Current Status, Hotspots, and Future Directions of Research on the Treatment of Medullary Thyroid Carcinoma: A Bibliometric Analysis and Systematic Evaluation

doi:10.21203/rs.3.rs-5277057/v1

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Current Status, Hotspots, and Future Directions of Research on the Treatment of Medullary Thyroid Carcinoma: A Bibliometric Analysis and Systematic Evaluation

https://doi.org/10.21203/rs.3.rs-5277057/v1

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Background

Medullary thyroid carcinoma (MTC) is a rare neuroendocrine tumor for which some of the current treatments are controversial or still in the preliminary stages of research.

Methods

In this study, we searched the relevant literature in the Web of Science core database from its inception to June 2024. After screening, we performed bibliometric analyses using CiteSpace and Microsoft Excel.

Results

In total, 1694 articles were included in this study. In this field of research, American and Italian institutes lead in the number of papers. Wells SA is the most influential author in this field and J CLIN ENDOCR METAB is the most cited journal. Management, calcitonin, RET gene, surgery, antiangiogenic therapy, tyrosine kinase inhibitors, and peptide receptor radionuclide therapy are the hot research areas in the field of MTC treatment. Prophylactic thyroidectomy, targeted therapy, peptide receptor radionuclide therapy, and positron emission tomography are future research frontiers and global trends.

Conclusions

Research in this field has focused on surgical treatment, targeted therapy, radiotherapy, imaging and treatment management. Based on the results of the bibliometric analysis, a systematic assessment of the current status and future research directions of various treatment options for MTC was conducted, providing new ideas for further research in the field of MTC treatment.

Medullary thyroid cancer

treatment

bibliometric analysis

evaluation

Medullary thyroid carcinoma (MTC) is a neuroendocrine tumor originating from thyroid parafollicular cells (C-cells) and secretes calcitonin; MTC accounts for about 2–4% of all thyroid malignancies¹. Clinically, MTC is classified into two major groups based on genetic characteristics. About 20% of MTC patients have a genetic association with the onset of the disease, referred to as hereditary MTC, and about 80% have sporadic MTC². Although MTC is less common in the clinic, the mortality rate of patients with medullary carcinoma can account for about 15% of all thyroid carcinoma (TC)³. For early-stage MTC, radical thyroidectomy is the only cure. However, MTC is more prone to invading local tissue or nerves, undergoing metastasis in cervical lymph nodes, and even undergoing hematogenous metastasis to distant organs throughout the body, resulting in a loss of opportunity for surgery. The signaling pathways involved in the development and progression of MTC include the PI3K/AKT/MTOR signaling pathway and the MAPK signaling pathway⁴. Targeted drugs have been developed to specifically bind to relevant receptors on the cell surface, such as vascular endothelial growth factor receptor (VEGFR), epidermal growth factor receptor (EGFR), fibroblast growth factor receptor (FGFR), and RET, to inhibit tumor neovascularization, thus preventing tumor progression⁵. Mutations in the RET gene lead to conformational changes within and outside the parafollicular cells of the thyroid gland, which are located in the structural domains of the intracellular tyrosine kinases and undergo phosphorylation. These changes activate downstream oncogenic signaling pathways, which is the main mechanism underlying cancer development⁶. Genetic testing can be considered for patients with confirmed MTC to guide the precision of targeted therapy. On the other hand, with the advent of the application of immunotherapy in various solid tumors, clinical trials of MTC immunotherapy are gradually being conducted and are expected to be applied in clinical treatment. Therefore, for MTC patients with advanced stage or with distant metastases, surgery combined with chemotherapy, radiotherapy, targeted therapy and immunotherapy can be considered to improve the prognosis. However, it is worth noting that there are some differences in the clinical treatment guidelines for MTC due to the differences in medical conditions, sociopolitical conditions of each country or region, and ethical and moral factors.

No bibliometric analysis of studies on MTC treatment is available. In this article, a bibliometric analysis of the relevant literature included in the Web of Science core database was conducted via CiteSpace software to systematically summarize the current status of MTC treatment, reveal the hotspots of research, and propose directions for future research.

Web of Science is a database that contains literature with wider coverage, higher quality, and easy access to information on article citations. Therefore, all data in this study were obtained from the literature included in the Web of Science Core Database (WOSCC). The Medical Subject Headings (MeSH) database was used to obtain search terms for the search strategy: TS = (“Parafollicular cell carcinoma of the thyroid” or “Parafollicular carcinoma of the thyroid” or “Medullary carcinoma of the thyroid” or “Medullary thyroid carcinoma” or “Medullary thyroid cancer” or “Medullary carcinoma of the thyroid gland”) AND TS = (therapy or therapies or treatment); Literature type: literature only in English; literature in other languages, along with conferences, books, etc. were excluded; time span: 1976 to June 2024.

Finally, 1694 documents were screened for inclusion in the analysis. The data were visualized and analyzed using CiteSpace (6.1. R6), and the raw data were converted into visualizations. The articles were also analyzed and plotted for the number of publications, countries, organizations, cited authors, cited journals, and keywords.

Year of publication and number of articles

A graph of the annual trend of publications related to the field of MTC therapy was plotted to illustrate the trend of the number of publications or attention index of research in this field from 1976 to June 2024. Overall Trend: The graph showed that the number of publications or attention indices in this field increased over time, indicating that with the continuous progress of medical technology and increasing understanding of the disease, research in this field has intensified, and new research findings continue to emerge (Fig. 1). Next, we analyzed and generalized from each time critical node in turn.

Starting point of analysis (1976): The number of publications in 1976 was four, which was the beginning of research in the field; the number of publications was low and attention to this field was minimal.

Growth period (1975–1994): During this period, the number of articles issued or the attention index increased, but the growth rate was relatively flat. This occurred probably due to the limitations of the level of medical technology at that time and the lack of awareness of the disease.

Accelerated period (1995–2021): Since the beginning of the 21st century, with the rapid development of medical technology and the continuous innovation of research methods, the number of publications and the attention index in this field increased significantly. Especially in the last decade, with the wide application of new therapeutic technologies, such as gene sequencing and targeted drug therapy, research in this field has advanced considerably.

The fluctuation period (2022–2024): A slow downward trend was recorded after 2021, but the overall trend showed an increase. The decline may be caused by the bottleneck in this research area and an increase in the difficulty of research. The value of the publication index in 2024 is expected to reach 93.6, indicating that the field will remain relevant and popular in the coming period. These findings indicate that future research on MTC therapy should be more in-depth and extensive, and more clinically significant results are expected.

States

A total of 65 countries worldwide were found to be involved in research related to MTC therapy. The top 11 countries that have contributed the most to the field include the United States, Italy, Germany, China, France, the United Kingdom, the Netherlands, Japan, Australia, Spain, and Switzerland. A table listing the countries that participated in the research and ranked in the top 11 in terms of the number of publications is presented to visualize and analyze the collaboration between the countries and map the distribution of the number of publications of the participating countries (Table 1; Figs. 2).

Table 1

Top 11 states in terms of the number of publications.
Ranking	States	Frequency of issuance	Centrality	Degree	Burst	Sigma
1	USA	608	0.23	38	10.12	8.32
2	Italy	232	0.06	33	0	1.00
3	Germany	169	0.06	35	9.48	1.78
4	China	135	0.05	20	13.82	2.06
5	France	134	0.02	33	12.18	1.26
6	UK	90	0.17	36	0	1.00
7	Netherlands	85	0.03	31	0	1.00
8	Japan	61	0.06	24	0	1.00
9	Australia	57	0.03	27	4.76	1.17
10	Spain	53	0.03	35	0	1.00
11	Switzerland	53	0.05	31	0	1.00

The United States, as the leading country in this research area, has contributed 608 articles to the field of MTC therapy research. Italy ranked second, contributing 232 articles, indicating that Italy also conducted intense research in this field. Countries such as Germany, China, France, and the UK also contributed to the field, but with fewer publications, and their respective research characteristics may vary between countries, e.g., differences in research-related fields, methods, or periods. In terms of dynamic changes and explosive growth, certain countries have experienced explosive growth in research over specific periods. For example, China showed the highest explosive value (13.82), which indicated that China significantly contributed to advancements in the field of MTC therapy within a certain period. Degree and centrality in the network attribute analysis reflect a country's position and importance in the research network. Countries with high degrees are likely to have more research collaborations or citation relationships with other countries. In contrast, those with high centrality are likely to be central to research networks in the field. The United States, for example, has the highest centrality value of 0.23.

Research activities in the field of MTC therapy are highly diverse around the world. The research contributions and dynamic changes in this field differ across countries. Further strengthening of international cooperation and exchange is required to promote advancements in research on MTC therapy.

Organization

In total, 568 internationally recognized cancer research centers and universities worldwide are involved in research related to MTC therapy. Institutions such as The University of Texas MD Anderson Cancer Center, University of Pisa, University of Wisconsin, Sloan-Kettering Cancer Center, and Massachusetts General Hospital have greatly contributed to research in this field. A table listing the top 10 organizations and institutions involved in the research in terms of the number of publications is presented to visualize and analyze the collaboration between the institutions (Fig. 3).

The University of Texas MD Anderson Cancer Center (Univ Texas MD Anderson Cancer Ctr) was the leading institution, with a frequency of 70 articles and the third-highest burst value of 6.36. The institution experienced a significant increase in research activity between 2014 and 2021, with degree and centrality values of 70 and 0.12, respectively, demonstrating the institution's importance in collaborative networks and research in general. The University of Pisa (Univ Pisa) ranked second, with 43 publications and a non-significant burst value. The University of Wisconsin (Univ Wisconsin) had 39 publications and a burst value of 6.62, with a significant increase in research activity between 2005 and 2022, indicating a long-term commitment to research. In terms of dynamic changes and explosive growth, institutions such as Univ Texas MD Anderson Canc Ctr and Univ Wisconsin all showed high explosiveness, suggesting that they significantly contributed to research in this field during certain periods.

Co-Cited Authors

The co-cited author graph showed the major co-cited authors and their academic impact on the field of MTC therapy. Authors such as Wells SA and Elisei R have made significant academic contributions to the field, as indicated by their high citation frequency and burst value. Other authors, such as Machens A, Mulligan LM, and Schlumberger M, have also significantly contributed to the development of the field through their research. The top 10 authors in terms of citation frequency are listed, and the cited authors are visualized and analyzed in Fig. 4.

Researcher Wells SA ranked first with 592 citations, indicating that Wells SA had a strong academic impact on the field of MTC therapy, with a burst value of 23.23, which indicated their significant contribution to growth or breakthrough in research over a certain period (2018–2024), and that their research results have received considerable attention. Elisei R has been cited 399 times, a high citation rate. Their burst value was ranked first at 29.06, indicating that their research contributed significantly and that their findings played an important role around 2015–2024. Other authors, such as Machens A, Mulligan LM, and Schlumberger M, had different citation frequencies and burst values, but they all contributed to the field to some extent. The degree indicates the number of co-citation relationships between authors, which reflects the degree of authors' connectivity in this network. For example, Wells SA had a degree of 132, indicating that he had co-citation relationships with many other authors. Additionally, centrality is a measure of an author's importance or influence in the network. Well SA had a relatively high centrality of 0.2, which indicated that he occupied an important position in the network. This statistical information provides insights into the research dynamics and academic network structure of MTC therapy among researchers.

Cited journals

The table of co-cited journals with the theme “Medullary Thyroid Cancer Treatment” shows the citation frequency, time span, network attributes, and co-citation relationships with other journals in the related research area. J CLIN ENDOCR METAB ranked first with 1104 citations, followed by THYROID and NEW ENGLJMED with 833 and 683 citations, respectively. CANCER-AM CANCER SOC, J CLIN ONCOL, CANCER RES, SURGERY, CLIN ENDOCRINOL, CANCER, and CLIN CANCER RES also had high citation frequencies. The top 10 journals in terms of citation frequency are listed, and the cited journals are visualized and analyzed in Fig. 5.

First, the J CLIN ENDOCR METAB topped the list with 1104 citations, indicating that the journal significantly influenced research related to the treatment of MTC and is an important source of references for researchers. THYROID and NEW ENGLJMED followed with 833 and 683 citations, respectively, demonstrating their dominance and strong influence. CANCER-AM CANCER SOC, J CLIN ONCOL, CANCER RES, SURGERY, CLIN ENDOCRINOL, CANCER, and CLIN CANCER RES also had high citation frequencies, and together, they formed a core group of journals for research in this area. Additionally, J CLIN ENDOCR METAB and CANCER-AM CANCER SOC had high degrees (121, 121) and degrees of centrality (0.05 and 0.07), indicating that they were at the core of the co-citation network and were more associated with other journals. This information is important for researchers to understand the research dynamics in the field, select important references, and formulate research directions.

Keyword co-occurrence, clustering, and timeline view

Keywords are used very frequently and hold a central position in research papers. First, the co-occurrence graph and frequency of occurrence of keywords revealed research hotspots and trends in the field of MTC treatment. Second, the cluster analysis of keywords showed the research hotspots, therapeutic strategies, and potential directions of development in the field. Finally, the keyword timeline graph provided an intuitive view of the development trajectory and key turning points of research in this field over the past few years (Figs. 6 and 7).

Keyword co-occurrence analysis

The keyword co-occurrence graph for the topic “medullary thyroid cancer treatment” showed the research hotspots and trends in the field of MTC treatment. Medullary thyroid cancer formed the core of the research topic and had the highest frequency of occurrence (677), which indicated that it is the research object of greatest interest in the field. The keywords such as“management” and “therapy”, which represent the therapeutic management and specific treatments of MTC, respectively, appeared more frequently (267 and 177 times, respectively) and had significant bursts, suggesting that the therapeutic strategies and methods of MTC were among the main focus of research in this field. The frequent use of the keywords mutation and expression (172 and 155, respectively) indicates that researchers have investigated the genetic and molecular basis of MTC. Calcitonin (Ctn) is an important biomarker of MTC, and its frequent use as a keyword (166) suggests that researchers have extensively investigated its application in diagnosing MTC. The frequent use (153 times) of the word “diagnosis” reflects the importance and challenges associated with early diagnosis of MTC.

Research on MTC and its related therapeutic strategies, molecular mechanisms, biomarkers, and diagnostics is the focus of research in this field. Moreover, the research activities are part of a long-term and continuous process, and the keywords form complex co-occurrence relationships in the network. These analyses provide important references for future research directions and collaborations.

Keyword cluster analysis

The keywords related to MTC treatment were clustered and analyzed using the CiteSpace software with the latent semantic indexing (LSI) algorithm. The analysis results revealed the research hotspots, therapeutic strategies, and potential development directions in this field. This clustering focused on the basic pathological features of MTC and its association with other endocrine system diseases, emphasized the multifactorial complexity of the disease and the importance of clinical recognition, and mentioned potential drug targets or therapeutic approaches for treating MTC.

The core keywords of Cluster 1 were antiangiogenic therapy, radioactive iodide, etc. This cluster focused on multiple therapeutic strategies for MTC and the assessment of their efficacy. Antiangiogenic therapy and radioactive iodide therapy are frequently mentioned as important tools, while the importance of pretreatment risk assessment for developing a personalized treatment plan is emphasized.

The core keywords of cluster 2 were peptide receptor radionuclide therapy, tyrosine kinase inhibitor, ret gene, noncoding RNA, and PD-1 inhibitor. This clustering showed the latest advances in molecularly targeted therapy for MTC. The emergence of novel therapeutic strategies, such as peptide receptor radionuclide therapy and tyrosine kinase inhibitors (TKIs), has provided more therapeutic options for patients with MTC, whereas the study of ret genes and noncoding RNAs has further improved our understanding of the pathogenesis of MTC.

The core keywords of cluster 3 were HSP90 inhibitor, RET inhibitor, adrenal insufficiency, adverse events, molecular imaging, and systemic therapy. This clustering emphasized the importance of systemic therapy and drug innovation in treating MTC. The development and application of novel drugs, such as HSP90 inhibitors and RET inhibitors, reflect possible complications or side effects during treatment, and the application of molecular imaging technologies offers new ways to improve the therapeutic efficacy of MTC.

The main keywords of cluster 4 were “Medullary Thyroid Cancer”, “Targeted Chemotherapy”, “Antiangiogenic Therapy”, “Tumor Marker”, “Tyrosine Kinase Inhibitor”, and “Systemic Therapy”. The cluster focused on targeted therapeutic strategies for MTC, including the use of drugs such as TKIs, highlighting the importance of antiangiogenic therapy in the treatment of MTC. The cluster also contained information on the application of tumor markers in diagnosing MTC and the similarities and differences between differentiated thyroid cancer and MTC treatment strategies.

The keywords in Cluster 5 included messenger RNA, transcriptional regulation element, sequence, glucocorticoid, identification, 1,25-dihydroxyvitamin D3, and procholecystokinin precursor. The cluster focused on the multifaceted functions of a particular gene or protein. These functions included mRNA generation, signaling, transcriptional regulation, molecular structure characterization, hormone and metabolic regulation, and protein precursor processing.

Clustering analysis of MTC therapeutic keywords revealed that research in this field is progressing, and significant advancements have been made from basic pathological features to clinical therapeutic strategies, molecularly targeted therapeutic techniques, and drug innovations. In the future, with a deeper understanding of the pathogenesis of MTC and the emergence of new drug trials, more effective therapeutic regimens may be developed to improve patient prognosis.

Timeline view analysis of keywords

The timeline chart covers the period from 1976 to June 2024 and reflects the dynamics of the research field related to MTC treatment. Overall, research in the field is progressing, with the focus expanding from basic disease management to more specific treatments and related biomarkers.

Beginning of the timeline and early focus (1976–2000): The beginning of the timeline emphasized “management”, “diagnosis”, “metastatic surgery”, “proto-oncogene”, “medullary thyroid cancer treatment”, “calcitonin”, and “carcinoembryonic antigen”, indicating that the terms were important. These findings suggested that at an early stage, researchers were concerned about the critical role of the clinical management and surgical treatment of MTC in controlling tumor metastasis. Researchers also focused on calcitonin and carcinoembryonic antigen (CEA) as biomarkers of MTC, the dynamics of which are important in monitoring diseases and assessing efficacy. Surgical treatment, especially in cases where metastases had already developed, was also an important area of research at that time.

Mid-term development (2000–2010): With advancements in research, gene expression and its regulatory mechanism have become popular research topics. In this period, researchers investigated the pathogenesis of MTC at the molecular level and simulated the tumor environment in the laboratory to investigate new therapeutic approaches. The focus on specific types of MTC increased, especially the link between gene mutations and therapeutic approaches. During this period, researchers identified specific genetic mutations (RET genes) associated with MTC and determined how these mutations affect the biological behavior of tumors and their response to different therapeutic techniques. Moreover, research on new treatments, such as prophylactic thyroidectomy, radionuclide therapy, and kinase inhibitors, was also initiated. The introduction of positron emission tomography (PET) showed the growing importance of imaging techniques in the diagnosis and therapeutic monitoring of MTC. PET technology, along with specific radiotracers, can achieve precise localization of MTC and its metastasis and provide a basis for developing individualized treatment plans.

Recent Hot Topics and Future Trends (2010–2024): The use of TKIs in the treatment of MTC has received much attention. TKIs such as Vandetanib are effective in treating MTC, especially in controlling disease progression and prolonging survival. Additionally, peptide receptor radionuclide therapy (PRRT) has become a research hotspot, providing new options for treating MTC patients. Moreover, an increase in the number of open-label trials indicates that research on MTC treatment is becoming more transparent and verifiable, which can help improve the credibility of the research and promote its clinical application.

This keyword timeline illustrates the evolution of research on MTC treatment over the past decade, from the early days of surgical treatment and clinical management to the mid-term assessment of molecular mechanisms and development of novel therapeutic approaches, and finally, to the more recent use of targeted therapeutic strategies and imaging techniques, each step contributing to the enrichment and advancement of this research field.

Along with traditional therapeutic methods, with continuous and in-depth research on gene expression and molecular signaling pathways in the field of precision medicine, the current mode of treatment for MTC is an integrated systematic therapy combining surgery, chemotherapy, radiotherapy, molecular targeted therapy, and immunotherapy. Based on the high-frequency keywords related to MTC treatment in this article, we systematically summarized the current status, hotspots, and future trends of each treatment method in this field.

Surgical treatment

Surgical treatment of the primary site

Surgery is the only curative treatment for MTC. Regardless of whether the tumor has local or distant metastases, total thyroidectomy is the preferred procedure for patients with operable primary foci. However, notably, for sporadic MTC and hereditary MTC, the choice of surgical approach for the primary focus is currently controversial for the prognosis of patients⁷.

For sporadic MTC, total thyroidectomy is the main surgical treatment. However, some researchers have suggested that unilateral thyroid lobectomy plus isthmus resection can be selected for sporadic MTC with small tumors, unilateral lesions, and no regional lymph node metastasis on preoperative examination⁸. However, such studies lack the support of the results of large-sample clinical trials, and the effect of surgical modality on the survival prognosis of patients is debatable.

The recommendation that total thyroidectomy should be performed for managing the primary focus of hereditary MTC, regardless of the size and location of the tumor, is indisputable⁹. Additionally, preoperative genetic testing is recommended for MTC patients to screen for specific types of MTC and grade the risk associated with their mutation sites¹⁰. Prophylactic thyroidectomy is the standard of care for patients with hereditary MTC who are genetically tested to carry mutated genes, especially those with familial MTC with mutations in the RET allele. This procedure has demonstrated superior efficacy in several clinical trials^11,12. According to the guidelines for the treatment of thyroid cancer published by the National Comprehensive Cancer Network (NCCN), patients with RET genes carrying high-risk mutations are recommended to undergo total thyroidectomy in the first year of life or during diagnosis¹³. According to the Chinese Society of Clinical Oncology (CSCO) guidelines for treating medullary thyroid cancer, the mutated RET gene should be risk-graded, and prophylactic thyroidectomy interventions should be performed in the first, third, and fifth years of life for pediatric patients with medullary carcinoma who have the highest risk, high risk, and intermediate risk, respectively, according to the level of risk¹⁴. However, the conclusions of the follow-up observations and the timing of prophylactic thyroidectomy are related to medical ethics and the legal regulations of each country, which are not supported by the results of large datasets. Therefore, academic exchanges between countries need to be strengthened to jointly develop treatment guidelines for prophylactic thyroidectomy for hereditary MTC.

Lymph node clearance

Medullary thyroid carcinoma (MTC) is often accompanied by lymph node metastasis in the neck or upper mediastinal region, and the extent of surgical lymph node dissection is determined by the risk of recurrence or metastasis of MTC, as determined by relevant preoperative and intraoperative examinations. However, MTC is often accompanied by recurrent metastases in the cervical lymph nodes after surgery, and the surgical indications for the extent of cervical lymph node dissection are controversial.

Central regional lymph nodes

Total thyroidectomy with bilateral cervical lymph node dissection is the recommended surgical procedure for all MTC patients, irrespective of tumor size and whether the tumor is accompanied by cervical lymph node metastasis. According to the NCCN Clinical Practice Guidelines in Oncology, total thyroidectomy and bilateral central cervical lymph node dissection are required for patients with tumors ≥ 1 cm in diameter or with bilateral MTC. For patients with tumors < 1 cm in diameter and unilateral MTC, total thyroidectomy is recommended, and bilateral central cervical lymph node dissection is viewed with skepticism¹³.

Lymph nodes in the lateral cervical region

When MTC is accompanied by central lymph node metastasis, bilateral lateral cervical lymph node dissection should be performed routinely¹⁵. In contrast, for patients with MTC without central lymph node metastasis, some differences exist in the national guidelines on whether to perform prophylactic lateral cervical zone lymph node dissection. As per the revised American Thyroid Association (ATA) guidelines (2015), whether to perform systematic lateral cervical zone lymph node dissection should be evaluated by combining preoperative genetic testing for RET gene mutations, serum Ctn levels, and central zone lymph node metastasis¹⁶. More extensive cervical lateral zone, lymph node dissection, was also strongly recommended in the later NCCN Clinical Practice Guidelines in Oncology for high-risk MTC patients (e.g., multiple endocrine neoplasia syndrome type 2) with tumors ≥ 1 cm in diameter and central zone lymph node metastasis¹³. Additionally, the European Society of Medical Oncology (ESMO) guidelines recommend that bilateral cervical lateral zone lymph node dissection should be considered only when preoperative imaging suggests positive ipsilateral lateral cervical zone lymph node metastases but negative contralateral lymph node metastases, and when serum calcitonin levels are ≥ 200 pg/mL¹⁷. In contrast, the CSCO recommends central zone plus lateral cervical zone lymph node dissection as a class I recommendation for all MTC patients¹⁴.

Therefore, the indications and recommended indices for the extent of therapeutic or prophylactic CLND differ across countries and regions. Many large-sample clinical studies have suggested that prophylactic cervical lymph node dissection in MTC patients with negative cervical lymph nodes, confirmed by preoperative examinations, is not associated with overall survival (OS)^18,19. However, individualized surgical treatment should be adopted along with the degree of tumor progression, accompanied by relevant complications or the patient's wishes.

External beam radiotherapy

External beam radiotherapy (EBRT) is often administered as a complementary treatment for postoperative MTC or advanced MTC. When radical lymph node dissection is not feasible in the presence of MTC, postoperative EBRT may be administered to reduce the risk of local recurrence. However, whether EBRT improves the prognosis of patients with MTC is controversial. In a clinical study on 2046 MTC patients in the SEER database for postoperative adjuvant EBRT, the five-year and 10-year survival rates of MTC patients who underwent EBRT were not 70.7% and 52.3%, respectively, and compared to those who did not undergo ERBT (70.7% and 52.3%), no difference was recorded in the five-year and 10-year specific survival rates, and the patient survival rates did not improve²⁰. In contrast, in a prospective study involving 1200 patients, radiotherapy similarly did not consistently affect OS but decreased the risk of local recurrence. However, radiotherapy may be considered in cases of lymph node involvement and extra-touch invasion of the thyroid gland²¹.

Radionuclide therapy

Early researchers noted that radionuclide-labeled molecules may be used for the treatment of advanced MTC, but research on this therapeutic tool was still in its early stages for several reasons, such as low tumor incidence, poor sensitivity to radiopharmaceuticals, and a lack of experience in clinical application²². In recent years, growth inhibitor analogs (SSA), as the main PRRT-labeled radionuclides, have been reported more frequently in related neuroendocrine tumors, and researchers have investigated PRRT for MTC.

In a clinical study in which 177Lu-DOTATATE peptide receptor radionuclide therapy was administered to patients with growth inhibitor receptor-positive metastatic MTC, 43 subjects had a median OS of 26 months (95% CI: 16.6–35.3) and a median progression-free survival (PFS) of 24 months (95% CI: 15.1–32.9). After PRRT was administered, patients whose calcitonin doubling time (CtnDT) was greater than 24 months, compared to those whose CtnDT was less than 24 months, had longer OS and PFS. All patients tolerated the treatment without serious adverse events, confirming that it could be a potential therapeutic option for patients with advanced MTC²³. Similarly, the efficacy and safety of 177Lu-DOTATATE peptide receptor radionuclide therapy were evaluated in another clinical study in which 177Lu-DOTATATE was used to treat metastatic MTC patients diagnosed with high levels of Ctn²⁴. Additionally, in a study on 220 patients with metastatic MTC, remission of biochemical and objective responses was observed in 37.2% and 10.6% of patients, respectively, after treatment with PRRT. The low number of adverse events (all mild cases) confirmed that it can be used as a palliative therapeutic option for advanced MTC, for which no specific therapeutic options are available²⁵.

However, although PRRT has demonstrated satisfactory results in many clinical trials, more high-quality samples and high-quality evidence-based medicines are lacking. Research in areas such as radiolabeled ligand-based diagnostic imaging needs to be optimized in the future, and more large-scale randomized controlled trials need to be performed to confirm its safety and effectiveness²⁶.

Molecularly targeted therapy

RET inhibitors

Most patients with hereditary MTC and half of the patients with sporadic MTC have mutations in the RET gene. RET is theoretically the most effective target for treating MTC. Highly selective RET inhibitors with enhanced antitumor activity and safety are an important part of precision therapy for MTC²⁷. Selpercatinib, a highly selective and potent RET kinase inhibitor, has long-lasting drug activity and satisfactory drug safety in several clinical trials. Among these trials, in a multicenter phase III randomized controlled clinical study (LIBRETTO-531) published in the New England Journal of Medical Research, the efficacy of selpercatinib (trial group) was compared to that of cabozantinib and vandetanib (control group) in patients with advanced or metastatic MTC with RET mutations. The results showed that the efficacy of selpercatinib in terms of 12-month PFS and disease remission rates and drug tolerability were significantly greater in the selpercatinib group than in the control group (86.8% vs 65.7%, 69.4% vs 38.8%, and 38.9% vs 77.3%), indicating that selpercatinib might serve as a more effective therapeutic drug option than TKIs^28,29.

Multitarget TKIs

Vascular endothelial growth factor receptor (VEGFR) is also highly expressed in MTC tumor cells. Many drug clinical trials and meta-analyses have confirmed the efficacy of small-molecule TKIs for treating MTC, which have become the most common therapeutic target for MTC. Specifically, cabozantinib and vandetanib have been approved as first-line targeted therapeutic agents for MTC in Europe and the United States; they have been intensively investigated for treating MTC³⁰.

Cabozantinib

Cabozantinib is a small-molecule multitarget TKI whose main targets are RET, MET, and VEGFR2. Cabozantinib has demonstrated significant efficacy in several clinical trials as it can strongly inhibit RET and VEGFR2. For example, in a phase III clinical trial in which cabozantinib was under assessment for the treatment of metastatic neo-MTC conducted by Elisei et al., 330 subjects were randomized into a cabozantinib trial group and a placebo group. The results showed median PFS and remission rates of 11.2 months and 28%, respectively, in the cabozantinib group, compared to four months and 0%, respectively, in the placebo group. Patients in the cabozantinib group achieved a one-year PFS rate of 47.3%, compared to 7.2% for patients in the placebo group³¹. Owing to the superior antitumor activity and safety of cabozantinib in MTC clinical studies, it was approved by the US Food and Drug Administration (FDA) as a first-line targeted therapy for treating MTC³².

Vandetanib

Vandetanib is also a small-molecule multitarget TKI with several primary targets, including RET, EGFR, and VEGFR2. It was approved by the FDA and the European Medicines Agency (EMA) in 2011 for use in unresectable and symptomatic or metastatic MTC and is recommended as a first choice for patients with MTC, as per the most recent NCCA guidelines^13,17. In a phase III trial in which vandetanib was used to treat patients with advanced MTC, the vandetanib group had significantly higher PFS, ORR, and DCR than the placebo group, which encouraged the large-scale application of the drug in MTC³³. Additionally, vandetanib was found to improve disease remission rates in pediatric and adolescent MTC patients in a pharmacological clinical study and might be a potential therapeutic option for these patients³⁴.

Although research on MTC-targeted therapy is quite popular and MTC therapy is expected to be the treatment of choice for patients with advanced or metastatic MTC, many issues need to be addressed in the future. For example: 1. Most of the therapeutic methods and drugs are still in the clinical trial stage, and the safety of the drugs and drug resistance after treatment need to be further evaluated. 2. Whether the combined administration of molecularly targeted drugs and traditional treatment can improve the therapeutic effect needs to be determined 3. Further clinical research on combination regimens of molecularly targeted drugs is needed. 4. Unknown targets or targeting pathways need to be identified to treat MTC. 5. Whether patients with locally advanced disease can be treated with neoadjuvant therapy before surgery needs to be determined to improve their prognosis.

Immunotherapy

With the continuous advancement of individualized precision medicine, molecular targeted therapy has become the main treatment modality for patients with advanced metastatic MTC. However, the cytotoxic effects of drugs, drug resistance, and side effects limit the efficacy of targeted therapy³⁵. With the advancement in tumor immunotherapy, many studies have confirmed that the tumor microenvironment of thyroid cancer is rich in immune lymphocytes and microvessels, which interact with each other to exacerbate tumor resistance to immunity and help tumor cells hide from immune surveillance, thus leading to sustained tumor proliferation and spread³⁶. PD-L1 expression in advanced thyroid cancer is closely related to tumor recurrence and metastasis, especially for immune checkpoint inhibitors in advanced thyroid cancer patients. Clinical studies have shown that the expression of PD-L1 can be combined with other therapeutic drugs to improve the antitumor activity of the drug and prolong the OS rate of patients^37,38. However, research on PD-L1 inhibitors and MTC is still in the preliminary stage, but drug clinical trials are ongoing. PD-L1 inhibitors are expected to effectively treat MTC and provide several effective options for treating MTC patients³⁹.

Postoperative management and follow-up monitoring

Postoperative management and long-term follow-up monitoring are equally important aspects of the systematic treatment of MTC patients and should be provided adequate attention. The prognosis of MTC patients needs to be improved to formulate further adjuvant and complementary postoperative treatments via risk assessment of intraoperative and postoperative recurrent metastatic factors. The choice of surgical approach plays a key role in the postoperative recurrence of MTC. Whether radical lymph node dissection can be performed is closely related to the surgical experience of the operator. Additionally, TNM staging of postoperative tumors in patients with MTC needs to be routinely performed to assess the size and location of tumors, extrathyroidal invasion, and lymph node metastasis. This method can be used to identify highly recurrent tumors and provide timely postoperative complementary therapy⁴⁰.

The serum Ctn and CEA levels are important indicators affecting the prognosis of MTC patients. The NCCN and ESMO guidelines recommend that MTC patients should be followed up and monitored for Ctn and CEA from the first to the third months of the postoperative period. If the indicators are persistently and significantly elevated, the patient should be alerted to residual lesions or local recurrence during the postoperative period. If the Ctn value is greater than 1,000 pg/mL, an imaging examination is necessary to determine whether the tumor has metastasized to distant organs^1,13. Additionally, some researchers have proposed using the ratio of postoperative calcitonin to preoperative calcitonin as a dynamic monitoring index to predict the recurrence of MTC. The prediction model they constructed had relatively good predictive ability and can be used for the postoperative monitoring of MTC to provide more guidance. However, these are small-sample clinical studies, and their rigor and practicality need to be examined in more clinical studies in the future^41,42.

Similarly, postoperative follow-up monitoring of serum Ctn, CEA, etc., and imaging are important monitoring methods. Color ultrasound is a simple and easily accessible treatment method that can be combined with a puncture biopsy to confirm whether tumor recurrence or metastasis has occurred. For patients with distant tumor metastasis, CT or PET/CT has become a commonly used examination method in the clinic. Regarding research hotspots, many studies have confirmed that PET/CT with different tracer imaging agents plays an important role in the follow-up monitoring of MTC and that there are slight differences in detection ability and direction^43–45. PET/CT may be a better option to assist in the diagnosis of patients whose lesions are not detected on routine examination.

Summary

Researchers are highly motivated to conduct studies in the field of MTC therapy, which is reflected by an increase in the number of publications. The research conducted in this field in the USA and Italy and the research organizations and institutions in these countries are major global contributors, ranking among the highest in the world. Authors such as Wells SA and Eliseir have greatly contributed to this field owing to their high citation frequency and burst value. Journals such as J CLIN ENDOCR METAB, THYROID, and NEW J CLIN ENDOCR METAB are among the most cited, which indicates that these journals are authoritative in the field of MTC treatment and have a wide range of influence. Management, calcitonin, RET gene, surgery, antiangiogenic therapy, tyrosine kinase inhibitor, peptide receptor radionuclide therapy, etc., are the hotspots of research in the field of MTC therapy. Prophylactic thyroidectomy, targeted therapy, peptide receptor radionuclide therapy, positron emission tomography, clinical trials, etc., are future research directions and global trends.

To summarize, in this article, we visualized and analyzed the treatment of MTC via bibliometric methods, revealing the current status, hotspots, and future trends of research in this field. The results of the bibliometric analysis were also combined to systematically summarize the current research progress of each treatment option for MTC in different countries and regions, and the controversial nature of the treatment guidelines, as well as to propose future research directions, which will provide new ideas for further research in the field of MTC treatment.

Ethics approval and consent to participate

Not applicable

Consent for publication

Not applicable

Competing interests

The authors declare that the study was conducted in the absence of any business or financial relationship that could be perceived as a potential conflict of interest.

Availability of data and materials

Raw data supporting the conclusions of this paper will be provided by the authors without reservation.

Funding

This study was supported by the Science and Technology Programme of Sichuan Province, People's Republic of China (2023YFS0473).

Author contributions

This work was conceived by TX. Data was collected and downloaded by TX, JW, RL and MY. The visualisation was done by TX. The manuscript was written by TX. XZ , JB , and YW helped to revise the manuscript and provided constructive comments. All authors contributed to the paper and approved the submitted version.

Acknowledgements

The authors would like to thank the North Sichuan Medical College and Beijing Anzhen Nanchong Hospital, Capital Medical University & Nanchong Central Hospital for their support of this work.

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Current Status, Hotspots, and Future Directions of Research on the Treatment of Medullary Thyroid Carcinoma: A Bibliometric Analysis and Systematic Evaluation

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Abstract

Background

Methods

Results

Conclusions

Figures

Introduction

Materials and methods

Results and analysis

Year of publication and number of articles

States

Organization

Co-Cited Authors

Cited journals

Timeline view analysis of keywords

Discussion

Surgical treatment

Surgical treatment of the primary site

Lymph node clearance

Central regional lymph nodes

Lymph nodes in the lateral cervical region

External beam radiotherapy

Radionuclide therapy

Molecularly targeted therapy

RET inhibitors

Multitarget TKIs

Cabozantinib

Vandetanib

Immunotherapy

Postoperative management and follow-up monitoring

Summary

Declarations

References

Additional Declarations

Status:

Version 1