Chemotherapy in dedifferentiated chondrosarcoma: From neoadjuvant to palliative treatment options.

Dedifferentiated chondrosarcoma (DCS) is an ultra-rare bone sarcoma subtype characterised by an abrupt transition from low-grade cartilage to high-grade non-cartilaginous sarcoma. Distant metastases are common (∼40-80%) and are often identified at the time of diagnosis (>20); contemporary 5-year overall survival (OS) is ∼7-24%. Such poor prognosis makes DCS the most aggressive chondrosarcoma (CS) subtype, however - alongside mesenchymal - one of the only two potentially chemosensitive as opposed to conventional, clear cell and periosteal CS. Yet, the use of CHT remains controversial due to limited (mainly retrospective) studies on the topic with varying outcomes. CHT regimens usually mimic those used in osteosarcoma, including methotrexate-doxorubicin-cisplatin (MAP), doxorubicin-ifosfamide (AI), or doxorubicin-cisplatin (AP) - albeit with lower pathological response rates and substantial haematological toxicity. Notably, in localised DCS, complete en bloc resection with wide margins is the principal determinant of control. In advanced disease (metastatic/unresectable) first-line CHT provides modest, non-curative activity - objective response rate (ORR) of ∼20% and median progression-free survival (PFS) ∼4-5 months - with single-agent therapy inferior to anthracycline-based combinations. Local metastases-directed interventions may improve patients outcomes; however, further validation is required. To aid clinical decision-making, we separately discussed perioperative (neoadjuvant, adjuvant) and palliative (first and further lines) CHT strategies and outcomes. Emerging systemic treatment strategies were also described. Prospective data on the inhibition of mutant IDH1 indicate that olutasidenib (NCT03684811) can control the disease, but its activity in DCS is limited (median progression-free survival (PFS) of 1.5 months, 95% confidence interval (CI) 0.2-not reached (NR)).