Lung cancer is the second most prevalent cancer and the most common cause of cancer-related deaths, with approximately 2.2 million new cases and 1.8 million deaths each year, accounting for one-tenth of diagnosed cancers and one-fifth of cancer deaths globally. This cancer has become the leading burden on worldwide health care (1). Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, accounting for approximately 85% of all lung cancer cases, which is further subdivided into three types: adenocarcinoma, squamous carcinoma, and large cell lung carcinoma (2, 3). The most common type is adenocarcinoma, which occurs in the peripheral bronchi and accounts for approximately 40% of all lung cancers. This is followed by squamous carcinoma, which arises in the main bronchi and comprises 25-30% of all diagnosed lung cancers. Large cell carcinoma accounts for 10%, occurring in the proximal part within the thorax (3, 4). NSCLC is a heterogeneous malignancy harboring a wide variety of driver genetic mutations. Over the past few decades, tremendous advances in NSCLC treatment, especially the advent of targeted and immunotherapy, have changed the landscape of NSCLC management. Individualized precision medicine based on genetic characteristics is gaining popularity. Currently, the options for NSCLC management mainly include surgery, radiotherapy, chemotherapy, targeted therapy, and immunotherapy. Among them, surgery has become a greatly recommended choice for resectable NSCLC, stereotactic ablative radiotherapy (SABR) techniques make radiotherapy more precise and less damaging, platinum-based chemotherapy remains the standard regimen for some advanced NSCLC patients, while small molecular tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs) have brought unprecedented benefit in particular patients (5–7). The emergence of new technologies and the obsolescence of old ones have been ongoing.

However, the evolution of NSCLC treatment over the last 20 years is not well defined previously. Textbook-style chapter summaries and systematic reviews fail to fully demonstrate a time-based research progress and to effectively analyze a large amount of data. In fact, it is difficult for scholars to perform an exhaustive analysis in the face of the vast amount of NSCLC treatment research findings over the last 20 years. It is even more challenging to assess the evolution of the subject according to its temporal dynamics. Bibliometric analysis is one of the best tools for studying temporal trends in a certain area, which offers more comprehensive and objective results (8–11). Therefore, bibliometrics may provide meaningful insight into NSCLC management. We have innovatively applied this approach in the field of NSCLC treatment. The volume of citations in a paper signifies the significance of the study, indicating the impact it has had on the understanding and treatment of the disease (12). To make the study representative, we filtered the 100 most-cited articles in NSCLC treatment based on bibliometric citation analysis. These articles stand for the most impressive achievements in NSCLC treatment. In the 21st century, when the treatment of NSCLC is rapidly evolving, all research is inseparable from the foundation of previous generations. We can gain a lot of inspiration and experience from the evolution of NSCLC treatment. The study may help clinicians and researchers quickly understand the evolution of NSCLC management and grasp research status quo. The data visualization can help them to have a more intuitive understanding of the 100 most-cited NSCLC papers. To our knowledge, this is the first comprehensive bibliometric study about the evolution of NSCLC treatment in the last 2 decades.

With the significant advancements and rapid changes in NSCLC treatments in the last 20 years, it is crucial to understand the progress and evolution of NSCLC management in the new era where many therapies coexist (5). However, available textbooks and papers lack such information. We selected 100 most impactful papers in this field as research data and applied the bibliometric analysis to systematically explore the output dynamics, research forces, topics, hotspots, and frontiers in the field of NSCLC treatment. It can help scholars quickly learn the basics, clarify study ideas, and learn the research status quo.

As can be seen from Figure 3 , top articles evidenced the merits of international cooperation and witnessed a multi-national cooperation network with the United States as the core. Half of the top 10 institutions are from the United States (rank 1, 2, 4, 9, 10 in Table 1 ). There are 57 corresponding authors belonging to the United States, reflecting the United States is the originator of most top papers and has the most specialists. Additionally, some European countries such as Germany, Britain, and Italy, Canada in North America, and China, Japan, and Korea in Asia, also have outstanding performance in the field In 2000, a phase III clinical trial conducted in the United States demonstrated for the first time that docetaxel monotherapy versus vinorelbine/ifosfamide could provide clinical benefit for patients with advanced NSCLC who had relapsed or progressed after receiving platinum-based chemotherapy (27). A phase II study performed in the United States in 2004 investigated the clinical efficacy of erlotinib and found that rash might be a clinical marker for efficacy prediction (28). About a decade ago, this country explored the toxicity and efficacy of stereotactic body radiation therapy in patients with early-stage inoperable NSCLC and concluded that the therapy had high local control rates and moderate adverse events (29). In recent years, the country has also made significant achievements in immunotherapy, such as a single-arm clinical trial covering 27 sites in the United States, France, Germany, and Italy, which revealed favorable efficacy and safety of nivolumab in previously treated patients with refractory advanced squamous NSCLC (30). The United States leads all areas of NSCLC treatment in the world.

As illustrated in Figure 4 , the Memorial Sloan Kettering Cancer Center is the foremost research institution for NSCLC management, with the most top-notch papers and highest TC, followed closely by Massachusetts General Hospital. AstraZeneca, the Dana-Farber Cancer Institute, and the Sungkyunkwan University also with exceptional academic results. These institutions all have a long history of distinguished contributions to the field of NSCLC therapy. We found that the major studies in which the Memorial Sloan Kettering Cancer Center was involved were divided into two parts: before 2015 the theme of research was targeted therapy, and after 2015 the topic was immunotherapy. In 2003, the institution participated in a phase II clinical trial that further demonstrated the benefit of gefitinib in improving post-chemotherapy NSCLC symptoms and inducing radiographic cancer regressions (31). In 2015, it was involved in a randomized, open-label, international phase III study comparing the efficacy of nivolumab and docetaxel in patients with non-squamous NSCLC that progressed during or after platinum-based dual chemotherapy, proved that nivolumab had longer overall survival (32). The study has been cited more than 5,000 times.

The major contributors (shown in Figure 5 ), such as Paz-Ares L., Reck M., and Wu Yl., come from different countries and are affiliated with different institutions. It is their long-lasting efforts and closer global collaboration that have driven the development of NSCLC treatment. We found that the distribution of the authors’ top papers seemed no correlation with time. Interestingly, both Paz-Ares L. and Reck M. had published remarkable results in 2018, and the topics were both centered on immunotherapy for NSCLC (33, 34). It was also in 2018 that the Nobel Prize in Physiology or Medicine Prize was granted to scientists James P. Allison (United States) and Tasuku Honjo (Japan) for their pioneering work in tumor immunotherapy. Thus, we assume that 2018 was an important time-point for NSCLC immunotherapy.

The distribution of the journals ( Figure 6A ) demonstrates the treatment of NSCLC is increasingly reliant on molecular, biological, and genetic fields. Thanks to breakthroughs in targeted therapeutic pathways, different targeted regimens have been applied to patients with different genetic mutations, such as EGFR-positive and ALK-positive mutations. Furthermore, that advancement can predict efficacy, safety, and prognosis of targeted therapy (35–37). The molecular mechanism of immune checkpoint blockade has been partially elucidated. Tumor mutation burden and PD-l expression levels were utilized to predict the outcome of immunotherapy (38, 39). The citations in journals related to immunology and computer science indicate that the field has moved toward multidisciplinary integration. Increasingly routine clinical application of targeted next-generation sequencing technology, immunohistochemical techniques, and comprehensive genomic profiling enables more precise NSCLC management and makes personalized management possible (38, 40, 41). Clinical trials and basic experiments are becoming growingly inseparable today, inaugurating the century of rapid advancement in NSCLC management.

From Figure 6B , the most authoritative journal in the field is the New England Journal of Medicine, which has the most top-cited papers, the fastest papers growth rate, the highest IF and TC, followed by Journal of Clinical Oncology, Lancet Oncology, etc. Papers published in these journals are likely to be of higher academic quality. The most cited paper in the New England Journal of Medicine is about 6,000 times. The paper reported an open-label, phase III trial for non-smoking or formerly lightly smoking untreated patients with adenocarcinoma in East Asia. It demonstrated superior progression-free survival with gefitinib as initial treatment over carboplatin-paclitaxel in this population (42).

As is presented in Figure 7A , chemotherapy and targeted therapy have been studied in a lot of top papers, while the counts of immunotherapy-related keywords, such as nivolumab, were relatively small, probably because it as an emerging regimen has not been heavily cited yet. Of note, the earliest article was published in 2000 on the topic of chemotherapy in NSCLC (27), and the most recent 3 publications published in 2018 and 2019, all focused on immunotherapy (33, 43, 44). The timeline of the keywords illustrated that the hotspots of NSCLC management have evolved from chemotherapy and radiotherapy to targeted therapy and then to immunotherapy.

Surgery and cytotoxic drugs were introduced to treat NSCLC in the 1960 and 1970, making the first leap forward in NSCLC treatment. Surgery is currently the most recommended method for NSCLC patients with stage I-II, yet 70% of patients are in advanced stage III-IV at the time of diagnosis. Cytotoxic drugs, targeted therapy, and immunotherapy are critical for patients with advanced NSCLC (41). Among 100 highly cited papers, there is no research with the theme of surgery for NSCLC, which may be related to the high maturity and effectiveness of video-assisted thoracic surgery (VATS) (45, 46). SABR is considered as a standard care for inoperable peripheral type early-stage NSCLC, showing meaningful clinical benefit (47). Over the past 21 years, the common cytotoxic chemotherapy, such as paclitaxel and docetaxel, remains the predominant therapy for advanced NSCLC to some extent, but with the development of targeted therapy, TKIs have become the first-line treatment for some driver gene mutation-positive NSCLC patients.

TKIs such as gefitinib, and anti-angiogenic agents such as bevacizumab, were approved by the Food and Drug Administration (FDA) for NSCLC treatment. New targeted therapeutics are continually being approved by the FDA. In 2003, gefitinib was granted for treatment of second-line, unselected advanced NSCLC (48). Then in 2006, bevacizumab plus paclitaxel and carboplatin became the first-line regimen for non-squamous NSCLC, approved by the FDA. Using ALK-TKIs and EGFR-TKIs as first-line in the 2010 updates the options for the therapy of NSCLC (41). Third-generation targeted agents, such as osimertinib, and new combination regimens, for example EGFR-TKI erlotinib in combination with anti-angiogenic agent ramucirumab approved for EGFR-mutant NSCLC in 2020, were also gradually being used in the clinical practice (5, 41). Along with the application of targeted therapies, researchers were also more devoted to studying gene mutations and growth-factor receptors, which are inextricably linked to the effectiveness of targeted therapy (40). There is no doubt that targeted therapy is a milestone in the treatment of NSCLC.

In Figure 7A , the large number of lines between treatment modalities implied combination application to different degrees, and the density of the lines did not decrease over time, pointing that combination medication has always been a concern for researchers and remains a hot academic topic, based on which we recommend scholars make more attempts on combination therapy for NSCLC. Keywords with higher burst strength may become the new turning point (49, 50), which can lead us to find emerging hotspots and frontiers of the field. Figure 7B show that after the research boom of targeted therapy represented by TKIs, immune checkpoint blockade represented by programmed cell death-1 (PD1) and programmed cell death ligand-1 (PD-L1) blockade, such as “nivolumab” with the burst strength of 3.85, may become turning points in NSCLC treatment. Actually, cytotoxic T-lymphocyte antigen-4 (CTLA-4) and PD-1/PD-L1 blockade are research frontiers. In 2015, the FDA authorized nivolumab for the treatment of patients whose tumor had progressed on or after platinum-based regimens, a dramatic breakthrough in the treatment of advanced NSCLC that foreshadowed an immune era in lung cancer treatment (5, 51). In 2016, pembrolizumab was approved as monotherapy for first-line treatment of NSCLC with PD-L1 ≥ 50%. Pembrolizumab combined with chemotherapy as first-line treatment for advanced non-squamous NSCLC, granted in 2017, provides survival benefit for patients without target gene mutations (41). Furthermore, durvalumab became a new treatment option for adjuvant therapy in 2018. In 2020, first-line treatment using nivolumab plus ipilimumab and double-platinum chemotherapy for advanced NSCLC also proved the effectiveness of ICIs therapy (52). Another PD-1 inhibitor, such as cemiplimab-rwlc, was approved for first-line treatment in 2021, further confirming the rise of immunotherapy (41). Immunotherapy is perhaps the most significant breakthrough in NSCLC treatment in the last 20 years. It has profoundly changed our treatment landscape and research outlook. More immunologic agents will be available for NSCLC management, while the comparison between different immunologic agents may be worth the attention of researchers. Indeed, immunotherapy has shown excellent anti-tumor effects and a better prognosis than conventional therapy for patients with advanced NSCLC without EGFR or ALK mutations. Although patients can benefit from ICIs, most of patients may develop resistance after use, and combination therapy is considered a viable approach to overcome acquired resistance (53, 54). At present, ICIs are being explored as combination or monotherapy in neoadjuvant or adjuvant settings for NSCLC management and the results were promising (34, 39, 44). New immunotherapies, such as tumor vaccines, are being developed (3, 55). Researchers are also paying more attention to issues such as drug safety and resistance (30, 56). In terms of trial design, “open label” trials with the burst strength of 4.01, and “phase iii” clinical trials, 2.77, were widely used in the top articles. The large sample size, multicenter, international collaborative RCTs and experiments are necessary to derive reliable studies. Top researchers preferred to explore the efficacy of the combination of various regimens in different types of NSCLC while are more passionate about seeking effective first-line treatment alternatives. Recently, in top-cited papers, immunotherapy and chemotherapy were often combined to treat NSCLC patients or used separately to compare clinical value (33, 43), which is also consistent with Figure 7B , where “chemotherapy” and “nivolumab” red bars overlap in some years.

As shown in Figure 8 , the treatment principles of diseases can be divided into two parts: eliminating the evil factors and supporting healthy energy, which is complementary to each other. We think that the management of lung cancer may also be divided based on this principle. Traditional therapy methods (surgery, chemotherapy, radiotherapy, targeted therapy) (54) kill tumor cells directly, in keeping with the principle of eliminating harmful factors. On the other hand, immunotherapy destroys tumor cells indirectly by triggering or improving the immune function of the body, supporting healthy energy. The search for more effective, safer, and sustainable first-line treatment options using a combination of chemotherapy, radiotherapy, surgery, targeted therapy, and immunotherapy is the focus of researchers and clinicians in nowadays. The potential of immunotherapy has not yet been fully explored, and a new therapeutic leap after it is yet to come. Nevertheless, researchers should actively consider what the next epoch-making breakthrough after immunotherapy will be and conceive the future landscape of NSCLC treatment. We speculate that this breakthrough should be based on genetic and molecular technology, relying on the body’s inherent anti-tumor ability rather than the direct killing of tumors, in line with the principle of supporting healthy energy.

We found that the United States is the strongest research nation and the Memorial Sloan Kettering Cancer Center is the most prominent institution over the last 20 years. Core authors, such as Paz-Ares L. and Reck M., have developed extensive international collaborations. The New England Journal is the most authoritative journal in the field. Molecular, biological, and genetic research plays a progressively important role in the treatment of NSCLC, while immunology and computer science have also been widely applied to this field. Hotspots of NSCLC management have almost undergone an evolution from chemotherapy and radiotherapy to targeted therapy to immunotherapy, while the exploration of combination therapy has never stopped. Immunotherapy and combination therapy are research frontiers. Encouraging progress has been made in the management of NSCLC in the last 2 decades, and more breakthroughs are sure to be explored in the future.

Overall, our study revealed leading countries, core institutions, distinguished authors, authoritative journals, citation relationships, topic dynamics, and research frontiers in the field of NSCLC management. That information may help researchers quickly sort out the historical progress of NSCLC treatment, provide insight into the future advancement of the field, and guide future research practice.

The original contributions presented in the study are included in the article/ Supplementary Material . Further inquiries can be directed to the corresponding authors.

ZL and SC designed the study. SC wrote the manuscript. SC, YH, and YQ selected the 100 most impactful papers and did the bibliometric analysis. YQ and JC guided the use of the software. SC, YQ, and JC framed the article. YL, JX, and PC proposed constructive opinions. ZH, DH, and YG helped retrieve data. ZL and YH led the team and revised the paper. All authors conducted the literature search and analyzed the data. All authors contributed to the article and approved the submitted version.

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.