Esophageal cancer is the eighth most common cancer and the sixth major cause of cancer-related death worldwide (1). In 2020, the world witnessed about 604,100 new cases and 544,100 deaths, equaling to the age-standardized morbidity and mortality rates of 6.3/100,000 and 5.6/100,000, respectively (2). Advanced esophageal squamous cell carcinoma (ESCC) is one of devastating tumors with the 5-year survival rate lower than 5% (3, 4). The etiology of esophageal cancer is not completely clear. Recognized risk factors include genetic predisposition, gastroesophageal reflux disease, alcohol consumption, smoking and obesity (5). The alternative clinical treatment for esophageal cancer mainly depends on the stage of the tumor and the specific condition of patients. For esophageal cancer, multidisciplinary approach is an effective strategy for managing this disease, which involves the use of surgery, radiotherapy, chemotherapy, targeted therapy, immunotherapy and other treatments (6). In recent years, the emergence of immunotherapy has brought new hope for esophageal cancer. With the recognition of tumor immunotherapy, the application of immune checkpoint inhibitors (ICIs) has gradually shifted from the back-line and second-line treatments to first-line and even perioperative treatments. PD-1/PD-L1 inhibitors have been approved to be used for the first-line treatment of advanced esophageal cancer, which significantly improves patient prognosis (7). The response rate of ICI alone in esophageal cancer varied from 9.9 to 33.3% in the reported studies (8).

A large number of articles regarding anti-PD-1/PD-L1 immunotherapy for esophageal cancer have been published in the past decade. However, no systematic analysis of the data in the available articles has been performed. The increasing number of publications makes it more necessary to illustrate the state of the development by bibliometric methods (9). Bibliometric analysis consists of the quantification and visualization of the data by applying mathematics and statistics (10). In this way, the research trend of the area can be objectively shown. The bibliometric analysis provides researchers valuable information on the development of a specific field from a macro perspective. The most important data source is the Web of Science Core Collection (WoSCC) database (11).

Up to now, there is no published bibliometric study has systematically evaluated the anti-PD-1/PD-L1 immunotherapy for esophageal cancer from 2012 to 2021. In this work, the research tendency and hotspots of anti-PD-1/PD-L1 immunotherapy for esophageal cancer were visually analyzed using HistCite, VOSviewer, and CiteSpace. The aim was to identify the characteristics of publications, build collaboration networks, present hot words, reveal research frontiers and direct the follow-up work (12, 13).

Esophageal cancer has a high degree of malignancy and poor prognosis. As a new therapeutic method, immunotherapy can significantly improve the prognosis of patients (40, 41). The anti-PD-1/PD-L1 antibody is the most commonly used ICI. Therefore, it is important to build an in-depth understanding of publications in this field. In this study, a bibliometric analysis of anti-PD-1/PD-L1 immunotherapy for esophageal cancer from 2012 to 2021 was performed, presenting the research hotspots and trends.

Figure 2 shows that the annual output maintained a rapid growth over the last decade. Literature published between 2012 and 2016 mostly focused on the expression and prognostic value of PD-1/PD-L1. In 2017, results of clinical trials of ICIs for esophageal cancer began to be published. From then on, the annual output increased rapidly, from 40 in 2017 to 216 in 2021. The annual growth rate also increased year by year.

In 2017, Toshihiko Doi (38) and Toshihiro Kudo (29) released their respective clinical trial results, which respectively demonstrated that Pembrolizumab and Nivolumab had certain anti-tumor effect in PD-L1(+) patients who failed second-line or back-like treatment. In 2018, Huang Jing et al. conducted a study on 30 patients with relapsed or metastatic advanced ESCC that showed chemoresistance previously (42). According to their results, the anti-PD-1drug SHR-1210 exhibited definite antitumor activity, with tolerable toxic and side effects. In 2019, the research data from multiple clinical trials were released, including KEYNOTE-180 (30), KEYNOTE-181 (43) and ATTRACTION-03 (28). As revealed by KEYNOTE-180 and KEYNOTE-181, Pembrolizumab had remarkable therapeutic effect and favorable safety on patients with PD-L1(+) advanced esophageal carcinoma, supporting the application of Pembrolizumab as the new second-line standard treatment for PD-L1(+) metastatic esophageal carcinoma. In 2019, Pembrolizumab was approved by the USA FDA to be used to treat relapsed, locally advanced or metastatic ESCC patients who had received first-line or later-line systemic treatment, with positive PD-L1 expression in tumor tissues (CPS≥10). In 2020, a breakthrough was made in the immunotherapy for esophageal carcinoma. The preliminary research results from KEYNOTE-590 demonstrated the satisfactory therapeutic effect and safety of Pembrolizumab combined with chemotherapy in the first-line treatment for advanced esophageal carcinoma (44). In the 2020 V5 version of NCCN guidelines, Pembrolizumab combined with platinum-based chemotherapeutic regimens was recommended in the first-line treatment of unresectable, locally advanced, locally relapsed or metastatic esophageal carcinoma with PD-L1 CPS≥10 and negative HER-2 expression. Additionally, CheckMate-577 ushered in the new chapter of adjuvant immunotherapy for esophageal carcinoma, which comprehensively evaluated the therapeutic effect of adjuvant nivolumab on patients with esophageal carcinoma and gastroesophageal junction carcinoma who did not achieve complete pathological remission after neoadjuvant radiochemotherapy (NRCT) (45). Clinical trials of neoadjuvant immunotherapy, such as NICE, KEEP-G 03, and PALACE-1, also reported the preliminary results. In March 2021, based on the KEYNOTE-590 research results, the USA FDA approved the use of Pembrolizumab combined with platinum-based chemotherapy as the first-line treatment for unresectable locally advanced or metastatic esophageal carcinoma or gastrointestinal junction carcinoma or those not suitable for radical radiochemotherapy, regardless of the PD-L1 expression status. The results of neoadjuvant immunotherapy combined with chemotherapy or radiochemotherapy were also released in 2021. The rapid development of immunotherapy for esophageal cancer suggests the great potential of the field in the future. Given that the feasibility and safety of anti-PD-1/PD-L1 immunotherapy have been confirmed, there might be more publications in the following years. The development prospects of immunotherapy for esophageal cancer could be expected.

China was the top 1 country ranked by total publications, which was consistent with epidemiological status that the incidence rate and fatality rate were high in this country. Although China had a huge number of publications, its citation was not impressive. Germany and France with less publications had high ratio of Citations/Paper, reflecting the high quality of their publications. The USA was the most active collaborator in Figure 3 and played an important role in international cooperation.

As China is one of the high-risk areas of esophageal cancer, 6 of the top 10 institutions are from China. However, the articles published in China were scarcely cited, reflecting the weak influence of these publications. Therefore, Chinese institutions need to find methods to improve the quality of publications.

Natl Canc Ctr and Natl Canc Ctr Hosp East located in Japan were institutions that not only productive but also influential. They were both participating institutions of several important clinical trials, including KEYNOTE-180, KEYNOTE-181 and KEYNOTE-590. Ken Kato from National Cancer Center Hospital together with Toshihiko Doi and Takashi Kojima from National Cancer Center Hospital East were all contributed to the three clinical trials. They were also the top 3 prolific authors. Kato Ken who was the most prolific author ranked second in terms of co-cited authors, and he was a key figure of ATTRACTION-3. The top 10 prolific authors were all from Japan, indicating that Japanese scientists made a tremendous contribution in this field.

The analysis of prolific journals guides scientists in identifying core journals for information access and manuscript submissions. Three journals were highly recommended to scientists in the field: Frontiers in Oncology, Cancer Science and Journal for Immunotherapy of Cancer. Moreover, Journal of Clinical Oncology, Lancet Oncology, and New England Journal of Medicine, were the most authoritative journals in this field according to the co-citation amount shown in Table 3 . As regard the subject categories shown in Figure 6 and Table 5 , ONCOLOGY and IMMUNOLOGY occupied central positions in this field, which were consistent with the analyzing results of the journals.

The current research hotspots were obtained from the high frequency keywords and cited references, which helped researchers to rapidly understand the direction of the research. This work lists the remarkable highlights of the research field as follows.

Clinical significance had the highest burst strength among the 34 keywords. It has always been significant in the field from 2014 to 2018. During this period of time, many studies focused on the prognostic value of PD-1/PD-L1 in patients with esophageal cancer. Numerous studies have suggested that, PD-L1 expression is related to the adverse clinical outcomes of esophageal cancer, supporting its role as a prognostic biomarker (39, 46–49). Further study found that PD-L1 expression in ESCC tumor cells was significantly associated with worse survival while no statistical significance was found between PD-L1 expression in ESCC tumor-infiltrating immune cells and survival (50). Recently, Peipei Wang et al. claimed that increased co-expression of PD-L1 and TIM3/TIGIT was associated with poor overall survival of ESCC (51).

Neoadjuvant chemotherapy was the hottest keywords in the last two years. With the moving forward of immunotherapy, more and more publications about NCT or NRCT plus immunotherapy are available at present. Multiple studies have evaluated the safety, feasibility and efficacy of neoadjuvant PD-1/PD-L1 inhibitors combined with chemotherapy in treating esophageal cancer patients (52–62). The neoadjuvant treatment of PD-1/PD-L1 inhibitor with chemotherapy produced satisfactory outcomes, indicating its potential as a promising neoadjuvant treatment for esophageal cancer. Besides, Wenqun Xing et al. designed a study to explore the impact of chemotherapy and toripalimab sequence on the pathological complete response (pCR) rate and safety of locally advanced ESCC patients (63). The initial results showed that delaying toripalimab to day 3 in chemoimmunotherapy might achieve a higher pCR rate than that on the same day. In the PERFECT trial, we investigated the feasibility and efficacy of NCRT combined with PD-L1 inhibitor (64). However, most of these studies were single-arm, phase I or II clinical trials. The long-term efficiency of this novel treatment and the validity of the present findings should be confirmed with more large-scale, longer follow-up and prospective comparative trials. In the existing clinical trials on neoadjuvant immunotherapy for esophageal carcinoma, no definite molecular biomarkers are available for selecting the possibly beneficial population. The previous research mainly focused on PD-L1, TMB, EGFR and CD8+ T cells. These studies not only help to identify the molecular biomarkers, but also provide ideas for the design of phase III clinical trials. Further studies should confirm more predictive biomarkers as well as indicators for the selection of a specific treatment.

The application of PD-1/PD-L1 inhibitors in esophageal cancer has achieved unprecedented successes. However, some treated patients exhibit non-response and severe immune-related adverse events. Therefore, immunotherapeutic markers are needed to assist in screening populations who can gain benefits from immunotherapy. At present, PD-L1 expression is used as the major biomarker for efficacy prediction in the application of PD-L1 inhibitors (65). With the deepening of research, DNA mismatch repair-deficient/microsatellite instability (dMMR/MSI) (66), tumor mutational burden (TMB) (67), copy number variation (CNV), polymerase epsilon (POLE) (68, 69), circulating tumor DNA (ctDNA) (70), inflamed gene expression profile (71, 72), tumor-infiltrating lymphocytes (TILs) (73), and immune gene signatures (74) have been suggested to show certain potential in predicting efficacy, which deserve further verification. Park R et al. Mentioned that, for esophageal cancer, there is no highly sensitive or specific marker apart from dMMR/MSI-H (75). Consequently, it is necessary to develop biomarkers for immunotherapy.

For the time being, the sensitivity and specificity of single biomarkers are not high enough. As a result, they may not be used as biomarkers alone. The combination of multiple biomarkers contributes more to predicting the immunotherapeutic efficacy in esophageal cancer. Moreover, when immunotherapy is used in combination with other treatments, whether a specific biomarker can maintain its prediction ability should be further analyzed. Whether predictors verified in advanced tumors can be applied in perioperative treatment is another important problem to be answered by on-going and future trials. In the future, it is promising to develop more precise tools to predict the anti-PD-1/PD-L1 therapeutic efficacy in esophageal cancer patients by standardizing and normalizing diverse biomarkers, intensively investigating the relations of different biomarkers, and applying computer technologies and medical databases, which is of great significance for individualized immunotherapy.

As far as we know, this is the first bibliometric study regarding anti-PD-1/PD-L1 immunotherapy for esophageal cancer in the past decade. The article hopes to guide scholars select research direction, references, cooperative institutions and authoritative journals. The data analysis was relatively objective and comprehensive, clearly displaying the research status visually. However, here are some limitations as follows.

Still, it is believed that this article provides the overall situation and research trend of anti-PD-1/PD-L1 immunotherapy for esophageal cancer. The results could provide readers a general overview of the landscape, especially to those without in-depth knowledge. The information could also be used to explore possible collaboration partners, potentially relevant publications, and promising research directions. Our study not only exhibits important milestones of esophageal cancer immunotherapy but also offers a better guide to the future. We sincerely hope that bibliometric and visual analyses will give us more ideas in this field.

To conclude, this article provides a comprehensive understanding of publications on anti-PD-1/PD-L1 immunotherapy for esophageal cancer from 2012 to 2021, providing valuable information to researchers in this field. This article presents data on the trend of annual output, countries/regions, institutions, journals, authors, subject categories, keywords, and co-cited references obtained using bibliometric analysis. Neoadjuvant chemotherapy, response, PD-1 blockade and CD8+ T cell were four latest research frontiers. Further studies and more cooperation are needed worldwide. Overall, our results could help the discovery of new perspectives and determine future directions.

Data were retrieved from 552 publications with VOSviewer on June 20, 2022. The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found in the article/ supplementary material.

Study conception, design and data analysis: YY. Paper writing: YY. Language polishing, paper review and editing: FW. All authors read and approved the submitted version. All authors contributed to the article and approved the submitted version.

This study was supported by Health Training Program Foundation for Young and Middle-Aged Innovative Talents of Science and Technology (YXKC2020017) and Programs for Medical Science and Technology Development of Henan Province of China (SBGJ202002080).

We thank Danyang Chen for assistance with manuscript preparation.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.