A bibliometric review of oncolytic virus research as a novel approach for cancer therapy

Background In recent years, oncolytic viruses (OVs) have drawn attention as a novel therapy to various types of cancers, both in clinical and preclinical cancer studies all around the world. Consequently, researchers have been actively working on enhancing cancer therapy since the early twentieth century. This study presents a systematic review of the literature on OVs, discusses underlying research clusters and, presents future directions of OVs research. Methods A total of 1626 published articles related to OVs as cancer therapy were obtained from the Web of Science (WoS) database published between January 2000 and March 2020. Various aspects of OVs research, including the countries/territories, institutions, journals, authors, citations, research areas, and content analysis to find trending and emerging topics, were analysed using the bibliometrix package in the R-software. Results In terms of the number of publications, the USA based researchers were the most productive (n = 611) followed by Chinese (n = 197), and Canadian (n = 153) researchers. The Molecular Therapy journal ranked first both in terms of the number of publications (n = 133) and local citations (n = 1384). The most prominent institution was Mayo Clinic from the USA (n = 117) followed by the University of Ottawa from Canada (n = 72), and the University of Helsinki from Finland (n = 63). The most impactful author was Bell J.C with the highest number of articles (n = 67) and total local citations (n = 885). The most impactful article was published in the Cell journal. In addition, the latest OVs research mainly builds on four research clusters. Conclusion The domain of OVs research has increased at a rapid rate from 2000 to 2020. Based on the synthesis of reviewed studies, adenovirus, herpes simplex virus, reovirus, and Newcastle disease virus have shown potent anti-cancer activity. Developed countries such as the USA, Canada, the UK, and Finland were the most productive, hence, contributed most to this field. Further collaboration will help improve the clinical research translation of this therapy and bring benefits to cancer patients worldwide.


Background
Cancer is a dreadful disease and one of the leading causes of morbidity and mortality worldwide. According to the latest assessment on cancer's global burden of cancer by the International Agency for Research on Cancer (IARC) in September 2018, the number of cancer patients has risen by 18.1 million new cases, and 9.6 million deaths [1]. Some of the factors behind the growing cancer burden can be population growth and ageing, prevalent reasons linked to the socio-economic development, and improvement in medical diagnostic procedures. According to a recent study, among the continents, Asia accounted for almost fifty percent of new cases and more than half of the cancer death [2]. There are several therapeutic procedures for cancer treatment, including chemotherapy, radiotherapy, targeted therapy, surgery, stem cell transplant, hormone therapy, and precision medicine. The therapy protocol depends on the site and staging of cancer, patient profile, and availability, among other factors [3,4]. Most cancer treatment modules are reported to have adverse effects leading to unsatisfactory quality of life and death. Thus, research for new treatment options, limiting the adverse effects, improving life quality during and after treatment, and increasing the efficacy, is ongoing for several years [5]. Oncolytic virotherapy is one of the recent developments in the treatment of cancer.
Oncolytic viruses (OVs) are a novel treatment modality that uses natural or genetically modified (GM) viruses, which, upon infection, selectively replicate and kill neoplastic cells without any severe effects on normal cells. Generally, OVs fall into two categories. The first category includes viruses that normally replicate rather in cancer tissue and are non-pathogenic in humans, such as, autonomous parvoviruses, Seneca Valley virus (SVV), myxoma virus, Reovirus (respiratory enteric orphan), and Newcastle disease virus (NDV). The other type includes viruses that are genetically engineered and/or genetically manipulated, such as vaccinia virus, poliovirus, adenovirus, measles virus, vesicular stomatitis virus (VSV), herpes simplex virus (HSV), and Zika virus [6][7][8][9].
There are several studies on OVs and their applications. In the present study, we use the bibliometric analysis method to examine the growth of studies on OVs. We extract bibliography data from the Web of Science (WoS) database from 2000 to March 2020. This study maps the overall research domain on the application of OVs as cancer therapy and extracts future research directions to guide further development in the field.

Review of bibliometric studies
Bibliometric analysis refers to the study of bibliographic information on published articles. As bibliometric analysis relies on statistical methods, it has emerged as a useful tool to assess the scientific publications in terms of quality and credibility. One of the most common bibliometric tools is the number of citations, which indicates the number of times an article has been cited by other articles. This method aims to identify the most impactful authors, institutions, countries, and journals within a defined subject area.
Studies using bibliometric analysis tools are common in the field of medical studies. For instance, Zou et al. [10] conducted the first study of OVs using data from January 2000 to December 2018; whereas, this study will broaden the coverage up to two more years (data until March 2020). The previous study listed impactful journal, author, country and institutions. In addition to these, this study contributes by mapping the intellectual structure of the field through dynamic co-citation analysis. Unlike the present study, previous studies focused only on the type of cancer diseases [11], prevention of cancer [12], basic epidemiologic methods [13], and some ecologic studies [14,15] focusing only on a specific country [14,15], community, or neighbourhood. This study will help oncologists deepen their understanding of the ongoing application of oncolytic viruses in cancer patients worldwide.

Methodology
On March 2020, the literature search was conducted for relevant articles on the WoS database with the Boolean operator (("Oncolytic virus*" OR "Oncolytic virotherap*") AND "Cancer")). The search resulted in 2529 articles, which were further refined to 1653 articles after excluding review studies (675), proceedings (28), meeting abstracts (80), editorial materials (66), book chapters (17), corrections (4), news items (4) and letters (2). Limiting only to the English language, the articles reduced to 1646 by excluding German (3), Chinse (2), and French (2). We manually reviewed the titles and abstracts of 1646 articles for relevance to our topic of interest and excluded 20 articles. Thus, the final sample for bibliometric analysis included 1626 articles published in 346 academic journals written by 7093 authors during the period of 2000-2020. Figure 1 presents the four steps filtering process. Once the sample was determined, we proceeded with citation and co-citation analysis using the Bibliometrix package [16] in the R-software. Only 32 articles were written by single authors, and on average, each article has 8.17 co-authors. In this study, we analyse previously published data and therefore did not need ethical approval.

Publication trends
The Bibliometric analysis method is useful in recognizing publication and citation trends in a field of study. As shown in Fig. 2a During this period two drugs, Talimogene laherparepvec (T-Vec) and Oncorine (H101), were approved by the US Food and Drug Administration (FDA) and the China FDA [17] and some OVs entered Phase III clinical trials.
Meanwhile, Fig. 2b reports Total Local Citations (TLCs) and Total Global Citations (TGCs). TLCs indicate citations received by the sample of 1626 studies, and TGC indicates citations by all records indexed by WoS. The trends in both TLC and TGC are identical and show an overall lower citation in recent years. This is logical as it takes time for an article to make an impact and get citations after publication.

Top journals
The top academic journals, based on both the number of publications and the TLCs, are reported in Table 1

Top institutions
The top 20 contributing institutions in OVs research are presented in Table 2 Table 3 Table 4 presents the top 20 locally cited articles in OVs research during 2000-2020. The ranking is based on the total local citations per year (TLC/t). The table also presents total global citation per year (TGC/t), list of journals publishing the most impactful articles, and their cited reference. Step-by-step literature search process Table 4, the most highly cited article was published in the journal Cell in 2017 by Ribas et al. [18] and topped the lists of TLC/t (14.  Table 4 some journals including Cancer Cell, Journal of Clinical Oncology, Cancer Immunology Research, Journal of Clinical Investigation, Cell, Cancer Research, and Mayo Clinic proceedings, have published one of the top articles. Also, four articles had authors only from the USA; one article had just one country contribution authors such as Canada, Israel, and Finland. The remaining 13 articles had authors from more than two countries, meaning they resulted from international cooperation.

Intellectual structure of the research domain
In this study, we use dynamic co-citation method for mapping the intellectual structure of the OVs research field. When two or more articles are cited together by other articles, they are called co-cited [37]. Co-cited articles are likely to share the same concepts as they were cited together by other studies. Hence, co-citation analysis allows us to map the intellectual structure of a research domain. Co-citation can also recognize knowledge networks and demonstrate their thematic progress over time, which we call dynamic co-citation. Hereafter, these sub-sampled articles were analysed using cocitation. Typically, co-citation analyses can be of three types depending on the unit of analysis (1) journal cocitation, (2) author co-citation, and (3) document cocitation. In this study, we conduct document co-citation network analyses. This approach helps to identify the growth and knowledge development of the OVs research over time. Figure 3 presents the change in the intellectual structure of the research field over time. In Fig. 3a, b and c, the number of documents analysed were 130, 469, and 1626, respectively. On the figures, each node represent an article. The size of the node presents the number of citations that the articles received. The line's thickness represents the strength of co-citations ties. The link and proximity between two items identify the co-citation relationship. The colour of the node indicates the associated cluster of an article. Each node was specified by the first author name and publication year of the article. Association strength normalisation algorithm has been used in the    Bibliometrix package to identify the clusters. Documents that are more often cited together are more likely to have a similar research topic, documents within the same cluster have a solid co-citation relationship and tend to portion similar research focus or theoretical basis.

OVs intellectual structure during 2000-2005
As shown in Fig. 3a, the green cluster is one of the strongest among the three with 28 papers. In this cluster, Bischoff et al. [38], and Khuri et al. [39] had a stronger co-citation link. These articles report that several viruses have been engineered as oncolytic viruses. Bischoff et al. [38] reported adenovirus as one of the oncolytic viruses that is useful in treating human cervical carcinoma. They also reported the dl1520 (Onyx-015) is the first genome modified Conditionally Replicative Adenoviruses based on human adenovirus type 2/5 chimaera. Meanwhile, Khuri et al. [39] confirmed that the OXYN-15, the E1B-55 kDa gene-deleted adenovirus, showed an anti-cancer effect in head and neck cancer. On the other hand, the red cluster is significant in terms of total co-citation link strength. This cluster is organised by 15 documents. Markert et al. [40] have the greatest connection strength and a strong link with both Mineta et al. [41] and Martuza et al. [42]. A diversity of oncolytic viruses are being studied in clinical trials, including gene deletion mutants such as adenovirus, herpes simplex virus. HSV is one of the most important oncolytic viruses and is extensively studied as anti-tumour agents, both experimentally and clinically. In this context, Mineta et al. [41] reported that HSV-1 G207 is effective in treating brain tumour in BALB/c mice. For this purpose, G207 has deletions at γ 34.5 (RL1) loci and an insertion of the Escherichia coli lacZ gene. The lacZ gene insertion inactivates the ICP6 gene (UL39) that encodes the large subunit of ribonucleotide reductase. Also, the first phase clinical trials by Market et al. [40] reported that HSV-1 G207, which belongs to the second generation genetically engineered HSV-1 mutants, has been shown to be effective in the brain tumour therapy.
Finally, the blue cluster is the smallest among the three containing seven articles. Stojdl et al. [21] has reported for the first time that vesicular stomatitis virus (VSV), a replication-competent oncolytic virus, is sensitive to the interferon response and is tumour-specific, owing to the deficiency of antiviral interferon signalling pathways in tumour cells. It is recognized to preferentially infect and lyse a wide-range of cancerous cells in pre-clinical models and in patients. Also, Coffey et al. [43] reported that to infect a cell with human Reovirus (respiratory enteric orphan) the virus needs to have an activated Ras signalling pathway. Furthermore, they demonstrated that this virus may have applicability in the treatment of cancer such as glioblastoma.

Extended OVs intellectual structure during 2000-2010
In Fig. 3b, we examine the co-citation network of the second sub-sample studies published between 2000 and 2010. In comparison to Fig. 3a, the current figure has changes in cluster structures, although some remain stable. The blue cluster from Fig. 3a breaks down to two clusters in Fig. 3b-the red cluster with Stojdl et al. [21] at the centre and the green cluster with Coffey et al. [43] at the centre. The figure shows that the intellectual structure of the oncolytic viruses has extended and changed over time.
The green cluster contains nine documents about Reovirus, Newcastle disease virus, and Herpes simplex virus. All of these documents confirmed that Reovirus has potent activity against cancers such as colon cancer, breast cancer, ovarian cancer, and malignant gliomas in vitro, in vivo, and ex vivo. Hirasawa et al. [44] revealed that the use of systemic delivery of Reovirus agent concerning immune-suppressive drugs effectively prolongs animal survival. Pecora et al. [45] reported that in the first phase trial of PV701, a replication-competent strain of Newcastle disease virus can provide a novel and potentially important therapy for patients with solid tumours after intravenous administration. The blue cluster (identical to the red cluster in Fig. 3a) has ten documents and almost all of the articles in this cluster focus on the oncolytic herpes simplex virus. Markert et al. [40], Mineta et al. [41], Martuza et al. [42], and Rampling et al. [46] have more document cocitations when compared to other studies. These studies confirmed the use of herpes simplex virus (ICP 34.5 null mutant 1716) in patients.
The purple cluster (identical to the green cluster in Fig. 3a) contains 15 documents, and it represents influential papers on adenovirus during 2000-2010. In this cluster, Khuri et al. [39], and Bischoff et al. [33] have more co-citations compared to the other authors. Meanwhile, we observed that several researchers worked on adenovirus in different clinical trial phases such as Reid et al. [47] and Khuri et al. [39] on Phase I, and Nemunaitis et al. [48] Phase II. Moreover, in the current cluster, we found that four review articles, Kirn [49], Kirn et al. [50], Alemany et al. [51], and Chiocca [52] have noticeable documents co-citations. Kirn [49] surveyed all the clinical trials about dl1520 (Onyx-015), which is the first genetically engineered agent to test on humans with an E1B-55 gene deletion. On the other hand, Alemany et al. [51] revealed types of conditionally replicative adenoviruses (CRAds) used as oncolytic agents till now.
The red cluster represents influential studies on OVs during 2000-2010, and consists of 16 documents. The majority of documents focus on applying vesicular stomatitis virus in the case of in vitro and in vivo studies on tumour cell lines model. We have also found that other OVs such as HSV, Measles, Adenovirus, and Vaccinia are potent anti-cancer agents. From these articles, four review articles by Kirn et al. [50], Parato et al. [53], Aghi and Martuza [54], and Liu et al. [55] explained the type of clinical trials of OVs. Vähä-Koskela et al. [56] investigated some of the recent additions to the panel of OVs including yaba-like disease virus, avian adenovirus, myxoma virus, bovine herpesvirus 4 (BHV-4), foamy virus, echovirus type 1, saimiri virus, sendai virus, feline panleukopenia virus, and the non-human coronaviruses. Also, Wein et al. [57] reported using preclinical and clinical

New developments during 2000-2019
As shown in Fig. 3a, documents in all three clusters (Red, Blue, and Green) are about different oncolytic viruses in the tumour cells model. Since the development in genetic engineering at the start of the 1990s, use of engineered oncolytic viruses for cancer therapy have increased [42]. Figure 3b represents the change in the intellectual structure of the oncolytic viruses during this period. Finally, Fig. 3c focuses on the new developments in oncolytic viruses during 2000-2019.
As shown in Fig. 3c, the purple cluster is one of the strongest among others, with 16 documents. In this cluster, the majority of the documents repeat from Fig. 3a and b, except Toda et al. [58] and Freeman et al. [27]. Freeman et al. [27] revealed that the NDV-HUJ strain of Newcastle disease virus had shown good tolerability in phase I/II clinical trial for the treatment of glioblastoma multiforme (GBM), as well as other cancers. Also, the authors confirmed that lentogenic NDV strains should also be surveyed in patients with lower-grade gliomas. Todo et al. [58] reported the use of soluble B7-1 in the context of oncolytic HSV for immune gene therapy and is clinically suitable in in-situ cancer vaccination.
The red cluster has 14 documents and concentrates on HSV, NDV, and vaccinia virus. Six of the papers in this cluster explored the HSV. In this cluster, six review articles-Kelly and Russell [59], Harrington et al. [60], Russell et al. [61], Lichty et al. [62], Miest and Cattaneo [63], and Kaufman et al. [64] had the most document cocitation. Russell et al. [61] and Andtbacka et al. [65] were the most co-cited studies of this cluster. Russell et al. [61] reported that oncolytic virotherapy is a novel therapeutic modality that uses replication-competent viruses against cancers. Additionally, Andtbacka et al. [65] revealed that T-VEC is the first oncolytic immunotherapy to display therapeutic profit against melanoma in phase III clinical trial. Also, it can represent a potential advance treatment for patients with injectable metastatic melanoma. However, in the current cluster, all of the documents are new document in co-citation, and these documents do not include in Fig. 3a or b. During this period (2000-2019) some development includes-the possibility of a singleshot virotherapy treatment, recognition of new drugs to speed up intratumoral virus diffusion, augmentation of the immunotherapeutic action of OVs, and clinical confirmation of a critical threshold of virus in the blood for vascular delivery and virus replication within the tumour [61].
The green cluster contains 11 documents among which some repeats from Fig. 3b except Obuchi et al. [66], Lichty et al. [67], Breitbach et al. [23], and Prestwich et al. [30]. Out of 11 documents, four are review studies. These studies surveyed three phases of the clinical trial of oncolytic viruses in different tumour cell models. Lichty et al. [67] described VSV as a therapeutic oncolytic virus. On the other hand, Prestwich et al. [30] discussed Reovirus as it generates adaptive antitumor immunity in vitro and in vivo studies. Additionally, Breitbach et al. [23] revealed that unappreciated and unanticipated interaction between VSV and vaccinia virus, and inflammatory response in the tumour.
The last cluster is the blue one with nine articles out of which five are review studies. This cluster consists of new studies except McCart et al. [68]. Liu and Kirn [69], Liu and Kirn [70], and Cttaneoet al. [71] reviewed some phases of the clinical trial of oncolytic viruses in different tumour cell models. Thorne [72] discussed oncolytic viruses, eukaryotic cells, and attenuated bacteria and the mechanisms to deliver them systemically to tumours, including in case of micro metastases. In this cluster, other studies by McCart et al. [68], Zhang et al. [73], and Park et al. [74] were focused on the oncolytic Poxviridae family. Moreover, for the first time, Breitbach et al. [75] reported that VSV is able to infect tumour neovasculature in vivo, but normal tissue vascular endothelium is resistant to the virus infection.

Discussion
This study discusses a diversity of OVs that has potential for types of anti-cancer therapy. Since its development, genetically engineered OVs are studied as a suitable alternative to non-engineered viruses (wild-type). As cancer therapy field has changed, OVs have an improved therapeutic index. Although the accumulated data has impressive recent development in cancer therapy using oncolytic viruses, it is prevented at many levels and may require assistance to reach full efficacy. Several studies also reported that oncolytic virotherapy could be utilised for antitumor treatment through different combination strategies such as chemotherapy, radiotherapy, systemic immunotherapies, etc. [7,56,76,77]. This combination has resulted in enhance apoptosis induction and showed significant result in a wide range of tumour models. Most popular drugs that fall into the classes are cyclophosphamide (CPA) doxorubicin, camptothecin (CPT), 5-fluorouracil (5-FU), ganciclovir (GCV), cisplatin, mitomycin C (MMC), paclitaxel, carboplatin, rapamycin, rituximab, and docetaxel [78][79][80]. Additionally, Vähä-Koskela et al. [56] reported OVs such as adenovirus in combination with chemotherapy, have been confirmed as a standard therapy to treat refractory nasopharyngeal cancer in China.
During the last decade, the fast extension of global OVs research resulted in benefits to the population. Son et al. [81] revealed the combination of OVs with various therapies leads to improved infection efficiency and increased antitumor effects. They suggested that the cytopathic effects of measles and mumps viruses' combination (MM) can improve the antitumor activity and tumour cell killing in vitro and in vivo. For further research, the study proposed explaining the ability of the antitumor reactions of oncolytic viruses and combination. Moreover, the recent study by Al-Shammari et al. [82] confirmed that combination therapy of oncolytic Newcastle disease virus and ribes rhizomes extract enhanced the anticancer activity. Interestingly, the study proposes the combination of OVs with herbal therapy which may result in novel anticancer therapy. Several studies measured the treating advantage of radionuclide therapy in combination with oncolytic viruses and external beam radiotherapy. The results showed that OVs combined with expressing the sodium iodide symporter (NIS) in various tumour models could restrict tumour growth and increase survival [83][84][85][86].
As shown in Table 4, North America, including the USA and Canada, has a strong effect on the oncolytic virus research, while European institutions, including the UK, Germany, and Finland, also play a prominent role. Demir et al. [87] revealed that countries with significant economic potency such as United States, Japan, the United Kingdom, Canada, Australia, and China could be the most impactful in terms of the number of publications which is in line with our results.
The USA, being the leading high-tech power upon the offset of the Second World War, leads many global research arenas. Such an issue was also considered in our study in terms of the numbers of articles, institutions, and scientists, showing that USA scientists have contributed greatest influence on virotherapy advancement. The science and technology operational impact policy, the rich financial support was driven from public foundations and private enterprises, and the implementation of new or better devices developed in the USA serves as the potential bases for the USA's most considerable contribution [88].

Limitation
The first publication regarding OVs' role in clinical or preclinical studies, was published in 1912 [59]. The database used in this study, WoS, only list publications from 1980 which left behind previous studies. But as a novel therapy, most development in OVs has occurred recently; therefore, recent studies would give a better overview of the current state of the study domain. This study did not cover scientific literature from Scopus and PubMed, and only journals with an impact factor (IF) are indexed in the WoS database. While this exclude studies published in the journals without an IF, eventually results a review of only high-quality studies. Moreover, studies confirmed the use of only the WoS for the bibliometric study exerts more reliable results than other databases of peerreviewed scientific literature such as Scopus and PubMed [87].

Conclusion
This study provides a holistic review of the present body of literature focusing on oncolytic viruses as one of the potential therapies in cancer treatment. This review maps the intellectual structure development of OV research during 2000 to 2020 using dynamic co-citation analysis. From the content analysis of the most co-cited studies, adenovirus, herpes simplex virus, Reovirus, and Newcastle disease virus have shown potent activity on the treatment of several cancer types. Based on citation analysis, the developed countries were the most productive in publications on OVs. Conducting multinational research studies would help other countries to enter into the research domain and get the possible benefit. The findings of this bibliometric review provide beneficial knowledge for clinicians, especially for oncologists and researchers, for exploring OVs considering development trends.