Simple SummaryDedifferentiated chondrosarcoma (DDCS) is a rare cancer that is aggressive and leads to high patient mortality. There are limited data on the efficacy of systemic treatments and the optimal agents to use. In this study, we pooled patient outcomes from five large academic sarcoma referral centers and analyzed patient characteristics, treatments received including surgery, radiation, and/or chemotherapy, as well as patient outcomes. We found that in general, prognosis was poor, with the long-term survival being only 32%, in patients diagnosed with localized cancer. Chemotherapy was the most widely used systemic therapy, but even with its use, patients had poor outcomes with a low rate of tumor shrinkage (4.9%). A few patients had prolonged tumor stability upon treatment with newer agents, such as VEGF inhibitors (pazopanib) and immune checkpoint inhibitors. Future studies should focus on exploring new therapeutics for this devastating disease.AbstractBackground: Dedifferentiated chondrosarcoma (DDCS) is a rare subset of chondrosarcoma. It is an aggressive neoplasm characterized by a high rate of recurrent and metastatic disease with overall poor outcomes. Systemic therapy is often used to treat DDCS; however, the optimal regimen and timing are not well defined, with current guidelines recommending following osteosarcoma protocols. Methods: We conducted a multi-institutional retrospective analysis of clinical characteristics and outcomes of patients with DDCS. Between 1 January 2004 and 1 January 2022, the databases from five academic sarcoma centers were reviewed. Patient and tumor factors, including age, sex, tumor size, site, location, the treatments rendered, and survival outcomes, were collected. Results: Seventy-four patients were identified and included in the analysis. Most patients presented with localized disease. Surgical resection was the mainstay of therapy. Chemotherapy was used predominantly in the metastatic setting. Partial responses were low (n = 4; 9%) and occurred upon treatment with doxorubicin with cisplatin or ifosfamide and single-agent pembrolizumab. For all other regimens, stable disease was the best response. Prolonged stable disease occurred with the use of pazopanib and immune checkpoint inhibitors. Conclusions: DDCS has poor outcomes and conventional chemotherapy has limited benefit. Future studies should focus on defining the possible role of molecularly targeted therapies and immunotherapy in the treatment of DDCS.