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

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 [6‐9].

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.

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.

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.

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. For dynamic co-citation mapping, we divide the sample of 1626 articles into three sub-samples based on their publication year grouping in an expanding horizon. For instance, in this study, the first group includes articles published during 2000–2005, the second group during 2000–2010 and the final group during 2000–2019. Hereafter, these sub-sampled articles were analysed using co-citation. Typically, co-citation analyses can be of three types depending on the unit of analysis (1) journal co-citation, (2) author co-citation, and (3) document co-citation. 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.

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 [78‐80]. 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 [83‐86].

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].

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 peer-reviewed scientific literature such as Scopus and PubMed [87].

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.