Past and present: a bibliometric study on the treatment of recurrent ovarian cancer

doi:10.21203/rs.3.rs-3583586/v1

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Past and present: a bibliometric study on the treatment of recurrent ovarian cancer

https://doi.org/10.21203/rs.3.rs-3583586/v1

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Background

Ovarian cancer (OC) is a gynecological malignancy with high mortality worldwide. The poor prognosis of OC is usually attributed to its recurrence-prone signature. Recently, mortality from OC has exhibited a downward trend. These favorable patterns likely find their main driving factor in advancements in novel therapeutic regimens. However, visualized analysis of the application of these new drugs on women with recurrent OC (ROC) is lacking. Therefore, we aimed to summarize changing paradigms in the ROC treatment using the bibliometric method.

Methods

Documents on ROC treatment were systematically collected from the MEDLINE database and Web of Science Core Collection (WOSCC). The retrieved documents were exported in the plain text file format, and files were named and saved to the paths specified by the Java application. Microsoft Excel (version 2010), Citespace (6.2.R4) and VOSviewer (1.6.19) were used for data analysis and included the following: (1) annual publication trend; (2) contributions of countries, institutions and authors; (3) co-citation of journals and references; and (4) co-occurrence of keywords.

Results

A total of 914 documents published in the MEDLINE and 9,980 ones in WOSCC were retrieved. There has been an upward trend in the productivity of publications on ROC treatment on by years. The United States was the leading contributor in this field, and the University of Texas System was the most productive institution. Giovanni Scambia and Maurie Markman were the research leaders for ROC treatment. Gynecologic Oncology was the journal with most citation frequency. The reference entitled with “Niraparib Maintenance Therapy in Platinum-Sensitive, Recurrent Ovarian Cancer” got highest centrality of 0.14 in the co-citation network. Keyword analysis indicated that current treatment of ROC mainly focused on the platinum-based anticancer drugs, paclitaxel, angiogenesis inhibitors (AIs) and poly (ADP-ribose) polymerase inhibitors (PARPis).

Conclusion

Scholars from all over the world have taken active part in the development of ROC treatment. International top journals and professional periodicals on gynecologic oncology have been the main sources of the hotspots and frontiers in this field. Maintenance treatment based on AIs or (and) PARPis has become an important adjunct to chemotherapy based on platinum agents and paclitaxel for ROC patients.

Recurrent ovarian cancer

Treatment

Bibliometrics

platinum-based chemotherapy

paclitaxel

angiogenesis inhibitors

poly (ADP-ribose) polymerase inhibitors

Ovarian cancer (OC) is a gynecological malignancy with high mortality worldwide. In China, the crude and age-standardized death rates of OC have risen to 9.49/100, 000 and 6.02/100, 000, and it has become the leading cause of death in the female reproductive tract tumors in urban areas of the country ¹. Likewise, the number of deaths caused by OC ranked five among all cancer types in women from the United States, and 13, 270 deaths are projected to occur for OC patients in 2023 ². The poor prognosis of OC is usually attributed to its recurrence-prone signature. Platinum-based chemotherapy has been the backbone of first-line treatment for advanced OC. However, 70% of tumors will recur within the first few years and eventually become platinum resistant ³. Non-platinum chemotherapy has been associated with low objective response rates and constantly shortened progress-free survival. This dismal destiny for patients with recurrent OC (ROC) has changed little in the past 3 decades.

Fortunately, mortality from OC exhibited a downward trend in recent years. Accelerated declines could be observed in OC mortality, from 2% per year to almost 4% per year from 2017 through 2020 ². The age-standardized OC death rate fall 6% to 4.3/100, 000 in 2022, and it was predicted to continue doing so until 2025 at least ^4,5. These favorable patterns likely find their main driving factor in advancements in novel therapeutic regimens ⁵. So, it is necessary to figure out the efficacy of these new drugs on women with ROC and the changing paradigms in the treatment of ROC. Compared to the narrative reviews, the bibliometric review could comprehensively include related studies and provide quantitative results ⁶. Therefore, we aim to conduct a bibliometrics in this study to present the evolution and current status of ROC treatment, supplying the researchers with hotspots and frontiers in this field.

Data retrieval

We systematically searched for the documents about ROC treatment in the MEDLINE database via the Pubmed website (https://pubmed.ncbi.nlm.nih.gov/) and Web of Science Core Collection (WOSCC) (https://www.webofscience.com/wos/woscc/basic-search). The search formula in the study was shown as follow: (“ovarian cancer*” OR “ovarian neoplasm*” OR “ovarian carcinoma”) AND (“recurren*” OR “relapse*”) AND (“therap*” OR “treatment*” OR “management”). The publication date and document types were unrestricted, while the final search was performed on September 30, 2023. Only articles published in English were included. Two authors independently conducted the data retrieval. Discrepancies were solved through discussion and when needed a third researcher was consulted. Ethics approval and consent to participate were not applicable for the study, since we retrospectively searched the data from public databases.

Data export

The retrieved documents were exported in the format of plain text file. One file comprised 500 records, and each record included author (s), title, publication year, document source, abstract, addresses, affiliations, document type, keywords, cited references, and total citations. Files were named and saved to the paths specified by the Java application.

Data analysis

Microsoft Excel (version 2010), Citespace (6.2.R4) and VOSviewer (1.6.19) were used for data analysis. We recorded the numbers of published documents yearly and presented the annual publication trend via Microsoft Excel. Citespace was utilized to evaluate the contributions of countries, institutions and authors to the ROC treatment, as well as the co-citation of journals and references. The co-occurrence of keywords in the field was depicted in the forms of cluster analysis, hotspot distribution and evolution tendency by VOSviewer.

1. Annual publication trends

In the light of our search strategies, 914 documents on ROC treatment were collected in the MEDLINE database from 1960 to 2023 and 9,980 ones were retrieved in the WOSCC between 1977 and 2023. Figure 1A showed the distribution of the related documents over the past few decades. Generally, there has been an upward trend in the productivity of publications by years. Two distinct phases could be observed in the ascent process: a phase of steep growth from 1990 to 1999, and a phase of steady rise from 2000 to 2022. The trend indicated that researches on the ROC treatment looked to usher a favorable turn after a period of frustration. In terms of the document type, original articles accounted for above two thirds (65.02%) in the MEDLINE and almost three quarters (74.22%) in the WOSCC. The proportion of other types could be seen in the Fig. 1B and C.

2. The contributions of countries/regions in the research of ROC treatment

Scholars from 66 countries/regions published at least one paper related to the treatment of ROC. Figure 2 depicted the contributions of these countries and the connections among them. The top 10 countries/regions ranked by the number of publications were the U.S.A, China, Italy, England, Germany, Japan, France, Canada, Australia and Spain (Table 1). It is worth noting that the developed countries have made the major contributions to the publications, although China ranked second with 1120 records. In addition, the U.S.A and Italy achieved the highest centrality (0.08), followed by France and Australia (centrality = 0.06) (Table 1). These countries played a crucial role in making breakthroughs in this research field, and were regarded as bridges to convey the innovative spirit to others.

Table 1

The top 10 countries contributing to the research of ROC treatment
Rank	Country	Counts	Centrality	Year
1	The U.S.A	3499	0.08	1993
2	China	1120	0.01	2000
3	Italy	1065	0.08	1993
4	England	785	0.04	1993
5	Germany	785	0.02	1993
6	Japan	677	0.01	1993
7	France	588	0.06	1993
8	Canada	568	0.04	1993
9	Australia	402	0.06	1993
10	Spain	392	0.01	1997
ROC: recurrent ovarian cancer

2. The contributions of institutions in the research of ROC treatment

A total of 109 institutions were involved in the research of ROC treatment independently or by collaboration. Figure 3 portrayed the contributions of these organizations and the relations between each other. The top 10 institutions listed by the productivity of publications were University of Texas System, UT MD Anderson Cancer Center, Harvard University, French Research Universities (UDICE), University of California System, Memorial Sloan Kettering Cancer Center, University of London, Catholic University of the Sacred Heart, University of Toronto and Dana-Farber Cancer Institute (Table 2). Among the top 10 organizations, six were from USA, which reflected its great scientific strength in this area. However, the institution with highest centrality (0.13) was University of London from England, followed by University of California System (centrality = 0.12) and Harvard University (centrality = 0.11) (Table 2).

Table 2

The top 10 institutions contributing to the research of ROC treatment
Rank	Institution	Counts	Centrality	Year
1	University of Texas System	506	0.09	1994
2	UT MD Anderson Cancer Center	435	0.09	1995
3	Harvard University	426	0.11	1994
4	French Research Universities (UDICE)	302	0.08	1996
5	University of California System	280	0.12	1994
6	Memorial Sloan Kettering Cancer Center	271	0.08	1993
7	University of London	254	0.13	2004
8	Catholic University of the Sacred Heart	241	0.04	2003
9	University of Toronto	228	0.06	2000
10	Dana-Farber Cancer Institute	201	0.08	2001
ROC: recurrent ovarian cancer

3. The contributions of authors in the research of ROC treatment

The number of authors with more than 2 papers in the field of ROC treatment was 162. The contributions of these authors and the pattern of interactions among them were delineated in the Fig. 4. The top 10 authors with the most amounts of publications were Giovanni Scambia, Robert L Coleman, Jalid Sehouli, Amit M Oza, Domenica Lorusso, Ursula A Matulonis, Nicoletta Colombo, Carol Aghajanian, Ignace Vergote and Anna Fagotti (Table 3). Among them, 4 were from Italy, 3 from the U.S.A, 1 from Germany, 1 from Canada and 1 from Belgium. Researchers from developed countries were the backbone in the field, and Robert L Coleman from the U.S.A occupied the core position in the network (centrality = 0.07), followed by Giovanni Scambia from Italy (centrality = 0.06) and Ursula A Matulonis from the U.S.A (centrality = 0.05) (Table 3).

Table 3

The top 10 authors contributing to the research of ROC treatment
Rank	Author	Count	Centrality	Year
1	Giovanni Scambia	119	0.06	2011
2	Robert L Coleman	110	0.07	2010
3	Jalid Sehouli	84	0.03	2008
4	Amit M Oza	65	0.02	2015
5	Domenica Lorusso	51	0.01	2017
6	Ursula A Matulonis	45	0.05	2012
7	Nicoletta Colombo	42	0.03	2015
8	Carol Aghajanian	38	0.02	2015
9	Ignace Vergote	35	0.02	2013
10	Anna Fagotti	32	0.00	2018
ROC: recurrent ovarian cancer

4. The analysis of co-cited authors in the field of ROC treatment

In total, 253 authors were co-cited by multiple articles due to their excellent research achievements in the field of ROC treatment. The pattern of citation for these authors and their cooperation were showed in the Fig. 5. The top 10 authors with the most co-citations were Maurie Markman, Eric Pujade-Lauraine, Robert F Ozols, Andreas du Bois, Robert L Coleman, Robert A Burger, Rebecca L Siegel, Ignace Vergote, William P McGuire and Nicoletta Colombo (Table 4). They were all from developed countries, and 6 of them were from the U.S.A. Research findings from Maurie Markman were well recognized and widely cited by experts in the field, so he got the highest centrality (0.12) (Table 4). Andreas du Bois and Robert A Burger were tied for second (centrality = 0.08), and Ignace Vergote ranked third (centrality = 0.06) (Table 4).

Table 4

The top 10 co-cited authors in the field of ROC treatment
Rank	Co-cited Author	Count	Centrality	Year
1	Maurie Markman	1540	0.12	1993
2	Eric Pujade-Lauraine	1221	0.05	2011
3	Robert F Ozols	1006	0.04	1993
4	Andreas du Bois	975	0.08	2004
5	Robert L Coleman	967	0.05	2013
6	Robert A Burger	930	0.08	2006
7	Rebecca L Siegel	870	0.00	2010
8	Ignace Vergote	830	0.06	2001
9	William P McGuire	817	0.03	1993
10	Nicoletta Colombo	741	0.02	1999
ROC: recurrent ovarian cancer

5. The analysis of co-cited journals in the field of ROC treatment

There were 283 journals co-cited in the papers about the therapy of ROC. The number and time of citation of these journals could be found in the Fig. 6. The top 10 journals ordered by frequency of citation were the Gynecologic Oncology, the Journal of Clinical Oncology, the New England Journal of Medicine, the Cancer Research, the Annals of Oncology, the Clinical Cancer Research, the International Journal of Gynecological Cancer, the British Journal of Cancer, the Lancet and the Cancer (Table 5). Two of the 10 journals fell into OBSTETRICS & GYNECOLOGY category, 7 belonged to ONCOLOGY category and 2 were in the category of GENERAL MEDICINE. In addition, there were 2 journals with impact factors above 100.0 (the New England Journal of Medicine and the Lancet), 4 with impact factors between 10.0 and 100.0 (the Annals of Oncology, the Journal of Clinical Oncology, the Clinical Cancer Research and the Cancer Research) and 4 with impact factors below 10.0 (the Gynecologic Oncology, the International Journal of Gynecological Cancer, the British Journal of Cancer and the Cancer). Details could be seen in the Table 6. Remarkably, the focal point journal was the Cancer Research with a centrality score of 0.12, followed by the Gynecological Cancer (centrality = 0.06) and England Journal of Medicine (centrality = 0.04) (Table 5).

Table 5

The top 10 co-cited journals in the field of ROC treatment
Rank	Co-cited Journal	Count	Centrality	Year
1	Gynecologic Oncology	6927	0.06	1993
2	Journal of Clinical Oncology	6579	0.03	1993
3	New England Journal of Medicine	4606	0.04	1993
4	Cancer Research	4007	0.12	1993
5	Annals of Oncology	3974	0.03	1993
6	Clinical Cancer Research	3859	0.02	1997
7	International Journal of Gynecological Cancer	3812	0.01	1998
8	British Journal of Cancer	3543	0.03	1993
9	Lancet	3021	0.01	1993
10	Cancer	2995	0.02	1993
ROC: recurrent ovarian cancer

Table 6

The impact factors of the top 10 co-cited journals in the field of ROC
Rank	Co-cited Journal	IF 2022–2023	IF 5 years
1	Gynecologic Oncology	4.7	5.0
2	Journal of Clinical Oncology	45.3	37.6
3	New England Journal of Medicine	158.5	115.7
4	Cancer Research	11.2	13.0
5	Annals of Oncology	50.5	32.4
6	Clinical Cancer Research	11.5	12.5
7	International Journal of Gynecological Cancer	4.8	4.0
8	British Journal of Cancer	8.8	8.4
9	Lancet	168.9	118.1
10	Cancer	6.2	6.8
ROC: recurrent ovarian cancer; IF: impact factors

6. The analysis of co-cited references in the field of ROC treatment

Two hundred and fifteen papers were identified and cited as references in the studies focus on the ROC therapy. In the Fig. 7, the size of the nudes represented the frequency of citation, the color layer of the nodes indicated the year of citation, and the links between nodes denoted that the two references were both cited by the same paper. The top 10 references with most citations were listed in the Table 7. Among them, 5 were published on the New England Journal of Medicine, 2 were on the Lancet, 2 were on the CA-A Cancer Journal for Clinicians and 1 were on the Journal of Clinical Oncology. The publication time of the 10 most cited references ranged from 2011 to 2020. The themes and subjects of these references mainly centered on maintenance therapy based on the poly (ADP-ribose) polymerase inhibitors (PARPis) (e.g., olaparib, niraparib and rucaparib), the angiogenesis inhibitors (AIs) (e.g., bevacizumab), and cancer statistics. The clinical trial entitled with “Niraparib Maintenance Therapy in Platinum-Sensitive, Recurrent Ovarian Cancer” by Mansoor R Mirza et.al published on New England Journal of Medicine in 2016 got the central location in the co-citation network with the highest centrality of 0.14, which has ushered in a new era of therapy for ROC.

Table 7

The top 10 co-cited references in the field of ROC
Rank	Title	Count	Centrality	Journal	Year	First Author
1	Cancer Statistics, 2017	571	0.05	CA-A Cancer Journal for Clinicians	2017	Rebecca L Siegel
2	Maintenance Olaparib in Patients with Newly Diagnosed Advanced Ovarian Cancer	421	0.04	New England Journal of Medicine	2018	Kathleen Moore
3	Olaparib tablets as maintenance therapy in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT-Ov21): a double-blind, randomised, placebo-controlled, phase 3 trial	421	0.08	Lancet	2017	Eric Pujade-Lauraine
4	Niraparib Maintenance Therapy in Platinum-Sensitive, Recurrent Ovarian Cancer	382	0.14	New England Journal of Medicine	2016	Mansoor R Mirza
5	Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3): a randomised, double-blind, placebo-controlled, phase 3 trial	368	0.05	Lancet	2017	Robert L Coleman
6	Niraparib in Patients with Newly Diagnosed Advanced Ovarian Cancer	312	0.03	New England Journal of Medicine	2019	Antonio González-Martín
7	Olaparib plus Bevacizumab as First-Line Maintenance in Ovarian Cancer	286	0.02	New England Journal of Medicine	2020	Isabelle Ray-Coquard
8	Bevacizumab Combined With Chemotherapy for Platinum-Resistant Recurrent Ovarian Cancer: The AURELIA Open-Label Randomized Phase III Trial	286	0.10	Journal of Clinical Oncology	2014	Eric Pujade-Lauraine
9	Global Cancer Statistics 2018: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries	252	0.00	CA-A Cancer Journal for Clinicians	2018	Freddie Bray
10	Incorporation of Bevacizumab in the Primary Treatment of Ovarian Cancer	251	0.13	New England Journal of Medicine	2011	Robert A Burger
ROC: recurrent ovarian cancer

7. The analysis of co-occurrence keywords about ROC treatment

We totally screened out 2,777 terms about the treatment of ROC based on the minimum number of occurrences (10) and the relevance score (60%). To eliminate non-specialized vocabularies and classify specialized keywords in the same fields, cluster analysis was performed. Hence, the remaining keywords were sorted into five clusters, as showed in the Fig. 8A. The yellow cluster represented the combination therapy strategies based on the first-generation platinum-containing anticancer drug (cisplatin), the blue cluster served as combined modality therapy centered on the second- and third-generation platinum-based chemotherapeutic agents (carboplatin and oxaliplatin) and paclitaxel, the purple cluster mainly meant the attempts of hormonal treatment, such as tamoxifen, the red cluster primarily spoke of the induction of immunotherapy, including anti-PD-1, AIs (bevacizumab) and anti-protein kinase receptors (cediranib and pazopanib), and the green cluster standed for the maintenance therapy based on PARPis (niraparib and rucaparib). The density map in Fig. 8B indicated that although targeted therapy have gradually become a hot topic, cytotoxic drugs such as platinum agents and paclitaxel were still pivotal for the management of ROC. The overlay visualization in Fig. 8C depicted the evolution trends of keywords in this area over time, suggesting the transitions from cytotoxic agents to targeted therapy drugs. From the timeline view in the Fig. 8D, we found that bevacizumab and PARPis have become popular since 2010 and 2016, respectively, but close links with cytotoxic drugs implied the great value of classical chemotherapy in the treatment of ROC.

To our knowledge, this was the first bibliometric study to explore the developing trends and the frontiers on the ROC treatment. In this study, we provided a visual analysis of the global research status for ROC therapy from multiple perspectives of countries, institutions, journals, authors and keywords. We hoped these results could play roles on the therapeutic regimen design for ROC as reference and basis.

4.1 General information

According to the trends of annual publication, research on ROC treatment has seen constant growth in the past few decades, and the number of published documents is expected to continue to grow in 2023. The drastic increase of the studies in the field in 1990s might be associated with the US Food and Drug Administration (FDA) approval of paclitaxel treatment indication for ROC in 1992 ⁷. From then on, there has been a great deal of clinical trials about the efficacy of paclitaxel on the patients with advanced carcinoma of the ovary after failure of first-line or subsequent chemotherapy ⁸. For this reason, more agents such as 5-fluorouracil, leucovorin, merbarone and tamoxifen, were under evaluation in clinical investigations, but few patients in the population gained benefits ^9–11. Until 2005, Pfisterer et al. demonstrated that the combination of gemcitabine with carboplatin significantly prolonged progression-free survival (PFS) of patients with advanced OC that has relapsed at least 6 months after completion of platinum based therapy ¹², and resulted in the next accelerated FDA approval in 2006 ¹³. Subsequently, the success of targeted therapy in various solid tumors encouraged researchers in this field to introduce these non-cytotoxic agents into ROC treatment. The publications from 2010 to 2020, therefore, have been characterized by steady growth, and the development of ROC treatment got into a golden age with the application of AIs and PARPis.

4.2 Contributions of countries, institutions, and authors

Dozens of countries have invested a great deal of effort and resources in the field of ROC treatment, indicating that management of patients with ROC has becoming a tough problem worldwide. The U.S.A has become the biggest stronghold to support ovarian cancer patients against recurrence: It contributed to the most publications with highest betweenness centrality; six of the top 10 institutions carrying out research on ROC treatment were governed by the U.S.A; three authors and six co-cited authors in the ranking lists were American. China was the only developing countries among the top 10 countries with the most publications, since the government has noticed the yearly increased mortality of OC in this region ¹⁴ and granted more findings in this field. However, the central score was still very low for China, and no authors, institutions or references have been seen in the top 10 lists, suggesting that more original and innovative articles are needed urgently in this country. Other developed countries were centered on the U.S.A and Italy, which got the highest centrality of 0.08 as well, and cooperated closely with each other. For instance, Amit M Oza from Canada has participated in the ARIEL3 study conducted by Giovanni Scambia (Italy) and Robert L Coleman (the U.S.A) to evaluate the efficacy of rucaparib maintenance treatment for ROC ¹⁵.

4.3 Analysis of co-cited journals and co-cited references

By analyzing the co-cited journals and co-cited references with high citations, we could roughly identify the source of the hotspots in this field. In this study, we mainly focused on journals and references with top ten co-citations to comprehend the frontiers in the treatment of ROC.

In the top ten co-cited journals, 2 were journals related to gynecologic tumors (the Gynecologic Oncology and the International Journal of Gynecological Cancer, 6 were oncologic journals (the Journal of Clinical Oncology, the Cancer Research, the Annals of Oncology, the Clinical Cancer Research, the British Journal of Cancer and the Cancer), and 2 were general medical journal (the New England Journal of Medicine and the Lancet). To be specific, the Journal of Clinical Oncology and the Annals of Oncology focus with specific interest on clinical trials about the efficacy of various anti-cancer drugs, the Clinical Cancer Research and the British Journal of Cancer publish clinical and translational cancer research studies that bridge the laboratory and the clinic, the Cancer Research and the Cancer provide oncological studies on basic, preclinical, clinical, prevention and epidemiological research, the Gynecologic Oncology and International Journal of Gynecological Cancer are devoted to publications relevant to the etiology, mechanism, diagnosis, and treatment of gynecologic malignancies, and the New England Journal of Medicine and the Lancet are the two world’s leading medical journals delivering high-quality research. From the aims and scopes of the ten most cited journals, we could see the studies about the therapy of ROC involved in the novel fundamental and clinical research, such as the mechanism of platinum resistance, application of genomic alterations, combined chemotherapy and targeted therapy. In addition, the journal with the highest impact factor (IF) in 2022–2023 is the Lancet (168.9), followed by the New England Journal of Medicine (IF = 158.5).There are 2 journals with IF༞40.0 (the Annals of Oncology and the Journal of Clinical Oncology), 2 with IF༞10.0 (the Cancer Research and the Clinical Cancer Research) and 2 with IF༞5.0 (the British Journal of Cancer and the Cancer). The Gynecologic Oncology is the official publication of the Society of Gynecologic Oncology with the second highest centrality scores, and the International Journal of Gynecological Cancer is the official journal of the International Gynecologic Cancer Society and the European Society of Gynecological Oncology. These data suggested that the hotspots in the field of ROC treatment were primarily derived from the international top-tier journals or professional periodicals about gynecologic oncology.

The references which ranked first and ninth were statistical analysis about the incidence and mortality of global cancer, and their authors were famous cancer epidemiologists. However, their work seemed to not have much to do with our topic, since epidemiological characteristics of OC was deem to be cited into the “background” section of each manuscript. The earliest published paper among the top 10 citations was titled with “Incorporation of Bevacizumab in the Primary Treatment of Ovarian Cancer” issued on the New England Journal of Medicine in 2011. In this study, Burger et al. incorporated bevacizumab, an AI, into the standard front-line therapy, and found this combination prolonged the median progression-free survival by about 4 months in patients with newly diagnosed advanced ovarian cancer ¹⁶. Three years later, Pujade-Lauraine et al. provided evidence that bevacizumab potentiated the efficacy of chemotherapy for ROC from their AURELIA study ¹⁷, which has got 286 co-citations according to our statistical data. These studies have contributed to the approval of bevacizumab for the OC management in 2018. The left 6 of the 10 top co-cited documents were all clinical trials related to the PARPis. Mirza et al. firstly conducted a randomized, double-blind and phase 3 trial named NOVA to evaluate the efficacy of niraparib as maintenance treatment for women with ROC, and described the success of niraparib in significantly extending the PFS duration ¹⁸. Their paper has soon attracted broad attention, and gained highest central scores. The Journal “New England Journal of Medicine” even published an editorial commenting that PARPis have the potential to change the therapy of ovarian cancer in ways that have not been seen since the introduction of paclitaxel in 1993 according to the results from NOVA study ¹⁹. Later on, the SOLO-2 study and the ARIEL-3 study showed that both olaparib and rucaparib provided a significant PFS improvement in relapsed ovarian cancer patients ^15,20. Documents derived from these two clinical trials have been well recognized worldwide as well, and rank 3 and 5 in the top 10 co-cited references, respectively. Considering the encouraging results in recurrent ovarian cancer, researchers continued to integrate PARPis into the first-line chemotherapy. The second and sixth most popular references in Table 6 confirmed that patients with newly diagnosed advanced ovarian cancer could also benefit from olaparib and rucaparib ^21,22. In recent years, there has been growing interest in the combination of AIs and PARPis. In 2022, the FDA has approved olaparib plus bevacizumab as maintenance treatment for ovarian cancer based on the PAOLA-1 study ²³, which has been the seventh most cited reference in our analysis.

4.4 Analysis of the co-cited keywords

Through co-occurrence analysis, we could cluster the keywords in the research field, and observe their hotspots, evolution and connections between each other.

4.4.1 The platinum-based chemotherapy

The vocabulary entry “cisplatin” and “carboplatin” clustered in the yellow group and blue group in Fig. 8A suggested that platinum-based combination chemotherapy was vital to the management of ROC. Most patients would attain a remission with initial treatment of platinum-based regimens. After OC recurred, patients were mainly classified into platinum-sensitive and platinum-resistant types according to the platinum-free interval (PFI). Gynecologic Cancer InterGroup (GCIG) has declaimed that platinum-sensitive recurrent (PSR) patients with OC could be considered for platinum agents again ²⁴. The first-generation platinum-containing drug, cisplatin, has laid the groundwork for OC chemotherapy since it was approved by the FDA in 1978. Carboplatin and cisplatin were two closely related drugs. However, carboplatin, the newer of the two, was somewhat less toxic than cisplatin, and has been used increasingly as the front-line agent in clinical practice ⁸. Oxaliplatin, which was the third-generation platinum agent and lacked large-scale clinical trials for ovarian cancer, mainly applied based on the previous medication experiences. Single agents generally produced only partial responses, thus it has become standard practice to administer several agents in combination. At first, the preferred regimen consisted of either cisplatin or carboplatin along with alkylating agents ⁸, such as cyclophosphamide, ifosfamide and melphalan described in the yellow cluster. Currently, platinum plus paclitaxel/gemcitabine/doxorubicin have been recommended as the chemotherapy combination for ROC ²⁵. For platinum-resistant recurrent (PRR) patients with OC, it was reasonable to try hormonal therapy, as shown in the purple cluster, when platinum-free chemotherapy would have a limited chance of success and a high likelihood of toxicity.

4.4.2 The targeted therapy

Targeted therapy was defined as the use of small-molecule drugs or monoclonal antibodies specifically targeting molecules on tumor cells or their microenvironment to inhibit tumor growth or spread, such as AIs, immune checkpoint inhibitors (ICIs), and PARPis.

Considering the close association between vascular endothelial growth factor (VEGF) and OC, clinical studies on AIs have been conducting. In 2005, a 60 year old patient with advanced, recurrent and refractory serous carcinoma of ovary firstly received the intravenous infusion of bevacizumab, and benefited an objective durable response lasting at least 5 months ²⁶. Soon afterwards, the AURELIA study demonstrated that bevacizumab significantly increased the antitumor efficacy of paclitaxel in patients with recurrent platinum-resistant OC ¹⁷. For platinum-sensitive OC, bevacizumab plus chemotherapy also significantly improved the objective response rate (ORR) and PFS in the OCEANS study ²⁷. Therefore, bevacizumab has become the only AI approved for ROC treatment by the FDA, which explained why the vocabulary entry “bevacizumab” localized in the network centrality in our clustering analysis. However, efficacy of ICIs has been suboptimal on ROC. Matulonis has concluded that single-agent pembrolizumab, a drug marketed by Merck that targets the programmed cell death 1 (PD-1) receptor, showed only modest activity in patients with ROC in the KEYNOTE-100 study ²⁸.

Fortunately, the introduction of PARPis has modified the therapeutic landscape. Multiple large scale phase III trials have shown the benefits of PARPis for patients with ROC. The SOLO2 study evaluated olaparib tablet maintenance treatment in platinum-sensitive, relapsed OC patients with a germline BRCA (gBRCA) mutation who had received at least two lines of previous chemotherapy, and found that olaparib provided a significant PFS and overall-free survival (OS) improvement with no detrimental effect on quality of life ^20,29. The OPINION analysis confirmed that patients without a gBRCA mutation still could gain clinical benefits from maintenance olaparib ³⁰. Data from the NOVA trial indicated that the median duration of PFS was significantly longer among patients with platinum-sensitive, recurrent ovarian cancer those receiving niraparib, regardless of the presence or absence of gBRCA mutations or homologous recombination deficiency (HRD) status ¹⁸. The FZOCUS-2 study from China demonstrated that fuzuloparib maintenance therapy conferred a statistically significant and clinically meaningful improvement in PFS for patients with platinum-sensitive, recurrent ovarian cancer, regardless of germline BRCA 1/2 mutation ³¹. PARPis maintenance strategy has opened up a new paradigm for ROC treatment, and sheds light of hope to these patients who have borne “cureless” cancers.

4.4.3 Combination of platinum-based chemotherapy and targeted therapy

Although we could observe the evolutionary history of ROC treatment from platinum-based chemotherapy to targeted therapy represented as AIs and PARPis in Fig. 8B, traditional chemotherapeutic drugs including cisplatin, carboplatin and paclitaxel were still hotspots in this field from the density map of Fig. 8C. The close links between traditional chemotherapy and targeted therapy showed in the Fig. 8D indicated that the applications of novel molecular targeted agents were dependent on the combination of cytotoxic drugs. In 2022, the FDA has withdrawn the indications of 3 PARPis (olaparib, rucaparib and niraparib) for the treatment of patients with deleterious gBRCA mutation advanced ovarian cancer who have been treated with three or more prior lines of chemotherapy ³. These actions suggested that benefits from PARPis should establish on the response to the platinum-based chemotherapy, which was in line with our viewpoints.

This study surely has several limitations. Firstly, we only considered the MEDLINE database and the WOSCC as the document retrieval source, which could make for the loss of some articles. However, our study was sufficient enough to summarize the ROC treatment research, because more than 10,000 articles have been included. Secondly, lack of literature screen might lead to information redundancy. We have deleted irrelevant words before program analysis in the Citespace and VOSviewer software to minimize the deficiency. Thirdly, bibliometric tools based on machine learning and natural language processing might bring out some inevitable system errors. For example, the different authors might share the same name, especially for Chinese authors, which could result in the discrepancy of the data of the authors’ publications.

In summary, the bibliometrics results showed that the number of articles about ROC treatment in the world has been increasing yearly since 1990.Scholars from developed countries represented by the U.S.A and Italy and developing countries, especially China, took active part in the development of ROC treatment. International top journals and professional periodicals on gynecologic cancer issuing large-scale clinical trials have been the main sources of the hotspots and frontiers in this field. Maintenance treatment based on AIs or (and) PARPis has become an important adjunct to chemotherapy based on platinum agents and paclitaxel for ROC patients.

OC: Ovarian cancer; ROC: recurrent OC; WOSCC: Web of Science Core Collection; AIs: angiogenesis inhibitors; PARPis: poly (ADP-ribose) polymerase inhibitors; FDA: Food and Drug Administration; PFS: progression-free survival; IF: impact factor; PFI: platinum-free interval; PSR: platinum-sensitive recurrent; PRR: platinum-resistant recurrent; ICIs: immune checkpoint inhibitors; VEGF: vascular endothelial growth factor; PD-1: programmed cell death 1; gBRCA germline BRCA; OS: overall-free survival; HRD: homologous recombination deficiency.

Acknowledgements

We would like to express our appreciations to all researchers and clinicians devoting to the ROC treatment.

Authors’ contributions

Wen-wei Song and Miao-ling Li searched the database and prepared the figures and tables. Xiao-yuan Hao analyzed the data and drafted the manuscript. Yi Guo contributed to the study conception and critical revision of the manuscript. All authors have read and approved the final manuscript. As the corresponding author, Yi Guo had the final responsibility for the decision to submit the article for publication.

Funding

This work was supported by the Natural Science Foundation of Jiangsu Province (Grants No BK 20201013) and “Shuang-Chuang Doctor” Project of Jiangsu Province (Grant No. 2020204003).

Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

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No competing interests reported.

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Past and present: a bibliometric study on the treatment of recurrent ovarian cancer

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