Chondrosarcoma: A Comprehensive Review of Tumor Biology, Clinical Behavior, and Therapeutic Advances

Abstract

Chondrosarcoma is a heterogeneous group of malignant bone tumors characterized by the production of neoplastic hyaline cartilage. These tumors are often indolent and typically resistant to conventional chemotherapy and radiotherapy, with surgical resection remaining the cornerstone of treatment. However, patients with unresectable or metastatic disease face poor outcomes due to the lack of effective systemic therapies. While advancements in systemic treatments – such as immunotherapy and anti-angiogenic agents – and novel radiation modalities like proton beam therapy and carbon ion therapy have shown some benefit in select cases, their overall efficacy remains limited, underscoring the urgent need for more effective treatment options. Emerging novel therapies are beginning to illuminate potential new treatment pathways. Current efforts are increasingly focused on targeting recurrent genetic alterations and dysregulated signaling pathways, including IDH mutations, DR5-mediated apoptotic pathway, hedgehog signaling, Src kinase pathway, the PI3K-Akt-mTOR axis, histone deacetylation, and angiogenesis. Although these targeted strategies are still under investigation, they show promise in overcoming therapeutic resistance and advancing personalized treatment. This review provides an overview of the clinical characteristics of major chondrosarcoma subtypes, key genetic alterations implicated in tumor pathogenesis, and recent advances in treatment strategies, including surgery, chemotherapy, radiotherapy, immunotherapy, and emerging targeted therapies.

Introduction

Chondrosarcoma (CS) is a malignant tumor originating in cartilage and represents a heterogeneous group of primary bone cancers characterized by the formation of neoplastic hyaline cartilage [1, 2]. It is the second most common primary malignant bone tumor after osteosarcoma, accounting for approximately 25–30% of bone cancer cases [3–5]. However, its proportion among bone cancers varies significantly across different regions of the world, ranging from less than 10% in India and Saudi Arabia to over 45% in Finland, Slovenia, and the Netherlands [5]. The global age-standardized incidence rate of CS is estimated at 0.1 – 0.3 per 100,000 people per year [5]. Notably, CS is the most common bone tumor in individuals over 30 years old, with most cases being diagnosed in patients aged 40 and older [6]. The mean age at diagnosis is approximately 51 years, with a slight male predominance [4].

CS is classified as either primary – if the tumor develops de novo – or secondary if it arises from pre-existing benign lesions such as enchondromas or osteochondromas. Secondary CS is most associated with solitary or multiple osteochondromas. A fraction of cases arises from other conditions, such as Maffucci syndrome and Ollier disease [7]. Histologically, CS consists of several subtypes, with conventional chondrosarcoma (CCS) being the most common, accounting for about 85% of cases. The remaining 15% includes rarer variants, such as dedifferentiated chondrosarcoma (DDCS), mesenchymal chondrosarcoma (MCS), and clear cell chondrosarcoma (CCCS) (Figure 1) [8, 9]. These subtypes exhibit distinct clinical behaviors, molecular profiles, and pathological characteristics, including radiographic and histological features, which underscore the need for tailored, subtype-specific therapeutic strategies.

Figure 1.

Relative proportion of chondrosarcoma cases by subtype

Conventional chondrosarcoma is the most common subtype, accounting for approximately 85% of all cases, followed by dedifferentiated (~10%), mesenchymal (~2%), clear cell (~2%), and other rare subtypes (<1%). Percentages are approximate and may vary across registries.

CS can develop in both the axial and appendicular skeleton. It most often arises within the long bones, especially the proximal femur, but can also occur in the pelvis, ribs, sternum, clavicle, and skull [6]. Tumors usually grow slowly, with symptoms often presenting 10 – 15 months before diagnosis [10]. Patients frequently report progressive, insidious bony or joint pain that worsens at night [11]. In the case of secondary CS arising from an osteochondroma, a palpable mass may be the first clinical sign and symptom [7]. Tumor-induced bone weakening may result in pathological fractures [12]. Rarely, some tumors in the pelvis or spine can compress adjacent structures, impairing bowel or bladder function [13].

Timely diagnosis and treatment are essential to reduce tumor burden and prevent metastasis. Initial evaluation includes plain radiographs, followed by cross-sectional imaging with CT and MRI to assess tumor characteristics and extent. Early diagnosis is often challenging due to nonspecific symptoms and the rarity of the disease ^[14]. Definitive diagnosis and grading require tissue biopsy from the most radiologically aggressive area ^[15]. While no validated early detection tools currently exist, circulating tumor DNA has emerged as a promising biomarker for diagnosis and monitoring of residual disease in CS and other malignancies [16].

In most cases, CS has a favorable prognosis, owing to its slow growth and low metastatic potential. The reported relative 5-year survival rate is 75.2% [6]. However, prognoses differ widely between subtypes, highlighting the need for individualized risk assessment. Surgical resection remains the cornerstone of treatment, with outcomes closely tied to tumor grade and the status of surgical margins [1]. Conventional chemotherapy and radiotherapy have limited efficacy, as CS is largely resistant to both [17, 18]. As a result, patients with unresectable or metastatic disease have limited therapeutic options. The lack of effective, evidence-based systemic therapies underscores a pressing need for therapeutic innovation. In response, increasing efforts are focused on developing novel strategies, particularly those targeting dysregulated signaling pathways and genetic alterations.

This review summarizes the clinical characteristics of major CS subtypes and outlines key genetic alterations implicated in tumor development, such as mutations in IDH, COL2A1, and EXT1/2, as well as abnormalities in genes involved in the p53 and Rb pathways. It also highlights recent advances in treatment, spanning surgery, chemotherapy, radiotherapy, immunotherapy, and anti-angiogenic therapy, as well as emerging targeted therapies aimed at gene mutations such as IDH and at dysregulated pathways including DR5-mediated apoptotic signaling, hedgehog signaling, Src kinase pathway, the PI3K-Akt-mTOR axis, and histone deacetylation.

Histopathological classification

Conventional chondrosarcoma

CCS comprises the largest group of malignant cartilaginous tumors and most commonly affects adults between the fourth and seventh decades of life [19]. CCS can be classified according to its site of origin in the bone. Central CCS accounts for approximately three-quarters of all CS cases and arises within the intramedullary cavity [20, 21]. Radiographically, these tumors often appear as mixed lytic and sclerotic areas, with the sclerotic zones forming the characteristic “rings and arcs” pattern due to chondral matrix mineralization [15, 22]. Peripheral CSs develop from the cartilage cap of osteochondromas on the bone surface and tend to affect younger individuals [23]. These tumors are usually well-differentiated, less aggressive than their central counterparts, and associated with a more favorable prognosis [23, 24]. Periosteal chondrosarcoma, (juxtacortical) arises from the periosteum and is the rarest subtype, accounting for less than 1% of cases [25]. It typically presents in younger patients and is associated with the most favorable clinical outcomes [6, 26].

Despite its malignant nature, CCS retains a chondroid phenotype and remains largely avascular, encased in a dense hyaline extracellular matrix. These features contribute to slow tumor growth, resistance to systemic therapies, and limited radiologic detectability [1, 27]. Approximately 90% of CCS cases are low- to intermediate-grade (grades 1–2), follow an indolent clinical course, and metastasize infrequently [1, 28]. Survival rates for grade 1 tumors show excellent outcomes, with 5-year survival rates ranging from 82% to 99% and 10-year survival ranging from 89% to 95%. Grade 2 tumors demonstrate more variable results, with 5-year survival ranging from 63% to 92% and 10-year survival ranging from 58% to 86%. In contrast, grade 3 tumors (5–10% of cases) are more aggressive, carry a significantly higher risk of metastasis [1], and are associated with significantly poorer outcomes, with 5-year survival between 0% and 77% and 10-year survival between 0% and 55% [21]. These survival distinctions underscore the importance of accurate grading in guiding treatment and predicting patient outcomes.

Dedifferentiated chondrosarcoma

DDCS is a highly aggressive subtype, accounting for approximately 10% of all CS cases, and typically presenting in patients aged 50–70 years [29–31]. Radiological evaluation typically reveals a large lytic lesion with aggressive features, such as bone destruction and soft tissue extension, in conjunction with a calcified lesion indicative of a low-grade cartilaginous origin [31, 32]. Histologically, it is defined by two distinct tumor components: one resembling enchondroma or conventional (low- to intermediate-grade) CS, and another composed of high-grade mesenchymal neoplasms, most commonly osteosarcoma, fibrosarcoma, or malignant fibrous histiocytoma [33, 34]. The high-grade, non-cartilaginous component is the primary determinant of poor prognosis, making its identification and quantification critical for prognostication and management [33]. It is believed that both tumor components share a common genetic origin, with the dedifferentiated (anaplastic) component acquiring additional mutations that drive the transition from a low-grade to a highly malignant phenotype [35–38].

DDCS retains several hallmark features of its parent CCS origin, such as a predilection for the long bones or pelvis [39], as well as molecular markers including mutations within p53, IDH1/2, SOX9, Bcl-2, NY-ESO, TERT, CDKN2A, and CDKN2B [40–43]. Clinically, however, DDCS behaves very differently from CCS. Unlike CCS, which is typically avascular, DDCS is highly vascularized and prone to early metastasis [44, 45]. This increased vascularity may render DDCS more responsive to therapeutic strategies that are largely ineffective against CCS. For instance, evidence indicates that DDCS demonstrates greater sensitivity to chemotherapy compared to its low-grade precursor [45–48]. Additionally, the frequent acquisition of PD-L1 expression in DDCS presents a potential opportunity for immunotherapy [49]. Despite these therapeutic possibilities, the aggressive nature of DDCS far outweighs any potential benefits. Its rapid progression and high metastatic potential make it extremely difficult to manage, and prognosis remains dismal, with a 5-year overall survival (OS) of less than 25% [30, 50]. Regardless of the treatment modality, most patients succumb to distant metastases within two years of diagnosis [45, 48], underscoring the significant clinical challenge this subtype of CS presents.

Mesenchymal chondrosarcoma

MCS, like DDCS, is a highly aggressive subtype, but it is extremely rare, accounting for <2% of all CS cases [20, 51]. While DDCS typically arises through malignant progression from existing CCS, MCS is believed to originate de novo from immature chondroblasts [52]. This distinction is also reflected in their respective age distributions: DDCS typically affects older patients, while MCS is most seen in adolescents and young adults, often during the second to third decades of life [53]. Histologically, MCS is characterized by a biphasic histologic pattern of small undifferentiated round cells intermixed with islands of well-differentiated cartilaginous matrix [53, 54]. On radiographs, MCS usually appears as a soft tissue mass or osteolytic lesion with indistinct or well-defined boundaries and frequent evidence of induration [52]. MCS has a broad anatomical distribution, including bones (mainly the jaw, ribs, ilium, vertebrae, and lower extremities), soft tissues and intracranial sites [55, 56].

The molecular basis of MCS is still not fully understood, but several genetic alterations have been identified. The most notable among them is the HEY1-NCOA2 fusion [57, 58], which has emerged as a defining molecular hallmark of MCS and plays a critical role in confirming diagnosis [59–61]. Less frequently, other gene fusions such as IRF2BP2-CDX [62] and EWSR1-FLI1 [63] have also been reported.

Prognosis in MCS is highly variable. The strongest predictors of poor survival are the presence of metastatic disease and larger tumor size. Reported OS rates are approximately 51% at 5 years and 43% at 10 years, with worse outcomes observed in those with tumors located in axial regions ^[64]. Achieving negative surgical margins significantly improves prognosis, and the addition of chemotherapy provides further benefit; therefore, complete surgical resection combined with perioperative chemotherapy should be considered the standard of care for localized disease [65–67]. Given the rarity of MCS, multicenter studies are needed to determine the most effective chemotherapy regimens. Because of the tumor’s marked tendency for local recurrence and late-onset metastasis, long-term follow-up is essential for effective disease management.

Clear cell chondrosarcoma

CCCS is an extremely rare variant of CS, accounting for less than 2% of all CS cases, and most commonly affects patients in the 3rd to 5th decades of life [20, 51, 68]. Radiographs typically show a predominantly lytic lesion with well-defined sclerotic margins, often mimicking a benign process, and less frequent matrix mineralization compared to CCS ^{[27, 31]}. Histologically, it is characterized by glycogen-rich cells with abundant clear, vacuolated cytoplasm [54]. This subtype commonly affects the proximal epiphyses of the femur and humerus [69], and may extend into the articular cartilage of the hip and shoulder joints [70, 71]. CCCS is generally considered a low-grade malignancy and often does not invade surrounding soft tissues. Reported 5-year survival rates range from 60% to 100% [4, 26, 72]. Similar to CCS, CCCS is resistant to chemotherapy. Surgical management with en bloc resection remains the mainstay of treatment [27, 73]. However, local recurrence has been reported even decades after initial surgery, necessitating long-term follow-up of patients ^{[68, 74]}.

Key genetic alterations

IDH1/2

Isocitrate dehydrogenase (IDH) is among the most extensively studied molecular targets in CS. As illustrated in Figure 2, IDH enzymes play a central role in the tricarboxylic acid (TCA) cycle by catalyzing the oxidative decarboxylation of isocitrate to α-ketoglutarate (α-KG), a reaction that concurrently uses NADP⁺ or NAD⁺ as a cofactor [75, 76]. In cancer-associated IDH mutations, this normal enzymatic activity is lost, and the mutant enzyme acquires a neomorphic function: the reduction of α-KG to the oncometabolite D-2-hydroxyglutarate (D-2HG) [77]. Accumulation of D-2HG inhibits α-KG-dependent dioxygenases, including the TET family of DNA demethylases and Jumonji-C domain-containing histone demethylases. This leads to widespread DNA and histone hypermethylation, resulting in epigenetic dysregulation and genomic instability. These changes impair cellular differentiation pathways and promote malignant transformation [78–80].

Figure 2.

Wildtype and Mutant IDH Metabolism

Humans express three distinct isoforms of isocitrate dehydrogenase (IDH): IDH1, IDH2, and IDH3. IDH1 is localized to the cytosol and peroxisomes, whereas IDH2 and IDH3 reside in the mitochondrial matrix and function as part of the tricarboxylic acid (TCA) cycle. IDH1 and IDH2 operate as homodimers, utilize NADP⁺ as a cofactor, and catalyze the reversible oxidative decarboxylation of isocitrate to produce α-ketoglutarate (α-KG), NADPH, and CO₂. In contrast, IDH3 is a heterotetramer that uses NAD⁺ as a cofactor and catalyzes an irreversible, rate-limiting step in the TCA cycle. Mutations in IDH1 or IDH2 (mIDH1/mIDH2) result in a loss of normal enzymatic activity and confer a neomorphic function: the reduction of α-KG to the (D)-enantiomer of 2-hydroxyglutarate (D-2HG), an oncometabolite that inhibits α-KG-dependent dioxygenases - including the TET family of 5-methylcytosine hydroxylases and Jumonji C domain-containing histone demethylases - leading to widespread DNA and histone hypermethylation and contributing to tumorigenesis. Created in BioRender.

Abbreviations: α-KG, α-ketoglutarate; CO₂, carbon dioxide; D-2HG, D-2-hydroxyglutarate; IDH, isocitrate dehydrogenase; mIDH, mutant isocitrate dehydrogenase; NAD⁺, nicotinamide adenine dinucleotide; NADH, reduced nicotinamide adenine dinucleotide; NADP⁺, nicotinamide adenine dinucleotide phosphate; NADPH, reduced nicotinamide adenine dinucleotide phosphate; TCA, tricarboxylic acid; TET, ten-eleven translocation.

Mutations in IDH1 and IDH2 are frequently observed in CS and several other cancer types such as glioma and acute myeloid leukemia [81, 82]. In CS, they are found in 52–59% of central CS cases and 57% of DDCS [40]. In a meta-analysis involving 488 CS patients across 14 studies, IDH1 mutations were identified in 38.7% and IDH2 mutations in 12.1% of cases [83]. Similarly, a genetic survey by Nakagawa et al. reported IDH1 mutations in 39% and IDH2 mutations in 13% of patients [84]. Given their high prevalence, IDH mutations are useful diagnostic markers, aiding in the differentiation of DDCS from undifferentiated pleomorphic sarcoma of the bone ^[85], and distinguishing high-grade CS from chondroblastic osteosarcoma, which typically lacks these mutations ^[40]. A large-scale genomic analysis of 550 patients across multiple institutional datasets further confirmed that IDH1/2 mutations are the most frequent genetic alterations in CCS after TP53, and that DDCS harbors a similar but more genomically unstable mutational profile with significantly elevated tumor mutational burden [86].

Clinically, IDH1/2 mutations have been associated with poorer prognosis. In a retrospective analysis of 80 patients, the 5-year OS was 64% in those with IDH1/2 mutations compared to 93% in those without. While the difference in mutation frequency across histological grades was not statistically significant, IDH1/2 mutations were observed in 21% of grade I tumors, 39% of grade II, and 44% of grade III CSs [87].

COL2A1

COL2A1 encodes the α1 chain of type II collagen, a primary structural component of the extracellular matrix in articular cartilage and a hallmark of chondrocytic differentiation [88]. Mutations in COL2A1 lead to the production of defective pro-collagen α-chains, which interfere with the proper assembly and maturation of collagen fibrils, ultimately compromising the integrity of the cartilage matrix [89]. The Cancer Genome Project identified COL2A1 mutations in approximately 37% of CS cases, with the majority occurring in central CCS, although they have also been reported in DDCS and CCCS subtypes [90, 91]. Notably, COL2A1 mutations are largely unique to CS among bone sarcomas, making them a potentially valuable diagnostic marker and offering insight into CS-specific tumor biology. While the exact oncogenic mechanism remains unclear, it is hypothesized that these mutations disrupt chondrocyte differentiation by compromising extracellular matrix integrity, thereby interfering with matrix-dependent signaling pathways such as those mediated by integrins, TGF-β, and other matrix-sensing processes.

TP53 pathway

TP53, often referred to as the “guardian of the genome,” is a key tumor suppressor gene that plays a critical role in maintaining genomic stability. It regulates multiple cellular processes, including cell cycle arrest, DNA repair, apoptosis, and cellular senescence. In response to genotoxic stress or DNA damage, TP53 halts cell cycle progression, primarily at the G1/S checkpoint, allowing time for DNA repair or inducing apoptosis if the damage is irreparable [92, 93]. In CS, TP53 alterations are common and include point mutations, gene deletions, and chromosomal abnormalities on chromosome 17, where TP53 is located [94, 95]. These alterations are associated with higher histologic grade, metastatic potential, and poorer prognosis [96]. Overexpression of TP53, frequently detected via immunohistochemistry, is typically seen in high-grade CS and often reflects underlying mutations.

In addition to direct TP53 mutations, cancer cells can circumvent the tumor-suppressive effects of TP53 through the upregulation of mouse double minute 2 homolog (MDM2). MDM2 is an E3 ubiquitin ligase that regulates TP53 via a negative feedback loop: TP53 activation induces MDM2 transcription, and in turn, MDM2 binds TP53, inhibits its transactivation domain, and promotes its degradation [97]. MDM2 overexpression has been observed in approximately 33% of high-grade central CCS cases, with expression levels correlating with tumor grade [98]. Similar overexpression has also been reported in DDCS [99]. These findings suggest that dysregulation of the MDM2-TP53 axis contributes to the pathogenesis of CS. Therapeutically, inhibiting the TP53-MDM2 interaction could help restore TP53 function, offering a promising strategy in cases where TP53 is functionally inactivated by MDM2 overactivity [100].

pRb pathway

The retinoblastoma protein (pRb) pathway is another critical regulator of cell cycle progression that is frequently disrupted in CS. Under physiological conditions, cyclin D1 binds to CDK4 to form an active complex that phosphorylates Rb, leading to the release of E2F transcription factors and subsequent entry into the S phase. This process is tightly controlled by p16, encoded by the CDKN2A gene, which inhibits CDK4 activity and prevents premature cell cycle progression [98, 101]. In CS, this regulatory balance is often disrupted through various mechanisms, including amplification of CDK4 or CCND1 and deletion or promoter hypermethylation of CDKN2A, resulting in reduced or lost p16 expression [98, 102]. Alterations in this pathway have been reported in up to 96% of high-grade central CS cases. Such changes drive uncontrolled cell proliferation and are closely linked to tumor progression. [98]. The high prevalence of these disruptions highlights their biological relevance in CS and supports their potential role as prognostic biomarkers and therapeutic targets.

EXT1/2

Hereditary multiple exostoses (HME) is an autosomal dominant disorder caused by heterozygous loss-of-function mutations in the EXT1 or −2 genes, which encode glycosyltransferases essential for heparan sulfate biosynthesis. These genes function as tumor suppressors, and their inactivation – particularly biallelic loss – leads to the formation of multiple osteochondromas, which are benign cartilage-capped bony outgrowths most commonly arising near the growth plates of long bones [103, 104]. The most severe complication of HME is malignant transformation of osteochondromas into secondary peripheral chondrosarcomas, occurring in a minority of affected individuals. This process typically follows a “two-hit” mechanism, with a germline EXT1 or −2 mutation followed by somatic loss of the remaining wild-type allele in chondrocytes, resulting in complete loss of EXT function and neoplastic transformation [103, 105]. Additional genetic events, such as inactivation of CDKN2A or TP53, may further drive malignant progression. Notably, the risk of chondrosarcoma and the severity of the clinical phenotype are generally higher in individuals with EXT1 mutations compared to EXT2[106] . In addition, evidence also suggests that, in some cases, secondary peripheral chondrosarcomas may arise from wild-type cells with functional EXT within the osteochondroma niche, indicating that EXT-independent mechanisms can contribute to oncogenesis [107]. Intraosseous chondroid neoplasms, including central chondrosarcomas, may also occur in HME patients, underscoring the need for careful evaluation of cartilaginous lesions in this population [108].

Treatment strategies

As described in Figure 3, CS requires multimodal therapeutic strategies combining surgery, radiation, and systemic treatments to overcome its complexity and resistance to conventional therapies. Surgery remains the primary approach when feasible, while advanced radiation modalities can improve outcomes when surgery is limited or not possible. Systemic therapies – including chemotherapy, immunotherapy, and emerging targeted agents – play variable roles depending on tumor subtype and molecular characteristics, highlighting the need for personalized therapeutic strategies.

Figure 3.

Multimodal treatment approaches in chondrosarcoma. Multimodal therapeutic strategies for chondrosarcoma integrate surgery, radiation, and systemic therapies to address the tumor’s complexity and resistance to conventional treatment. Surgery remains the mainstay and most effective curative option, particularly when wide margins can be achieved. In cases where surgery is infeasible or margins inadequate, radiation therapy - especially advanced modalities like proton or carbon ion therapy - may improve outcomes. Chemotherapy generally plays a limited role due to the tumor’s poor vascularization and inherent resistance, though it may offer benefits in select subtypes such as MCS and DDCS. Immunotherapy has shown limited success, particularly in dedifferentiated disease with PD-L1 expression. Anti-angiogenic therapy has shown limited activity in advanced diseases. Emerging targeted therapies - including those aimed at IDH mutations, the DR5-mediated apoptotic pathway, hedgehog signaling, Src kinase activity, the PI3K-Akt-mTOR pathway, and histone deacetylation - offer promising avenues for improving outcomes in this challenging malignancy, although several of these strategies remain under clinical investigation at various stages. Created in BioRender.

Abbreviations: CS, chondrosarcoma; CTLA-4, cytotoxic T-lymphocyte-associated protein 4; DDCS, dedifferentiated chondrosarcoma; DR5, death receptor 5; HDAC, histone deacetylase; IDH, isocitrate dehydrogenase; IHH, Indian hedgehog; MCS, mesenchymal chondrosarcoma; mIDH1/2, mutant isocitrate dehydrogenase 1/2; PD-1, programmed death-1; PD-L1, programmed death-ligand 1; PI3K-Akt-mTOR, phosphoinositide 3-kinase-protein kinase B-mechanistic target of rapamycin; Src, Src proto-oncogene tyrosine-protein kinase.

Surgery

Surgery is the primary and most effective treatment for CS, serving as the cornerstone of management for localized disease. The goal is complete tumor excision with a surrounding margin of healthy tissue to ensure the thorough removal of malignant cells. Achieving wide surgical margins is critical, as it remains one of the few modifiable risk factors under the clinician’s control [109, 110]. Positive margins – where tumor cells remain at the edges of the resected tissue – are strongly associated with increased risk of local recurrence and distant metastasis [111, 112]. Additionally, some evidence suggests a survival benefit from surgery even in patients with metastatic CS at initial diagnosis. Specifically, patients with conventional subtypes and Grade II malignancies who underwent primary tumor resection had better survival outcomes compared to those who did not [113].

While achieving adequate margins in bone is usually straightforward, soft tissue involvement - particularly in pelvic CS – poses a greater challenge. These tumors often extend into the abdominopelvic cavity and lie near critical structures such as the rectum, bladder, and major blood vessels, increasing the risk of surgical complications and margin positivity. For high-grade tumors, wide excision offers a significant survival benefit compared to marginal or intralesional resections. Given the difficulty of reliably distinguishing tumor grade preoperatively, aggressive resection aimed at achieving wide margins is generally recommended ^[114]. Fortunately, the use of computer-assisted navigation has enhanced the precision of pelvic resections, leading to lower rates of margin positivity and local recurrence while preserving more surrounding tissue [115, 116].

In low-grade cases involving long bones, intralesional curettage combined with adjuvant therapy is often sufficient [117]. Common adjuvants include argon plasma, phenol, cryotherapy, or polymethyl methacrylate, a bone cement that generates high temperatures during polymerization [118]. For high-grade tumors, wide resection followed by limb salvage surgery is typically necessary. Reconstruction may involve an endoprosthesis, bone graft, or both, with endoprostheses being the most used [119, 120]. However, in older patients or those with significant comorbidities, reconstruction may not be feasible [121, 122]. Therefore, treatment plans must be individualized based on tumor characteristics, anatomical considerations, and overall patient health.

When wide margins are achievable, internal hemipelvectomy with limb preservation is generally preferred. The choice of reconstructive approach depends on tumor size, location, and involvement of surrounding structures. Isolated lesions in the iliac wing (Type I) or pubic rami (Type III) can often be managed with straightforward resections. In contrast, periacetabular tumors (Type II) present greater challenges, requiring a more complex surgical strategy to balance oncologic control with functional preservation [11]. Successful limb salvage hinges on the preservation of at least two of three critical structures: the hip joint, femoral neurovascular bundle, and sciatic nerve. When this is not possible, hindquarter amputation may be necessary ^{[112, 123]}.

Although amputation is inherently more mutilating, advances in anesthetic and perioperative care have reduced associated mortality to around 1% [124]. Younger patients, in particular, often experience favorable survival and functional outcomes following amputation [125]. Nevertheless, ongoing improvements in imaging, surgical techniques, and reconstruction have made limb salvage a viable option for the majority of patients [126], with amputation typically reserved for extensive periacetabular disease ^[127]. Modern limb salvage techniques achieve survival rates comparable to those of amputation but with significantly reduced morbidity ^[128]. Consequently, amputation is generally considered a last resort ^[122].

Radiotherapy

As previously noted, CS is relatively resistant to conventional radiation therapy. However, it may still be indicated in certain clinical contexts – particularly following incomplete resection or when surgery is not feasible due to anatomical constraints or the risk of unacceptable morbidity ^{[17, 129]}. Given CS’s inherent radioresistance, effective local control typically requires doses exceeding 60 Gy, which are often unachievable with standard photon-based therapy. To overcome this limitation, advanced radiation modalities such as proton beam therapy and carbon ion therapy have been developed. These approaches allow for the precise delivery of high-dose radiation to the tumor while minimizing collateral damage to surrounding healthy tissues ^{[27, 130, 131]}.

Proton therapy, due to its greater mass and linear energy transfer, can deposit higher energy at the tumor site while minimizing the “overpenetration” commonly associated with photon beams [132]. Its efficacy in treating skull-base CS is well-established and has demonstrated improved clinical outcomes compared to conventional photon therapy [133]. Multiple independent investigations have reported local control rates ranging from 85–100%, with mixed photon-proton or proton-only protocols in these tumors [134–138]. A recent large-scale outcome analysis in pediatric patients with skull-base CS further supported these observations, indicating that conventional grade 1–2 tumors can be effectively managed with subtotal resection followed by adjuvant proton therapy, using dose regimens comparable to those in adults [139]. Another promising modality is carbon ion therapy, which builds on the same physical principles as proton therapy but employs heavier particles with greater energy. Notably, it has achieved comparable results to proton therapy in treating skull base CS, with control rates exceeding 90% and grade III toxicity rates at or below 10% [140–144]. These encouraging results highlight the potential of high-dose hadron therapy as a valuable component in the multidisciplinary management of this rare malignancy.

Table 1 summarizes key prospective clinical trials evaluating particle therapy in CS. NCT00592748 is the first and largest randomized dose-escalation trial of proton therapy for skull base CS, with 30-year follow-up demonstrating excellent local control at 70 GyRBE without benefit from dose escalation to 76 GyRBE [145]. NCT01182753 is the only randomized phase III trial directly comparing proton and carbon ion therapy alone for skull base CS, designed to assess non-inferiority of carbon ions (60 GyRBE in 20 fractions) relative to protons (70 GyRBE in 35 fractions) with respect to 5-year local progression-free survival (PFS); however, the last reported update was in 2010, and no results have yet been published [146]. NCT05861245 explores a novel hypofractionated proton approach (35 GyRBE in 5 fractions), with early results showing 100% local control at a median follow-up of 12 months, though late grade 3 temporal lobe necrosis was observed in two patients [147]. Additional trials are evaluating high-dose proton therapy and comparative particle therapy strategies across various anatomical sites, including the skull base, spine, sacrum, and pelvis.

Table 1: Radiation Therapy Clinical Trials in Chondrosarcoma.

NCT No.	Modality	Dose/Fractionation	Study Population	Anatomical Site	Design	Study Status	Publication
00592748	Proton RT	70 vs. 76 GyRBE (1.8 – 1.92 GyRBE/fx)	Chordoma/CS	Skull base and cervical spine	Randomized dose-escalation, phase I/II	Completed	Ioakeim-Ioannidou et al. 2026 [145]
01182753	Proton vs. Carbon ion RT	Proton: 70 GyRBE (2.0 GyRBE/fx, 35 fx); Carbon: 60 GyRBE (3.0 GyRBE/fx, 20 fx)	CS	Skull base	Randomized, phase III	Unknown	Nikoghosyan et al. 2010 [146]
01449149	Proton RT	72.0–79.2 GyRBE (1.8 GyRBE/fx, 40–44 fx)	Chordoma/CS	Skull base and spine	Prospective, Feasibility / II	Completed	Baumann et al. 2019 [153]
05861245	Hypofractionated proton RT	35 GyRBE (7.0 GyRBE/fx, 5 fx)a	Chordoma/CS	Skull base	Prospective, phase II	Recruiting	Sallabanda et al. 2023 [147]
00496522	Proton RT (± photon RT)	Up to 70 CGE (2.0 CGE/fx, 35 fx)	CS	Skull base	Prospective, phase II	Active (not recruiting)
05033288	Carbon ion vs. Proton RT vs. Surgery	Per institutional protocol	Pelvic bone sarcomas including CS	Pelvis	Prospective, comparative	Recruiting
01346124	Proton RT (IMPT)	High-dose IMPT ± surgical resection	Chordoma/CS	Spine, sacrum, and skull base	Prospective, phase II	Active (not recruiting)

^aDose for chondrosarcoma; chordoma patients received 37.5 GyRBE / 5 fx in the same trial.

Abbreviations: CS, chondrosarcoma; RT, radiotherapy; GyRBE, Gray relative biological effectiveness; fx, fractions; CGE, cobalt gray equivalent; IMPT, intensity-modulated proton therapy.

For the present, the availability of hadron therapy centers remains limited. However, according to data from the Particle Therapy Co-Operative Group (PTCOG), there are now well over one hundred particle therapy centers in clinical operation worldwide, the majority of which provide proton therapy, with a limited number offering carbon ion therapy. As this total continues to rise, these advanced treatment modalities are expected to become increasingly accessible to a broader patient population. Looking ahead, integrating high-dose radiation therapies with systemic approaches – such as immunotherapy, targeted agents, and novel chemotherapeutic strategies – holds great potential to further improve patient outcomes. The combination of conventional photon-based radiotherapy with radiosensitizing agents has also been explored as a strategy to overcome the intrinsic radioresistance of CS. Rhomberg et al. reported that photon irradiation (median dose 60 Gy) combined with razoxane, a topoisomerase II inhibitor with radiosensitizing properties, achieved a 75% response rate among eight evaluable CS patients, with a median duration of response of 22 months [148]. At the preclinical level, PARP inhibitors have been one of the most extensively studied class of radiosensitizers in CS. Talazoparib has demonstrated synergy with radiation in CS cell lines irrespective of IDH mutation status [149], and olaparib significantly enhanced the cytotoxicity of photon irradiation in CS cells, although this radiosensitizing effect was notably absent with carbon ion irradiation [150]. Other preclinical radiosensitizing strategies under investigation include gadolinium oxide nanoparticles and disulfiram/copper complexes [151, 152]. While these approaches remain in early stages, they represent promising avenues for improving the efficacy of radiotherapy in CS, particularly when particle therapy is unavailable.

Chemotherapy

Like radiotherapy, chemotherapy is generally ineffective in most cases of CS due to several intrinsic factors[17, 154]. These include low mitotic activity, a dense cartilaginous matrix that acts as a physical barrier, and poor vascularization, all of which impede drug penetration [155, 156]. Additionally, the overexpression of antiapoptotic proteins ^[157] and multidrug resistance transporters ^[156] further contribute to the tumor’s chemoresistance. Moreover, evaluating the efficacy of chemotherapy in CS remains challenging, as available data are limited and largely derived from small, retrospective studies.

Nevertheless, some studies suggest that chemotherapy, though generally of limited benefit, may still hold therapeutic value – particularly in mesenchymal and dedifferentiated subtypes of CS. In a cohort study of 180 patients with advanced CS, Italiano et al. reported response rates of 31% for MCS, 20.5% for DDCS, 11.5% for CCS, and 0% for CCCS, with doxorubicin- and ifosfamide-based regimens being the most commonly used [45]. Retrospective data also suggest that adjuvant or neoadjuvant chemotherapy, when combined with surgery, may improve outcomes in DDCS compared to surgery alone [48, 158]. Similarly, chemotherapy in MCS has been associated with reduced recurrence and improved survival [53, 65, 159]. For patients with unresectable CCS, systemic treatment – most often with doxorubicin-based regimens – has been linked to a survival benefit, with a 3-year OS of 26% in treated patients, compared to 8% in untreated patients [160].

Although research into chemotherapeutic sensitivity in CS is still limited, recent high-throughput drug screening efforts have identified several compounds with potent anti-tumor effects in CS cell lines. Notably, many of these candidate agents target pathways involved in cell cycle regulation, DNA repair, and apoptosis – mechanisms frequently dysregulated in tumors. Some also demonstrate synergistic lethality when used in combination, offering a promising avenue for therapeutic development [161]. Follow-up in vivo studies aimed at evaluating these combinations in models of tumor progression and metastasis will be critical for informing future clinical trial designs. If validated, these findings could lay the groundwork for more effective, targeted systemic therapies in CS.

Immunotherapy

Immune checkpoint inhibition (ICI) therapy has revolutionized the treatment of various cancers. Antibodies targeting programmed death-1 (PD-1) and its ligand PD-L1 have demonstrated unprecedented response rates, particularly in tumors with high tumor mutational burden (TMB) and elevated PD-L1 expression [162–164]. This aligns with the mechanism of checkpoint inhibitors, which lift inhibitory signals on the immune system – thereby enabling a more robust antitumor response. Tumors with high mutational loads tend to present more neoantigens, making them more immunogenic and susceptible to ICI. However, these characteristics are largely absent in CS, rendering it a challenging target for PD-1/PD-L1-based immunotherapies.

Sarcomas, including CS, are generally genomically stable and characterized by low TMB. In a large-scale analysis of over 100,000 cancer genomes spanning 167 tumor types, CS ranked among the lowest 10% in TMB ^[165]. PD-L1 expression is also typically low in sarcomas; a pooled analysis of three clinical trials found PD-L1 expression (≥1% in tumor cells) in only 13.6% (21 of 154) of sarcoma patients [166]. These characteristics may contribute to the limited clinical benefits observed in trials evaluating ICI in soft tissue (STS) and bone sarcomas. For instance, a multicenter phase II trial testing pembrolizumab with metronomic cyclophosphamide demonstrated tumor shrinkage in only 3 of 50 evaluable patients with advanced STS [167]. In the SARC028 trial (NCT02301039), pembrolizumab achieved an objective response rate (ORR) of 18% in the STS cohort and only 5% in patients with bone sarcomas [168]. Efforts to improve ICI efficacy have led to exploration of combination strategies. In a randomized phase II study, nivolumab monotherapy produced an overall response rate of 5%, compared to 16% when combined with the CTLA-4 inhibitor ipilimumab in patients with metastatic sarcoma ^[169].

Despite the generally poor immunogenic profile of CS, specific subtypes – particularly DDCS – may be more responsive to immunotherapy. DDCS has demonstrated comparatively higher PD-L1 expression, which may enhance its susceptibility to PD-1/PD-L1 blockade [49, 170]. In tissue microarrays, PD-L1 expression was observed in 41% (9 of 22) of DDCS cases but absent in other CS subtypes [49]. Notably, PD-L1 expression was confined to the dedifferentiated component of the tumor and was positively correlated with other immune-related features, including increased tumor-infiltrating lymphocytes and HLA class I expression ^[49]. These findings provide a rationale for including DDCS patients in clinical trials targeting the PD-1/PD-L1 axis ^[168]. Recent data from a phase 2 trial of sunitinib plus nivolumab in advanced bone sarcomas demonstrated a median PFS of 9.5 months (95% CI, 0–19.3) in CCS (n=10). Among the 38 patients who reached the study endpoint, only two achieved a partial response, one of whom had DDCS. This finding is noteworthy given that the study included only four patients with DDCS, corresponding to an ORR of 25% in this subgroup. The patient with DDCS experienced durable disease control lasting more than four years. In contrast, none of the 10 patients with CCS responded to treatment ^[171]. These findings are consistent with the SARC028 trial, which reported a 20% ORR to pembrolizumab in DDCS, with another patient achieving long-term stable disease ^[168]. In parallel, a phase II clinical trial (NCT04458922) is currently investigating the PD-L1 inhibitor atezolizumab in patients with CS, including those with high grade CCS and DDCS (NCT04458922) (Table 2). Beyond checkpoint inhibitors, early-phase data suggest that antibody-drug conjugates (ADCs) targeting the immune checkpoint molecule B7-H3 (CD276) may also warrant investigation in CS; a phase 1/2 study of YL201 (NCT06057922) (Table 2), a B7-H3-targeting ADC, reported a disease control rate of 90% and a median PFS of 11.7 months in 10 patients with relapsed or refractory CS, although the objective response rate was low at 10% [172].

Table 2: Active clinical trials in chondrosarcoma.

NCT No.	Treatment	Target	Study Population	Study Status	Phase
04458922	Atezolizumab	PD-L1	Inoperable or metastatic CS or clear cell sarcoma	Active (not recruiting)	II
04278781	Ivosidenib (AG-120)	mIDH1	Advanced/metastatic or recurrent CS with IDH1 mutation	Active (not recruiting)	II
06127407	Ivosidenib (AG-120)	mIDH1	Locally advanced or metastatic CCS with IDH1 mutation	Recruiting	III
06176989	Enasidenib (AG-221)	mIDH2	Sinonasal and skull base cancers with IDH2 mutation	Recruiting	II
04521686	LY3410738 Gemcitabine Cisplatin	mIDH1/2 DNA synthesis DNA synthesis	Advanced solid tumors with IDH1/2 mutations	Active (not recruiting)	I
04762602	HMPL-306	IDH1/2	Advanced solid tumors with IDH1/2 mutations	Terminated	I
04950075	Ozekibart (INBRX-109)	DR5	Advanced conventional CS	Active (not recruiting)	II
04040205	Abemaciclib	CDK4/6	Bone and soft tissue sarcoma with CDK pathway alteration	Recruiting	II
01267955	Vismodegib (GDC-0449)	Hedgehog signaling	Advanced CS	Active (not recruiting)	II
04340843	Belinostat Guadecitabine Decitabine Cedazuridine	Histone deacetylase DNA methyltransferase DNA methyltransferase Cytidine deaminase	Inoperable and metastatic CCS	Active (not recruiting)	II
06057922	YL201	B7-H3	Advanced solid tumors	Active (not recruiting)	I/II

Abbreviations: CS, chondrosarcoma; CCS, conventional chondrosarcoma; PD-L1, programmed death-ligand 1; mIDH1, mutant isocitrate dehydrogenase 1; mIDH2, mutant isocitrate dehydrogenase 2; DR5, death receptor 5; CDK4/6, cyclin-dependent kinases 4 and 6; B7-H3, B7 homology 3.

Anti-angiogenic therapy

Although CS are typically hypovascular, as these tumors progress to higher histological grades or undergo dedifferentiation, they often acquire increased vascularity. This shift facilitates neovascularization, which supports tumor growth, invasiveness, and metastatic potential [44, 173, 174]. The transition to a more vascularized phenotype is typically accompanied by alterations in the tumor microenvironment, such as increased hypoxia and the upregulation of pro-angiogenic signaling. Accordingly, there has been growing interest in targeting angiogenic pathways as a therapeutic strategy in CS.

Pazopanib (Votrient) is a multi-targeted tyrosine kinase inhibitor (TKI) that acts on key angiogenic growth factor receptors, including stem cell growth factor receptor (c-KIT), fibroblast growth factor receptor (FGFR), platelet-derived growth factor receptor (PDGFR), and vascular endothelial growth factor receptor (VEGFR) [175]. It has been FDA-approved for the treatment of metastatic STS following failure of anthracycline-based chemotherapy, based on a phase III trial demonstrating a significant improvement in PFS compared with placebo [176]. Although CS is classified as a bone sarcoma and falls outside this approved indication, the clinical experience with pazopanib in STS has provided a rationale for its investigation in CS. In a phase II, single-arm trial (NCT01330966) (Table 3), pazopanib treatment in patients with unresectable or metastatic CCS yielded a disease control rate of 43% and a median OS of 17.6 months [177]. A case report further documented a partial response in a patient with metastatic grade 2/3 CCS that was previously refractory to doxorubicin and ifosfamide, with symptomatic improvement sustained for six months [178]. In addition, a retrospective multicenter study involving ten patients with advanced CS treated with either pazopanib or the VEGFR2-targeting antibody ramucirumab found no partial responses but noted prolonged disease stabilization in several patients, with a median PFS of 22.6 months in those with CCS and CCCS [179]. Another retrospective case from a DDCS cohort reported 20 weeks of stable disease with pazopanib treatment  [180]. In summary, although pazopanib may not induce dramatic responses in CS, targeting angiogenesis has demonstrated potential to stabilize disease and prolong survival, particularly in advanced or metastatic settings where conventional therapies have proven ineffective.

Table 3: Completed clinical trials in chondrosarcoma.

NCT No.	Treatment	Target	Study Population	Phase	Publication(s)
02073994	Ivosidenib (AG-120)	mIDH1	Advanced solid tumors with IDH1 mutation	I	Tap et al. 2020 [181] Tap et al. 2025 [182]
03684811	Olutasidenib ( FT-2102)	mIDH1	Advanced solid tumors with IDH1 mutation	I/II
02273739	Enasidenib (AG-221)	mIDH2	Advanced solid tumors with IDH2 mutation	I/II
03715933	Ozekibart (INBRX-109)	DR5	Advanced solid tumors including CS	I	Subbiah et al. 2023 [183]
01609179	IPI-926	Hedgehog signaling	Basal cell carcinoma and CS	N/A
01310816	IPI-926	Hedgehog signaling	Inoperable or metastatic CS	II
01330966	Pazopanib	VEGFR, PDGFR, c-KIT, FGFR	Inoperable or metastatic CS	II
00928525	Imatinib	Bcr-Abl	Desmoid tumor and advanced CS	II
04260113	Apatinib	VEGFR-2	Inoperable, advanced CS	N/A	Xie et al. 2020 [184]
02389244	Regorafenib	VEGFR, TIE2	Metastatic bone sarcomas	II	Duffaud et al. 2021 [185]
00949325	Temsirolimus Doxorubicin	PI3K-AKT-mTOR Topoisomerase II	Recurrent sarcoma	I/II	Trucco et al. 2018 [186]
02821507	Sirolimus Cyclophosphamide	PI3K/AKT/mTOR Alkylating DNA	Inoperable or metastatic myxoid liposarcoma and CS	II
00401388	Perifosine	PI3K-AKT-mTOR	CS, alveolar soft part sarcomas, and extraskeletal myxoid CS	II
02496741	Metformin Chloroquine	Glucose metabolism Heme polymerase	Glioma, intrahepatic cholangiocarcinoma, and CS with IDH1/2 mutations	Ib	Khurshed et al. 2021 [187]
00112463	Romidepsin	Histone deacetylase	Inoperable or metastatic soft tissue sarcoma	II
00073983	Gemcitabine Docetaxel	DNA synthesis Microtubule stability	Recurrent osteosarcoma or Ewing’s sarcoma Inoperable or locally recurrent CS	II	Fox et al. 2012 [188]
03277924	Sunitinib and/or nivolumab	VEGFR, PDGFR, c-KIT PD-1	Advanced soft tissue and bone sarcomas	I/II	Palmerini et al. 2025 [171]

Abbreviations: CS, chondrosarcoma; mIDH1, mutant isocitrate dehydrogenase 1; mIDH2, mutant isocitrate dehydrogenase 2; DR5, death receptor 5; VEGFR, vascular endothelial growth factor receptor; PDGFR, platelet-derived growth factor receptor; FGFR, fibroblast growth factor receptor; PD-1, programmed cell death protein 1; PI3K, phosphoinositide 3-kinase; AKT, protein kinase B; mTOR, mechanistic target of rapamycin.

Emerging novel targeted therapy

Given the limited effectiveness of conventional therapies and the modest benefits of immune checkpoint inhibitors, there has been an increasing focus on identifying novel molecular targets in CS. Recent advances in genomic and molecular profiling have uncovered recurrent mutations and key dysregulations, paving the way for targeted therapy development. Efforts have focused on targeting IDH mutations, the death receptor 5 (DR5)-mediated apoptotic pathway, epigenetic regulators, and key signaling pathways such as Hedgehog, Src, and PI3K-Akt-mTOR. Several of these targets have progressed to advanced-stage clinical trials while others remain under active investigation in both preclinical and early clinical settings. Among these, the IDH1 inhibitor ivosidenib and the DR5 agonist ozekibart represent the most clinically advanced candidates, with ongoing or completed randomized trials that may establish the first approved systemic therapies for advanced CS. Although results have been mixed, these studies highlight a promising shift toward precision medicine in CS, with the goal of tailoring treatment based on individual tumor biology and overcoming the intrinsic resistance that has long characterized this malignancy.

Mutant IDH inhibitors

As previously discussed, mutations in IDH1 or IDH2 are frequently observed in CS and serve as important diagnostic markers. Their presence across multiple cancer types has made them a major focus of targeted therapy development [9]. In 2017, the U.S. FDA approved enasidenib (AG-221), an IDH2 inhibitor, for the treatment of relapsed or refractory acute myeloid leukemia (AML) [189, 190]. This was followed in 2018 by the approval of ivosidenib (AG-120), an IDH1 inhibitor, for the same indication [191]. More recently, olutasidenib – another IDH1 inhibitor – was also approved for AML [192, 193], while vorasidenib, a dual IDH1/2 inhibitor, received approval for astrocytoma and oligodendroglioma [194]. Several other IDH-targeted agents remain under investigation in preclinical and clinical studies:

• BAY1436032 (NCT02746081)

• FT-2102 (NCT02719574)

• HMPL-306 (NCT04762602; NCT04764474; NCT06387069)

• ID305 (NCT02381886)

• NEO212 (NCT06047379), and

• SH1573 [195]

CS has increasingly entered the therapeutic landscape for IDH-targeted treatment. The first clinical trial to evaluate an IDH inhibitor in CS was NCT02273739 (Table 3), which tested enasidenib in patients with glioma, T-cell lymphoma, and a small subset of CS (3 out of 21 total participants). While the drug was well tolerated, the small cohort and lack of published results limited conclusions about its efficacy in CS. A more targeted effort was made in the phase I study NCT02073994 (Table 3), which investigated ivosidenib in patients with advanced IDH1-mutant solid tumors, including 21 with CS. The study demonstrated minimal toxicity, significant reductions in D-2HG levels, and durable disease control, with a 6-month PFS rate of 39.5%. Notably, patients with CCS showed more favorable outcomes than those with DDCS, with 6-month PFS rates of 53.8% and 0%, respectively [181]. Long-term follow-up from this trial confirmed sustained disease control in a subset of CCS patients, with an ORR of 23.1%, a median PFS of 7.4 months, and a median duration of response of 53.5 months among responders [182]. Building on these findings, the phase 3 CHONQUER study (NCT06127407) (Table 2) is currently evaluating the efficacy of ivosidenib versus placebo in patients with locally advanced or metastatic IDH1-mutant CCS who are untreated or have received one prior systemic regimen.

While clinical data described above are tentatively encouraging, they remain limited in demonstrating clear efficacy. Preclinical studies conducted alongside these trials have produced mixed findings. For instance, the selective IDH1 inhibitor AGI-5198 [196] was shown to impair colony formation and reduce migration in IDH1-mutant CS cell lines [197]. A follow-up study using CRISPR/Cas9 to knock out the mutant IDH1 in the same cell lines replicated these findings, and xenograft models derived from the knockout cells showed significantly reduced tumor growth compared to controls [198]. Further supporting these findings, Rey et al. reported that enasidenib treatment led to complete tumor growth arrest in patient-derived xenografts [199]. However, contrasting studies have shown that IDH1 inhibition had no significant impact on the tumorigenic properties of certain CS cell lines [200, 201]. Together, these findings suggest that CS may become independent of IDH mutations over time, potentially due to additional genetic or epigenetic alterations. As a result, experts increasingly advocate for more personalized therapeutic strategies based on distinct molecular subgroups within CS [202].

DR5-mediated apoptotic pathway

DR5, also known as TRAIL-R2, is a member of the tumor necrosis factor receptor superfamily. Upon binding its ligand TRAIL (TNF-related apoptosis-inducing ligand), DR5 undergoes trimerization and assembles the death-inducing signaling complex (DISC) by recruiting the adaptor protein, Fas-associated protein with death domain (FADD), which in turn recruits initiator procaspases. Activated caspase-8 then cleaves and activates downstream effector caspases, ultimately triggering extrinsic apoptosis [203, 204]. DR5 preferentially mediates apoptosis in malignant cells while sparing most normal tissues, and its expression has been documented across multiple sarcoma subtypes, including CS [205–207]. Since DR5 agonists directly engaged the apoptotic pathway, they have the potential to bypass the low mitotic activity and poor vascularization that render CS resistant to conventional therapies.

Early-generation DR5 agonists failed to demonstrate meaningful clinical benefit, attributed in part to insufficient receptor clustering and intrinsic tumor resistance [204]. Ozekibart (INBRX-109) is a third-generation, tetravalent DR5 agonist antibody engineered to achieve optimal receptor clustering while minimizing hepatotoxicity [183, 208]. In the phase I trial (NCT03715933) (Table 3), ozekibart demonstrated a disease control rate of 87.1% and a median PFS of 7.6 months in patients with advanced CS, comparing favorably with conventional chemotherapy [183]. The subsequent randomized, placebo-controlled, phase II ChonDRAgon trial (NCT04950075) (Table 2) - the largest randomized trial in advanced CCS (n=206) - met its primary endpoint, with ozekibart significantly prolonging median PFS compared to placebo (5.5 vs. 2.7 months). The disease control rate was also higher with ozekibart (54.0% vs. 27.5%), and ozekibart delayed quality-of-life deterioration. Overall survival data remain immature [209].

Indian Hedgehog (IHH) inhibitors

The Indian Hedgehog (IHH) signaling pathway plays a central role in the regulation of chondrocyte proliferation and differentiation and is essential for normal cartilage development and endochondral ossification [210]. Given its critical involvement in chondrogenesis, targeting IHH signaling in CS has been explored as a potential therapeutic strategy. In mammals, IHH binds to the receptor Patched (PTCH1), relieving its inhibition of Smoothened (SMO), which in turn activates GLI transcription factors and downstream cellular responses [211]. Preclinical studies have demonstrated that SMO inhibitors like HPI-4 and IPI-926 can impair the growth of CS cells, with IPI-926 showing efficacy in both in vitro experiments and xenograft models [212, 213]. However, translating these promising findings into clinical success has been challenging. Two separate phase II clinical trials in advanced CS – one evaluating IPI-926 [214] and the other vismodegib (GDC-0449) [215] – failed to demonstrate meaningful clinical benefit. These disappointing outcomes highlight the complexity of targeting developmental pathways in cancer, particularly in slow-growing tumors like CS with intricate signaling networks. Despite these setbacks, research into IHH pathway modulation is ongoing, with continued efforts to refine and optimize therapeutic approaches. As insights into the IHH signaling pathway in CS continue to evolve, they may support the development of more targeted and efficacious therapeutic strategies.

Src tyrosine kinase

Src tyrosine kinase is a key mediator in multiple cell surface receptor signaling pathways [216, 217], and its elevated activity has been observed across various sarcoma subtypes [218, 219]. In synovial sarcoma, for instance, Src signaling is essential for tumor cell growth [220]. Similarly, aberrant Src activation has been observed in CS, implicating its involvement in disease progression [221–224]. These findings suggest that Src may represent a promising therapeutic target in sarcomas, including CS. Preclinical studies support this potential. Dasatinib, a small-molecule inhibitor of Src kinase activity, inhibits migration and invasion in various sarcoma cell types and selectively blocks the survival of bone sarcoma cells, including osteosarcoma and Ewing sarcoma models [218]. In CS-specific models, dasatinib reduced viability in seven of nine tested cell lines [221]. A subsequent investigation in doxorubicin-resistant CS cell lines found that dasatinib monotherapy not only reduced cell migration but also re-sensitized cells to doxorubicin, with the combination treatment inducing apoptosis [223]. These results underscore the dual potential of Src inhibition – as a direct antitumor approach and as a means to overcome chemoresistance.

Despite promising preclinical data, the phase II SARC009 trial, which evaluated dasatinib monotherapy in patients with advanced sarcomas (including CS), did not demonstrate significant clinical benefit   [225]. Consequently, attention has shifted to employing dasatinib as part of a combination approach. Beyond doxorubicin, dasatinib has demonstrated synergistic activity with various other antineoplastic agents in preclinical models  [226–229]. Notably, sunitinib – a multi-tyrosine kinase inhibitor with activity against Src -showed activity in DDCS when combined with the immune checkpoint inhibitor nivolumab in the phase I/II NCT03277924 trial (Table 3).

PI3K-Akt-mTOR inhibitors

The PI3K-Akt-mTOR signaling pathway, which involves phosphoinositide 3-kinase (PI3K), protein kinase B (Akt), and mammalian target of rapamycin (mTOR), plays a central role in regulating essential cellular processes, including growth, proliferation, metabolism, angiogenesis, autophagy, and survival [230, 231]. Dysregulation of this pathway is frequently observed in various cancers, including CS, prompting significant research into its potential as a therapeutic target [232]. Despite substantial efforts, clinical outcomes with pathway-specific inhibitors have been inconsistent, with limited efficacy observed in trials thus far. This highlights both the potential and challenges of targeting this signaling pathway in CS, with ongoing research focused on refining therapeutic strategies.

Among the targeted agents, the rapamycin analogs everolimus and sirolimus, which selectively inhibit mTOR complex 1 (mTORC1), have shown some promise in CS. In an orthotopic rat CS model, treatment with everolimus suppressed macroscopic tumor progression and prevented recurrence from microscopic residual disease ^[233]. A retrospective clinical study further demonstrated that combining sirolimus with cyclophosphamide yielded encouraging results in patients with unresectable CS, achieving a 70% disease control rate and a median PFS of over one year [234]. Building on these findings, a phase II clinical trial investigating this combination in patients with conventional, dedifferentiated, and mesenchymal CS (NCT02821507) (Table 3) was completed in 2021, although the results have yet to be published. Additionally, a separate phase II trial initiated in 2014 aimed to evaluate everolimus as neoadjuvant therapy in patients with primary or relapsed CS (NCT02008019), but it was suspended in 2016 due to drug unavailability, and no efficacy data were reported.

Histone deacetylase inhibitors

Epigenetic dysregulation is a hallmark of many cancers, including CS, as discussed in the section on IDH mutations. One key epigenetic mechanism involves histone acetylation, which regulates chromatin accessibility and gene expression. Histone deacetylases (HDACs) are enzymes that catalyze the removal of acetyl groups from histones, leading to chromatin condensation and transcriptional repression. In cancer, including CS, HDACs are frequently dysregulated, resulting in aberrant gene silencing and contributing to tumorigenesis and progression [235, 236]. The inhibition of HDACs has demonstrated antitumor activity through multiple mechanisms, including reversal of malignant phenotypes, induction of cellular differentiation, cell cycle arrest, and apoptosis [237, 238]. These effects are also evident in CS, where HDACs play a role in sustaining the tumor’s epigenetic landscape and supporting cancer cell survival [239, 240].

Several HDAC inhibitors have received regulatory approval, including suberanilohydroxamic acid (SAHA or vorinostat) and romidepsin for cutaneous T cell lymphoma, belinostat and romidepsin for peripheral T cell lymphoma, and panobinostat for multiple myeloma [241]. Romidepsin was evaluated in a phase II clinical trial for patients with metastatic or unresectable STS, including extraskeletal CS (NCT00112463) (Table 3). However, the trial was prematurely terminated in 2008 due to high-grade toxicity and low response rates, with only one of forty patients completing the study. Despite this early setback, more recent preclinical investigations have demonstrated that CS cells are highly sensitive to romidepsin, independent of histological subtype or IDH mutation status. In addition to its single-agent activity, romidepsin enhanced the efficacy of glutaminolysis inhibitors and Bcl-2 family protein inhibitors, suggesting a role for HDAC inhibitors as sensitizers in combination regimens [240]. Supporting this, a high-throughput drug screening study identified panobinostat, a potent histone-deacetylase inhibitor, which also enhances the ferroptosis pathway [242], as one of the most potent cytotoxic compounds in CS models, exhibiting strong synergistic effects when paired with other chemotherapeutic agents [161].

Further investigations have also explored dual epigenetic targeting strategies. One study demonstrated the combination of SAHA with the DNA methyltransferase (DNMT) inhibitor 5-aza-2′-deoxycytidine significantly inhibited CS cell proliferation in vitro and in xenograft models [243]. Additionally, the same study showed that combining belinostat with the second-generation DNMT inhibitor guadecitabine (SGI-110) resulted in similarly significant anti-tumor efficacy [243]. Based on these findings, a phase II trial evaluating this combination in unresectable or metastatic CS (NCT04340843) (Table 2) is ongoing, with completion expected in 2027.

Conclusions

CS is a rare and often indolent malignancy that can remain asymptomatic for years, frequently delaying diagnosis until it reaches an advanced and often unresectable stage. Surgical resection remains the cornerstone of treatment for localized diseases and offers the best chance for long-term control and potential cure. However, for patients with unresectable, metastatic, or recurrent CS, therapeutic options are limited. The tumor’s resistance to therapies such as chemotherapy, radiotherapy, and immunotherapies presents a significant clinical challenge. While these treatments may offer benefits in select cases, they have not consistently led to improved overall clinical outcomes.

Recent advances in molecular and genetic research have begun to shed light on the underlying mechanisms driving CS, offering promising avenues for the development of targeted therapies. While many of these investigations remain in early stages, the identification of specific molecular alterations holds significant potential for more effective and individualized treatment approaches. Continued research is critical to overcoming the intrinsic therapeutic resistance that has long limited management options for this malignancy. These ongoing efforts may pave the way for improved treatment strategies, ultimately enhancing clinical outcomes and quality of life for patients facing this challenging disease.

Highlights.

• Chondrosarcoma remains largely resistant to chemo- and radiotherapy

• Histologic grade and surgical margins determine prognosis

• IDH inhibitors demonstrate durable disease control in clinical trials

• DR5 agonist therapy shows progression-free survival benefit in a randomized trial

• Targeted therapies are advancing precision treatment strategies