PD-1/PD-L1 inhibitors related adverse events: A bibliometric analysis from 2014 to 2024

ABSTRACT

Programmed cell death-1 (PD-1) inhibitors and programmed cell death ligand 1 (PD-L1) inhibitors are considered effective alternatives for the primary treatment of recurrent metastatic cancers. However, they can induce various adverse events affecting multiple organ systems, potentially diminishing patients’ quality of life, and even leading to treatment interruptions. Adverse events related to PD-1/PD-L1 inhibitors differ from those associated with CTLA-4 inhibitors and are more commonly observed in the treatment of solid tumors. This study aimed to address the knowledge gap regarding adverse events related to PD-1/PD-L1 inhibitors. A visual bibliometric network was constructed using VOSviewer, CiteSpace, R software, and the Web of Science Core Collection (WoSCC) to quantitatively analyze this research field. Future research directions were also explored. The USA ranked first in publication count and total citations. Over time, publication types transitioned from case reports to clinical trials. Research on for nivolumab was the most prevalent. The spectrum of cancers treated by PD-1/PD-L1 inhibitors expanded beyond melanoma and lung cancer to include renal cell carcinoma, esophageal cancer, and others. Common adverse events included pneumonitis, myasthenia gravis, and vitiligo. There was a significant increase in multi-phase clinical trials and studies related to biomarkers. This study offers valuable insights for potential collaborators and institutions, highlighting trends in the study of adverse events related to PD-1/PD-L1 inhibitors. The management of these adverse events has become more refined and standardized. Biomarker research and multi-phase clinical trials are likely to be key areas of focus in future studies.

Introduction

Over the past decades, immunotherapy has had a profound impact on cancer treatment, offering relief to patients and extending survival outcomes.¹ Immune checkpoints are crucial molecules and pathways within the immune system that help prevent healthy cells from being destroyed by immune responses. However, tumor cells often exploit these checkpoints to evade the body’s immune system. T lymphocytes play a key role in targeting and destroying tumor cells.² Immune checkpoint inhibitors (ICIs) are a novel class of drugs that can restore the function of suppressed T lymphocyte by binding to specific ligands, ultimately allowing the immune system to clear tumors.³ Widely used ICIs include programmed cell death-1 (PD-1) inhibitors, programmed cell death-ligand-1 (PD-L1) inhibitors, and cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) inhibitors, all of which aim to restore T lymphocyte activity to target tumor cells. Immunotherapy is considered an effective treatment option for recurrent metastatic cancers, but it is also associated with various immune-related adverse events (irAEs) that can affect multiple organ systems.⁴ These irAEs may cause treatment interruptions and in some cases, long-term consequences that significantly impair patients’ quality of life.⁵ More than 90% of patients treated with CTLA-4 inhibitors⁶ and over 70% of patients treated with PD-1/PD-L1 inhibitors⁷ report experiencing adverse events across nearly all organ systems, including the hematologic. digestive, endocrine, respiratory, neuromuscular, cardiovascular, cerebrovascular, ocular, skin, and urinary systems.^8–10 However, there are notable differences between the adverse events associated with CTLA-4 inhibitors and those caused by PD-1/PD-L1 inhibitors. CTLA-4 inhibitors more commonly cause enteritis, hypophysitis and skin toxicity. The incidence of gastrointestinal adverse events is significantly higher with CTLA-4 inhibitors compared toPD-1/PD-L1 inhibitors.¹¹ Currently, there is no optimal treatment strategy for managing immunotherapy-related toxicities. Contemporary guidelines for treating immunotoxicity are largely based on retrospective analyses and experiences from cancer treatment trials.^12,13 Furthermore, existing studies have not thoroughly analyzed analysis the adverse effects of PD-1/PD-L1 inhibitors separately,^14,15 and not all malignancies have benefited from sufficient screening and management methods.¹⁶ Therefore, it is crucial to conduct in-depth research on the adverse effects of PD-1/PD-L1 inhibitors and explore new strategies for cancer screening and management.

CiteSpace is a Java-based application designed to analyzed and visualize hotspots and frontiers within scientific literature focusing on a specific discipline or knowledge domain through bibliometric, co-occurrence, and clustering analyses.¹⁷ To date, no bibliometric analysis of PD-1/PD-L1 inhibitors related adverse events has been published. The aim of this article is to address this gap by creating a global knowledge map of scientific publications concerning PD-1/PD-L1 inhibitors. This study reviews existing research from 2014 to 2024, enabling a comprehensive and detailed analysis of the data. It offers valuable insights into the current state of research on PD-1/PD-L1 inhibitors related adverse events, including the knowledge base, research trends, and emerging topics, with the hope of providing fresh perspectives for researchers.

Date and methods

Data collection

The search data were obtained from the Core Collection database of Web of Science (WoSCC), including SCI-EXPANDED, SSCI, A&HCI, CPCI-S, CPCI-SSH, BKCI-S, BKCI-SSH, ESCI, CCR-EXPANDED, and IC. All searches were completed and downloaded on January 18, 2024. To prevent bias caused by daily database updates, publications were independently verified by two authors. The publication types included regular articles and review articles, and only publications in English were considered. For further analysis, relevant literature information was extracted, with each downloaded study containing data on authors, title, abstract, descriptors and identifiers. The data were saved in plain text format (.txt), including complete records and cited references. (14). After agreement among senior literature retrieval experts and all authors, the search strategy was formulated as follows: [TS = (” PD-L1 Inhibitor*” OR ” PD L1 Inhibitor*” OR ” Programmed Death-Ligand 1 Inhibitor*” OR ” Programmed Death Ligand 1 Inhibitor*” OR “PD-1-PD-L1 Blockade” OR “PD 1 PD L1 Blockade” OR ” PD-1 Inhibitor*” OR ” PD 1 Inhibitor*” OR ” Programmed Cell Death Protein 1 Inhibitor*”) AND (” adverse event*” OR ” side effect*” OR ” complication*” OR ” adverse reaction*” OR ” adverse effect*” OR “toxicity” OR “toxicities”)], the specific search criteria are included in the annex.

Inclusion criteria

The inclusion criteria were: (1) Original peer-reviewed published articles, including both basic and clinical studies, addressing adverse reactions following tumor immunotherapy. (2) Database up to January 18, 2024. (3) Articles retrieved from the Web of Science.

Exclusion criteria

The exclusion criteria were (1) Articles that were not officially published. (2) Conference papers and abstracts collections of abstracts. (3) Duplicate publications. (4) Articles that were not relevant to the topic.

Quality assessment

English articles that met the inclusion criteria and were categorized as either “articles” or “reviews” were included in the analysis.

Methods

We employed a range of visualization tools for data analysis, including Citespace (version 5.7.R5), VOSviewer (version 1.6.18) and an online platform (https://bibliometric.com/), as well as two R packages: Bibliometrix and Biblioshiny (version 4.1.2).¹⁸ In this study, the centrality of nodes computed by CiteSpace was used to assess their significance within the network and to identify highly cited references and keywords that exhibited citation spikes during specific time periods. VOSviewer was utilized to construct and visualize co-occurrence networks of key terms extracted from the scientific literature.¹⁹ Each node represents parameters such as country, institution, journal, author, or keyword. The node size reflects its frequency of occurrence, while the thickness of the link indicates the strength of the network association. In this study, we primarily conducted co-authorship and co-occurrence analyses to investigate collaborative relationships between authors and institutions. Additionally, we used an online bibliometric visualization platform(https://bibliometric.com/) to illustrate international cooperation between nations.

Results and discussion

Status of publications

An overview of the study steps is presented in Figure 1. A total of 1,477 publications on adverse events of related to PD-1/PD-L1 inhibitors were included, consisting of 973 articles and 504 reviews. These papers came were published across 455 journals, with 9,387 authors contributing. The data spanned from the database’s inception construction to January 18, 2024. The average annual growth rate for these publications was 5.24%. Notably, 18.28% of the publications involved international collaboration. Figure 2 illustrates the number of publications from the top 10 countries, with the USA, China, and Japan leading in the number of publications (Figure 3). Publications first appeared in 2014, and their distribution showed two distinct phases: a period of steady growth from 2014 – 2018, followed by rapid growth from 2018 – 2020. The study of adverse events related to PD-1/PD-L1 inhibitors has remained a prominent research focus from 2020 – 2023, with 71.43% of the publications emerging during this period. This indicates that adverse events caused by PD-1 and PD-L1 inhibitors have become a significant research hotspot in recent years.

Figure 1.

Process and key steps of the study.

Figure 2.

Top 10 countries in terms of number of publications. Different colors represent different countries, and the size of each color area is proportional to the number of articles published.

Figure 3.

Distribution of countries with publications. The color gradient in the visualization represents the number of publications, where darker colors indicate more publications and lighter colors indicate fewer publications.

Citations and country cooperation

In terms of both publication count and total citations, the USA ranked first with 450 publications, averaging 56.00 citations per publication. China and Japan followed closely. Although France ranked second in the number of published articles, it was surpassed by China in terms of total citations. Switzerland, despite publishing only 26 papers, ranked first in total citations, indicating that Swiss publications were of higher quality and influence. These results are detailed in Table 1.

Table 1.

The total number of citations and the average citations of per article in the top 15 countries.

Rank	Country	Articles	Citations	Citations of per publication
1	USA	450	25195	56.00
2	CHINA	280	4427	52.70
3	JAPAN	154	3118	20.20
4	ITALY	92	3103	11.10
5	FRANCE	84	2311	50.20
6	AUSTRALIA	46	2127	23.10
7	CANADA	41	1759	44.00
8	UNITED KINGDOM	40	1563	42.20
9	GERMANY	37	1540	44.00
10	SPAIN	35	1351	33.00
11	SWITZERLAND	26	903	82.10
12	NETHERLANDS	24	833	32.00
13	GREECE	21	498	20.80
14	KOREA	19	358	18.80
15	POLAND	13	332	41.50

The USA, Italy, and Australia demonstrated extensive international collaboration. China, Italy, the UK, and Australia emerged as key collaborators for the USA. Similarly, France, Germany, Italy, the UK, and China frequently collaborated with the USA (Figure 4). Thus, the USA holds a leading position in terms of publication count, citations, and collaboration, highlighting its crucial role in this research field.

Figure 4.

Cooperation between countries. The different colors represent various countries, with the size of each color area reflecting the number of papers, while the lines depict collaborations between countries. The thicker the line, the more frequent the cooperation between countries.

Top 10 institutions in publication frequency and co-institute

Six institutions produced more than 100 publications (Table 2) related to PD-1/PD-L1 inhibitor adverse events. The UNIVERSITY OF TEXAS SYSTEM and the UT MD ANDERSON CANCER CENTER led with 198 publications. Of the top nine institutions, the majority were based in the USA and France, highlighting their dominant role in research on PD-1/PD-L1 inhibitors and associated adverse events.

Table 2.

Frequency of publications of top 10 institutions.

Rank	Affiliation	Country	Number of Articles
1	UNIVERSITY OF TEXAS SYSTEM	USA	198
2	UT MD ANDERSON CANCER CENTER	USA	198
3	HARVARD UNIVERSITY	USA	171
4	ASSISTANCE PUBLIQUE HOPITAUX DE PARIS	France	118
5	UNIVERSITE PARIS CITE	France	118
6	UNICANCER	France	101
7	MASSACHUSETTS GENERAL HOSPITAL	USA	96
8	HARVARD MEDICAL SCHOOL	USA	93
9	UNIVERSITE PARIS SACLAY	France	83
10	PEKING UNION MEDICAL COLLEGE	China	79

Institutions such as the University of Texas MD Anderson Cancer Center, Memorial Sloan Kettering Cancer Center, Harvard Medical School, Vanderbilt University, and Massachusetts General Hospital demonstrated sustained research efforts in this field. Notably, Memorial Sloan Kettering Cancer Center maintained particularly close collaboration with Johns Hopkins University and Weill Cornell Medical College. Brigham & Women’s Hospital had a strong association with the Dana-Farber Cancer Institute. Additionally, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, and the National Cancer Institute experienced citation bursts, signifying their key roles in PD-1/PD-L1 inhibitor adverse events research. The cooperation relationships are depicted in Figure 5.

Figure 5.

Cooperation relationship. Each node in the graph represents an institution, with the color of the circle indicating the year of study and the size of the circle reflecting the number of published papers during that year. The connections between nodes represent collaborative relationships among these institutions. Nodes with purple circles around them represent institutions that play an important role in the field.

Top 10 journals in publication frequency

A total of 10 journals published more than 20 articles on PD-1/PD-L1 inhibitor adverse events. Among these, the Frontiers series from Switzerland had the highest number of publications. FRONTIERS IN ONCOLOGY led with 64 publications, followed by CANCERS and FRONTIERS IN IMMUNOLOGY. Notably, the JOURNAL FOR IMMUNOTHERAPY OF CANCER was the only journal among the top 10 with an impact factor exceeding 10, ranking fifth in citation frequency, demonstrating its strength in both the quantity and quality of publications. The top 10 journals by publication frequency are listed in Table 3.

Table 3.

The top 10 journals in the number of publications.

Rank	Journal	Number of publications	Country	IF	JCR-c
1	FRONTIERS IN ONCOLOGY	64	Switzerland	4.7	Q2
2	CANCERS	51	Switzerland	5.2	Q2
3	FRONTIERS IN IMMUNOLOGY	50	Switzerland	7.3	Q1
4	JOURNAL FOR IMMUNOTHERAPY OF CANCER	37	England	10.9	Q1
5	EUROPEAN JOURNAL OF CANCER	35	England	8.4	Q1
6	ONCOLOGIST	35	USA	5.8	Q1
7	FRONTIERS IN PHARMACOLOGY	28	Switzerland	5.6	Q1
8	IMMUNOTHERAPY	27	England	2.8	Q4
9	CANCER IMMUNOLOGY IMMUNOTHERAPY	22	USA	5.8	Q1
10	JOURNAL OF ONCOLOGY PHARMACY PRACTICE	21	Switzerland	4.7	Q2

Co-authorship

Among the top 10 authors with the most publications, all had 12 or more publications. JOHNSON DB had the highest number of published papers, with his H-index and citation count also ranking first. NAIDOO J followed closely with 20 publications. Notably, although LARKIN J had only 12 publications, these were cited 2,039 times, highlighting the significant impact and influence of their work in the field.²⁰ The top 10 authors listed in Table 4 have made substantial contributions to the advancement of research in this area.

Table 4.

Top 10 authors with most publications.

Rank	Author	Articles	H-index	Citation times
1	JOHNSON DB	26	16	2569
2	NAIDOO J	20	12	2502
3	ZHANG L	18	8	155
4	WANG Y	16	10	729
5	CARLINO MS	13	10	1624
6	MENZIES AM	13	10	1402
7	LARKIN J	12	10	2039
8	LAMBOTTE O	12	11	1287
9	MICHOT JM	12	11	876
10	DOUGAN M	12	9	490

Collaboration among authors (Figure 6) and the “author river map” (Figure 7) further highlighted the importance of teamwork in research. Johnson, Douglas B. collaborated closely with Carlino MS and Heinzerling Lucie. Similarly, Curry, Jonathan I. worked closely with Rapini, Ronald p., Patel, Anisha B., and Torres-Cabala, Carlos. In addition, Choueiri Tonik and Harshman Lauren C. maintained a strong partnership, as did Van der Veldt, Astrid A. M. and Blank, Christian U. Another notable collaboration was between Tortora Giampaolo and Rossi Ernesto. Additionally, Ohe Yuichiro, Yamamoto Noboru, and Arami Toko frequently collaborated. The “author river map,” which illustrates the associations between authors, institutions, and keywords in this research field, showed that many authors were linked to multiple institutions, indicating a high level of collaboration across different authors and institutions.

Figure 6.

The authors’ cooperation. The same color represents the same cluster, and the size of nodes represents the number of publications.

Figure 7.

The author river map. The length of different nodes represents the number of publications, and the lines represent the connections between authors, institutions, and keywords.

Number of publication citations

The number of citations serves as an indicator of an article’s influence. Based on citation counts, BRAHMER JR’s 2018 article holds the highest number of citations, reaching 2,138. This publication, appearing in J Clin Oncol, which has an impact factor of 44.544, is a clinical guideline detailing the management of adverse reactions caused by immune checkpoint inhibitors. Drawing from previous publications, the guidelines compile the clinical experiences of physicians from various departments.²¹ The second most cited publication, authored by MARTINS F in 2019, was published in Nat Rev Clin Oncol, with an impact factor of 66.675. This article provides an overview of different types of immunosuppressive adverse reactions, presenting their epidemiology as well as strategies for screening and monitoring.²² NAIDOO J’s publication, the third most frequently cited, reviewed clinical studies on PD-1/PD-L1 monotherapy and combination therapies with other standard anticancer treatments across multiple tumor types. It summarized major adverse events reported in these studies and their corresponding management strategies.²³ FREEMAN-KELLER M and HARATANI K also published highly cited clinical research. Their studies demonstrated that adverse events related to nivolumab were associated with improved efficacy in patients with advanced or relapsed non-small-cell lung cancer (NSCLC) and increased overall survival in patients with metastatic melanoma.²⁴

The top 10 publications primarily consist of guidelines, reviews, retrospective studies, and clinical research. Their content spans the epidemiology, classification, identification, and management of adverse events associated with PD-1/PD-L1 inhibitors (Table 5).

Table 5.

Total citations of top 10 articles.

Rank	Title	Citation times	Year	First Author	Journal
1	Management of Immune-Related Adverse Events in Patients Treated with Immune Checkpoint Inhibitor Therapy: American Society of Clinical Oncology Clinical Practice Guideline.	2138	2018	BRAHMER JR	J CLIN ONCOL
2	Adverse effects of immune-checkpoint inhibitors: epidemiology, management and surveillance.	1021	2019	MARTINS F	NAT REV CLIN ONCOL
3	Toxicities of the anti-PD-1 and anti-PD-L1 immune checkpoint antibodies.	953	2015	NAIDOO J	ANN ONCOL
4	Association of Immune-Related Adverse Events with Nivolumab Efficacy in Non-Small-Cell Lung Cancer.	630	2018	HARATANI K	JAMA ONCOL
5	Nivolumab in Resected and Unresectable Metastatic Melanoma: Characteristics of Immune-Related Adverse Events and Association with Outcomes.	596	2016	FREEMAN-KELLER M	CLIN CANCER RES
6	Management of toxicities of immune checkpoint inhibitors.	587	2016	SPAIN L	CANCER TREAT REV
7	Treatment of the Immune-Related Adverse Effects of Immune Checkpoint Inhibitors: A Review.	558	2016	FRIEDMAN CF	JAMA ONCOL
8	Anti-PD-1 therapy in patients with advanced melanoma and preexisting autoimmune disorders or major toxicity with ipilimumab.	554	2017	MENZIES AM	ANN ONCOL
9	Immune-related adverse events of checkpoint inhibitors.	546	2020	RAMOS-CASALS M	NAT REV DIS PRIMERS
10	Immune-related adverse events and anti-tumor efficacy of immune checkpoint inhibitors.	540	2019	DAS S	J IMMUNOTHER CANCER

Analysis of keywords

Frequency of keyword occurrence and citation burst

To categorize and discuss keyword occurrences, frequencies were grouped based on immunotherapy drugs, cancer types, and adverse events. Keywords with frequencies above 4 are summarized in Table 6. The most frequently mentioned immunotherapy drug was nivolumab, with a centrality score of 0.67. Nivolumab, a PD-1 inhibitor, was featured in 63 studies investigating its combination with other treatments. The U.S. Food and Drug Administration (FDA) has approved nivolumab for the treatment of patients with advanced squamous non-small cell lung cancer NSCLC who have undergone prior treatments, as well as for metastatic melanoma.²⁵ The second most frequent drug was ipilimumab, a CTLA-4 inhibitor approved by the FDA in 2011 for the treatment of advanced melanoma.²⁶ this study because of its frequent use in combination with PD-1/PD-L1 inhibitors. Nivolumab plus ipilimumab is commonly used in the treatment of advanced melanoma.²⁷ Other frequently mentioned drugs were pembrolizumab, atezolizumab, durvalumab, and camrelizumab. Pembrolizumab, another PD-1 inhibitor, has shown superior performance compared to ipilimumab in stage III/IV unresectable melanoma and has been widely studied across numerous cancers.²⁸ Atezolizumab, a PD-L1 inhibitor, is primarily used in combination with carboplatin and etoposide as a first-line treatment for patients with extensive-stage small cell lung cancer. There has been growing research on atezolizumab combined with other treatments, such as bevacizumab for unresectable hepatocellular carcinoma and chemotherapy for metastatic non-squamous NSCLC.^29–31 PD-1 inhibitors like nivolumab and atezolizumab, along with CTLA-4 inhibitors like ipilimumab, displayed high centrality values, indicating their key role in immunotherapy studies. Nivolumab, atezolizumab, and ipilimumab were identified as central to this research field. Durvalumab, another PD-L1 inhibitor, is primarily used for extensive-stage small cell lung cancer and stage III NSCLC.^32,33 Nivolumab and pembrolizumab had the highest frequency of occurrence, reflecting the higher likelihood of adverse events associated with these drugs. This may also be related to their wider use, warranting further exploration into whether the dosage of these drugs is associated with the occurrence of adverse events.

Table 6.

Frequency and centrality of key words.

Types	Key Words	Count	Centrality	Year
immunotherapy drugs	nivolumab	816	0.67	2015
	ipilimumab	526	0.47	2014
	pembrolizumab	467	0.06	2016
	atezolizumab	72	0.55	2017
	combined nivolumab	63	0.04	2018
	nivolumab plus ipilimumab	49	0.18	2018
	durvalumab	18	0	2020
	camrelizumab	6	0	2022
types of cancer	non-small cell lung cancer	286	0.06	2017
	melanoma	268	0.14	2015
	metastatic melanoma	152	0.24	2015
	advanced melanoma	151	0.17	2016
	squamous cell carcinoma	34	0.21	2017
	renal cell carcinoma	21	0.04	2021
	esophageal cancer	10	0.08	2022
	hepatocellular carcinoma	6	0.13	2022
	breast cancer	6	0	2023
	urothelial carcinoma	5	0	2022
adverse reactions	pneumonitis	76	0.06	2018
	myasthenia gravis	56	0.26	2017
	vitiligo	46	0.09	2015
	myocarditis	44	0.08	2019
	hypophysitis	27	0.12	2017
	colitis	23	0	2020
	myositis	19	0	2019
	arthritis	13	0.05	2018
	hepatitis	11	0.02	2020
	cardiovascular toxicity	9	0.07	2020
	hypothyroidism	8	0.02	2021
	fulminant myocarditis	6	0	2020
	uveitis	5	0.02	2021
	autoimmune hemolytic anemia	5	0	2019
	polymyalgia rheumatica	5	0	2022
	acute kidney injury	5	0	2021
	autoimmune disease	5	0	2019

Melanoma was the first cancer to be treated with immunotherapy. From 2017 to 2023, the use of immunotherapy expanded to other cancer types, including non-small cell lung cancer, renal cell carcinoma, esophageal cancer, hepatocellular carcinoma, urothelial carcinoma, and breast cancer. Among the adverse events caused by PD-1/PD-L1 inhibitors, pneumonitis was the most frequent, while myasthenia gravis had the highest centrality.

Our study showed that the most commonly used PD-1 inhibitors were nivolumab, pembrolizumab, and camrelizumab, while atezolizumab and durvalumab were the most frequently used PD-L1 inhibitors. The incidence of adverse events was lower for PD-L1 inhibitors compared to PD-1 inhibitors, with the latter potentially causing more serious adverse events. This difference might be related to PD-L1 inhibitors preserving the PD-L2 pathway, which helps maintain local homeostasis of PD-L2 in macrophages. Additionally, combining PD-1/PD-L1 inhibitors with other therapies appears to be safer, with fewer serious adverse events observed. Combined strategies involving PD-1/PD-L1 inhibitors remain a key area of future research.

The keyword burst detection generated by CiteSpace analyzed the temporal distribution of keywords to identify terms that experienced rapid increases in frequency, helping researchers track the evolution of research hotspots, identify emerging topics, and explore the development trends in this field. Table 7 lists the keywords with the strongest citation bursts. From 2015 to 2017, meta-analysis, case reports, and reviews were research focal points, gradually shifting to reviews and phase I clinical trials. In 2017, “diagnosis and management” emerged, indicating that the management of PD-1/PD-L1-related events was being systematically studied. The range of cancers being studied expanded from metastatic melanoma and non-small cell lung cancer to include cervical cancer, hepatocellular carcinoma, and others. Adverse events that have been extensively studied over time include myasthenia gravis, neurologic complications, dermatologic toxicity, rheumatic irAEs, and neuromuscular complications. Current research hot topics include esophageal cancer, the use of atezolizumab combined with bevacizumab, and advanced lung cancer

Table 7.

Key words with the strongest citation bursts.

Co-occurring keywords analysis

From a timeline perspective, the keywords from 2014 to 2015 were mainly focused on terms such as CTLA-4, lung cancer, squamous cell carcinoma, ipilimumab, and metastatic melanoma. Between 2016 and 2019, the primary keywords shifted to dermatologic toxicity, cutaneous, case reports, chemotherapy, PD-L1 inhibitors, radiotherapy, combined nivolumab, nivolumab plus ipilimumab, and monotherapy. From 2021 to 2024, keywords like biomarkers, meta-analysis, immune-related adverse events, carcinoma, durvalumab, bevacizumab, and thyroid dysfunction became the focal points (Figure 8). This indicates that the use of immunosuppressants was increasingly combined with other treatment modalities, such as chemotherapy, radiotherapy, and targeted therapy. Additionally, the focus of cancer research expanded beyond lung cancer and melanoma to include a wider variety of cancers. Research on PD-1 and PD-L1 inhibitor-related adverse events evolved from case reports to clinical trials, with meta-analyses becoming more common. The clustering analysis resulted in 12 groups categorized by study type, cancer type, treatment modality, adverse reaction type, and outcome measures.

Figure 8.

Keyword clustering timeline view on PD-1 inhibitor and PD-L1 inhibitor’s adverse events studies. Lines represent keywords that appeared together. The purple circle represents an explosion in the number of the keywords.

The keywords contained within each cluster are presented in the supplementary document. Studies on the adverse events of PD-1 inhibitors and PD-L1 inhibitors mainly focused on clinical studies, and few animals or cell studies were concluded. The research types included retrospective studies, real-world studies, multicenter real-life retrospective portraits, prospective and retrospective cohort studies, prospective clinical trials, and clinical practice guidelines. The populations in these studies ranged from nationwide or district-level cohorts to single-center or multicenter investigations. There were also scattered case reports (such as individual cases, case-based reviews, and spontaneous reports), secondary studies (e.g., machine learning analyses, meta-analyses, reviews, and literature analyses), consensus statements, pharmacovigilance studies, visualized research, and sub-analyses of larger studies. In terms of treatment, in addition to PD-1/PD-L1 inhibitors, patients were also treated with chemotherapy, surgery, radiotherapy, tyrosine kinase inhibitors, and targeted therapies. The diseases studied were predominantly advanced solid-organ tumors and hematological malignancies, frequently described as unresectable advanced cancers, metastatic cancers, or refractory cancers. The tumor sites included the mucosa, lung, liver, kidney, bladder, urothelium, endometrium, esophagus, stomach, colorectum, mammary gland, lymph nodes, blood, and nasopharynx.

Common adverse events associated with PD-1/PD-L1 inhibitors involve toxicity across multiple systems and organs. These include cutaneous and mucosal toxicity, nervous system toxicity, cardiovascular toxicity, renal toxicity, hepatotoxicity, hematological toxicity, ocular toxicity, thyroid toxicity, pituitary complications, pulmonary toxicity, as well as pancreatic toxicity, gastrointestinal toxicities, adrenocortical hypofunction, neuromuscular toxicity, and systemic inflammation. Adverse events can be further categorized based on their timing, with acute toxicities and late-onset toxicities. Common acute toxicities include acute renal failure and acute neurological events. Keywords were also classified based on the severity of adverse events, such as grade III-IV toxicities and fatal adverse events. Severe or fatal reactions include severe neurological toxicity, multi-organ toxicity, and fatal gastrointestinal toxicity.

Keywords co-occurrence network

Keywords such as nivolumab, ipilimumab, safety, melanoma, toxicity, immunotherapy, immune-related adverse event, immune checkpoint inhibitor, and open-label studies have remained research hotspots from 2015 to 2024, highlighting their central role in the study of adverse event management in immunotherapy for malignant tumors. Nivolumab is closely associated with terms like immune-related adverse events and metastatic melanoma. Other significant burst keywords include nivolumab, ipilimumab, myasthenia gravis, squamous cell carcinoma, double-blind, bevacizumab, atezolizumab, single-arm studies, toxicity, and patient, indicating their prominence in this research field. The keywords co-occurrence network is depicted in Figure 9.

Figure 9.

Keywords co-occurrence network. The node size represents the frequency of keyword occurrence. The color of the outer ring and the lines between nodes represents the current year. The distance between nodes represents the strength of the relationship between keywords. The outermost purple ring of the node means that the keyword was suddenly cited in large numbers.

Current trends and future trends

The most significant current trends include the increasing number of clinical trials and guidelines, as well as the proposal of more biomarkers to monitor PD-1/PD-L1 inhibitor-related adverse events and predict their therapeutic effects. This reflects the ongoing efforts to make the management of PD-1/PD-L1-related adverse events more precise and standardized. Adverse events such as myasthenia gravis, neurological complications, dermatologic toxicity, rheumatic irAEs, and neuromuscular complications have remained key research areas and may lead to better treatment approaches in the future. As treatment options continue to evolve and new drugs are developed, PD-1/PD-L1 inhibitors are being used more effectively across a broader range of cancer types. For advanced and refractory cancers, such as esophageal cancer, advanced lung cancer, hepatocellular carcinoma, advanced melanoma, and renal cell carcinoma, newly approved PD-1/PD-L1 inhibitors and expanded applications of these therapies offer hope where effective treatment options are limited. Moreover, the onset of irAEs may serve as a clinical biomarker of ICI response. Patients who developed irAEs during treatment with PD-1 or PD-L1 inhibitors often experienced improved survival outcomes. Predictive biomarker studies have primarily focused on tumor characteristics, such as MSI status, tumor mutational burden, and PD-L1 expression.^34,35 However, a significant proportion of patients do not respond to these therapies, highlighting the need for prospective and comprehensive studies exploring the relationship between the characteristics of irAEs (e.g., site, severity, timing, and management) and the efficacy of ICIs.

To address the low responsiveness to PD-1/PD-L1 inhibitors, a promising approach involves combining these inhibitors with other anti-tumor agents that target different pathways to enhance the immunogenicity of the tumor microenvironment. Our study revealed that ICIs are frequently combined with other treatment modalities, including surgery, radiotherapy, tyrosine kinase inhibitors, and targeted therapies. The most common combination therapies involve either the use of two or more ICIs or the combination of ICIs with bevacizumab, with the pairing of atezolizumab and bevacizumab emerging as a key focus. Additionally, combination therapies with ICIs have demonstrated significant progress in treating NSCLC,^36,37 unresectable hepatocellular carcinoma,³⁰ and cervical cancer.³⁸ For example, the combination of anti – PD-L1 antibody with bevacizumab and chemotherapy has shown clinical benefits in patients with EGFR- or ALK-mutated NSCLC who have progressed following targeted therapy.³⁹ Moreover, ICIs are used in combination with chemotherapy and/or targeted therapies to treat NSCLC after resistance to EGFR mutation-targeted therapy.⁴⁰ This combination strategy offers new therapeutic options for patients with EGFR mutant NSCLC, especially those who exhibit a limited response to treatment with single-agent ICIs.

Conclusion

The investigation of adverse events induced by PD-1/PD-L1 inhibitors has gained increasing attention and continues to rise in prominence. Using CiteSpace, a visual network of citations related to PD-1/PD-L1 inhibitor adverse events was constructed, allowing us to discuss key clusters, established research models, and emerging trends. The research hotspots identified can be summarized as follows:

1. The USA played a central role in this field and demonstrated extensive collaboration with countries such as China, Italy, England, and Australia.

2. Nivolumab was the most commonly studied PD-1/PD-L1 inhibitor, while newly approved inhibitors still require more comprehensive research.

3. Publication types have gradually shifted from case reports and comprehensive reviews to clinical trials. There has been an increase in standardized clinical studies, including prospective and retrospective studies as well as multi-phase clinical trials. Additionally, biomarker studies related to PD-1/PD-L1 inhibitor adverse events have become more prevalent.

4. The spectrum of cancers treated by PD-1/PD-L1 inhibitors has expanded beyond melanoma and lung cancer to include a wide range of advanced, progressive, and refractory cancers, indicating the continued broadening of cancer types targeted by these therapies.

5. The study of PD-1/PD-L1 inhibitor-related adverse events has become increasingly refined and standardized.

6. Combined strategies involving PD-1/PD-L1 inhibitors remain a key area of future research.

In conclusion, this study offers valuable insights for potential collaborators and institutions, highlighting current trends in the study of adverse events associated with PD-1/PD-L1 inhibitors. As immunotherapy research progresses, the therapeutic scope of PD-1/PD-L1 inhibitors will continue to expand, treatment regimens will diversify, and the management of adverse events will become more refined and standardized – areas that are expected to be major focuses of future research.

Funding Statement

The study was supported by High Level Chinese Medical Hospital Promotion Project - Special Project on Formulation R&D and New Drug Translation for Medical Institutions (HLCMHPP2023037); High Level Chinese Medical Hospital Promotion Project - Special Project on Formulation R&D and New Drug Translation for Medical Institutions [HLCMHPP2023037] and National Natural Science Foundation of China [82474354].

Disclosure statement

No potential conflict of interest was reported by the author(s).

Authors contributions

Qingya Song designed the research, and wrote the main part of manuscript. Zongliang Yu formulated the search strategy, wrote a part of the manuscript, and analyzed the data. Qingya Song and Zongliang Yu had made equal contributions to this manuscript. Zhili Zhuo contributed in part of the writing, modified and polished the article. Wenping Lu designed the research, supported the study, and contributed to the language modification and manuscript revision. Lei Chang and Heting Mei revised the manuscript. Yongjia Cui edited the figures and tables. Dongni Zhang contributed to reference search. All authors contributed to the article and approved the submitted version.

Data availability statement

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

Ethics approval and consent to participate

This study did not require ethical approval as publicly available data were analyzed.

Supplementary material

Supplemental data for this article can be accessed on the publisher’s website at https://doi.org/10.1080/21645515.2024.2424611

The introduction of the corresponding author

Wenping Lu is a chief physician, professor, doctoral supervisor, and deputy director of oncology department at Guang’anmen Hospital of the China Academy of Chinese Medical Sciences. She is also a member of American Society of Clinical Oncology, a member of Chinese Clinical Oncology Society, and an evaluation expert of National Natural Science Foundation of China. Professor Lu specializes in both clinical and basic research on breast cancer and gynecological malignancies. As the responsible investigator , she has led numerous projects, including those funded by the National Natural Science Foundation of China, and has garnered numerous awards, such as the Second Prize of Beijing Science and Technology, the third prize of Science and Technology Progress of the State Administration of Traditional Chinese Medicine.