/AYA subsets. Due to the significant haematological, cardiac, renal and neurotoxic risks associated with Ewing-type regimens, careful patient selection, individualised dosing and multidisciplinary discussions are essential. Priority research directions include prospective, MCS-specific cohorts with predefined response and necrosis criteria; adaptive peri-operative strategies aligned to early response; and biomarker-guided trials of anti-angiogenic TKIs, trabectedin within translocation-related frameworks, and BCL2 or PI3K–mTOR inhibition. The establishment of international registries is crucial for generating precise estimates of effect and refining patient selection. Keywords: mesenchymal chondrosarcoma; perioperative chemotherapy; anthracyclines; HEY1-NCOA2 fusion; neoadjuvant treatment; adjuvant therapy

Piotr Remiszewski
Maria Sklodowska- Curie National Research Institute of Oncology

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This page is a summary of: Chemotherapy Strategies and Their Efficacy for Mesenchymal Chondrosarcoma, Current Oncology, November 2025, MDPI AG,
DOI: 10.3390/curroncol32110615.
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