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Philippos Costa, MD, and Hari Deshpande, MD, discuss chondrosarcoma staging, diagnosis, surgery, and future research avenues in this clinician-focused FAQ.
On International Chondrosarcoma Awareness Day, OncLive® sat down with Philippos Costa, MD, and Hari Deshpande, MD, to discuss frequently asked questions about the complexities of chondrosarcoma management. The following FAQ, adapted from their conversation, provides clinical insights into chondrosarcoma staging, diagnosis, and disease biology; the importance of surgery as the primary treatment for localized chondrosarcoma; and the potential role for IDH1-targeted therapy and DR5 agonists in this rare disease subtype.
Deshpande is an associate professor of medicine, clinical research team leader in sarcoma, and the director Medical Oncology Inpatient Consult Service in the Section of Medical Oncology at Yale School of Medicine in New Haven, Connecticut. Costa is an oncologist and assistant professor of Medicine (Medical Oncology and Hematology) at Yale School of Medicine.
Costa began by explaining that chondrosarcomas are a heterogeneous group of bone tumors originating from chondrocytes that produce a collagenous matrix. Because these cells typically thrive in low-oxygen, low-nutrient environments, they are naturally resistant to many classical treatments.
The disease is classified by grade, and the grading system is as follows:
Key histological subtypes include:
The rarity of chondrosarcoma often leads to clinical pitfalls, emphasizing the need for expert intervention at the onset of symptoms, Costa explained. A frequent issue in the sarcoma field is the "oops surgery," where a malignant lesion is mistaken for a benign growth and removed without proper oncologic margins. To avoid this, any abnormal or growing bone tumor should be referred to a tertiary sarcoma center before intervention.
Another common issue is pathology errors, he stated, adding that there is approximately a 30% chance of an inaccurate diagnosis when a sarcoma is evaluated by a non-soft tissue specialist. Expertise is required to distinguish chondrosarcoma from similar diseases like osteosarcoma.
To ensure accurate grading and preserve the tumor’s architecture, Costa prefers to perform biopsies using a core needle rather than fine-needle aspiration.
Deshpande noted that the clinical behavior of chondrosarcoma is broad; some low-grade tumors can be followed for years with minimal growth, while others are highly aggressive.
In regards to imaging, Deshpande stated that once a biopsy confirms the diagnosis of chondrosarcoma, the primary site should be staged using MRI to provide surgeons with precise anatomical boundaries. For systemic staging, CT/PET Scans can be used to detect metastasis. Chondrosarcomas typically spread through the blood to the lungs; lymph node involvement is rare, so significant lymphadenopathy should prompt reconsideration of the patient’s diagnosis.
Imaging of other sites, like the brain, is reserved for patients presenting with specific symptoms like headaches.
For localized chondrosarcoma, the primary objective is complete surgical removal, Deshpande said. Complete surgical resection remains the only curative treatment, as there is currently no standard chemotherapy or radiation that significantly affects outcomes for most localized cases.
Other potential interventions include:
Deshpande noted that disease management should ideally take place within a multidisciplinary sarcoma tumor board involving specialized surgeons, pathologists, and radiologists.
Approximately 40% to 60% of chondrosarcomas harbor a mutation in the IDH1 gene, Costa said. This mutation alters cellular metabolism, driving proliferation.
In a phase 1 trial (NCT06127407) of the IDH1 inhibitor ivosidenib (Tibsovo), 23.1% of patients with IDH1-mutated advanced conventional chondrosarcoma achieved an objective response. and the median duration of response was 53.5 months.1 All patients (n= 21 of 21) experienced AEs, with 15 experiencing treatment-related AEs. According to Costa, this therapy may be particularly appropriate for grade 1/2 tumors, although there may still be benefit with the regimen as mutations to accumulate.
Additional data from the phase 2 ChonDRAgon trial (NCT04950075) highlight the potential for DR5 agonists in chondrosarcoma.2 Positive topline findings from the study showed a 52% reduction in the risk of disease progression or death with the DR5 agonist ozekibart (INBRX-109) compared with placebo (stratified HR, 0.479; 95% CI, 0.33-0.68); P < 0.0001) in patients with advanced or metastatic chondrosarcoma.
Unlike chemotherapy, which requires DNA damage that these cells often resist, DR5 agonists trigger apoptosis, essentially forcing the cancer cells to "kill themselves". These drugs have shown increased progression-free survival in clinical trials and are generally well-tolerated by patients, Costa stated.
Other treatment options under investigation include:
Costa and Deshpande highlighted that future strategies may involve combining targeted agents with other therapies to overcome resistance. Examples under investigation include:
Investigating DR5 agonists in the neoadjuvant setting is also a priority, as these agents could potentially shrink tumors before surgery to facilitate limb-salvage procedures rather than amputation.
Deshpande also noted growing interest in engineering immune cells to recognize and attack specific proteins on sarcoma cell surfaces, a concept already applied successfully in synovial sarcoma and certain lymphomas.
Costa emphasized that understanding the basic biology of sarcomas remains critical, particularly the exact mechanisms of the fusions found in mesenchymal subtypes. This knowledge is essential to formulate more effective therapeutic targets and guide the development of novel interventions.
