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Nakano, K. Systemic Therapy Investigations for Bone Sarcomas. Encyclopedia. Available online: https://encyclopedia.pub/entry/21737 (accessed on 19 December 2025).
Nakano K. Systemic Therapy Investigations for Bone Sarcomas. Encyclopedia. Available at: https://encyclopedia.pub/entry/21737. Accessed December 19, 2025.
Nakano, Kenji. "Systemic Therapy Investigations for Bone Sarcomas" Encyclopedia, https://encyclopedia.pub/entry/21737 (accessed December 19, 2025).
Nakano, K. (2022, April 14). Systemic Therapy Investigations for Bone Sarcomas. In Encyclopedia. https://encyclopedia.pub/entry/21737
Nakano, Kenji. "Systemic Therapy Investigations for Bone Sarcomas." Encyclopedia. Web. 14 April, 2022.
Systemic Therapy Investigations for Bone Sarcomas
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This entry is adapted from the peer-reviewed paper 10.3390/ijms23073540

Bone sarcoma is a rare component of malignant solid tumors that accounts for only ~0.2% of malignancies. Bone sarcomas present various histological types, and genomic mutations differ markedly by the histological types. Although there are vast mutations in various bone sarcomas, most of them are non-actionable, and even potential targetable mutations that are actionable targets in other malignancies have not shown the appropriate responses in clinical trials for bone sarcomas. Investigations of new systemic therapy, including molecular targeted therapies for bone sarcomas, have thus not progressed like those for other solid tumors. Another problem is that high rates of pediatric/adolescent and young adult patients have bone sarcomas such as osteosarcoma, and patient recruitment for clinical trials (especially randomized trials) is challenging. For pediatric patients, evaluations of tolerability and appropriate dose modifications of new drugs are needed, as their findings could provide the threshold for investigating new drugs for bone sarcomas. 

Osteosarcoma Sarcoma Chondrosarcoma

1. Osteosarcoma

1.1. Overview of the History of Systemic Therapy for Osteosarcoma

Osteosarcoma is the most major bone sarcoma, accounting for 20%–40% of all bone sarcomas [1]. The median patient age at the diagnosis of osteosarcoma is 20 years old, and the peak incidence of osteosarcoma is in adolescence and young adulthood, but osteosarcoma accounts for only ~2–3% of all malignant diseases in these populations [2][3]. Regarding genetic risk factors for osteosarcoma, it has been shown that Li-Fraumeni syndrome, known for the mutation of tumor suppressor gene TP53, is associated with osteosarcoma [4].
Due to this cancer’s high risks of recurrence and metastasis, the prognosis of osteosarcoma patients was very poor in the era without systemic chemotherapy; the long-term survival of localized osteosarcoma patients was only ~20% or less [5]. Perioperative chemotherapies with cytotoxic antitumor drugs were investigated in the 1970s, and the long-term survival rate then improved remarkably to 60%–70% [6]. After various single-agent and multidrug combination clinical trials, methotrexate, doxorubicin, cisplatin, and ifosfamide have been considered the key drugs in systemic treatments of osteosarcoma (of note, methotrexate is contraindicated for patients aged ≥40 years because of the toxicity risk). As perioperative therapy, neoadjuvant chemotherapy is strongly recommended; the rate of tumor necrosis provided by neoadjuvant chemotherapy is known to be related to prognoses [7][8]. Thus, the current standard perioperative chemotherapy for osteosarcoma consists of MAP (methotrexate, doxorubicin, cisplatin) before and after surgery, and the appropriate indication and timing for adding ifosfamide are under investigation [9][10].
However, if recurrence or metastasis occurs, the prognosis of osteosarcoma patients remains poor; the 5-year overall survival (OS) rate of patients with recurrent or metastatic osteosarcoma has been unchanged at <20% since the 1980s [11][12]. Most long-term survivors of metastatic osteosarcoma have been patients who had limited pulmonary metastatic lesions and underwent a successful metastasectomy [13][14][15], and patients with bone lesions at recurrence have been suggested to have poor OS [16]. Clinical evidence of standard salvage chemotherapy that improves the overall survival of recurrent/metastatic osteosarcoma patients has not been obtained.

1.2. Clinical Trials of Therapies Targeting Osteosarcomas

Until ~2005, prospective clinical trials of new systemic therapy for recurrent and/or metastatic osteosarcoma evaluated mainly cytotoxic drugs that were similar to traditional standard regimens [17]. Of them, the addition of muramyl tripeptide (MTP, a synthetic derivative of Bacille Calmette-Guérin) to the standard MAP perioperative chemotherapy was suggested to prolong patients’ survival in the INT-0133 (CCG-7921/POG-9351) randomized clinical trial though the analysis showing that the survival benefit of MTP has some limitations [18], which resulted in the drug’s approval in Europe and some other countries. Topotecan-based chemotherapy and gemcitabine-based chemotherapy have also shown some prospective and/or retrospective efficacy data, but the survival benefits of these regimens are not established and the drugs are not officially approved for the treatment of osteosarcoma [19][20][21][22].
In 2008, the number of phase II trials of molecular targeted drugs and immunotherapy for osteosarcoma exceeded (for the first time) those of cytotoxic chemotherapies, and since then, phase II trials of molecular targeted drugs and immunotherapy have been consistently performed more frequently than those of cytotoxic chemotherapies [23].
A large number of tyrosine kinase inhibitors (TKIs) have been investigated in the 21st century for many malignant diseases, both hematologic diseases and solid tumors, including osteosarcoma. There have been many prospective phase II trials of TKIs as treatments for osteosarcoma, such as sorafenib with or without everolimus, apatinib, regorafenib, cabozantinib and lenvatinib [23][24][25][26][27][28][29][30], mainly targeting vascular endothelial growth factor receptor (VEGFR) and its downstream signaling pathway.
In the recent National Comprehensive Cancer Network (NCCN) guideline, some of these TKIs with efficacy data obtained in prospective trials are listed as a treatment option for salvage systemic therapy for recurrent or metastatic osteosarcoma despite this being an off-label use [31].
Monoclonal antibodies are another potential molecular targeted therapy for osteosarcoma: GD2, GPNMB, HER2, and PD-1 are candidate targets of antibody treatment and prospective clinical trials have performed, but none of the monoclonal antibodies has exhibited potential clinical benefits similar to those provided by TKIs.
The disialoganglioside GD2 is a glycosphingolipid that is expressed in some pediatric malignant tumor cells including osteosarcoma [32], and it is thus considered the therapeutic target for an antibody. The investigations of the anti-GD2 antibody dinutuximab were begun in the 20th century, and the results of a phase I trial for pediatric malignancies (neuroblastoma and osteosarcoma) were published in 1998 [33]. Based on the results of a phase III trial (ANBL0032) [34], dinutuximab was approved for pediatric high-risk neuroblastoma as a maintenance therapy, but a phase II trial (AOST1421) of dinutuximab for osteosarcoma did not meet the primary endpoint [35].
GPNMB (glycoprotein non-metastatic b) is a transmembrane glycoprotein normally expressed in cells related to tissue repair, and it is overexpressed in some malignant cells including osteosarcoma [36]. Preclinical studies of glembatumumab vedotin (CDX-011), an antibody-drug conjugate with the combination of anti-GPNMB antibody and monomethyl auristatin E (vedotin), suggested an antitumor effect [37][38], but in the prospective phase II trial (AOST1521), osteosarcoma patients achieved only limited responses to glembatumumab vedotin (of the 22 patients enrolled, an objective response was observed in only one patient) [39].
Human epidermal growth factor receptor 2 (HER2) is well known as the target in many cancer treatments. HER2-targeted therapy is established as the standard treatment for breast cancer and gastric adenocarcinoma [40][41], and it is recently being investigated for other solid tumors such as non-small cell lung cancer and colorectal cancer [42][43]. Overexpression of HER2 is observed in approximately 30% of osteosarcoma cases and was suggested to be poor-prognosis factor [44][45], and thus HER2 could be a candidate for the targeted therapy of osteosarcoma. A phase II trial of the anti-HER2 antibody trastuzumab for osteosarcoma with the combination of conventional chemotherapy did not show clinical benefits [46]. After the failure of trastuzumab, the development of HER2-targeted therapy for osteosarcoma stopped, although new HER2-targeted drugs (antibody, antibody-drug conjugates or TKIs) were investigated and approved for other malignancies.
Immune checkpoint inhibitors were introduced to cancer therapy in the 2010s, and their use has increasingly changed the standard therapy for many malignant diseases [47]. Programmed cell death-1 (PD-1) is the representative target of immune checkpoint inhibitors, and programmed cell death-ligand 1 (PD-L1) expression is known as the response biomarker of anti-PD-1 antibody [48]. PD-L1 expression was observed in 14.0%–80.6% of osteosarcoma cells and was suggested to be associated with poor prognosis [49]. However, prospective clinical trials of anti-PD-1 antibody for treating osteosarcoma did not reveal meaningful responses [50][51]. Regarding immunotherapy, the clinical benefit of adding interferon-alpha (IFN-α) to standard perioperative chemotherapy was evaluated in a large-scale randomized clinical trial (EURAMOS-1), and no survival benefit was observed [52].
Some of these potential antibody targets might be candidates for chimeric antigen receptor-modified T-cell immunotherapy; some clinical and preclinical trials evaluated HER2- or GD2-specific chimeric antigen receptor-modified T cell immunotherapy for sarcoma (dominantly osteosarcoma), and the results demonstrated the therapy’s tolerance and safety; the objective response rate has not been reported at this time [53][54].

2. Ewing Sarcoma of Bone

2.1. Overview of the History of Systemic Therapy for Ewing Sarcoma

Ewing sarcoma is pathologically characterized by small round cell and translocation (dominantly EWSR1-FLI1) fusion gene from t(11;22)(q24;q12) translocation, and it is known to be sensitive to cytotoxic chemotherapy. Combination chemotherapy regimens have been investigated and have progressed since the 1970s [55].
The INT-0091 (CCG-7881/POG-8850) trial conducted in 2003 with non-metastatic Ewing sarcoma patients showed that the alternating chemotherapy using vincristine, doxorubicin and cyclophosphamide (VDC; doxorubicin was changed to dactinomycin after the achievement of a cumulative doxorubicin dose at the threshold with the high risk of cardiotoxicity), and ifosfamide and etoposide (IE), was superior to VDC-alone based on the event-free survival (EFS) rate, and the alternating regimen became the standard strategy for Ewing’s sarcoma [56]. Several clinical trials comparing a higher dose intensity or dose density of these alternating regimens were then performed, and a higher dose intensity (i.e., biweekly chemotherapy administration rather than triweekly) showed more effective results [57][58].
High-dose chemotherapy (HDCT) and autologous stem cell transplantation (ASCT) were investigated for Ewing sarcoma patients who were high-risk and refractory to conventional chemotherapy or in a recurrent/metastatic setting [59][60]. According to the recent Euro-E.W.I.N.G. 99 and Ewing-2008 trials, HDCT/ASCT resulted in survival rates that were superior to those provided by salvage chemotherapies for non-metastatic patients with refractory Ewing sarcoma to induction chemotherapy [61]. However, the survival benefit of HDCT/ASCT was not observed for Ewing sarcoma patients with pulmonary and/or pleural metastasis compared to the patients treated with salvage chemotherapy and whole lung irradiation, in terms of OS [62].
The progress made regarding multimodal strategies including optimal combination chemotherapy has resulted in a 5-year survival rate >70% among non-metastatic Ewing sarcoma patients, but for recurrent and/or metastatic patients, the 5-year survival rate remains at <30% [63]. As noted above, neither an alternating regimen nor HDCT/ASCT provided meaningful survival benefits to metastatic patients, and a standard salvage chemotherapy has not yet been established.

2.2. Clinical Trials of Targeted Therapy for Ewing Sarcomas

Cytotoxic chemotherapy regimens for Ewing sarcoma were actively investigated until recently. Temozolomide-based salvage chemotherapy was evaluated prospectively for approximately 20 years and showed promising objective responses [64][65][66][67][68], and a temozolomide-based regimen was under investigation as a first-line therapy [69]. Topotecan-based therapies also provided objective clinical responses [19][70][71], but the use of topotecan-based combination chemotherapy as a first-line treatment failed to show survival benefit in a phase III trial [72].
There have been fewer prospective clinical trials of targeted therapy such as TKIs or monoclonal antibodies for Ewing sarcoma compared to osteosarcoma. In a phase II trial of the TKI cabozantinib (which was also mentioned above in the Osteosarcoma section), a cohort of Ewing sarcoma patients was examined and the efficacy and safety of cabozantinib for Ewing sarcoma were evaluated. An objective response was observed in 10 of 39 patients with measurable lesions (objective response rate [ORR]: 26%, 95% confidence interval [CI]: 13–42) [29], and the NCCN guideline describes this TKI as a treatment option for recurrent/metastatic Ewing sarcoma, without official approval [31]. The EWSR1-FLI1 fusion gene is thought to function as a regulator of the expression of insulin-like growth factor 1 (IGF1), and overexpression of IGF1 receptor (IGF1R) is observed in Ewing sarcoma cells [73]; the IGF1R pathway could thus be a target in Ewing sarcoma cases. Clinical trials of IGF1R inhibitors, such as figitumumab, cixutumumab, and ganitumab, showed limited clinical benefits [74][75][76][77][78]. There has been recent progress in the development of molecular targeted drugs that directly target EWS-FLI1 [79], but information on their efficacy remains to be obtained.

3. Chondrosarcoma

Chondrosarcoma is the third major bone sarcoma, and in adults, chondrosarcoma is the most common primary bone cancer, accounting for approximately 20% of the cases of adult bone sarcoma [1]. Unlike osteosarcoma and Ewing sarcoma, chondrosarcoma is resistant to systemic therapies, at least those using cytotoxic chemotherapeutic agents. Based on an analysis of the Surveillance, Epidemiology, and End Results (SEER) database, systemic chemotherapy did not help prolong the overall survival of dedifferentiated chondrosarcoma patients [80]. There have been reports that adjuvant chemotherapy can improve prognosis, but the evidence is still limited and standard regimens have not been established [81]. Targeted drugs, such as TKIs, might not show benefits for chondrosarcoma. For example, a result of a randomized phase II trial evaluating regorafenib compared to a placebo did not meet the primary endpoint concerning the progression-free survival (PFS) rate at 12 weeks, although the PFS of regorafenib tended to be longer than that of placebo (median PFS: 19.9 weeks on regorafenib and 8.0 weeks on placebo) [82]. In the NCCN guidelines, dasatinib and pazopanib are introduced as treatment options based on non-randomized phase II trials [83][84], but the efficacy data of these TKIs are not very different from those of regorafenib.
A potential targetable mutation of chondrosarcoma, that is, IDH gene encoding isocitrate dehydrogenase (IDH), has various isoforms including IDH1 and IDH2 and key metabolic enzymes that convert isocitrate to α-ketoglutarate [85]. IDH mutations are observed in more than half of all cases of chondrosarcoma, and most of them are IDH1-related [86]. A clinical trial evaluating the treatment of chondrosarcoma with ivosidenib (an oral inhibitor of mutant IDH1) was performed, and its tolerability was confirmed [87]. Further evaluation of its efficacy is needed, and a phase II clinical trial is ongoing [88].

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