A 10-year bibliometric analysis of osteosarcoma and cure from 2010 to 2019

Osteosarcoma, a common primary bone malignancy in children and adolescents, occurs primarily in the metaphysis of long bones and is characterized by early lung metastasis, high mortality and poor prognosis [1]. Limited by primitive medical care, amputation was the mainstream osteosarcoma treatment, with a 5-year survival rate of approximately 20%, and the defective appearance and function of the affected limb has a serious impact on patient psychology [2]. With the rapid development of medical science and technology, limb salvage in osteosarcoma has been adopted at a rate of more than 80% in the clinic and has gradually replaced the majority of amputation cases, but the survival rate is still poor [3]. This outcome might be related to many unsolved issues, such as complex pathogenesis, lack of novel adjuvant drugs and an imperfect evaluation system. Currently, the widely accepted strategy for osteosarcoma is surgery combined with neoadjuvant chemotherapy, which has a great capacity to shrink tumours and eliminate small lesions to ensure complete surgical resection and reduce tumour recurrence and metastasis [4]. Since the surgical method is generally determined, the key to improving the survival rate is drug therapy, which is also a difficulty and a hot issue for global orthopaedic and oncology experts.

Bibliometric analysis has become the best tool for exploring the detailed research trends in a certain field over time [5]. This analysis objectively presents the research contributions of different countries, institutions, journals and authors in scientific fields via qualitative and quantitative analysis and forecasts the research trends or hotspots. At the same time, it is worth explaining that the hotspots refer to the problems in a specific filed that has not been solved and is highly concerned by global scholars, or the research direction that needs to be broken through urgently and of great significance in the future. In addition, bibliometric analysis has also played a momentous role in formulating policy and clinical guidelines on various diseases [6]. However, no current bibliometric analysis has been conducted on osteosarcoma and cure, and even less attention has been focused on prediction of research hotspots. Our previous publications demonstrated that bi-clustering analysis has great advantages in exploring key areas of research and the related representative literature and can also be applied to verify hotspots [7, 8]. This study aims to conduct a comprehensive investigation of the current academic status and clinical issues in osteosarcoma, with a focus on cure and chemoresistance, and to predict the potential progress in this field over the next decades. We also summarize the representative clinical trials of drug therapy for osteosarcoma.

Our statistical and quantitative analysis found a significant improvement in research on osteosarcoma and cure from 2010 to 2019, and an increasing number of orthopaedic and oncology experts focused their insights on this field. Although those studies have been highly extensive, they are relatively chaotic and lack hotspot analysis. Osteosarcoma metastasis, recurrence and multi-drug resistance (MDR) are the three major obstacles in the clinic, we discussed and explained the main 8 clusters obtained from co-word bi-clustering. In addition, we also collated 41 completed clinical trials in osteosarcoma that passed phase II (Table 5) and predicted future research trends by addressing these barriers.

Cluster 0 addresses the new insights on metastatic pattern. The survival rate of osteosarcoma is closely related to tumour metastasis in that 15–20% of patients were diagnosed with distant metastatic lesions at their first visit [14]. Previous studies have recognized that the lung is the most sensitive site, but the occurrence of abdominal metastasis reveals an unusual pattern in which osteosarcoma is more prone to occur in soft tissue [15]. Changes in the tumour microenvironment and extracellular matrix composition seriously affect osteosarcoma metastasis, e.g., the “seed and soil hypothesis”. The rich bone microenvironment constitutes a fertile “soil” that favours the growth of both primary and metastatic tumoural “seeds”, and the host “soil” is transferred to undergo biological changes in advance to adapt to the invasion of “seeds” [16]. Clinicians should be aware of the development of metastatic patterns in patients with osteosarcoma, and the exploration of microenvironmental tumour genetic disorders between primary occurrence and metastasis is the subject of future basic research.

Cluster 1 investigates new methods for evaluating the sensitivity of chemotherapeutic drugs. The sensitivity of osteosarcoma to chemotherapeutics drugs plays a critical role in the choice of operation and in tumour recurrence. Current standard treatments for osteosarcoma include neoadjuvant multidrug chemotherapy, growth factor support, surgery (amputation or limb salvage), and radiotherapy [17]. It is known that limb salvage surgery still has many complications, such as local recurrence, and amputees are more likely to suffer from metastasis and a lower survival rate and that all of those complications are attributed to insufficient chemotherapy [18]. Hence, a new reliable method for determining the effectiveness of chemotherapeutic drugs prior to surgery is expected to aid surgeons in choosing surgical tactics, such as radiological functional imaging (dynamic contrast enhanced magnetic resonance imaging, magnetic resonance diffusion weighted and deoxyglucose positron emission tomography). These approaches were applied to clinical studies (Table 5; No. 9, 17).

Cluster 2 involves alternatives to cytotoxic chemotherapy. Currently, no effective alternative therapy is available to treat osteosarcoma after failure of traditional chemotherapy and surgery. Based on the literature in the past 10 years, we found that researchers at home and abroad are actively exploring strategies to replace systemic chemotherapy for osteosarcoma: (1) immunotherapy, including active (cancer vaccine, adoptive T-cell transfer (Table 5; No. 36), checkpoint inhibitor (programmed cell death-ligand 1, T-cell immunoglobulin, mucin-domain containing-3, Indoleamine 2,3-di-oxygenase) and cytokines) and passive (monoclonal antibodies and adjuvants (Table 5; No. 11, 15, 22, 23)) approaches [19]; (2) local chemotherapy in which implantable drug delivery systems with anticancer drugs and bone substitutes as carriers can protect drugs from rapid metabolism in circulation and ensure the objective therapeutic effect of low dose therapies such as cyclodextrins, poly-lactic-co-glycolic acid and cyclodextrins [20], and nanoparticle albumin binding paclitaxel could increase the drug concentration in tumour cells (Table 5; No. 21); (3) radiotherapy, including stereotactic radiosurgery, carbon-ion radiotherapy, etc. [21, 22]; (4) genetic engineering, e.g., biological genetic engineering-edited miRNAs that target RNA molecules [23]; (5) stem cell therapy (Table 5; No. 13, 37); and (6) novel alternative therapeutic drugs originating from Chinese herbal extracts. These two points are discussed in detail later on. In terms of the future, with the rapid development of biotechnology, current research is focusing on alternative methods of impairing osteosarcoma outside of cytotoxic chemotherapy.

Cluster 3 explores new prognostic markers for osteosarcoma. The urgent need exists for early diagnosis, and it is beneficial to adopt a better therapeutic schedule. The existing clinical trials focus on that topic (Table 5). Studies have shown that a variety of miRNAs in osteosarcoma tissues or blood samples have been altered and are closely associated with poor prognosis of either deaths or events [24], such as high expression of miRNA 210, 17–92 cluster, 128, 9, 214, 542-5p, 130b, 130a, and 199b-5p and low expression of miRNA 132, 145, 382, 133a, 26a, 340, 20a, 92a, 143, 451, 144, 22, 195, 124, 449a, 99a, and 224 [25]. In addition, large-scale prospective studies are expected to elucidate the prognostic role of miRNAs in osteosarcoma, and the role of these miRNAs in assessing tumour progression and therapeutic responses will depend on additional clinical trials.

Cluster 4 is related to synergistic therapy of mesenchymal stem cells (MSCs) and drugs. Tumour cells in osteosarcoma are similar to osteoblasts in that they present osteoblastic differentiation and produce malignant osteoid, not only in osteoblastic areas but also in chondroblast or fibroblast areas, which suggests that osteosarcoma cells might originate from MSCs. We know that MSCs are highly prone to tumour stroma and can promote MDR by increasing the expression of multi-drug resistance genes or by paracrine pathways (STAT3, IL-6, IL-8, etc.) [26]. By taking advantage of this knowledge, we can load MSCs with therapeutic drugs to exert their anticancer capacity more effectively. It has been reported that rhBMP-2 and MSCs combined with conventional antitumour therapy might be an efficient therapeutic strategy against osteosarcoma [27]. However, conventional chemicals as the carriers in MSCs might disrupt the normal function of MSCs and cause drug delivery failure. Duchi found that photodynamic therapy, in which MSCs are stimulated by light activation to release toxic drugs that kill the surrounding tumour cells and induce their own death, might be a good option [28]. Furthermore, MSCs transfected with adenovirus carrying the osteoprotegerin gene inhibited osteosarcoma growth and bone destruction [29]. In addition to cytotoxic drugs and viral vectors, anti-angiogenic agents and immunostimulants can also be delivered to tumour lesions by MSCs [30]. Existing clinical trials explored stem cell transplantation to treat sarcomas (Table 5, No. 13, 37). In the next few decades, MSCs are expected to certainly display their advantages in carrying targeted drugs or antitumour genes for osteosarcoma treatment and are an exploration direction for researchers.

Cluster 5 focuses on reverse chemoresistance. Studies over the past 10 years reflect that chemotherapy for osteosarcoma has entered a bottleneck period. Even with increasing the dose, the types of drugs combined with chemotherapy and alteration of the delivery pathway still cannot improve the 5-year survival rate. Although MAP (methotrexate, doxorubicin and cisplatin) has become the preferred clinical treatment regimen, the problem of MDR still exists due to the following mechanisms: the reduction of effective intracellular accumulation, the abnormal content or activity of drug metabolism enzymes, and the genomic complexity and tumour heterogeneity of osteosarcoma [31]. Enhanced cell detoxification, DNA damage repair, apoptosis inhibition and autophagy-related chemoresistance also contributed to the emergence of osteosarcoma MDR, which is the main reason for the low survival rate. Targeted and precise individual therapy is the key step in overcoming MDR [32]. Exploration of MDR-related molecules such as proteins, enzymes, miRNA, lncRNA, circular RNA, cholesterol, folic acid, etc., and development of those molecules to biological targets for reversal of MDR have become a current focus [33‐39]. For example, clinical trials with folic acid and enzymes have been conducted, as shown in Table 5 (No. 1, 5, 25). It is worth noting that invariant NKT cells, a lymphocyte lineage with features of both T and NK cells, can significantly enhance the cytotoxicity induced by cisplatin, doxorubicin and methotrexate on osteosarcoma cells [40]. T-cell transplantation has advantages in metastatic paediatric sarcomas treatment (Table 5; No. 36). Efforts to actively reveal additional potential molecular mechanisms of MDR, develop novel molecular-targeted drugs depending on the related signalling pathways, and conduct drug evaluation experiments are expected to remain a hot topic from past and present to the future.

Cluster 6 focuses on drug discovery of Chinese herbal extracts that interfere with apoptosis of tumour cells. As described in the previous paragraph, chemoresistance of osteosarcoma is the most prominent clinical dilemma. Recently, traditional Chinese medicines have become increasingly vital in treatment of tumours and are a good source of new anticancer drugs due to advantages of fewer side effects and the absence of chemoresistance [41]. For instance, eribulin mesylatein has been applied to clinical trial (Table 5’ No. 4). Tracing back through the past decade of traditional Chinese medicine studies on osteosarcoma, we found that many of them focused on interfering with the apoptosis of tumour cells, which was considered as the main way to eradicate cancer, and several natural ingredients with potential clinical applications have been explored, such as celastrol, honokiol, berberine, chamaejas-mine and artemisinin [42‐46]. In addition, natural compounds responded well to cell cycle arrest and apoptosis with increased reactive oxygen species and could improve the 5-year survival rate. Therefore, it is necessary to find additional Chinese herbal extracts that regulate the oxidative stress level to intervene in the apoptosis of osteosarcoma cells.

Cluster 7 addresses drug discovery of Chinese herbal extracts that interfere with autophagy of tumour cells. It is well known that autophagy-induced cell death is another important indicator for evaluating anticancer drugs in addition to apoptosis. In fact, autophagy can promote cell survival and lead to cell death [47, 48]. This critical process of autophagy is deregulated in osteosarcoma, but it can be induced [49]. Consistently, regulation of tumour cell autophagy by natural Chinese herbal medicine ingredients is also a current hot topic with substances such as riccardin and celastrol [45, 50]. Notably, autophagy is still highly related to MDR and prognosis of osteosarcoma, which further solidifies the discoverability among osteosarcoma chemoresistance, traditional Chinese medicine extracts and autophagy [51]. The occurrence of osteosarcoma does not follow a simple pattern. The complexity of the genome promotes the drug resistance of osteosarcoma and supplies infinite possibilities for new medicine. Phenotypic screening of various active ingredients in natural Chinese herbal medicine is expected to promote the development of new compounds based on apoptosis and autophagy.

Nevertheless, we were aware of several potential limitations of this study. First, those novel and less-focused MeSH terms may not be involved. Second, the number of related papers on osteosarcoma and cure may increase rapidly, that the constant updating of the database may lead to a difference between the bibliographic analysis data and the actual research progress. Finally, the error of the database itself may lead to a deviation of the result, such as Web of Science may mislabel document types, so that the dataset may contain papers that should be filtered out and miss papers that should be included.

In our study, we collected new ideas on the metastasis pattern of osteosarcoma, emphasizing the abnormality of the tumour microenvironment genetics. The existence and prevalence of multi-drug resistance make the emergence of new alternative tactics and multi-dimensional evaluation systems to replace systemic chemotherapy a crucial effort. Ongoing clinical trials and a 10-year literature search also corroborated that the development of novel drugs to overcome chemoresistance is a top priority, and extracts from traditional Chinese medicine offer new resources. Overall, we believe that this article is of guiding significance for osteosarcoma and that the above hotspots might contribute to a breakthrough in the future.