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  • Published: 11 March 2021

Evaluating cancer research impact: lessons and examples from existing reviews on approaches to research impact assessment

  • Catherine R. Hanna   ORCID: orcid.org/0000-0002-0907-7747 1 ,
  • Kathleen A. Boyd 2 &
  • Robert J. Jones 1  

Health Research Policy and Systems volume  19 , Article number:  36 ( 2021 ) Cite this article

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Performing cancer research relies on substantial financial investment, and contributions in time and effort from patients. It is therefore important that this research has real life impacts which are properly evaluated. The optimal approach to cancer research impact evaluation is not clear. The aim of this study was to undertake a systematic review of review articles that describe approaches to impact assessment, and to identify examples of cancer research impact evaluation within these reviews.

In total, 11 publication databases and the grey literature were searched to identify review articles addressing the topic of approaches to research impact assessment. Information was extracted on methods for data collection and analysis, impact categories and frameworks used for the purposes of evaluation. Empirical examples of impact assessments of cancer research were identified from these literature reviews. Approaches used in these examples were appraised, with a reflection on which methods would be suited to cancer research  impact evaluation going forward.

In total, 40 literature reviews were identified. Important methods to collect and analyse data for impact assessments were surveys, interviews and documentary analysis. Key categories of impact spanning the reviews were summarised, and a list of frameworks commonly used for impact assessment was generated. The Payback Framework was most often described. Fourteen examples of impact evaluation for cancer research were identified. They ranged from those assessing the impact of a national, charity-funded portfolio of cancer research to the clinical practice impact of a single trial. A set of recommendations for approaching cancer research impact assessment was generated.

Conclusions

Impact evaluation can demonstrate if and why conducting cancer research  is worthwhile. Using a mixed methods, multi-category assessment organised within a framework, will provide a robust evaluation, but the ability to perform this type of assessment may be constrained by time and resources. Whichever approach is used, easily measured, but inappropriate metrics should be avoided. Going forward, dissemination of the results of cancer research impact assessments will allow the cancer research community to learn how to conduct these evaluations.

Peer Review reports

Cancer research attracts substantial public funding globally. For example, the National Cancer Institute (NCI) in the United States of America (USA) had a 2020 budget of over $6 billion United States (US) dollars. In addition to public funds, there is also huge monetary investment from private pharmaceutical companies, as well as altruistic investment of time and effort to participate in cancer research from patients and their families. In the United Kingdom (UK), over 25,000 patients were recruited to cancer trials funded by one charity (Cancer Research UK (CRUK)) alone in 2018 [ 1 ]. The need to conduct research within the field of oncology is an ongoing priority because cancer is highly prevalent, with up to one in two people now having a diagnosis of cancer in their lifetime [ 2 , 3 ], and despite current treatments, mortality and morbidity from cancer are still high [ 2 ].

In the current era of increasing austerity, there is a desire to ensure that the money and effort to conduct any type of research delivers tangible downstream benefits for society with minimal waste [ 4 , 5 , 6 ]. These wider, real-life benefits from research are often referred to as research impact. Given the significant resources required to conduct cancer research in particular, it is reasonable to question if this investment is leading to the longer-term benefits expected, and to query the opportunity cost of not spending the same money directly within other public sectors such as health and social care, the environment or education.

The interest in evaluating research impact has been rising, partly driven by the actions of national bodies and governments. For example, in 2014, the UK government allocated its £2 billion annual research funding to higher education institutions, in part based on an assessment of the impact of research performed by each institution in an assessment exercise known as the Research Excellence Framework (REF). The proportion of funding dependent on impact assessment will increase from 20% in 2014, to 25% in 2021[ 7 ].

Despite the clear rationale and contemporary interest in research impact evaluation, assessing the impact of research comes with challenges. First, there is no single definition of what research impact encompasses, with potential differences in the evaluation approach depending on the definition. Second, despite the recent surge of interest, knowledge of how best to perform assessments and the infrastructure for, and experience in doing so, are lagging [ 6 , 8 , 9 ]. For the purposes of this review, the definition of research impact given by the UK Research Councils is used (see Additional file 1 for full definition). This definition was chosen because it takes a broad perspective, which includes academic, economic and societal views of research impact [ 10 ].

There is a lack of clarity on how to perform research impact evaluation, and this extends to cancer research. Although there is substantial interest from cancer funders and researchers [ 11 ], this interest is not accompanied by instruction or reflection on which approaches would be suited to assessing the impact of cancer research specifically. In a survey of Australian cancer researchers, respondents indicated that they felt a responsibility to deliver impactful research, but that evaluating and communicating this impact to stakeholders was difficult. Respondents also suggested that the types of impact expected from research, and the approaches used, should be discipline specific [ 12 ]. Being cognisant of the discipline specific nature of impact assessment, and understanding the uniqueness of cancer research in approaching such evaluations, underpins the rationale for this study.

The aim of this study was to explore approaches to research impact assessment, identify those approaches that have been used previously for cancer research, and to use this information to make recommendations for future evaluations. For the purposes of this study, cancer research included both basic science and applied research, research into any malignant disease, concerning paediatric or adult cancer, and studies spanning nursing, medical, public health elements of cancer research.

The study objectives were to:

Identify existing literature reviews that report approaches to research impact assessment and summarise these approaches.

Use these literature reviews to identify examples of cancer research impact evaluations, describe the approaches to evaluation used within these studies, and compare them to those described in the broader literature.

This approach was taken because of the anticipated challenge of conducting a primary review of empirical examples of cancer research impact evaluation, and to allow a critique of empirical studies in the context of lessons learnt from the wider literature. A primary review would have been difficult because examples of cancer research impact evaluation, for example, the assessment of research impact on clinical guidelines [ 13 ], or clinical practice [ 14 , 15 , 16 ], are often not categorised in publication databases under the umbrella term of research impact. Reasons for this are the lack of medical subject heading (MeSH) search term relating to research impact assessment and the differing definitions for research impact. In addition, many authors do not recognise their evaluations as sitting within the discipline of research impact assessment, which is a novel and emerging field of study.

General approach

A systematic search of the literature was performed to identify existing reviews of approaches to assess the impact of research. No restrictions were placed on the discipline, field, or scope (national/global) of research for this part of the study. In the second part of this study, the reference lists of the literature reviews identified were searched to find empirical examples of the evaluation of the impact of cancer research specifically.

Data sources and searches

For the first part of the study, 11 publication databases and the grey literature from January 1998 to May 2019 were searched. The electronic databases were Medline, Embase, Health Management and Policy Database, Education Resources Information Centre, Cochrane, Cumulative Index of Nursing and Allied Health Literature, Applied Social Sciences Index and Abstract, Social Services Abstracts, Sociological Abstracts, Health Business Elite and Emerald. The search strategy specified that article titles must contain the word “impact”, as well as a second term indicating that the article described the evaluation of impact, such as “model” or “measurement” or “method”. Additional file 1 provides a full list of search terms. The grey literature was searched using a proforma. Keywords were inserted into the search function of websites listed on the proforma and the first 50 results were screened. Title searches were performed by either a specialist librarian or the primary researcher (Dr. C Hanna). All further screening of records was performed by the primary researcher.

Following an initial title screen, 800 abstracts were reviewed and 140 selected for full review. Articles were kept for final inclusion in the study by assessing each article against specific inclusion criteria (Additional file 1 ). There was no assessment of the quality of the included reviews other than to describe the search strategy used. If two articles drew primarily on the same review but contributed a different critique of the literature or methods to evaluate impact, both were kept. If a review article was part of a grey literature report, for example a thesis, but was also later published in a journal, the journal article only was kept. Out of 140 articles read in full, 27 met the inclusion criteria and a further 13 relevant articles were found through reference list searching from the included reviews [ 17 ].

For the second part of the study, the reference lists from the literature reviews were manually screened [ 17 ] ( n  = 4479 titles) by the primary researcher to identify empirical examples of assessment of the impact of cancer research. Summary tables and diagrams from the reviews were also searched using the words “cancer” and “oncology” to identify relevant articles that may have been missed by reference list searching. After removal of duplicates, 57 full articles were read and assessed against inclusion criteria (Additional file 1 ). Figure  1 shows the search strategy for both parts of the study according to the guidelines for preferred reporting items for systematic reviews and meta-analysis (PRISMA) [ 18 ].

figure 1

Search strategies for this study

Data extraction and analysis

A data extraction form produced in Microsoft ® Word 2016 was used to collect details for each literature review. This included year of publication, location of primary author, research discipline, aims of the review as described by the authors and the search strategy (if any) used. Information on approaches to impact assessment was extracted under three specific themes which had been identified from a prior scoping review as important factors when planning and conducting research impact evaluation. These themes were: (i) categorisation of impact into different types depending on who or what is affected by the research (the individuals, institutions, or parts of society, the environment), and how they are affected (for example health, monetary gain, sustainability) (ii) methods of data collection and analysis for the purposes of evaluation, and (iii) frameworks to organise and communicate research impact. There was space to document any other key findings the researcher deemed important. After data extraction, lists of commonly described categories, methods of data collection and analysis, and frameworks were compiled. These lists were tabulated or presented graphically and narrative analysis was used to describe and discuss the approaches listed.

For the second part of the study, a separate data extraction form produced in Microsoft ® Excel 2016 was used. Basic information on each study was collected, such as year of publication, location of primary authors, research discipline, aims of evaluation as described by the authors and research type under assessment. Data was also extracted from these empirical examples using the same three themes as outlined above, and the approaches used in these studies were compared to those identified from the literature reviews. Finally, a set of recommendations for future evaluations of cancer research impact were developed by identifying the strengths of the empirical examples and using the lists generated from the first part of the study to identify improvements that could be made.

Part one: Identification and analysis of literature reviews describing approaches to research impact assessment

Characteristics of included literature reviews.

Forty literature reviews met the pre-specified inclusion criteria and the characteristics of each review are outlined in Table 1 . A large proportion (20/40; 50%) were written by primary authors based in the UK, followed by the USA (5/40; 13%) and Australia (5/40; 13%), with the remainder from Germany (3/40; 8%), Italy (3/40; 8%), the Netherlands (1/40; 3%), Canada (1/40; 3%), France (1/40; 3%) and Iran (1/40; 3%). All reviews were published since 2003, despite the search strategy dating from 1998. Raftery et al. 2016 [ 19 ] was an update to Hanney et al. 2007 [ 20 ] and both were reviews of studies assessing research impact relevant to a programme of health technology assessment research. The narrative review article by Greenhalgh et al. [ 21 ] was based on the same search strategy used by Raftery et al. [ 19 ].

Approximately half of the reviews (19/40; 48%) described approaches to evaluate research impact without focusing on a specific discipline and nearly the same amount (16/40; 40%) focused on evaluating the impact of health or biomedical research. Two reviews looked at approaches to impact evaluation for environmental research and one focused on social sciences and humanities research. Finally, two reviews provided a critique of impact evaluation methods used by different countries at a national level [ 22 , 23 ]. None of these reviews focused specifically on cancer research.

Twenty-five reviews (25/40; 63%) specified search criteria and 11 of these included a PRISMA diagram. The articles that did not outline a search strategy were often expert reviews of the approaches to impact assessment methods and the authors stated they had chosen the articles included based on their prior knowledge of the topic. Most reviews were found by searching traditional publication databases, however seven (7/40; 18%) were found from the grey literature. These included four reports written by an independent, not-for-profit research institution (Research and Development (RAND) Europe) [ 23 , 24 , 25 , 26 ], one literature review which was part of a Doctor of Philosophy (Ph.D) thesis [ 27 ], a literature review informing a quantitative study [ 28 ] and a review that provided background information for a report to the UK government on the best use of impact metrics [ 29 ].

Key findings from the reviews: approaches to research impact evaluation

Categorisation of impact for the purpose of impact assessment

Nine reviews attempted to categorise the type of research impact being assessed according to who or what is affected by research, and how they are affected. In Fig.  2 , colour coding was used to identify overlap between impact types identified in these reviews to produce a summary list of seven main impact categories.

The first two categories of impact refer to the immediate knowledge produced from research and the contribution research makes to driving innovation and building capacity for future activities within research institutions. The former is often referred to as the academic impact of research. The academic impact of cancer research may include the knowledge gained from conducting experiments or performing clinical trials that is subsequently disseminated via journal publications. The latter may refer to securing future funding for cancer research, providing knowledge that allows development of later phase clinical trials or training cancer researchers of the future.

The third category identified was the impact of research on policy. Three of the review articles included in this overview specifically focused policy impact evaluation [ 30 , 31 , 32 ]. In their review, Hanney et al. [ 30 ] suggested that policy impact (of health research) falls into one of three sub-categories: impact on national health policies from the government, impact on clinical guidelines from professional bodies, and impact on local health service policies. Cruz Rivera and colleagues [ 33 ] specifically distinguished impact on policy making from impact on clinical guidelines, which they described under health impact. This shows that the lines between categories will often blur.

Impact on health was the next category identified and several of the reviews differentiated health sector impact from impact on health gains. For cancer research, both types of health impact will be important given that it is a health condition which is a major burden for healthcare systems and the patients they treat. Economic impact of research was the fifth category. For cancer research, there is likely to be close overlap between healthcare system and economic impacts because of the high cost of cancer care for healthcare services globally.

In their 2004 article, Buxton et al. [ 34 ] searched the literature for examples of the evaluation of economic return on investment in health research and found four main approaches, which were referenced in several later reviews [ 19 , 25 , 35 , 36 ]. These were (i) measuring direct cost savings to the health-care system, (ii) estimating benefits to the economy from a healthy workforce, (iii) evaluating benefits to the economy from commercial development and, (iv) measuring the intrinsic value to society of the health gain from research. In a later review [ 25 ], they added an additional approach of estimating the spill over contribution of research to the Gross Domestic Product (GDP) of a nation.

The final category was social impact. This term was commonly used in a specific sense to refer to research improving human rights, well-being, employment, education and social inclusion [ 33 , 37 ]. Two of the reviews which included this category focused on the impact of non-health related research (social sciences and agriculture), indicating that this type of impact may be less relevant or less obvious for health related disciplines such as oncology. Social impact is distinct from the term societal impact, which was used in a wider sense to describe impact that is external to traditional academic benefits [ 38 , 39 ]. Other categories of impact identified that did not show significant overlap between the reviews included cultural and technological impact. In two of the literature reviews [ 33 , 40 ], the authors provided a list of indicators of impact within each of their categories. In the review by Thonon et al. [ 40 ], only one (1%) of these indicators was specific to evaluating the impact of cancer research.

Methods for data collection and analysis

In total, 36 (90%) reviews discussed methods to collect or analyse the data required to conduct an impact evaluation. The common methods described, and the  strengths and weaknesses of each approach, are shown in Additional file 2 : Table S1. Many authors advocated using a mixture of methods and in particular, the triangulation of surveys, interviews (of researchers or research users), and documentary analysis [ 20 , 30 , 31 , 32 ]. A large number of reviews cautioned against the use of quantitative metrics, such as bibliometrics, alone [ 29 , 30 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 ]. Concerns included that these metrics were often not designed to be comparable between research programmes [ 49 ], their use may incentivise researchers to focus on quantity rather than quality [ 42 ], and these metrics could be gamed and used in the wrong context to make decisions about researcher funding, employment and promotion [ 41 , 43 , 45 ].

Several reviews explained that the methods for data collection and analysis chosen for impact evaluation depended on both the unit of research under analysis and the rationale for the impact analysis [ 23 , 24 , 26 , 31 , 36 , 50 , 51 ]. Specific to cancer research, the unit of analysis may be a single clinical trial or a programme of trials, research performed at a cancer centre or research funded by a specific institution or charity. The rationale for research impact assessment was categorised in multiple reviews under four headings (“the 4 As”): advocacy, accountability, analysis and allocation [ 19 , 20 , 23 , 24 , 30 , 31 , 32 , 33 , 36 , 46 , 52 , 53 ]. Finally, Boaz and colleagues found that there was a lack of information on the cost-effectiveness of research impact evaluation methods but suggested that pragmatic, but often cheaper approaches to evaluation, such as surveys, were least likely to give in depth insights into the processes through which research impact occurred [ 31 ].

Using a framework within a research impact evaluation

Applied to research impact evaluation, a framework provides a way of organising collected data, which encourages a more objective and structured evaluation than would be possible with an ad hoc analysis. In total, 27 (68%) reviews discussed the use of a framework in this context. Additional file 2 : Table S2 lists the frameworks mentioned in three or more of the included reviews. The most frequently described framework was the Payback Framework, developed by Buxton and Hanney in 1996 [ 54 ], and many of the other frameworks identified reported that they were developed by adapting key elements of the Payback framework. None of the frameworks identified were specifically developed to assess the impact of cancer research, however several were specific to health research. The unit of cancer research being evaluated will dictate the most suitable framework to use in any evaluation. The unit of research most suited to each framework is outlined in Additional file 2 : Table S2.

figure 2

Categories of impact identified in the included literature reviews

Additional findings from the included reviews

The challenges of research impact evaluation were commonly discussed in these reviews. Several mentioned that the time lag [ 24 , 25 , 33 , 35 , 38 , 46 , 50 , 53 , 55 ] between research completion and impact occurring should influence when an impact evaluation is carried out: too early and impact will not have occurred, too late and it is difficult to link impact to the research in question. This overlapped with the challenge of attributing impact to a particular piece of research [ 24 , 26 , 33 , 34 , 35 , 37 , 38 , 39 , 46 , 50 , 56 ]. Many authors argued that the ability to show attribution was inversely related to the time since the research was carried out [ 24 , 25 , 31 , 46 , 53 ].

Part II: Empirical examples of cancer research impact evaluation

Study characteristics.

In total, 14 empirical impact evaluations relevant to cancer research were identified from the references lists of the literature reviews included in the first part of this study. These empirical studies were published between 1994–2015 by primary authors located in the UK (7/14; 50%), USA (2/14; 14%), Italy (2/14; 14%), Canada (2/14; 14%) and Brazil (1/14; 14%). Table 2 lists these studies with the rationale for each assessment (defined using the “4As”), the unit of analysis of cancer research evaluated and the main findings from each evaluation. The categories of impact evaluated, methods of data collection and analysis, and impact frameworks utilised are also summarised in Table 2 and discussed in more detail below.

Approaches to cancer research impact evaluation used in empirical studies

Categories of impact evaluated in cancer research impact assessments

Several of the empirical studies focused on academic impact. For example, Ugolini and colleagues evaluated scholarly outputs from one cancer research centre in Italy [ 57 ] and in a second study looked at the academic impact of cancer research from European countries [ 58 ]. Saed et al. [ 59 ] used submissions to an international cancer conference (American Society of Clinical Oncology (ASCO)) to evaluate the dissemination of cancer research to the academic community, and Lewison and colleagues [ 60 , 61 , 62 , 63 ] assessed academic, as well as policy impact and dissemination of cancer research findings to the lay media.

The category of the health impact was also commonly evaluated, with particular focus on the assessment of survival gains. Life years gained or deaths averted [ 64 ], life expectancy gains [ 65 ] and years of extra survival [ 66 ] were all used as indicators of the health impact attributable to cancer research. Glover and colleagues [ 67 ] used a measure of health utility, the quality adjusted life year (QALY), which combines both survival and quality of life assessments. Lakdawalla and colleagues [ 66 ] considered the impact of both research on cancer screening and treatments, and concluded that survival gains were 80% attributable to treatment improvement. In contrast, Glover and colleagues [ 67 ] acknowledged the importance of improved cancer therapies due to research but also highlight the major impacts from research around smoking cessation, as well as cervical and bowel cancer screening. Several of these studies that assessed health impact, also used the information on health gains to assess the economic impact of the same research [ 64 , 65 , 66 , 67 ].

Finally, two studies [ 68 , 69 ] performed multi-dimensional research impact assessments, which incorporated nearly all of the seven categories of impact identified from the previous literature (Fig.  2 ). In their assessment of the impact of research funded by one breast cancer charity in Australia, Donovan and colleagues [ 69 ] evaluated academic, capacity building, policy, health, and wider economic impacts. Montague and Valentim [ 68 ] assessed the impact of one randomised clinical trial (MA17) which investigated the use of a hormonal medication as an adjuvant treatment for patients with breast cancer. In their study, they assessed the dissemination of research findings, academic impact, capacity building for future trials and international collaborations, policy citation, and the health impact of decreased breast cancer recurrence attributable to the clinical trial.

Methods of data collection and analysis for cancer research impact evaluation

Methods for data collection and analysis used in these studies aligned with the categories of impact assessed. For example, studies assessing academic impact used traditional bibliometric searching of publication databases and associated metrics. Ugolini et al. [ 57 ] applied a normalised journal impact factor to publications from a cancer research centre as an indicator of the research quality and productivity from that centre. This analysis was adjusted for the number of employees within each department and the scores were used to apportion 20% of future research funding. The same bibliometric method of analysis was used in a second study by the same authors to compare and contrast national level, cancer research efforts across Europe [ 58 ]. They assessed the quantity and the mean impact factor of the journals for publications from each country and compared this to the location-specific population and GDP. A similar approach was used for the manual assessment of 10% of cancer research abstracts submitted to an international conference (ASCO) between 2001–2003 and 2006–2008 [ 59 ]. These authors examined if the location of authors affected the likelihood of the abstract being presented orally, as a face-to-face poster or online only.

Lewison and colleagues, who performed four of the studies identified [ 60 , 61 , 62 , 63 ], used a different bibliometric method of publication citation count to analyse the dissemination, academic, and policy impact of cancer research. The authors also assigned a research level to publications to differentiate if the research was a basic science or clinical cancer study by coding the words in the title of each article or the journal in which the paper was published. The cancer research types assessed by these authors included cancer research at a national level for two different countries (UK and Russia) and research performed by cancer centres in the UK.

To assess policy impact these authors extracted journal publications from cancer clinical guidelines and for media impact they looked at publications cited in articles stored within an online repository from a well-known UK media organisation (British Broadcasting Co-operation). Interestingly, most of the cancer research publications contained in guidelines and cited in the UK media were clinical studies whereas a much higher proportion published by UK cancer centres were basic science studies. These authors also identified that funders of cancer research played an critical role as commentators to explain the importance of the research in the lay media. The top ten most frequent commentators (commenting on > 19 media articles (out of 725) were all representatives from the UK charity CRUK.

A combination of clinical trial findings and documentary analysis of large data repositories were used to estimate health system or health impact. In their study, Montague and Valentim [ 68 ] cited the effect size for a decrease in cancer recurrence from a clinical trial and implied the same health gains would be expected in real life for patients with breast cancer living in Canada. In their study of the impact of charitable and publicly funded cancer research in the UK, Glover et al. [ 67 ] used CRUK and Office for National Statistics (ONS) cancer incidence data, as well as national hospital databases listing episodes of radiotherapy delivered, number of cancer surgeries performed and systemic anti-cancer treatments prescribed, to evaluate changes in practice attributable to cancer research. In their USA perspective study, Lakdawalla et al. [ 66 ] used the population-based Surveillance, Epidemiology and End Results Program (SEER) database to evaluate the number of patients likely to be affected by the implementation of cancer research findings [ 66 ]. Survival calculations from clinical trials were also applied to population incidence estimates to predict the scale of survival gain attributable to cancer research [ 64 , 66 ].

The methods of data collection and analysis used for economic evaluations aligned with the categories of assessment identified by Buxton in their 2004 literature review [ 34 ]. For example, three studies [ 65 , 66 , 67 ] estimated direct healthcare cost savings from implementation of cancer research. This was particularly relevant in one ex-ante assessment of the potential impact of a clinical trial testing the equivalence of using less intensive follow up for patients following cancer surgery [ 65 ]. These authors assessed the number of years it would take (“years to payback”) of implementing the hypothetical clinical trial findings to outweigh the money spent developing and running the trial. The return on investment calculation was performed by estimating direct cost savings to the healthcare system by using less intensive follow up without any detriment to survival.

The second of Buxton’s categories was an estimation of productivity loss using the human capital approach. In this method, the economic value of survival gains from cancer research are calculated by measuring the monetary contribution from patients surviving longer who are of working age. This approach was used in two studies [ 64 , 66 ] and in both, estimates of average income (USA) were utilised. Buxton’s fourth category, an estimation of an individual’s willingness to pay for a statistical life, was used in two assessments [ 65 , 66 ], and Glover and colleagues [ 67 ] adapted this method, placing a monetary value on the opportunity cost of QALYs forgone in the UK health service within a fixed budget [ 70 ]. One of the studies that used this method identified that there may be differences in how patients diagnosed with distinct cancer types value the impact of research on cancer specific survival [ 66 ]. In particular, individuals with pancreatic cancer seemed to be willing to spend up to 80% of their annual income for the extra survival attributable to implementation of cancer research findings, whereas this fell to below 50% for breast and colorectal cancer. Only one of the studies considered Buxton’s third category of benefits to the economy from commercial development [ 66 ]. These authors calculated the gain to commercial companies from sales of on-patent pharmaceuticals and concluded that economic gains to commercial producers were small relative to gains from research experienced by cancer patients.

The cost estimates used in these impact evaluations came from documentary analysis, clinical trial publications, real-life data repositories, surveys, and population average income estimates. For example, in one study, cost information from NCI trials was supplemented by using a telephone phone survey to pharmacies, historical Medicare documents and estimates of the average income from the 1986 US Bureau of the Census Consumer Income [ 64 ]. In their study, Coyle et al. [ 65 ] costed annual follow up and treatment for cancer recurrence based on the Ontario Health Insurance plan, a cost model relevant to an Ottawa hospital and cost estimates from Statistics Canada [ 71 ]. The data used to calculate the cost of performing cancer research was usually from funding bodies and research institutions. For example, charity reports and Canadian research institution documents were used to estimate that it costs the National Cancer Institute in Canada $1500 per patient accrued to a clinical trial [ 65 ]. Government research investment outgoings were used to calculate that $300 billion was spent on cancer research in the USA from 1971 to 2000, 25% of which was contributed by the NCI [ 66 ] and that the NCI spent over $10 million USD in the 1980s to generate the knowledge that adjuvant chemotherapy was beneficial to colorectal cancer patients [ 64 ]. Charity and research institution spending reports, along with an estimation of the proportion of funds spent specifically on cancer research, were used to demonstrate £15 billion of UK charity and public money was spent on cancer research between 1970 and 2009 [ 67 ].

Lastly, the two studies [ 68 , 69 ] which adopted a multi-category approach to impact assessment used the highest number and broadest range of methods identified from the previous literature (Additional file 2 : Table S1). The methods utilised included surveys and semi-structured telephone interviews with clinicians, documentary analysis of funding and project reports, case studies, content analysis of media release, peer review, bibiliometrics, budget analysis, large data repository review, and observations of meetings.

Frameworks for cancer research impact evaluation

Only two of the empirical studies identified used an impact framework. Unsurprisingly, these were also the studies that performed a multi-category assessment and used the broadest range of methods within their analyses. Donovan et al. [ 69 ] used the Payback framework (Additional file 2 : Table S2) to guide the categories of impact assessed and the questions in their researcher surveys and interviews. They also reported the results of their evaluation using the same categories: from knowledge production, through capacity building to health and wider economic impacts. Montague and Valentim [ 68 ] used the Canadian Academy Health Services (CAHS) Framework (Additional file 2 : Table S2). Rather than using the framework in it is original form, they arranged impact indicators from the CAHS framework within a hierarchy to illustrate impacts occurring over time. The authors distinguished short term, intermediate and longer-term changes resulting from one clinical cancer trial, aligning with the concept of categorising impacts based on when they occur, which was described in one of the literature reviews identified in the first part of this study [ 33 ].

Lastly, the challenges of time lags and attribution of impact were identified and addressed by several of these empirical studies. Lewison and colleagues tracked the citation of over 3000 cancer publications in UK cancer clinical guidelines over time [ 61 ], and in their analysis Donovan et al. [ 69 ] explicitly acknowledged that the short time frame between their analysis and funding of the research projects under evaluations was likely to under-estimate the impact achieved. Glover et al. [ 67 ] used bibliometric analysis of citations in clinical cancer guidelines to estimate the average time from publication to clinical practice change (8 years). They added 7 years to account for the time between funding allocation and publication of research results giving an overall time lag from funding cancer research to impact of 15 years. The challenge of attribution was addressed in one study by using a time-line to describe impacts occurring at different time-points but linking back to the original research in question [ 68 ]. The difficultly of estimating time lags and attributing impact to cancer research were both specifically addressed in a companion study [ 72 ] to the one conducted by Glover and colleagues. In this study, instead of quantifying the return on cancer research investment, qualitative methods of assessment were used. This approach identified factors that enhanced and accelerated the process of impact occurring and helped to provide a narrative to link impacts to research.

This study has identified several examples of the evaluation of the impact of cancer research. These evaluations  were performed over three decades, and mostly assessed research performed in high-income countries. Justification for the approach to searching the literature used  in this study is given by looking at the titles of the articles identified. In only 14% (2/14) was the word “impact” included, suggesting that performing a search for empirical examples of cancer research impact evaluation using traditional publication databases would have been challenging. Furthermore, all the studies identified were included within reviews of approaches to research impact evaluation, which negated the subjective decision of whether the studies complied with a particular definition of research impact.

Characteristics of research that were specifically relevant to cancer studies can be identified from these impact assessments. Firstly, many of these evaluations acknowledged the contribution of both basic and applied studies to the body of cancer research, and several studies categorised research publications based on this distinction. Second, the strong focus on health impact and the expectation that cancer research will improve health was not surprising. The focus on survival in particular, especially in economic studies looking at the value of health gains, reflects the high mortality of cancer as a disease entity. This contrasts with similar evaluations of musculoskeletal or mental health research, which have focused on improvements in morbidity [ 73 , 74 ]. Third, several studies highlighted the distinction between research looking at different aspects of the cancer care continuum; from screening, prevention and diagnosis, to treatment and end of life care. The division of cancer as a disease entity by the site of disease was also recognised. Studies that analysed the number of patients diagnosed with cancer, or population-level survival gains, often used site-specific cancer incidence and other studies evaluated research relating to only one type of cancer [ 64 , 65 , 68 , 69 ]. Lastly, the empirical examples of cancer research impact identified in this study confirm the huge investment into cancer research that exists, and the desire by many research organisations and funders to quantify a rate of return on that investment. Most of these studies concluded that cancer research investment far exceeded expectations of the return on investment. Even using the simple measure of future research grants attracted by researchers funded by one cancer charity, the monetary value of these grants outweighed the initial investment [ 69 ].

There were limitations in the approaches to impact evaluation used in these studies which were recognised by reflecting on the findings from the broader literature. Several studies assessed academic impact in isolation, and studies using the journal impact factor or the location of authors on publications were limited in the information they provided. In particular, using the journal impact factor (JIF) to allocate funding research which was used in one study, is now outdated and controversial. The policy impact of cancer research was commonly evaluated by using clinical practice guidelines, but other policy types that could be used in impact assessment [ 30 ], such as national government reports or local guidelines, were rarely used. In addition, using cancer guidelines as a surrogate for clinical practice change and health service impact could have drawbacks. For example, guidelines can often be outdated, irrelevant or simply not used by cancer clinicians and in addition, local hospitals often have their own local clinical guidelines, which may take precedent over national documents. Furthermore, the other aspects of policy impact described in the broader literature [ 30 ], such as impact on policy agenda setting and implementation, were rarely assessed. There were also no specific examples of social, environmental or cultural impacts and very few of the studies mentioned wider economic benefits from cancer research, such as spin out companies and patents. It may be that these types of impact were less relevant to cancer research being assessed, however unexpected impacts may have be identified if they were considered at the time of impact evaluation.

Reflecting on how the methods of data collection and analysis used in these studies aligned with those listed in Additional file 2 : Table S1 bibliometrics, alternative metrics (media citation), documentary analysis, surveys and economic approaches were often used. Methods less commonly adopted were interviews, using a scale and focus groups. This may have been due to the time and resource implications of using qualitative techniques and more in depth analysis, or a lack of awareness by authors regarding the types of scales that could be used. An example of a scale that could be used to assess the impact of research on policy is provided in one of the literature reviews identified [ 30 ]. The method of collecting expert testimony from researchers was utilised in the studies identified, but there were no obvious examples of testimony about the impact of cancer research from stakeholders such as cancer patients or their families.

Lastly, despite the large number of examples identified from the previous literature, a minority of the empirical assessments used an impact framework. The Payback Framework, and an iteration of the CAHS Framework were used with success and these studies are excellent examples of how frameworks can be used for cancer research impact evaluation in future. Other frameworks identified from the literature (Additional file 2 : Table S2) that may be appropriate for the assessment of cancer research impact in future include Anthony Weiss’s logic model [ 75 ], the research impact framework [ 76 ] and the research utilisation ladder [ 77 ]. Weiss’s model is specific to medical research and encourages evaluation of how clinical trial publication results are implemented in practice and lead to health gain. He describes an efficacy-efficiency gap [ 75 ] between clinical decision makers becoming aware of research findings, changing their practice and this having impact on health. The Research Impact Framework, developed by the Department of Public Health and Policy at the UK London School of Hygiene and Tropical Medicine [ 76 ], is an aid for researchers to self-evaluate their research impact, and offers an extensive list of categories and indicators of research which could be applied to evaluating the impact of cancer research. Finally, Landry’s Research Utilisation Ladder [ 77 ] has similarities to the hierarchy used in the empirical study by Montegue and Valentim [ 68 ], and focuses on the role of the individual researcher in determining how research is utilised and its subsequent impact.

Reflecting on the strengths and limitations of the empirical approaches to cancer research impact identified in this study, Fig.  3 outlines recommendations for the future. One of these recommendations refers to improving the use of real-life data to assess the actual impact of research on incidence, treatment, and outcomes, rather than predicting these impacts by using clinical trial results. Databases for cancer incidence, such as SEER (USA) and the Office of National Statistics (UK), are relatively well established. However, those that collect data on treatments delivered and patient outcomes are less so, and when they do exist, they have been difficult to establish and maintain and often have large quantities of missing data [ 78 , 79 ]. In their study, Glover et al. [ 67 ] specifically identified the lack of good quality data documenting radiotherapy use in the UK in 2012.

figure 3

1 Thonon F, Boulkedid R, Teixeira M, Gottot S, Saghatchian M, Alberti C. Identifying potential indicators to measure the outcome of translational cancer research: a mixed methods approach. Health Res Policy Syst. 2015;13:72

Suggestions for approaching cancer research impact evaluation.

The recommendations also suggest that impact assessment for cancer and other health research could be made more robust by giving researchers access to cost data linked to administrative datasets. This type of data was used in empirical impact assessments performed in the USA [ 64 , 66 ] because the existing Medicare and Medicaid health service infrastructure collects and provides access to this data. In the UK, hospital cost data is collected for accounting purposes but this could be unlocked as a resource for research impact assessments going forward. A good example of where attempts are being made to link resource use to cost data for cancer care in the UK is through the UK Colorectal Cancer Intelligence Hub [ 80 ].

Lastly, several empirical examples highlighted that impact from cancer research can be increased when researchers or research organisations advocate, publicise and help to interpret research findings for a wider audience [ 60 , 72 ]. In addition, it is clear from these studies that organisations that want to evaluate the impact of their cancer research must also appreciate that research impact evaluation is a multi-disciplinary effort, requiring the skills and input from individuals with different skill sets, such as basic scientists, clinicians, social scientists, health economists, statisticians, and information technology analysts. Furthermore, the users and benefactors from cancer research, such as patients and their families, should not be forgotten, and asking them which impacts from cancer research are important will help direct and improve future evaluations.

The strengths of this study are the broad, yet systematic approach used to identify existing reviews within the research impact literature. This allowed a more informed assessment of cancer research evaluations than would have been possible if a primary review of these empirical examples had been undertaken. Limitations of the study include the fact that the review protocol was not registered in advance and that one researcher screened the full articles for review. The later was partly mitigated by using pre-defined inclusion criteria.

Impact assessment is a way of communicating to funders and patients the merits of undertaking cancer research and learning from previous research to develop better studies that will have positive impacts on society in the future. To the best of our knowledge, this is the first review to consider how to approach evaluation of the impact of cancer research. At the policy level, a lesson learned from this study for institutions, governments, and funders of cancer research, is that an exact prescription for how to conduct cancer research impact evaluation cannot be provided, but a multi-disciplinary approach and sufficient resources are required if a meaningful assessment can be achieved. The approach to impact evaluation used to assess cancer research will depend on the type of research being assessed, the unit of analysis, rationale for the assessment and the resources available. This study has added to an important dialogue for cancer researchers, funders and patients about how cancer research can be evaluated and ultimately how future cancer research impact can be improved.

Availability of data and materials

Additional files included. No primary research data analysed.

Abbreviations

National Cancer Institute

United States of America

United States

United Kingdom

Cancer Research UK

Medical subject heading

Preferred reporting items for systematic reviews and meta-analysis

Gross Domestic Product

American Society of Clinical Oncology

Surveillance, Epidemiology and End Results Program

Journal impact factor

Research evaluation framework

Health Technology Assessment

Doctor of Philosophy

Research and Development

Quality adjusted life year

Canadian Academy of Health Sciences

Office for National Statistics

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Acknowledgements

We would like to acknowledge the help of Ms Lorraine MacLeod, specialist librarian from the Beatson West of Scotland Cancer Network in NHS Greater Glasgow and Clyde for her assistance in formulating the search strategy. We would like to acknowledge that Professor Stephen Hanney provided feedback on an earlier version of this review.

Dr. Catherine Hanna has a CRUK and University of Glasgow grant. Grant ID: C61974/A2429.

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Additional file 1..

Research Council UK Impact definition, summary of search terms for part one, and inclusion criteria for both parts of the study.

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Dietary patterns and cancer risk

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Over the past decade, the search for dietary factors on which to base cancer prevention guidelines has led to the rapid expansion of the field of dietary patterns and cancer. Multiple systematic reviews and meta-analyses have reported epidemiological associations between specific cancer types and both data-driven dietary patterns determined by empirical analyses and investigator-defined dietary indexes based on a predetermined set of dietary components. New developments, such as the use of metabolomics to identify objective biomarkers of dietary patterns and novel statistical techniques, could provide further insights into the links between diet and cancer risk. Although animal models of dietary patterns are limited, progress in this area could identify the potential mechanisms underlying the disease-specific associations observed in epidemiological studies. In this Review, we summarize the current state of the field, provide a critical appraisal of new developments and identify priority areas for future research. An underlying theme that emerges is that the effectiveness of different dietary pattern recommendations in reducing risk could depend on the type of cancer or on other risk factors such as family history, sex, age and other lifestyle factors or comorbidities as well as on metabolomic signatures or gut microbiota profiles.

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Acknowledgements

S.E.S. and E.A.M. are co-principal investigators of a Susan G. Komen Graduate Training in Disparities Research grant (GTDR 17500160). This work was funded by grants from the National Institutes of Health (1R01CA218578) and the American Institute for Cancer Research (359566).

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Supplementary information.

(HEI). An a priori diet quality score based on adherence to the US Dietary Guidelines.

(aHEI). An a priori diet quality score based on overall chronic disease prevention guidelines.

(DASH). An a priori dietary pattern based on the dietary recommendations employed in the DASH randomized controlled trial, which demonstrated a significant effect of the diet intervention on blood pressure.

(DII). An a priori algorithm for scoring diet quality based on weighted inflammatory effect scores for up to 45 dietary components, as determined by previous literature related to diet, and six inflammatory biomarkers.

(FFQ). A closed-ended questionnaire used to obtain information about the usual consumption of foods and beverages (frequency and sometimes portion sizes) over a specific period of time.

(MDS). An a priori diet quality score based on adherence to dietary components comprising the traditional Mediterranean diet.

Epidemiological studies in which diet is assessed prior to cancer development and participants are followed prospectively over time to determine cancer endpoints.

Epidemiological studies in which patients with cancer and healthy control individuals are enrolled and diet is assessed retrospectively.

(RRR). A data-driven outcome-dependent statistical technique that typically employs an intermediate marker to first define a dietary pattern based on its ability to explain variation in the marker and then examine associations with cancer risk.

A field of research related to measuring small-molecule metabolic products (metabolites) in body cells, fluids or tissues, often with an agnostic approach to discovering relationships between metabolites and disease.

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Steck, S.E., Murphy, E.A. Dietary patterns and cancer risk. Nat Rev Cancer 20 , 125–138 (2020). https://doi.org/10.1038/s41568-019-0227-4

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Published : 17 December 2019

Issue Date : February 2020

DOI : https://doi.org/10.1038/s41568-019-0227-4

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Breast cancer is one of the most common diseases in women; it can have long-term implications and can even be fatal. However, early detection, achieved through recent advancements in technology, can help reduce mortality. In this paper, different machine intelligence techniques [machine learning (ML), and deep learning (DL)] were analysed in the context of breast cancer. In addition, the classification of breast cancer into malignant and benign using different breast cancer image modalities were discussed. Furthermore, the diagnosis of breast cancer using various publicly and privately available image datasets, pre-processing techniques, feature extraction techniques, comparison between conventional ML and different convolutional neural network (CNN) architectures, and transfer learning techniques were discussed in detail. It also correlates the parameters and attributes impact in case of different methods applied. Advantages and the limitations of the machine intelligence approaches were highlighted based on the discussion and analysis. A total of 162 research publications was considered for the time period of 2015–2021. These are in the chronological order of their appearance. This systematic literature review will be helpful to the researchers due to the detailed analysis of different methodologies and in conducting further investigations.

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Nemade, V., Pathak, S. & Dubey, A.K. A Systematic Literature Review of Breast Cancer Diagnosis Using Machine Intelligence Techniques. Arch Computat Methods Eng 29 , 4401–4430 (2022). https://doi.org/10.1007/s11831-022-09738-3

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Cancer research studies look for and find better ways to prevent, diagnose, and treat cancer. Doctors and scientists can design these studies in many ways to answer the questions they have. No study design is perfect. Each has strengths and limits.

When you are researching information about your or your loved one's cancer, it is important to understand how studies are designed. This can help you figure out what the results mean to you. Some research is very preliminary or "early", which means it will be a long time before the results affect patient care. Other research results may have an immediate impact on how doctors care and treat people with cancer.

There are 3 main types of cancer research studies:

Preclinical studies. This type of study is used in a laboratory to test whether a change in approach, called an intervention, may be useful to treat a cancer, and whether it appears to be safe. These studies are often done in cancer cells either in a petri dish or in an animal like a mouse. These results are very important for deciding which interventions to eventually test in people. Often, a lot of time will go by between testing interventions in the laboratory and having them available to treat people with cancer.

Experimental studies, called clinical trials. This type of study gives a group of volunteers an intervention. The intervention is the focus of the study. For instance, it may be a new treatment, medical device, or process. Researchers often compare the results of the intervention group to a group that does not get the intervention. This is known as the control group. For many studies, who does and does not get the intervention is selected at random, called randomization. In other studies, every person gets the intervention. Finally, there are some studies that use a specific selection process to make decisions about treatment.

Experimental studies and clinical trials help researchers learn more about how cancer starts or spreads. These studies can also test new imaging methods and ways to improve quality of life. Learn more about clinical trials .

Observational studies. This type of study observes groups of people in a natural setting. Researchers do not give an intervention. Instead they study the results of interventions already in place. For instance, researchers may find out whether a group of people has more cancer diagnoses than another group.

Observational research helps with the study of epidemiology. Epidemiology looks at how different risks influence, cause, or spread a disease in a community.

What are the types of experimental cancer research studies?

Experimental studies are more reliable than observational studies. This is because people in these studies are placed in the intervention group or control group, usually at random. Randomization lowers the chance that what they or the researchers assume or prefer will change the study results. These assumptions or preferences are called bias.

This type of study also helps researchers to better find and control for such features as age, sex, and other factors that can affect the results of the study.

Researchers may create specific rules, called eligibility criteria , when they ask people to join an experimental study. This often includes the type of cancer and the stage of cancer. This is to make sure the study's participants have specific things in common so the results are helpful for similar patients in the future.

Clinical trials and experimental studies test:

The effectiveness or safety of a new drug or combination of drugs

A new way of giving a kind of treatment, such as radiation therapy or surgery

A new treatment or way to prevent cancer

A new way to lower the risk of cancer coming back, called recurrence

A new way to relieve a side effect of cancer or its treatment

Researchers do clinical trials in segments called phases. Each phase of a clinical trial gives different answers about the intervention being tested. There are 4 phases of clinical trials .

In a phase 3 clinical trial, people in the study are usually randomly placed in either the intervention group or control group. Researchers can prevent bias in a clinical trial by keeping those people and themselves, or just those people, from knowing who is in each group. This is a process called "blinding."

The types of experimental studies include:

Double-blind randomized trial. The people in the study and the researchers do not know who belongs to the intervention group or control group. They find out only when the study ends. Most researchers feel this type of clinical trial produces the best study data.

Single-blind randomized trial. The people in the study do not know whether they belong to the intervention group or control group, but the researchers know.

Open or unblinded trial. The people in the study and the researchers know who belongs to each test group. This approach is used when it is not possible to use blinding. For instance, the study may be comparing a surgical treatment to a drug.

What are the types of observational cancer research studies?

In observational studies, researchers have less control over the people in the study. This means that certain factors could affect the results. However, these studies provide data that can help guide future research.

Types of observational studies include:

Case-control studies. These studies compare 2 groups of people. For instance, researchers could compare information about people with cancer and those who do not have cancer. People who have cancer are the case group. People who do not have cancer are then the control group. Researchers may look for lifestyle or genetic differences between the groups. By doing this, they hope to find out why one group has a disease and the other group does not. These studies are called retrospective. That means researchers study an event that has already occurred.

Cohort studies. These studies are prospective. That means researchers study an event as it occurs. They watch a group of volunteers for a long period of time and track something. For instance, they could track any new cancer diagnoses. This type of study can look at whether certain nutrients, exercise, or other action can prevent cancer. This approach can also find cancer risk factors. For instance, cohort studies have looked at whether postmenopausal hormone replacement therapy increases the risk of breast cancer.

Case reports and case series. Case reports are detailed reports of one person's medical history. If many people receive a similar treatment, the reports may be grouped into a case series. The results of case series studies are descriptions of patients' histories within a specific group. As such, doctors should not use them to choose treatment options. But case reports can help doctors think of new ideas for research studies in the future.

Cross-sectional studies. These studies look at how diseases interact with other factors within a specific group at one point in time. For example, a study might evaluate how patients who took a certain medication are doing ten years later to see who has and has not developed cancer. Because these studies only measure a point in time, they cannot prove that something causes cancer, but they can help scientists with future research.

What are cancer research review articles?

Medical journals publish many cancer research studies each year. This is good for adding to the scientific knowledge about cancer that lead to better treatment and care. However, the fast pace makes it hard for doctors, people with cancer, and caregivers to keep up with all of the new advances. Research studies are always shaping and reshaping the scientific understanding of cancer. But no single study is the final word on a type of cancer treatment. As a result, review articles are very helpful. Review articles study and sum up the findings of already published research on a certain topic.

Types of review articles include:

Systematic reviews. These articles summarize the best existing research on a specific topic at that time. Researchers use an organized method to find, gather, and review a number of research studies on a topic. By combining the findings of these studies, researchers can draw more reliable conclusions.

Meta-analyses. These articles combine data from several research studies on the same topic. This lets researchers find trends that are hard to see in single studies.

How do I know if cancer research results are reliable?

These questions can help you evaluate the quality of research study results:

Was the study peer-reviewed by the journal that published it? Peer review means that researchers who are not a part of the study looked over and approved the study's design and methods. Results from a study are more reliable if they are peer-reviewed. Learn more about peer review .

How long did a study last and how many people took part? A study is more useful and credible if the same results occur in many people over time. However, this rule does not apply to studies of rare types of cancer or cancer that is hard to treat. This is because there are fewer people to study. Also, cancer prevention trials are often much longer than treatment clinical trials. This is because it often takes longer to find out if a prevention strategy works compared to treatment of an existing cancer.

What is the phase of a new treatment study? Phase I and phase II clinical trials often tell researchers more about the safety of a treatment than how well it works. These studies tend to have less people than phase III clinical trials. Phase III clinical trials compare a new treatment with the standard of care. Doctors consider phase III clinical trials to be the most reliable.

Does the study overstate or oversimplify its results? Each study is a small piece of the cancer research puzzle. Medical practice rarely changes because of the results of 1 study. New results are exciting. But other researchers must confirm the results before the medical field accepts them as fact. Review articles are of special interest.

Questions to ask your health care team

Some patients decide to gather research study findings that may apply to their type and stage of cancer. Always talk with your health care team about how a specific study may or may not relate to your treatment plan. It is important to not stop or change your current treatment based only on something you read.

Consider asking your health care team these questions:

I saw a study about a new treatment. Is this treatment related to my type and stage of cancer? Were people like me included in that study?

What publications can I read to learn more about my cancer type ?

Are there medical journals that focus on the type of cancer I have?

Should I think about joining a clinical trial?

What clinical trials are open to me? Where are they located, and how do I find out more about them?

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  • Published: 13 February 2024

Anastrozole for the prevention of breast cancer in high-risk postmenopausal women: cost-effectiveness analysis in the UK and the USA

  • XiaoXia Wei 1   na1 ,
  • Jiaqin Cai 1   na1 ,
  • Huiting Lin 2 ,
  • Wenhua Wu 2 ,
  • Jie Zhuang 1 &
  • Hong Sun 1  

BMC Health Services Research volume  24 , Article number:  198 ( 2024 ) Cite this article

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The effectiveness of anastrozole for breast cancer prevention has been demonstrated. The objective of this study was to evaluate the cost-effectiveness of anastrozole for the prevention of breast cancer in women with a high risk of breast cancer and to determine whether anastrozole for the primary prevention of breast cancer can improve the quality of life of women and save health-care resources.

A decision-analytic model was used to assess the costs and effects of anastrozole prevention versus no prevention among women with a high risk of breast cancer. The key parameters of probability were derived from the IBIS-II trial, and the cost and health outcome data were derived from published literature. Costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios (ICERs) were calculated for the two strategies,One-way and probabilistic sensitivity analyses were performed.

In the base case, the incremental cost per QALY of anastrozole prevention was £125,705.38/QALY in the first 5 years compared with no prevention in the UK, above the threshold of WTP (£3,000/QALY),and in the 12-year period, the ICER was £8,313.45/QALY, less than WTP. For the US third-party payer, ICER was $134,232.13/QALY in the first 5 years and $8,843.30/QALY in the 12 years, both less than the WTP threshold ($150,000/QALY).

In the UK and US, anastrozole may be a cost-effective strategy for the prevention of breast cancer in high-risk postmenopausal women. Moreover, the longer the cycle of the model, the higher the acceptability. The results of this study may provide a scientific reference for decision-making for clinicians, patients, and national medical and health care government departments.

Peer Review reports

Introduction

In recent years, with in-depth research into breast cancer pathogenesis, breast cancer treatment has become increasingly personalised and 5-year survival rates has increased annually [ 1 ]. However, as the incidence of breast cancer continues to rise, the burden of breast cancer is intensifying. Breast cancer has now surpassed lung cancer as the world's most common cancer, according to the latest global cancer data for 2020, and is a major threat to women's health worldwide. Many high-income countries, including the United Kingdom(UK) and the United States(USA), are facing the burden of disease for the growing number of breast cancer patients [ 2 ].

Breast cancer also negatively affects the economic growth of countries, with an enormous economic cost of $2.0 trillion in international dollars (INT) [ 3 ]. Primary preventive care for breast cancer is urgently needed to reduce the huge burden of breast cancer, including screening for risk factors, lifestyle modifications, risk-reducing surgery, and drug prevention [ 4 ]. However, breast cancer prevention efforts are not used effectively and cannot keep up with breast cancer treatment [ 5 ].

In 1998, the selective oestrogen receptor modulator tamoxifen became the first FDA-approved drug for breast cancer prevention, especially in premenopausal patients and those with dysplasia. In 2007, the FDA approved the preventive effect of raloxifene in postmenopausal women [ 6 ]. However, tamoxifen and raloxifene increase the risk of thromboembolism and endometrial cancer, so many doctors are reluctant to prescribe drug prophylaxis. This is also a concern for patients and a reason for them to stop taking the drugs. Studies have shown that the uptake of therapeutic agents for the prevention of breast cancer is low, and long-term persistence is often insufficient for women. Therefore, the prevention of tamoxifen or raloxifene has not been widely used in clinical practice [ 7 ].

Oestradiol is an important carcinogen of breast cancer, and aromatase can convert oestrogen into oestradiol, which has an important catalytic effect on oestradiol production, so reducing the level of oestradiol can reduce the risk of breast cancer [ 8 ]. Anastrozole, a third-generation aromatase inhibitor, has been used for more than 20 years to treat postmenopausal women with oestrogen receptor-positive breast cancer by blocking oestrogen production in the body [ 9 ]. By 2003, the International Breast Cancer Intervention Study II (IBIS-II) began to explore the preventive value of anastrozole in postmenopausal women at high risk of breast cancer and to evaluate its safety and efficacy in the primary prevention of breast cancer. The five years result showed that anastrozole reduced the risk of aggressive oestrogen receptor-positive breast cancer in postmenopausal high-risk women without new toxic side effects and may become the drug of good choice for prevention in postmenopausal women at high risk for breast cancer [ 10 ]. Anastrozole was included in the UK and US breast cancer drug prevention guidelines in 2017 and 2019. The recently published long-term follow-up results of the IBIS-II trial showed a significant reduction in the incidence of breast cancer in women 7 years after discontinuation of anastrozole (49%), equivalent to every 29 women taking anastrozole for 5 consecutive years, and one case of breast cancer can be prevented in 12 years [ 11 ]. However, as a drug, anastrozole is costly and may have adverse reactions during its use. For this reason, it is necessary to return to the outpatient clinic for regular check-ups and follow-ups. This means that to prevent one case of breast cancer in 12 years, 29 women at risk would need to take anastrozole for five years. Is this "value for money", or does it take up medical resources and cause extra burden for patients? Can it be supported at a time of rising health care costs?

This information is important to the third-party payers, the organization that pays the bills for a patient's health care, as well as to the general public. An important next step is to conduct a cost-effectiveness analysis to assess the potential costs and health outcomes to provide the data needed to advocate for anastrozole prevention in women. Therefore, this study intends to evaluate the economic value of anastrozole for the prevention of breast cancer in women with high risk from the third payer’s perspective in the UK and the USA.

Materials and methods

Study subjects.

For mathematical simulations, the construction of an economic model requires the collection of the probability of occurrence of relevant events. So the key clinical parameters, such as breast cancer incidence, death, other cancers, and the rate of major adverse events were derived from the long-term results of anastrozole for breast cancer prevention (IBIS-II) [ 11 ]. IBIS-II is an international, randomized, double-blind, placebo-controlled trial that included 153 breast cancer treatment centres across 18 countries, such as the United Kingdom, the United States, Switzerland, Germany, France, etc. The researchers recruited postmenopausal women aged 40–70 years who were at increased risk of breast cancer. Exclusion criteria were premenopausal, previous breast cancer (including ductal carcinoma in situ) diagnosed more than 6 months before the start of the trial, current or previous use of tamoxifen, raloxifene or other selective oestrogen receptor modulator (SERM) for more than 6 months, participated in IBIS-I [ 10 ], intended to continue oestrogen-based hormone replacement therapy unless on at least 5 years of off-trial treatment, or had previously performed or planned to undergo prophylactic mastectomy. Patients with the above criteria were the population simulated by our economic model.

Treatment strategies

Base on the IBIS-II trail, the treatment decisions in our model were receiving anastrozole (1 mg daily, orally) or the equivalent placebo for a 5-year treatment period, with annual follow-up, during which the experiment was carried out by laboratory examination and imaging evaluation. After treatment, women continued to be followed annually to collect data on the incidence, death, other cancers, and major adverse events (cardiovascular and fractures), with the main outcome being breast cancer, including the treatment period. A total of 12 years of follow-up was carried out [ 11 ].

Model establishment

In this study, from the perspective of third-party payers in the UK and the USA, a decision-analytic model was developed by using TreeAge Pro 2023 (TreeAge Software LLC., Williamstown, MA, USA) to evaluate costs and health outcomes of anastrozole or placebo for breast cancer prevention in high-risk postmenopausal women. Because the IBIS-II study pointed out that during the 12-year follow-up, among those who died, the main cause of death was other cancers, cardiovascular or unknown, and only a very small proportion of deaths were due to breast cancer, we cannot accurately obtain the transition probability from the progression state of the disease to the death state. The Markov model was not applicable, so we chose the decision-analytic model. At the same time, the follow-up results of the IBIS-II study found that prophylactic use of anastrozole significantly reduces the incidence of non-melanoma tumours in addition to reducing the incidence of breast cancer.There was no significant difference in the incidence of other cancers between the two groups. Therefore, referring to the outcome of the IBIS-II study, we divided the progression status of this model into four statuses: invasive breast cancer, noninvasive breast cancer, nonmelanoma, and without progression (Fig.  1 ). The probability parameters of relevant events were input into the model. According to the follow-up results of the IBIS-II study, the model was established with a cycle period (cycle) of 1 year and operation periods (time horizon) of 5 years and 12 years. This study followed the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) reporting guidelines [ 12 ].

figure 1

The decision-analytic model

Model assumptions

According to the IBIS-II trial [ 10 ], there was no significant difference in adverse events between the anastrozole group and the placebo group, so we did not consider the cost and utility of adverse reactions in the model. In addition, we used the same nonmelanoma incidence data in both run cycles because the study did not specify the time period of nonmelanoma incidence. Since the study did not introduce the follow-up treatment plan for patients diagnosed with invasive breast cancer, noninvasive breast cancer, and nonmelanoma, we set the follow-up-related treatment plan and follow-up plan according to the guidelines and published literature. Patients diagnosed with invasive breast cancer underwent a breast cancer biopsy, eight cycles of chemotherapy followed by surgical resection of breast cancer, semiannual laboratory evaluations and outpatient management fees were paid once, and annual breast cancer imaging evaluations (X + MRI). Patients diagnosed with noninvasive breast cancer were treated with breast cancer surgery without chemotherapy, and the rest of the follow-up plans were the same as those of patients with invasive breast cancer [ 13 , 14 ]. Patients diagnosed with nonmelanoma underwent a single diagnosis, laboratory evaluation (biopsy and dermatopathology), and surgical resectionr [ 15 , 16 ]. The follow-up plan for patients without progression is the same as for patients with invasive breast cancer. The progress of each state in the anastrozole group and the placebo group was monitored and treated according to the above protocol.

Costs and utilities

A cost-effectiveness analysis was perform from the perspective of the third-party payers, so the model only considered direct medical costs. The direct non-medical costs, indirect costs and intangible costs were not covered by health insurance. Costs were calculated as direct medical costs, including drug, examination, surgery, treatment, outpatient management, etc. The unit price of the items was derived from related literature published in the UK and the USA [ 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 ]. Input costs were reported in 2023 GBP or USD. Where necessary, input costs were adjusted to 2023 GBP or USD using the medical care component of the Consumer Price Index.

The cost of the drug was mainly anastrozole. In calculating dosage amounts of anastrozole was derived from IBIS-II trials(1 mg daily, orally for 5-year treatment period). The costs of disease management include follow-up-related treatment and outpatient follow-up examinations. Patients diagnosed with invasive breast cancer received a breast cancer biopsy, eight cycles of chemotherapy followed by surgical resection, patients diagnosed with noninvasive breast cancer were treated with breast cancer surgery without chemotherapy, patients diagnosed with nonmelanoma underwent a single diagnosis, laboratory assessment (biopsy and dermatopathology), and surgical resection. And all patients received semiannual laboratory assessment, annual breast cancer imaging evaluations (X-ray/MRI), and outpatient management. Combined calculations based on the above probability of occurrence of disease events, frequency of disease management and corresponding unit prices by TreeAge Software. Details of each cost parameter and the range of values are shown in Table  1 .

This study used quality-adjusted life years (QALYs) as an outcome measure, and health utility values were used to convert one year of survival in a diseased state to one year in a fully healthy state (that is, 1 QALY). The utility value is 1 in the fully healthy state and 0 in the dead state. The health utility values for each state were obtained from published articles on pharmacoeconomics (Table  1 ) [ 30 , 31 , 32 ].

Cost-effectiveness analysis

Results of the study output included cost, quality-adjusted life year (QALY) and incremental cost-effectiveness ratio (ICER). The ICER results were compared with the willingness to pay (WTP) as a threshold. In pharmacoeconomic analysis, the WTP is a threshold used to assess whether the ICER is acceptable or not. If the ICER is less than the threshold, the intervention is economic compared to the control, and conversely, it is not. For UK payers, the WTP threshold was set at GBP £30,000 according to The National Institute for Health and Care Excellence (NICE) guidance [ 33 ], and for USA payers, the WTP threshold was set at $150,000/QALY [ 34 ].

Sensitivity analysis

In the one-way sensitivity analysis, each parameter was varied within a set range, and the effect of each parameter on the results was evaluated. Publicly available data with upper and lower bounds were included, and for those values that were not available, costs were varied within ± 20% of the baseline value, and the value of health utility was varied within ± 10% as a sensitivity analysis. The maximum health utility value is 1. When the value exceeds 1, it is taken as 1. Followed the economic evaluation guidelines in recommending that in Reference Case analyses, costs and health effects should be discounted at the same rate. A discount rate of 3.5% per annum has been used for UK payers [ 33 ], and 3% per annum has been used for USA payers, with a range of 0% to 8% used for sensitivity analysis in our mode [ 35 ].

The influence of changes within the range on the results and the specific parameter change ranges are shown in Table  1 , and the results arranged in the order of the magnitude of the influence of parameter changes on the model results are represented by a storm diagram. The corresponding distributions were set for the model parameters for probabilistic sensitivity analysis (Table  1 ). The Monte Carlo simulation used 1 000 iterations to examine the influence of parameter uncertainty on the results.

Basic results

For the UK third-party payer, the total costs of anastrozole prevention vs. no prevention were £11,470.08 and £7,364.87 with gained 4.594 QALYs and 4.562 QALYs, respectively, and the incremental cost-effectiveness ratio (ICER) was £125,705.38/QALY in the 5-year time horizon model, crosses the threshold of the WTP(£3,000/QALY). In the 12-year time horizon model, the two groups’ costs were £19,154.45 and £15,680.53 and gained 9.909 QALYs and 9.491 QALYs, and the ICER was £8,313.45/QALY (Table  2 ), less than the WTP.

For the third-party payer in the USA, the results showed that in the 5-year time horizon model, the costs of the two groups of anastrozole prevention and no prevention were $16,096.51 and $11,671.55 and gained 4.638 QALYs and 4.605 QALYs, respectively, and the ICER was $134,232.13/QALY. In the 12-year time horizon model, the two groups’ costs were $27,516.61 and $23,821.30 and gained 9.909 QALYs and 9.491 QALYs, and the ICER was $8,843.30/QALY, all less than the WTP threshold ($150,000/QALY) (Table  2 ). Clearly, anastrozole had advantages in cost-effectiveness for the prevention of breast cancer in high-risk postmenopausal women.

One-way sensitivity analysis

The results of the one-way sensitivity analyses are presented in the tornado diagram arranged in order of the degree of influence on the ICER. (Fig.  2 ). In the first 5 years, the parameters within the range of variation were all above the threshold of the WTP(£3,000/QALY) for the UK. Although the ICER was below the US WTP threshold ($150,000/QALY), the utility of breast cancer, the costs of anastrozole, laboratory assessment and imaging assessment had the greatest impact on the ICER in the US model. However, at the 12-year time horizon, the tornado diagram showed that all variables in the model had no effect on ICER, whether in the UK or US model. The ICERs were also sensitive to the time horizon, particularly in the first 5 years.

figure 2

One-way sensitivity analysis for anastrozole prevention versus placebo. A UK of 5-year time horizon model; B UK of 12-year time horizon model; C USA of 5-year time horizon model; D USA of 12-year time horizon model)

Probabilistic sensitivity analysis

The probabilistic sensitivity analysis results are shown in a scatter plot (Fig.  3 ) and the cost-effectiveness acceptability curve (Fig.  4 ). The scatter plot indicated that the acceptable proportion of anastrozole prevention for UK was 0% at the £30,000/QALY WTP threshold in the 5-year horizon and approximately 67% in the 12-year horizon. The probability for the USA was approximately 59.9% at the $150,000/QALY WTP threshold in the 5-year horizon and approximately 81.4% in the 12-year horizon. Furthermore, models for 5 and 12 years show that the probability that anastrozole prevention is economical increases with the value of WTP, and the longer the cycle of the model is, the higher the acceptability.

figure 3

Cost-Effectiveness scattar plot of probabilistic sensitivity analysis for anastrozole prevention versus placebo. A UK of 5-year time horizon model; B UK of 12-year time horizon model; C USA of 5-year time horizon model; D USA of 12-year time horizon model)

figure 4

Cost-Effectiveness acceptability curve of probabilistic sensitivity analysis for anastrozole prevention versus placebo. A UK of 5-year time horizon model; B UK of 12-year time horizon model; C USA of 5-year time horizon model; D USA of 12-year time horizon model)

Breast cancer remains the leading cancer-related cause of disease burden for women and is a serious public health concern in high-income countries. Although a reduction in breast cancer risk is important for clinical and treatment outcomes, it is essential to evaluate additional costs to the health care system [ 36 ]. Therefore, we created a cost-effectiveness analysis of anastrozole for the prevention of breast cancer in high-risk postmenopausal women based on the IBIS II findings. From the perspective of third-party payers in the UK and the USA, the results of the model suggested that anastrozole increases health care costs but reduces the risk of breast cancer and improves QALYs compared with no prevention. It was a cost-effective advantage of prophylaxis with anastrozole for 12 years. With the extension of the follow-up period, the anastrozole intervention program has a higher economic value. At the same time, in the 5-year-horizon model of the United Stated, we found that the cost of anastrozole is the most important factor affecting the stability of the model, and a higher price of anastrozole may affect the results of ICER, even greater than the WTP threshold, making the whole result uneconomical. In contrast, if its price is lowered, more women at high-risk will benefit. However, in UK economic models, we found a lower acceptance of anastrozole for prevention in high-risk women,which may be related to the lower WTP threshold in the UK. We believe that our findings can provide some reference information for the UK and US healthcare sector.

Currently, the only oestrogen receptor modulators tamoxifen and raloxifene are FDA-approved drugs for breast prevention in postmenopausal women with high risk of breast cancer. After the FDA approved indications for the prevention of these two drugs, there have also been cost-effective studies, especially tamoxifen. Most of the results show that tamoxifen is a cost-effective strategy for preventing breast cancer in high-risk, but most of these trials were done in the 2000s [ 37 ], before long-term outcome data on endocrine prophylaxis were available, and the costs of drugs and breast cancer treatment and care have changed over time. Recent results on aromatase inhibitors for breast cancer prevention have shown that AIs have fewer serious adverse events (i.e., endometrial cancer and venous thromboembolism) than tamoxifen or raloxifene, which may offset their higher upfront drug costs. Although none of the AIs are currently FDA approved for breast cancer prevention, many authoritative prevention guidelines, such as NCCN, ASCO, USPSTF, and NICE, recommend them as viable options for the endocrine prevention of breast cancer in postmenopausal women [ 6 ]. We also hope that more clinical and economic evidence will help endocrine therapy for the prevention of breast cancer to find a place in routine clinical practice, so that more patients can benefit and the incidence of breast cancer can be reduced.

As we know, this is the first study that focus on the cost-effectiveness of anastrozole for the prevention of breast cancer in high-risk postmenopausal women. However, our present study has several limitations. First, due to the limited follow-up time of the IBS-II study and the lack of PFS and OS survival curves for breast cancer and melanoma, this study used a decision-analytic model to simulate the early progression of the disease and did not consider risk factors for breast cancer or ethnicity of patients. Stratified analysis by ethnicity, age at menopause, body mass index, etc. However, we have carried out sensitivity analysis, and the results show that the model we constructed is relatively robust. Second, our model does not take into account the impact of adverse reactions. Although the study shows that there is no significant difference in adverse reactions between the two groups, adverse reactions will inevitably occur in related treatment and surgery. The progression of diseases is complex and may have an impact on the final outcome. Third, due to differences in economic development, local per capita income and local development GDP are different, and the value of WTP will also be different, so the final results of this study may also be different. Fourth, in low- and middle-income countries(LMICs), due to weak health infrastructure and subsequently poor survival outcomes, prevention for breast cancer remains a challenge [ 2 ]. Our study only analysed high-income countries, the UK and the US, and the results cannot be generalised to other LMICs. The cost-effectiveness of anastrozole for the prevention of breast cancer in postmenopausal women at high risk of breast cancer in other countries needs to be further explored.

Conclusions

In conclusion, this study demonstrates a cost-effective advantage of anastrozole for breast cancer prevention in postmenopausal high-risk women from the perspective of third-party payers in the UK and the USA. The results of this study may provide a reference for the rationality of clinical medication for clinicians and patients and the scientific decision-making of national government departments for medical and health care.

Availability of data and materials

The datasets supporting the conclusions of this article are included within the article. The link of IBIS-II trial is https://pubmed.ncbi.nlm.nih.gov/31839281/ .

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Acknowledgements

The authors wish to thank all of the authors who contributed to the special.

This study was supported in part by grants from the Natural Science Foundation of Fujian,China (No.2021J01397 and No. 2022J011004). And the Fujian provincial health technology project (No.2022GGA010).

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XiaoXia Wei and Jiaqin Cai contributed equally to this work.

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Department of Pharmacy, Shengli Clinical Medical College of Fujian Medical University, Fujian Provincial Hospital, No. 134, East Street, Gulou District, Fuzhou, 350001, P. R. China

XiaoXia Wei, Jiaqin Cai, Jie Zhuang & Hong Sun

School of Pharmacy, Fujian Medical University, No. 1 Xuefu North Road, University Town, Fuzhou, 350122, P. R. China

Huiting Lin & Wenhua Wu

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Xiaoxia Wei and Hong Sun were involved in the design of the study. Jiaqin Cai, Xiaoxia Wei, Huiting Lin and Wenhua Wu collected the data and performed the economic analysis. Jie Zhuang checked the data and the parameters of the model. Xiaoxia Wei and Jiaqin Cai wrote the first draft of the manuscript, which was critically revised by Hong Sun. All authors have read and agreed to the published version of the manuscript.

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Wei, X., Cai, J., Lin, H. et al. Anastrozole for the prevention of breast cancer in high-risk postmenopausal women: cost-effectiveness analysis in the UK and the USA. BMC Health Serv Res 24 , 198 (2024). https://doi.org/10.1186/s12913-024-10658-0

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Received : 27 December 2022

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DOI : https://doi.org/10.1186/s12913-024-10658-0

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A review of literature about involving people affected by cancer in research, policy and planning and practice

Affiliation.

  • 1 Cancer Care Research Centre, Department of Nursing and Midwifery, University of Stirling, Stirling FK9 4LA, United Kingdom. [email protected]
  • PMID: 16860517
  • DOI: 10.1016/j.pec.2006.02.009

Objective: To systematically review the literature on involving people affected by cancer in healthcare research, policy and planning and practice.

Methods: Database searches, cited author, and grey literature searches were conducted.

Results: 131 documents were included. Rationales for the agenda of involvement represent two polar characteristics of modernity: individualism and collectivism. In research, people acted as advocates, strategists, advisors, reviewers and as participatory researchers. In policy and planning, people were involved in one-off involvement exercises and in longer-term partnerships. Men, those with rare cancers, children, and people who are socially deprived have been rarely involved. There is little research evidence about the impact of involvement. Training and information, resources and a change in attitudes and roles are required to implement an agenda of involvement.

Conclusion: The USA, the UK, followed by Canada and Australia have promoted an agenda of involvement.

Practice implications: A dissemination strategy to share good practice; involvement of all types of people; an individualised and flexible approach; training, resources and a shift in thinking from paternalism towards partnership working are required. More research is needed about the impact of involvement and relationships between rationales for involvement and implementation.

Publication types

  • Benchmarking
  • Community Participation
  • Data Collection
  • Data Interpretation, Statistical
  • Decision Making, Organizational
  • Evidence-Based Medicine / organization & administration
  • Health Planning / organization & administration*
  • Health Policy*
  • Health Services Needs and Demand
  • Information Dissemination
  • Medical Oncology / organization & administration*
  • Neoplasms / psychology*
  • Neoplasms / therapy
  • Patient Participation / methods
  • Patient Participation / psychology*
  • Patient-Centered Care / organization & administration
  • Power, Psychological
  • Research / organization & administration*
  • Research Design

CASE REPORT article

Successful salvage of a severe covid-19 patient previously with lung cancer and radiation pneumonitis by mesenchymal stem cells: a case report and literature review.

Xiaohua Huang,&#x;

  • 1 Department of Hematology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
  • 2 Department of Hematology, Dongzhimen Hospital of Beijing University of Chinese Medicine, Beijing, China
  • 3 Department of Rehabilitation Medicine, Southern Theater General Hospital, Guangzhou, China
  • 4 The First Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou, China
  • 5 Department of Respiratory and Critical Care Medicine, Yantai Yuhuangding Hospital, Yantai, China
  • 6 Department of Hematology, Shenzhen Qianhai Shekou Pilot Free Trade Zone Hospital, Shenzhen, China

During the COVID-19 pandemic, elderly patients with underlying condition, such as tumors, had poor prognoses after progressing to severe pneumonia and often had poor response to standard treatment. Mesenchymal stem cells (MSCs) may be a promising treatment for patients with severe pneumonia, but MSCs are rarely used for patients with carcinoma. Here, we reported a 67-year-old female patient with lung adenocarcinoma who underwent osimertinib and radiotherapy and suffered from radiation pneumonitis. Unfortunately, she contracted COVID-19 and that rapidly progressed to severe pneumonia. She responded poorly to frontline treatment and was in danger. Subsequently, she received a salvage treatment with four doses of MSCs, and her symptoms surprisingly improved quickly. After a lung CT scan that presented with a significantly improved infection, she was discharged eventually. Her primary disease was stable after 6 months of follow-up, and no tumor recurrence or progression was observed. MSCs may be an effective treatment for hyperactive inflammation due to their ability related to immunomodulation and tissue repair. Our case suggests a potential value of MSCs for severe pneumonia that is unresponsive to conventional therapy after a COVID-19 infection. However, unless the situation is urgent, it needs to be considered with caution for patients with tumors. The safety in tumor patients still needs to be observed.

1 Introduction

Since the winter of 2019, the pandemic of coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has threatened global public health. COVID-19 is a self-limiting disease for most people. However, approximately 22.97% of cases of COVID-19 developed into acute respiratory distress syndrome (ARDS), and 9.68% of patients needed admission to intensive care unit, with a mortality rate of 1.28% in 2020 ( 1 ). The virulence of SARS-CoV-2 has significantly weakened nowadays ( 2 ). However, people with old age or frail condition still face a high risk of progression to severe or critical disease of COVID-19. The risk factors associated with severe disease include age more than 60 years old, smoking, being unvaccinated against COVID-19, HIV infection, and underlying noncommunicable illness ( 1 , 3 ). Any kind of malignancy history was an independent risk factor for severe illness ( 4 ) and mortality ( 5 ). The estimated pooled mortality rate was 5.6% for the whole population. Nevertheless, it significantly increased to 22.4% for all malignancies, and 32.9% for lung cancer ( 6 ). Therefore, lung cancer patients were at a greater risk of death than other types of carcinoma in the pandemic of COVID-19 ( 7 ).

As a self-limiting disease, supportive care is essential for all patients ( 3 ). Furthermore, the frontline drugs strongly recommended by WHO are nirmatrelvir/ritonavir for non-severe disease and corticosteroids, interleukin-6 (IL-6) receptor blockers, and baricitinib for severe or critical illness ( 8 ). The conditional treatments include ruxolitinib, tofacitinib, convalescent plasma, molnupiravir, remdesivir, and so on ( 8 ). Nirmatrelvir/ritonavir can significantly reduce the 30-day risk of hospitalization or death by approximately 11.16 per 1000 patients. There are patients (approximately 2.30%) who did not respond to this drug, which include 0.25% who needed ICU admission, 0.083% under mechanical ventilation, and 0.125% who died ( 9 ). It is believed that tissue damage co-exists with cytokine storms caused by hyper-activating the immunity system in severe and critical disease ( 10 ). On the other hand, baricitinib and tocilizumab, two widely used inflammatory factor inhibitors, also improve the survival of patients with severe or critical COVID-19. However, approximately 18.0% of patients treated with baricitinib and 24% of patients treated with tocilizumab did not respond to these drugs, among whom 56.0% and 46.7%, respectively, progressed to death ( 11 , 12 ). Thus, the therapy that possesses the ability of inflammatory modulation and tissue repair might be the ideal choice for those who do not respond to frontline treatment. Mesenchymal stem cells (MSCs) have been reported to possess multi-potency ( 13 ), which leads to MSCs being widely used in regenerative medicine and tissue engineering. Nowadays, MSCs’ ability related to immunomodulation is proven as well ( 14 ). Therefore, MSCs can theoretically be used to treat severe and critical COVID-19 patients who do not respond to frontline drugs, and the efficacy has been proven by many clinical trials ( 15 – 35 ). However, MSCs are rarely used in cancer patients due to concerns about safety and neoplasm recurrence. Hence, the safety and efficacy of MSCs for cancer patients are still unclear. Here, we report a patient with lung cancer. She suffered from severe pneumonia caused by COVID-19 following radiation pneumonitis and was finally successfully salvaged by treatment with MSCs after the failure of the first-line treatment, which brings in hopes of offering clinicians evidence and confidence in MSCs utilization.

2 Case presentation

2.1 recent medical history.

A 67-year-old female patient had suffered from a recurring pain in the neck, shoulder, and left upper limb for more than 3 months since August 2021, so she visited the Yantai Yuhuangding Hospital on November 26, 2021. The laboratory tests indicated that carcinoembryonic antigen (CEA) was at 34.5 ng/mL and neuron-specific enolase (NSE) was at 19.1 ng/mL, and a BI-RADS 4a focal and bilateral axilla lymphadenectasis were detected by color ultrasonic scan. The CT scan suggested a large focal in the left lung superior lobe. No evidence proved the existence of an infectious disease, and therefore she was hospitalized and went through a CT-guided percutaneous core needle biopsy of the lung on December 2, 2021. The pathological and molecular biological results supported the diagnosis of non-small cell lung cancer (adenocarcinoma) with epidermal growth factor receptor (EGFR) and TP53 mutation. She was finally diagnosed with lung adenocarcinoma of the left superior lobe (cT3NxM1c, with hilar, mediastinum, neck vertebra, and lumbar vertebra metastasis and EGFR and TP53 mutation). She visited the oncology department and received oral EGFR inhibitor osimertinib based on the doctor’s recommendations and the National Comprehensive Cancer Network (NCCN) guidelines. The periodic lung CT examination after oral osimertinib showed a significant reduction of lung lesions. Then, she underwent irradiation therapy from June to August 2022. In November, she began coughing, with phlegm, and later developed shortness of breath, with no fever, and had chest pain, and she was hospitalized in Yantaishan Hospital. She was diagnosed with tuberculosis, aspergillus, and pneumocystis jirovecii infection and treated with isoniazid, pyrazinamide, ethambutol, quinolone antibiotics, sulfamethoxazole/trimethoprim, voriconazole, and glucocorticoid. The symptoms were significantly alleviated after the anti-infective therapy, but she still had cough and phlegm sometimes. The respiratory symptoms were exacerbated again on December 18, 2022, so the patient visited the respiratory department of Yantai Yuhuangding Hospital on December 19, 2022 and was hospitalized. She felt dyspnea and had no fever at admission. The test for SARS-CoV-2 RNA performed 1 day before hospitalization yielded a negative result.

2.2 Medical history

The patient had a history of hypertension stage 2 and coronary atherosclerotic cardiopathy (CAD) for approximately 20 years, but recently, her blood pressure was normal and she had no sign of CAD without any intervention.

2.3 SARS-CoV-2 vaccination history

The patient was vaccinated with a first dose of inactivated anti-SARS-CoV-2 vaccine (Vero cell) on May 20, 2021, and the second dose was received on June 17, 2021.

2.4 Physical examination

At admission, her body temperature was 36.7°C, her pulse rate was 97/min, her respiratory rate was 23/min, and her blood pressure was 146/79 mmHg. SpO 2 was 99% with a 3 L/min of nasal oxygen supply. Other physical examinations revealed no specific signs, but the Velcro rale was auscultated.

2.5 Laboratory test at hospitalization

The emergency laboratory test results were as follows: blood routine—white blood cell count (WBC), 8.02 × 10 9 /L; neutrophil count (NEU), 7.53 × 10 9 /L; hemoglobin (HGB), 99 g/L; platelet (PLT), 176 × 10 9 /L; lymphocyte count (LYM), 0.22 × 10 9 /L; D-dimer (DDi), 2.24 mg/L; procalcitonin (PCT), 0.0916 ng/mL; and high sensitivity C-reactive protein (hs-CRP), 42.65 mg/L. ProBNP, cardiac biomarkers, hepatic and kidney function tests, and electrolyte panel were not significantly abnormal.

2.6 Therapeutic intervention and outcome

2.6.1 frontline treatment and outcome.

Given the patient’s poor lung condition caused by radiation therapy and suppressed immunity caused by anti-tumor agents, the patient was at a high risk of opportunistic infection. Sulfamethoxazole/trimethoprim (SMZ/TMP, 0.96 g q6h), moxifloxacin (400 mg qd), piperacillin-tazobactam (4.5 g q8h), ganciclovir (0.25 g q12h), methylprednisolone (80 mg qd), and supportive therapy were empirically administrated on the first day. However, the patient’s symptoms were not significantly alleviated after 2 days of treatment. The heart rate accelerated and SpO 2 were decreased, which meant a more serious anoxia than before. The test results for SARS-CoV-2 RNA (swab), (1,3)- β -D-glucan (peripheral blood), and galactomannan (peripheral blood) were negative. A chest X-ray tomography was arranged on December 22, 2022, and it indicated a multiple ground-glass shadow of the lung. Considering the poor immunity result from a previous carcinoma history, intravenous immunoglobulin (10 g qd) was used from December 21 to 27, 2022. Moxifloxacin and piperacillin–tazobactam were ceased, and voriconazole (200 mg q12h) was added by December 22, 2022, given her history of aspergillus and high risk of aspergillus re-infection, and we reduced methylprednisolone as well (40 mg qd) ( Figure 1 ).

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Figure 1 Symptom and treatment.

After observing the abovementioned treatment for another week, the patient’s condition was still unsatisfactory. Although the body temperature and blood pressure were normal, the patient often coughed with phlegm, had dyspnea, and was fatigued. The SpO 2 fluctuated between 84% and 94% with nasal oxygen supply. On December 29, 2022 the COVID-19 RNA test was positive. Chest computerized tomography suggested new bilateral interstitial pneumonia ( Figure 2 ). Ganciclovir was ceased, and paxlovid was administrated from December 29, 2022. Cefoperazone–sulbactam (3 g q8h) was also added starting December 30, 2022.

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Figure 2 Characteristics of CT graphs.

However, no alleviation of the patient’s symptoms was observed after the 5-day treatment including nirmatrelvir/ritonavir. Although we tried the addition of linezolid (200 mg q12h) since January 3, 2023, the symptoms were still serious. Therefore, we advised the utilization of MSCs for salvage therapy.

2.6.2 Salvage treatment by MSCs

2.6.2.1 mscs preparation and ethical consideration.

Clinical-grade human umbilical cord mesenchymal stem cells (hUC-MSCs) were supplied by the umbilical cord blood bank of Shandong Province. The preparation was completed in a GMP laboratory. Samples of human umbilical cords were collected and cut into 2- to 3-mm pieces to be processed for MSCs isolation. Small cylindrical fragments ( d = 2 mm) were removed from the mucous connective tissue (Wharton’s jelly matrix), avoiding blood vessels and amniotic epithelium. They were transferred to culture dishes without any blood serum for adherent culture. Wharton’s jelly fragments were incubated in human MSCs growth medium at 37°C in a humidified incubator under a 21% O 2 and 5% CO 2 atmosphere. After 7–10 days of culture, the first colonies of WJ-MSCs were observed. Then, the cells were pursued until subconfluence; the non-adherent cells were removed, and the stromal cells were detached (0.05% trypsin-ethylenediaminetetraacetic acid (trypsin-EDTA)) and then transferred into 25-cm 3 flasks at an initial density of 5 × 10 3 /cm 3 and cultured up to 70%–80% confluence before collection for subsequent passages. Cells at passages P5 were used and had the International Society for Cell & Gene Therapy (ISCT)-recommended cell surface characteristics of MSCs, including expression (95%) of clusters of differentiation 73 (CD73), CD90, and CD105 and lack of cell surface presentation (<2%) of CD34, CD45, CD14 or CD11b, CD79 α or CD19, and human leukocyte antigen-DR (HLA-DR).

Intravenous administration was used. Before the intravenous drip, the hUC-MSCs were suspended in 100 mL of normal saline, and the total number of transplanted cells was calculated as 1 × 10 6 cells/kg. The MSCs were infused through the patient’s right cubital veins for approximately 1 h (35 drops/min).

It had received approval from the Ethics Committee of Yantai Yuhuangding Hospital for compassionate use. Informed consent was obtained from the patient and her family members.

2.6.2.2 Efficacy of MSCs

The first dose (4.93 × 10 7 cells) of MSCs was intravenously infused on January 4, 2023. Her difficulty in breathing was slightly alleviated. The second dose (4.88 × 10 7 cells) was infused on January 8, which led to an advancing improvement. SpO 2 was higher than before and fluctuated between 95% and 99% after the second dose of MSCs. However, on January 14, 2023, the chest CT indicated a slightly extending bilateral pneumonia and novel pneumothorax of the left lung. Serum interleukin-6 (IL-6) was 34.17 pg/mL ( Figure 3 ), which was believed to be relative to severe COVID-19 ( 36 ). PCT was 0.0785 ng/mL and hs-CRP was 9.68 mg/L. We were concerned that the patient’s condition would be exacerbated again, so the third dose (4.94 × 10 7 cells) of MSCs was arranged in the morning of January 16, 2023. Although the patient had six times of hemoptysis at night, it was quickly controlled the next day and the condition became much better 3 days later. Cefoperazone–sulbactam was changed into ceftizoxime (2 g q12h) in January 14 as well because of limited evidence of serious bacterial infection (low level of PCT detected and normal count of WBC and NEU on weekly surveillance). The fourth and last dose (4.95 × 10 7 cells) of MSCs for consolidation therapy was administrated on January 24, 2023. The patient no longer relied on middle to high oxygen concentration since January 25, 2023. A lung X-ray suggested an improvement of right pneumonia and absorption of the left pneumothorax. All symptoms were alleviated significantly, and her performance status recovered. We prescribed oral antibiotics since February 2, 2023, and the patient was eventually discharged 2 days later. The patient is still alive since the last follow-up on July 15, 2023.

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Figure 3 Laboratory Inspection. (A) Blood routine test and proportion of different blood cells. NEU: neutrophil, LYM: lymphocyte. (B) Lymphocyte subgroup analysis. (C) PCT: Procalcitonin. (D) DDi: D-Dimer. (E) BNP: B-type natriuretic peptide.

3 Discussion

We report a patient with a poor lung condition due to carcinoma and radiotherapy. Complex infections, including bacteria, fungus, and COVID-19, further impaired the lung. Nevertheless, bacteria and fungus might not be the vital pathogen in this case because of continuously low levels of PCT, WBC, NEU, and (1,3)- β -D-glucan and the characteristics of chest CT. The utilization of broad-spectrum antibiotics and antifungal agents did not effectively reverse the pneumonia. The patient received nirmatrelvir/ritonavir immediately when the SARS-CoV-2 RNA test was positive. It was suggested that the hospital admission or death rate of patients who were given nirmatrelvir/ritonavir was only 2.1% ( 37 ). However, she developed a severe disease in a short time. The mortality of all lung cancer patients with COVID-19 was 31.0% in a multi-country pooled analysis ( 38 ). It increased to 58.4% when patients developed severe disease ( 39 ). Therefore, lung cancer patients are at higher risk of death, and the risk would incredibly increase when patients progress to severe COVID-19. We believed that the patient’s condition was less likely to alleviate without advance treatment, and it was urgent and necessary at that time to find a suitable treatment as soon as possible to reverse the disease quickly. The lung injury due to inflammation and former radiation pneumonitis (RP) were a concern, and she needed a treatment option that had a function of immunomodulation and injury repair. The frontline inflammatory inhibitor baricitinib (JAK inhibitor) and tocilizumab (IL-6 inhibitor) could be choices, but they were both hard to acquire at that time and had no evidence of tissue repair effect. In addition, remdesivir is also an option. However, the Chinese Food and Drug Administration did not approve the marketing of remdesivir in China, which may be because, according to the results of several randomized controlled trials, Chinese patients may not benefit from the drug. These trials showed that there was no significant difference in the recovery rate and the risk of progression to severe disease between remdesivir and the control group ( 40 – 42 ). The patient received four doses of MSCs infusion and finally achieved a surprisingly effective outcome. The case indicates that patients with a poor condition of the lung and serious inflammation may benefit from MSCs.

3.1 Potential mechanism of MSCs

ARDS or acute lung injury caused by SARS-CoV-2 induces cytokine storm characterized by severe hypoxemia, high-permeability pulmonary edema, and reduced compliance of the integrated respiratory system as a result of widespread compressive atelectasis and fluid-filled alveoli ( 43 ). Moreover, the virus triggers alveolar and interstitial fibrin deposition, endothelial dysfunction, and pulmonary intravascular coagulation, which may also contribute to the persistence of abnormal inflammatory and disease progress. Recent studies revealed that the biological mechanism of MSCs for the treatment of infectious lung injury might involve multiple pathways. However, immunomodulation and tissue repair might be both crucial.

3.1.1 Immunomodulation

SARS-CoV-2 enters cells, and cells’ capillary permeability increases, allowing more viruses to transfer into cells, resulting in ARDS. The virus activates an immune response involving natural killer (NK) cells, CD4 + T cells, CD8 + T cells, and B cells in COVID-19 patients, causing the abnormal production of cytokines ( 44 ). The abnormal cytokine profile results in excessively activated but dysfunctional immunity reactions in patients with severe COVID-19, which presents a delayed or failed elimination of virus. It has been proven that MSCs affect both innate and acquired immunity to modulate the abnormal immune reaction in patients.

Induction of inflammatory cytokines from macrophages by the nucleocapsid (N) protein of SARS-CoV-2 has been proven. N-protein could promote tumor necrosis factor (TNF), interleukin-1 β (IL-1 β ), interleukin-6 (IL-6), and monocyte chemoattractant protein-1 (MCP-1) secretion of macrophages, which was associated with the occurrence of severe COVID-19 ( 45 ). MSCs affect macrophages through contact-dependent interaction, paracrine-mediated mechanisms, autophagy, mitophagy, and oxidative stress ( 46 ). With MSCs’ existence, pro-inflammatory macrophages secrete anti-inflammatory factors and pro-inflammatory cytokines were downregulated, consequently resulting in the enhancement of phagocytic properties and macrophage type switch ( 47 ). In an experiment in mice, a significant reduction in inflammatory cell and alveolar hemorrhage were observed, and the total number of macrophages and neutrophils, respectively, were remarkably decreased ( 48 ).

In patients with severe COVID-19, NK cell was activated by activating ligands or pro-inflammatory cytokines produced by NK cell itself ( 49 ) or other cells. However, activating receptors on NK cells and transcription factor T-bet were both downregulated, and transforming growth factor- β (TGF β ) inhibited the function of NK cells. This resulted in NK cell exhaustion, impairment, disability to degranulate, and cytotoxicity ( 50 ). The immunological profile in patients with COVID-19 is characterized by the contraction of immature CD56 bright and expansion of mature CD57 + Fc ϵ Rlγ neg adaptive NK cells, which might lead to hyperactive inflammation ( 51 ). Several studies have proven that CD107 α expression of NK cells was observed when NK cells were co-cultured with MSCs, which suggested that MSCs could effectively assist in NK cell degranulation ( 52 ).

Dendritic cells (DCs) are major antigen-presenting cells of innate immunity and bridge adaptive immunity. SARS-CoV-2 promotes the expression of major histocompatibility complex (MHC) molecules and co-stimulatory receptors of DCs that represent its maturation. Additionally, the nuclear factor- κ B (NF- κ B) pathway, which is believed to be vital to the signal responsible for the expression and secretion of pro-inflammatory cytokines, is activated when DCs interact with virus protein ( 53 , 54 ). MSCs have the capacity to inhibit DC maturity and induce mature DC (mDC) differentiation into regulatory DC by many pathways involving notch-1/Jagged-1 signal ( 55 – 57 ), Akt signal ( 58 ), C-C motif chemokine receptor 7 (CCR7) gene degradation ( 59 ), T helper 17 (Th17) cell inhibition ( 60 ), and so on.

At the aspect of T cell, the virus-specified T cell and bystander T cell are both activated in the early stage of infection ( 61 ). However, the unresolved inflammation due to high exposure dose or rapid replication of virus, age, and deficient immunity may result in prolonging the activation of bystander T cells, which can produce pro-inflammatory cytokines continuously ( 62 ). Those long-lasting T cells in severe COVID-19 are dysfunctional and pathological, and massive activation-induced cell death is observed ( 63 , 64 ). MSCs demonstrate an immunomodulatory effect on CD4 + T cells’ subgroup balance and an immunosuppressive effect on CD3 + T cells. MSCs inhibited Th17 and induced Treg differentiation, which led to the attenuation of lung injury caused by the virus ( 65 ). On the other hand, when MSCs were injected in mice with viral pneumonia, attenuated proliferation of both CD3 + , CD4 + and CD4 + , CD8 + T cells was observed, resulting in the significant suppression of pro-inflammation factor level and the protection of mice alveolar epithelial cells from inflammatory injury similar to severe COVID-19 ( 66 ).

The antibody against SARS-CoV-2 is secreted by B cells. In patients with a severe disease, an impaired germinal center response and a robust extrafollicular response were observed compared to those with a mild infection, which might be associated with an elevated level of antibody (perhaps low-mutation IgG1) and pro-inflammatory cytokines. The abnormal activation of extrafollicular B cells in severe COVID-19 is similar to autoimmune response and correlated to an increasing level of inflammation hallmarks and death ( 67 – 69 ). When co-cultured with MSCs, most proteins of the pathway activating B cells were significantly reduced, resulting in the reduction of cell proliferation and transcription gene expression involving terminal differentiation into plasma cell of B cell ( 70 ). Regulatory B cell (Breg) is a new subgroup recently defined with a function similar to Treg, and Breg is increased by MSCs. IL-10 secreted by Breg was increased, and immunoglobulin production was further inhibited ( 71 ). MSCs were believed to ameliorate lung tissue injury by inhibition of chemotaxis gene and immunoglobulin expression at the aspect of humoral immunity ( 72 ).

In summary, MSCs are believed to be effective for severe COVID-19 by the immunity pathways of reducing pro-inflammatory factor through multiple signal pathways, consequently promoting macrophage phenotype switch, NK cell degranulation, regulatory DC generation, Treg differentiation, and B cell activation inhibition.

3.1.2 Tissue repair

There are two types of lung damage relative to severe COVID-19: one induced by inflammation, which possibly induces ARDS and the other connected with fibrosis, also known as post-COVID pulmonary fibrosis. At first, in the acute phase, the virus causes diffuse and severe alveolar damage, including critical endothelial injury, microangiopathy, and obstruction of the alveolar capillaries. After this, the pulmonary surfactant becomes dysfunctional and deficient, contributing to edema and fibrosis. In severe cases, the abovementioned process is continuous and transforms normal lung tissue into fibrous tissue eventually ( 73 ).

MSCs demonstrate multi-potency and high proliferation ability in many studies, which make MSCs an ideal option for regenerative medicine. The extracellular vesicles (EVs) from MSCs are released and contact with the target recipient cell. Afterward, the damaged lung tissue is protected from inflammatory injury and renewed ( 74 , 75 ). When MSCs were co-cultured with injured lung tissue in vitro , 44 kinds of proteins were secreted to accelerate airway epithelium repair by stimulating migration, proliferation, and differentiation. MSCs enhanced anti-apoptosis signal pathways, restored matrix metalloproteinases function, and reduced the percentage of type II alveolar epithelial cells ( 76 – 78 ). An analysis of EVs’ miRNA indicated that miR-223-3p, which is associated with the alleviation of pulmonary fibrosis, was abundant in EVs, and it could attenuate the deposition of fibrosis-related factors. In vitro , EVs restricted the activation and proliferation of fibroblasts ( 79 ). Additionally, miR-214-3p and miR-466f-3p derived from MSCs mediated prevention from radiation injury and inhibited lung fibrosis by downregulating the ATM/P53/P21 signaling and inhibiting the AKT/GSK3 β pathway, respectively ( 80 , 81 ).

Therefore, MSCs repair injured lung tissue caused by severe COVID-19 disease probably through promoting molecules involved in airway epithelium proliferation and differentiation, activation of anti-apoptosis signal pathways, and inhibition of fibroblasts.

3.2 Clinical use and research

3.2.1 case reports.

MSCs have been tried as a salvage treatment for critically ill pneumonia patients after the outbreak of the pandemic. In 2020, Chinese physicians successively shared several cases of severe pneumonia treated with MSCs ( 82 – 88 ), and then similar cases began to be reported in other countries and regions ( 87 – 96 ). The dose range for an intravenous drip of MSCs was ( 1 – 3 ) × 10 6 kg in most of the cases ( 82 – 90 , 96 ). It is also important to note that none of these cases had a history of cancer, except for three cases reported in Sweden in 2022 ( 96 ) ( Table 1 ).

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Table 1 Characteristics of public case reports of mesenchymal stem cells (MSCs) for patients with severe pneumonia.

3.2.2 Clinical trials

Many trials have been performed to explore the efficacy of MSCs for patients with severe pneumonia. The common dose of MSCs for intravenous injection was 0.5 to 3 × 10 6 cell/kg each time for one to three administrations. However, the clinical outcome was varied.

In some small-sample single-arm trials, MSCs demonstrated ideal efficacy with a survival rate of more than 80% ( 15 , 18 , 19 ), while it was just almost 60% in a large-sample single-arm trial ( 17 ). A significantly better survival and time to improvement ( 24 ) were likewise observed in some cohort studies ( 23 , 24 ), but MSCs therapy did not dramatically shorten hospital duration ( 22 , 24 , 25 ). In many small-sample randomized controlled trials, MSCs therapy could significantly decrease mortality ( 27 – 29 , 31 ), shorten hospital time, and increase the rate of clinical improvement ( 26 , 27 , 30 , 31 , 97 ). However, the diagnosis of all eligible subjects was COVID-19 pneumonia, without malignancy under treatment.

A long-time follow-up was described in only one trial, but the risk of secondary cancer was not mentioned ( 97 ). Limited by a small sample, all other trials also did not explore the risk of secondary malignancy in a long time after MSCs administration ( Table 2 ).

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Table 2 Characteristics of public clinical trials of mesenchymal stem cells (MSCs) for patients with severe pneumonia.

3.3 Drawbacks and risk of MSCs

The most controversial drawback is its uncertain effect on tumor generation. Some laboratory studies indicate that MSCs might promote cancer progression and therapeutic resistance. MSCs may secrete prostaglandin E2 (PGE2), IFN-γ, IL-4, TGF-β1, and VEGF to inhibit anti-tumor immune response ( 98 ), stimulate angiogenesis ( 99 ), promote cancer cells metastasis ( 100 ) and proliferation ( 101 ), and protect them from apoptosis ( 102 ), thereby promoting tumor growth. Furthermore, MSCs protect chronic myeloid leukemia cells and ovarian cancer cells against anti-tumor drugs by downregulation of caspase 3 via CXCL12/CXCR4 axis ( 103 , 104 ). A similar phenomenon of drug resistance associated with MSCs was also observed in multiple myeloma and colorectal cancer via the production of CXCL13 ( 105 ) and IL-6 ( 106 ), respectively. Moreover, the multipotential of MSCs brings about concerns that MSCs themselves might be the potential cancer stem cells when MSCs are cultured for the long term ( 107 ).

Clinically, caution needs to be taken regarding some adverse events (AEs) of MSCs. A meta-analysis summarized the AEs of MSCs application over the past 15 years. The most frequent major AEs were fever and administration site conditions, and meaningfully common minor AEs were constipation, fatigue, and insomnia ( 108 ). No increasing risk of tumor generation had been observed ( 109 ). However, given the ethics principle, MSCs’ risk of promoting tumor relapse is still unclear because patients with cancer have been excluded from almost all clinical trials.

4 Conclusion

This is a rare case, with lung cancer and radiation pneumonitis, who suffered from severe infection and was successfully benefit from MSCs infusion. MSCs perhaps reverse the clinical outcomes by immunomodulation and tissue repair. Our case fills the gap of MSCs application for patients with carcinoma accompanied with severe pneumonia. MSCs may be an option for a refractory case in such a period without sufficient and effective drugs.

Data availability statement

The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.

Ethics statement

The studies involving humans were approved by Ethics Committee of Yantai Yuhuangding Hospital. The studies were conducted in accordance with the local legislation and institutional requirements. The participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.

Author contributions

XH: Investigation, Writing – original draft. XT: Investigation, Writing – original draft. XX: Investigation, Writing – original draft. TJ: Conceptualization, Writing – review & editing. YX: Supervision, Validation, Writing – review & editing. ZL: Conceptualization, Supervision, Validation, Writing – review & editing.

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was supported by funding from the National Natural Science Foundation of China (project no. 81903973, project no. 81873426), Shenzhen Science and Technology Plan Project (project no. JCYJ20220530151613030), Shenzhen Nanshan District Technology R&D and Creative Design Project Sub-funded Health Science and Technology Project (project no. NS2022004).

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher’s note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

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100. Martin FT, Dwyer RM, Kelly J, Khan S, Murphy JM, Curran C, et al. Potential role of mesenchymal stem cells (MSCs) in the breast tumour microenvironment: Stimulation of epithelial to mesenchymal transition (EMT). Breast Cancer Res Treat (2010) 124:317–26. doi: 10.1007/s10549-010-0734-1

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Keywords: severe pneumonia, COVID-19, mesenchymal stem cells, lung cancer, immune modulation, tissue repairment

Citation: Huang X, Tan X, Xie X, Jiang T, Xiao Y and Liu Z (2024) Successful salvage of a severe COVID-19 patient previously with lung cancer and radiation pneumonitis by mesenchymal stem cells: a case report and literature review. Front. Immunol. 15:1321236. doi: 10.3389/fimmu.2024.1321236

Received: 13 October 2023; Accepted: 04 January 2024; Published: 06 February 2024.

Reviewed by:

Copyright © 2024 Huang, Tan, Xie, Jiang, Xiao and Liu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Zenghui Liu, [email protected]

† These authors have contributed equally to this work and share first authorship

Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.

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New Insights into Oral Cancer—Risk Factors and Prevention: A Review of Literature

Soussan irani.

1 Dental Research Centre, Department of Oral Pathology, Dental Faculty, Hamadan University of Medical Sciences, Hamadan, Iran

2 School of Medicine, Griffith University, Gold Coast, Australia

The oral cancer constitutes 48% of head and neck cancer cases. Ninety percent of oral cancer cases are histologically diagnosed as oral squamous cell carcinomas (OSCCs). Despite new management strategies, the 5-year survival rate of oral cancer is still below 50% in most countries. Head and neck cancers are heterogeneous tumors, and this characteristic of them provides a challenge to treatment plan. Due to the poor outcomes in oral cancer, prevention is a necessity. In this review, a relevant English Literature search in PubMed, ScienceDirect, and Google Scholar from 2000 to mid-2018 was performed. All published articles related to oral cancer and its prevention were included. The risk factors of oral cancer and strategies of oral cancer prevention will be discussed.

Introduction

Head and neck cancer is the sixth most common human cancer,[ 1 , 2 ] and the oral cancer constitutes 48% of head and neck cancer cases.[ 3 ] Ninety percent of oral cancer cases are histologically diagnosed as oral squamous cell carcinomas (OSCCs).[ 4 ] Despite new management strategies, the 5-year survival rate of oral cancer is still below 50% in most countries.[ 5 ] Head and neck cancers are heterogeneous tumors, and this characteristic of them provides a challenge to treatment plan.[ 6 ] Due to the poor outcomes in oral cancer, prevention is a necessity.[ 7 ] The development of OSCC is a multistep process which starts from some changes in the normal mucosa and continues until the development of invasive cancer and metastasis.[ 1 ] During this progress, the accumulation of multiple genetic and chromosomal alterations occurs.[ 1 , 4 ] Oral cancer is a multifactorial lesion and the risk factors include tobacco and alcohol, chronic inflammation, ultra violet (UV) radiation (for lip cancer), human papilloma virus (HPV) or Candida infections, immunosuppression, genetic predisposition, and diet.[ 8 ] Among them, tobacco use and alcohol consumption are considered as the main risk factors to develop malignancy in the oral cavity.[ 9 ] Oral inflammation is another suggested hypothesis for development of oral cancer due to involvement of several inflammation-related molecular pathways such as cyclooxygenase-2 (COX-2), epidermal growth factor receptor (EGFR), p38a MAP kinase, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB), and STAT (signal transducer and activator of transcription).[ 10 ] Candida albicans genotype A strains have significantly been detected in oral cancer patients compared with non-cancer patients, and C. albicans has also been associated with leukoplakic lesions.[ 9 ] Immunosuppression has also been indicated as a risk factor for development of oral cancer in patients with renal transplant or bone marrow transplantation.[ 11 ] This review article aims to discuss the risk factors and some of new strategies for prevention of oral cancer.

Materials and Methods

A relevant English Literature search in PubMed, ScienceDirect, and Google Scholar from 2000 to mid-2018 was performed. All published articles related to oral cancer and its prevention were included in this review.

Risk factors

Tobacco, smokeless tobacco, and alcohol consumption.

Tobacco smoking and alcohol consumption are considered as the main causal factors for oral cancer.[ 12 ] Besides, the World Health Organization (WHO) has labeled smokeless tobacco (SLT) as a carcinogenic agent although there is a controversy regarding the potential role of SLT in carcinogenesis. Naswar , a mixture of dried tobacco leaves, is kept in the buccal sulcus of the mouth and the active agents are absorbed through the oral mucosa. Naswar is cheap nicotine and is used in replacement therapy for people trying to quit smoking. The amount of carcinogenic agents differs among the different brands in the market. Thus, the risk of oral cancer associated with Naswar is challenging.[ 13 ] Cigarette smoke contains different compounds which have some effects on the gastrointestinal tract including oral cavity. Among them, nicotine is well known for its biological effects on the brain and other organs such as oral cavity.[ 14 , 15 ] Oral snuff and pipe tobacco also contain nicotine similar to cigarette tobacco.[ 15 ] The nicotine metabolites 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and N′-nitrosonornicotine (NNN) have carcinogenic properties.[ 16 ] NNK and NNN bind to the nicotinic acetylcholine receptor to promote cell proliferation and create a microenvironment for tumor growth.[ 16 ] Alcohol alone has no association with cancer progression but synergistically functions with tobacco to develop cancer.[ 12 ] It is not clear how alcohol plays a role in oral carcinogenesis, but several mechanisms have been proposed. First, ethanol is metabolized into acetaldehyde, a known carcinogen. As acetaldehyde is a tumor promoter, the chronic consumption of alcohol promotes the development of oral cancer.[ 17 ] Second, alcohol contains some carcinogenic impurities such as polycyclic aromatic and nitrosamines. Finally, alcohol may contribute in solubilizing of other carcinogenic compounds that may increase the permeability of oral epithelium to these compounds and enhance the penetration of carcinogens into target tissues. The previous studies revealed that alcohol increases the permeability of oral mucosa that results in epithelial atrophy. Besides, alcohol decomposes the lipid composition of the epithelial cell membrane of oral mucosa, which facilities the penetration of carcinogens.[ 18 ] High levels of acetaldehyde production have been associated with certain Streptococcus species, Neisseria species, and other bacteria. Overgrowth of such bacteria has been demonstrated in smokers and heavy drinkers. These bacteria can metabolize ethanol to carcinogenic acetaldehyde and, therefore, are associated with the risk of head and neck squamous cell carcinoma (HNSCC).[ 19 ] Besides, Candida may also contribute to acetaldehyde production.[ 20 ]

HPV infection

HPV and human immunodefiency virus (HIV) are mainly involved viruses in the development of oral cancer.[ 20 ] HPV is a small virus containing a circular double-stranded DNA genome of approximately 8 kb. In head and neck area, HPV16 is the most common type associated with carcinogenesis, followed by HPV18. Regarding oropharyngeal squamous cell carcinoma (OPSCC), HPV infection is the main risk factor due to sexual behavior. The prevalence peak was found in older people especially in men showing a longer duration of infection at older ages.[ 21 ] In cases of oropharyngeal cancer, HPV positivity was mostly found in tonsils (94%), followed by base of the tongue (62%).[ 22 , 23 ] The possible mechanism is direct passage of pathogens like HPV from the mucosal lining of the tonsil and tonsillar crypts.[ 24 ] A previous published work indicated a high prevalence of genital HPV infection among U.S. men.[ 25 ] In addition, another study found the overall prevalence of oral HPV infection is 6.9% in the United States.[ 26 ] HPV16 has a higher risk for OPSCC.[ 22 ] E6 and E7 are the early proteins of HPV which have a key role in HPV-related OPSCC. E6 inhibits p53 and E7 binds to pRb, retinoblastoma protein.[ 27 ] It is suggested that some factors facilitate the oral infection of HPV.[ 28 ] For instance, it is believed that oral epithelial wound is a site for entry of the virus. Also, a previous study found a significant correlation between the number of extracted teeth and prevalence of oral HPV presence.[ 29 ] It is suggested that the basal layer of oral epithelium is infected by HPV as it happens for cervical epithelium.[ 28 ] It is also suggested that poor oral hygiene results in gingival inflammation which may help the penetration of HPV via the oral epithelial superficial layers to invade the basal layer.[ 28 ] HPV persistence can lead to a pre-malignant lesion which progresses to an invasive squamous cell carcinoma (SCC). Interestingly, it is proposed that smoking is associated with a higher risk for oral HPV infection. Although the exact mechanism of this association is not clear, it is believed that smoking induces pro-inflammatory and immunosuppressive effects that increase the risk of HPV oral infection.[ 30 , 31 ] HPV has been suggested as a critical etiological factor for OSCC in non-smokers and non-alcoholic drinkers as well.[ 32 ] In healthy control group, HPV positivity was detected in 12% of samples;[ 33 ] however, HPV positivity was demonstrated 2 to 3 times more in pre-cancerous lesions such as leukoplakia, erythroplakia, and oral submucous fibrosis, and 4.7 times more in oral cancer.[ 23 ] Regarding the oral site for distribution of HPV in cases of OSCC, tongue is the most prevalent site (50%) and the floor of mouth is the least prevalent site (26.8%).[ 34 ] In addition, HPV has been demonstrated as the etiology of some benign oral lesions including squamous papilloma and focal epithelial hyperplasia.[ 35 ] Interestingly, several studies have reported that HPV-related oral or oropharyngeal cancer have a better prognosis.[ 36 ] Prevention of cervical cancer associated with HPV16 and HPV18 infections has been done by vaccination of girls prior to sexual initiation which has an effective impact on oral and oropharyngeal cancer.[ 37 ]

The role of inflammation in cancer development

Chronic inflammation has an essential role in the development of some epithelial cancers such as oral and pharyngeal neoplasms.[ 38 ] Tumor microenvironment is connected to different steps of tumorigenesis and composed of different types of cells such as fibroblasts, myofibroblasts, adipose cells, immune and inflammatory cells, and extracellular matrix (ECM). ECM is composed of collagens, elastin, and proteoglycans/glycosaminoglycans. In pathological conditions, the biomechanical characteristics of ECM change and enhance cell migration which is essential for cancer development.[ 4 ] Besides, ECM is a reservoir for growth factors including fibroblast growth factors (FGFs), hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF), bone morphogenetic proteins (BMPs), and transforming growth factor beta (TGF-β).[ 39 ] Matrix metalloproteinases (MMPs) are necessary to degrade ECM.[ 40 ] For example, MMP2 and MMP9 degrade type IV collagen to facilitate invasion.[ 41 ] In HNSCC patients, the over-expression of MMP9 and MMP2 is associated with lymph node involvement.[ 42 , 43 ] A growing body of studies shows the overexpression of COX-2 in 80% of head and neck pre-malignant and malignant tissue samples. Besides, overexpression of COX-2 is associated with lymph node metastasis in head and neck cancer cases.[ 44 ] COX-2 induces carcinogenesis in murine models.[ 44 , 45 ]

Oral microbiome

Several cancers are linked to microorganisms such as HPV (cervical cancer, oropharyngeal cancer),[ 46 ] EBV (head and neck cancer),[ 47 ] hepatitis B and C virus (hepatocellular carcinoma),[ 48 ] Helicobacter pylori (gastroduodenal cancer),[ 49 ] and Porphyromonas gingivalis (orodigestive cancer).[ 50 , 51 ] More than 700 different bacterial species colonize the human oral cavity, called the oral microbiome.[ 52 ] The oral microbiota has a critical role in human health such as immune response, nutrient digestion, and carcinogen metabolism. Gingivitis and periodontitis are the most common inflammatory tooth structure conditions[ 53 ] and the main causative microorganism for periodontitis is Porphyromonas gingivalis. A previous study on OSCC showed that P. gingivalis interacts with oral cancer cells.[ 54 ] Another published work demonstrated that periodontitis promotes the development of oral leukoplakia in a dose-dependent manner.[ 55 ] Poor oral health is correlated to elevated risk of several diseases including cancers such as head and neck cancer, esophagus cancer, stomach cancer, and pancreas cancers. The mechanism is not clear, perhaps oral microbiome such as H. pylori causes chronic inflammation which in turn participates in cancer pathogenesis such as gastric cancer and oral cancer.[ 52 , 53 , 56 , 57 , 58 ]

Genetic predisposition

Genetic predisposition plays a critical role in the development of OSCC, especially tongue and buccal mucosa cancers.[ 4 , 59 ] It is suggested that in 29.5% of first-degree relatives of head and neck cancer patients, other cancers such as respiratory tract and upper orodigestive tract cancers can develop.[ 60 ] However, in terms of oral cancer, it is hard to determine genetic or familial disposition due to coexistence of risk factors such as smoking and alcohol. Some investigators believe that people who inherit the inability to metabolize carcinogens or pro-carcinogens are not able to repair DNA damage; therefore, they are susceptible to develop an oral malignancy. For example, in cases of tobacco-induced head and neck cancers, genetic polymorphisms of the P450 enzymes, and xenobiotic metabolizing enzymes (XMEs) which are responsible for tobacco carcinogen metabolism play an essential role in the genetic predisposition.[ 61 ] The inactivation of p53 and pRb tumor suppressor gene leads to the accumulation of genomic alterations, inhibition of the apoptotic signaling, and an increase of the telomerase activity.[ 24 , 62 ] Epithelial-mesenchymal transition (EMT) process contributes to cancer stemness and cancer metastasis.[ 63 , 64 , 65 , 66 ] Prior study demonstrated that areca nut extract or arecoline activates several EMT-related molecules, such as vimentin, in oral epithelial cells.[ 67 ]

Precancerous lesions and the field cancerization

It is estimated that 50% of oral cancers develop from precursor lesions.[ 5 ] Therefore, early detection and proper management of the pre-malignant lesions play a critical role in preventive programs.[ 7 ] However, a prior published paper indicated that surgically treated pre-cancerous lesions cannot reduce the rate of malignant transformation perhaps due to field cancerization.[ 5 ] The concept of field cancerization, first coined by Slaughter et al . in 1953, explains the development of multiple primary tumors and recurrent local tumors. This term is a phenomenon by which molecular alterations develop in normal-appearing tissue and, overtime, form premalignant lesions which progress to dysplasia and finally to a frank cancer.[ 68 ] In the beginning, the oral epithelium exposed to a carcinogen may look like a normal mucosa.[ 3 ] Oral epithelial dysplasia is a precancerous change and has a high risk of progressing to oral cancer.[ 7 , 69 ] Oral premalignant lesions include leukoplakia, erythroplakia, submucous fibrosis, reverse smoking, lichen planus,[ 69 , 70 ] and discoid lupus erythematosus.[ 7 ] Tobacco smoking is one of the factors which increases the risk of malignant changes in oral epithelium. Increased proliferation rate of oral epithelium due to tobacco smoking occurs even after cessation of smoking which suggests that smoking involves field cancerization.[ 3 ] Loss of chromosomal material in 3p, 9q, and 17p has been reported as the early markers of carcinogenesis in dysplastic lesions.[ 71 ] Braakhuis et al . updated the model of field cancerization. According to their proposal, the stem cells of the proliferative basal layer are involved in carcinogenesis.[ 72 ] Van Houton et al . demonstrated the p53 gene-mutated cells called patches as an early event in oral cancer. They proposed that the altered cells acquire more mutations and spread laterally to replace the normal epithelial cells.[ 73 ] These cluster of cells show TP53 mutation especially in patients with multiple primary head and neck tumors.[ 72 ] Overtime, the accumulation of mutations within the fields results in invasive carcinoma with metastatic potential.[ 74 ] Lydiatt et al . found that clinically normal appearing oral mucosa surrounding cancer harbors early pre-malignant genetic alterations. The field of cancerization may extend from 4 mm to 7 cm.[ 75 ] Figure 1 summarizes the mechanism of genetic alteration and field cancerization to develop oral carcinoma.

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Schematic mechanism of genetic alteration and field cancerization to develop a carcinoma

Oral cancer prevention strategies

Recently published studies assessed microbial compositions in patients with OSCC. Interestingly, the microbial flora of patients was different from healthy individuals. It is suggested that some factors such as diet, age, and smoking have effects on the microbial composition and development of OSCC. It is assumed that cytokines and other secretory mediators of bacteria lead to malignant transformation. There are accumulating evidence to indicate a higher incidence of oral cancer in patients with poor oral hygiene.[ 76 ] Probiotics are live microorganisms which provide a health benefit on the host. The probiotic products mostly contain lactic acid bacteria and help host for the maintenance of intestinal microbial balance. Recent data on probiotic products show a protective effect against the carcinogenic activity of mediators of bacteria. Among them, Lactobacillus acidophilus and Lactobacillus casei have been known for reducing the level of cytokines and mediators of bacteria. Besides, consuming the probiotics significantly reduces Streptococcus mutans counts which prevents tooth decay, improves periodontitis, and is effective for the treatment of oral candidiasis.[ 76 ] Previous studies have shown that consumption of probiotics is useful for treatment of periodontitis and elimination of halitosis[ 76 ] as well as controlling oral candidiasis and hyposalivation in elderly patients.[ 77 ] Also, probiotics have potential for prevention of tumor formation and metastasis. A daily probiotic drink for 6 months enhances the clearance of HPV and cervical pre-malignant lesions.[ 78 ]

Chemoprevention

Chemoprevention is a promising plan to inhibit, suppress, or control the carcinogenesis. Regarding oral lesions, leukoplakia and postoperative oral cancer patients are the best target population for chemoprevention.[ 79 ] There are some natural products to prevent oral cancer such as polyphenols and strong antioxidants like vitamin C, E, and carotenoids.[ 2 ] Vitamin A, isotretinoin (13-cis retinoic acid), green tea extract, and some medicinal herbs have been used as chemo-preventive agents.[ 79 ] Curcumin, an active constituent of turmeric, is a polyphenol used as a spice or medicine in India.[ 80 , 81 ] Curcumin has anticancer effects in HNSCC due to anti-inflammatory effect via down-regulation of NF-κB and pro-apoptotic effects through up-regulation and activation of p53 and p21.[ 82 , 83 ] Besides, curcumin inhibits tumor growth via targeting VEGF, the most powerful angiogenic factor, and the EGFR.[ 82 , 84 ] Interestingly, curcumin inhibits HPV oncoprotein transcription via inhibiting AP-1 transcription factor and via interaction between curcumin and P53 binding site of E6 protein of HPV16.[ 85 ] Other sources of polyphenols are grape seed extract, green tea extract, cocoa extract, and coffee.[ 86 , 87 , 88 ] Previous epidemiological studies found an association between coffee consumption and reduced cancer incidence or mortality.[ 89 ] A previous study revealed that coffee consumption can reduce the risk of oral cancer.[ 90 ] Another meta-analysis found an association between reduced risk of oral cancer and tea consumption.[ 91 ] Hong et al . used isotretinoin to treat oral leukoplakia. They showed isotretinoin could decrease the size of the lesion and also reversed oral dysplastic changes,[ 92 ] even though isotretinoin could prevent recurrence of tumor in HNSCC patients in a dose-dependent manner.[ 82 ] In addition, isotretinoin in combination with interferon-α and α-tocopherol (vitamin E) has a great effect on oral pre-malignant lesions.[ 93 ] Luteolin, a flavonoid, found in vegetables like cabbage, celery, broccoli, and parsley, is absorbed by the oral epithelium and has anti-inflammatory effects by blocking the NF-κB pathway. Delivery of luteolin in nanoparticles inhibited the growth of HNSCC tumors in vitro and in vivo .[ 94 ] Lycopene, a natural compound in red-colored carotenoid especially in tomatoes, decreases the risk of cancer. Anti-cancer effect of lycopene acts by different mechanisms. For example, lycopene inhibits VEGF-mediated angiogenesis and also decreases plasma levels and activity of MMP-2 and MMP-9 to inhibit invasion and metastasis.[ 82 ] Pomegranate, the fruit of the tree Punica granatum , has anti-oxidant and anti-inflammatory effects. The polyphenol-rich fractions of pomegranate contain polyphenol which inhibits the growth of cancer cells such as breast cancer. Pomegranate decreases the expression levels of VEGF and hypoxia-inducible factor 1-alpha (HIF-1α).[ 95 ] Omega-3 fatty acids are also used for cancer prevention. Omega-3 fatty acids reduce production of cytokines such as interleukin-1 (IL-1), IL-6, and tumor necrosis factor (TNF).[ 96 ] Resolvin D-series (RvDs) are endogenous lipid mediators derived from omega-3 fatty acids and have anti-cancer and analgesic effects on OSCC.[ 97 ] Diets containing vegetables like broccoli, cabbage, and cauliflower are associated with reduced risk of HNSCC. It is clear that broccoli extracts promote detoxication of chemical carcinogens found in tobacco smoke and the airborne pollutants acrolein and benzene.[ 98 ] Besides, salted food and some that contain preservatives develop head and neck cancer. Improper diet and nutrition including lack of vegetables, fruits, and vitamins are suggested to be another risk factor for oral cancer, as some food contain antioxidants which can inhibit DNA mutation and change in enzyme activity.[ 52 , 99 ] Mediterranean diet (MD), rich in monounsaturated fatty acids from olive oil, vegetables fruits, fish, low-fat dairy, moderate alcohol intake, and low red meat consumption, reduces the risk of developing many diseases including head and neck cancer due to α-tocopherol and phenol oils and being good sources of dietary fiber and antioxidants.[ 100 ] Pterostilbene, a pantropical genus of trees, inhibits DNA synthesis. Pterostilbene induces apoptosis of oral cancer cells via activation of caspase-3, -8, and -9. Iranian orthodox black tea extracts induces apoptosis in oral cancer cells in vitro .[ 2 ] H. pylori is a resident in the oral cavity especially in the developing countries. Eradication of H. pylori infection is difficult.[ 56 , 57 , 58 ] Sulforaphane, a compound obtained from cruciferous vegetables such as broccoli, Brussels sprouts, and cabbages, kills H. pylori which is recognized as the main cause of stomach cancer.[ 101 , 102 ]

The role of anti-inflammatory drugs on cancer prevention

Celecoxib (CXB), a selective COX-2 inhibitor, is approved for use in early cancer prevention in some lesions such as familial adenomatous polyposis. CXB has different anti-cancer progression molecular mechanisms including anti-angiogenesis activity via decreasing VEGF production and anti-EMT properties.[ 103 ] In murine model study, CXB inhibited EMT phenomenon in OSCC.[ 104 ] Aspirin, another anti-inflammatory drug, significantly reduces the risk of colorectal cancer.[ 105 ] A previous study on aspirin and its role in head and neck cancer found an association between the reduction of risk of cancer especially in people with low to moderate exposure to cigarette smoke or alcohol consumption.[ 106 ] Another study demonstrated an improved survival rate in patients with head and neck cancer who used aspirin after diagnosis.[ 107 ] However, a recent published work did not find any effect of aspirin on survival or recurrence of HNSCC cases.[ 108 ]

Cancer screening, early detection

Cancers detected at early stages can be treated more successfully. Delay in diagnosis has effect on cancer-related morbidity and mortality. Therefore, screening and early clinical diagnosis help to provide more safe and cheap treatments. Awareness of health care providers has a great impact on early diagnosis.[ 52 , 109 , 110 ] It is critical that oral health professionals understand the importance of oral screening examination for pre-malignant and malignant lesions.[ 110 , 111 , 112 , 113 ] Dentists are usually the first health care professionals who examine the oral cavity and, therefore, have the opportunity to screen oral cancer.[ 1 , 4 , 111 , 112 , 113 , 114 ] A visible precancerous lesion helps the practitioners in early detection and treatment.[ 115 ] Moreover, the mouth self-examination is another way to detect oral cancer at early stage.[ 116 ] Salivary biomarkers can also help in the diagnosis of potentially malignant and malignant disorders of the mouth. For example, Cyfra-21-1, tissue polypetide antigen [TPA], and cancer antigen CA-125 are tumor markers which are significantly increased in saliva of patients with OSCC.[ 117 ] Choline and pipecolate can be detected in the saliva of patients with OSCC even in early stages.[ 118 ] Altogether, the best diagnostic technique is experience and training. Salivary biomarkers help in early detection of oral cancer. Some other methods such as toluidine blue staining and lugol staining are helpful in the screening of pre-malignant and malignant lesions of the oral cavity. Besides, tissue biopsy and histopathological examination should remain the gold standard for oral cancer diagnosis.[ 119 ] Like the cervical cancer, the incidence of OPSCC in women is decreasing in the United States due to increased preventive health care such as screening.[ 120 ]

The role of biomarkers for oral cancer detection

Carcinogenesis is a multistep process, and recent studies on molecular biology have indicated the genetic basis of the process of carcinogenesis.[ 63 , 121 ] Secretory leukocyte protease inhibitor (SLPI) has broad anti-microbial and anti-inflammatory properties and has been considered as a potential diagnostic and prognostic biomarker in head and neck cancer. Besides, SLPI protects against head and neck cancer development. Salivary SLPI reduces transmission of HIV in the oral cavity and also protects against oral HPV infection. It is suggested that SLPI protects oral mucosa against proteolysis, epithelial tissue damage, and degradation in cases of prolonged epithelial cell exposure to carcinogens such as tobacco and alcohol. SLPI protein expression decreases the risk of lymph node metastases.[ 122 ] CD44, a cell surface transmembrane glycoprotein, is overexpressed in pre-malignant lesions of the larynx and stomach.[ 123 , 124 ] CD44 is found in body fluids such as saliva; a prior study suggested CD44 and total protein as reliable markers to test and screen increased risk of oral cancer.[ 125 ] Previous studies on OSCC and mucoepidermoid carcinoma, the most prevalent malignant salivary gland tumor, suggested CD44 as an effective head and neck cancer biomarker.[ 63 , 65 ] Zhong et al . detected telomerase activity in the saliva of the 75% of patients with OSCC. They suggested the telomerase detection as an assistant marker in the OSCC.[ 126 ] Different molecular biomarkers have been investigated regarding the heterogeneity of head and neck cancers[ 7 , 63 , 64 , 65 ] such as E-cadherin and VE-cadherin as the components of adherent junctions involved in EMT. Also DNA repair proteins like BRCA1/2 are linked to treatment outcomes.[ 121 ] BRCA1/2 genes are involved in DNA repair in cancers such as breast cancer and ovarian cancer. A recent published work revealed the BRCA1/2 mutations in salivary gland tumors.[ 121 ] In addition, miRNAs also have an impact on the head and neck cancer growth and metastasis.[ 6 , 7 , 127 ] Several recently published works demonstrated circular miRNAs as a non-invasive biomarker in early detection of different cancers.[ 6 , 84 , 128 ] Knowledge about biomarkers may help to predict prognosis and decrease the rate of mortality due to finding a new target therapy.[ 129 ] Table 1 gives a summary of risk factors and the prevention strategies of oral cancer.

Summary of risk factors and prevention strategies of oral cancer

Conclusions

Several risk factors might be involved in the development of oral cancer. Among them, tobacco smoking, alcohol consumption, and HPV are the most studied risk factors. Besides, inflammation and genetic susceptibility are believed to play an essential role. Many studies have focused on oral cancer risk factors, early detection, and cancer treatments. Due to high morbidity and mortality rates of oral cancer, more effective strategies and treatment plans are needed. Surgery is the main treatment strategy for patients with oral cancer. Radiotherapy and chemotherapy are reserved for patients who are not able to tolerate surgery.[ 130 ] On the contrary, all the aforementioned treatment strategies have serious consequences such as emotional and physical disorders. Oral cancer prevention and early detection can reduce those serious consequences. Currently, the role of probiotics and natural products in the prevention and treatment of oral cancer has been studied, but further studies are required to evaluate the benefits of them in oral cancer prevention and treatment. Thus, the awareness of public and clinicians of the risk factors and early signs of oral cancer has a great impact on prevention. In addition, better understanding of molecular pathways in the development of oral cancer improves prevention and early detection. Much work has to be done to identify strategies to decrease morbidity and mortality rates of oral cancer.

Financial support and sponsorship

Conflicts of interest.

There are no conflicts of interest.

Acknowledgment

The author would like to thank Hamadan University of Medical Sciences for financial support.

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  3. Nutrition and Breast Cancer: A Literature Review on Prevention

    Data from the published literature suggest that a healthy dietary pattern characterized by high intake of unrefined cereals, vegetables, fruit, nuts and olive oil, and a moderate/low consumption of saturated fatty acids and red meat, might improve overall survival after diagnosis of BC.

  4. Evaluating cancer research impact: lessons and examples from existing

    Empirical examples of impact assessments of cancer research were identified from these literature reviews. Approaches used in these examples were appraised, with a reflection on which methods would be suited to cancer research impact evaluation going forward. Results In total, 40 literature reviews were identified.

  5. Literature Review: Overview of Cancer Treatment and ...

    First Online: 16 April 2021 347 Accesses Part of the Advanced Information and Knowledge Processing book series (AI&KP) Abstract The purpose of this chapter is to provide a literature survey through an overview of the research fields relevant to cancer treatment and prediction approaches based on machine learning.

  6. Review Articles in 2022

    Alexander Ring Bich Doan Nguyen-Sträuli Nicola Aceto Review Article 09 Dec 2022 Targeting DNA damage response pathways in cancer Genes encoding DNA damage response factors are frequently...

  7. Dietary patterns and cancer risk

    World Cancer Research Fund & American Institute for Cancer Research. ... The 2018 Third Expert Report provides an update and comprehensive review of the literature on diet and cancer. Krebs-Smith ...

  8. A systematic literature review of real-world treatment... : Medicine

    cancer (SCLC) prior to the global introduction of immunotherapies for this disease. Methods: Searches were conducted in MEDLINE and Embase to identify articles published in English from October 1, 2015, through May 20, 2020. Searches were designed using a combination of Medical Subject Heading (Medline), Emtree (Embase subject headings), and free-text terms such as SCLC. Observational studies ...

  9. Review of cancer from perspective of molecular

    Introduction Cancer is the second leading cause of mortality worldwide. Overall, the prevalence of cancer has actually increased; just in the United States alone, approximately 1,665,540 people suffered from cancer, and 585,720 of them died due to this disease by 2014 1.

  10. The Supportive Care Needs of Cancer Patients: a Systematic Review

    28 Citations 4 Altmetric Explore all metrics Abstract Cancer, and the complex nature of treatment, has a profound impact on lives of patients and their families. Subsequently, cancer patients have a wide range of needs. This study aims to identify and synthesise cancer patients' views about areas where they need support throughout their care.

  11. Cancer Literature Review

    Literature Reviews Cancer Literature Review Cancer Literature Review Finding solutions to cancer - World Cancer Day 2020 Diamond Light Source is playing its part in reducing the global impact of cancer and supporting the aims of World Cancer Day.

  12. Systematic reviews and cancer research: a suggested stepwise ...

    Systematic reviews and cancer research: a suggested stepwise approach Systematic reviews, with or without meta-analysis, play an important role today in synthesizing cancer research and are frequently used to guide decision-making.

  13. A Systematic Literature Review of Breast Cancer Diagnosis ...

    1 Introduction According to the GLOBOCAN, 2020 report, 19.3 million cancer cases and 10 million deaths were recorded in 2020 [ 1, 2 ]. The number of female breast cancer cases has surpassed that of lung cancer, with 2.3 million new cases predicted [ 3, 4, 5, 6, 7 ].

  14. Cancer Survivorship Research: A Review of the Literature and Summary of

    This paper provides a review of interventional and observational cancer survivorship research efforts as well as a summary of current cancer survivorship research projects being conducted by National Cancer Institute-designated cancer centers in an effort to identify areas that need further attention.

  15. Understanding Cancer Research Study Design and How to Evaluate Results

    Research studies are always shaping and reshaping the scientific understanding of cancer. But no single study is the final word on a type of cancer treatment. As a result, review articles are very helpful. Review articles study and sum up the findings of already published research on a certain topic. Types of review articles include: Systematic ...

  16. Writing a literature review

    Writing a literature review requires a range of skills to gather, sort, evaluate and summarise peer-reviewed published data into a relevant and informative unbiased narrative. Digital access to research papers, academic texts, review articles, reference databases and public data sets are all sources of information that are available to enrich ...

  17. Literature Review: Overview of Cancer Treatment and Prediction

    Ahmed Maalel University of Sousse Mahbouba Hattab University of Sousse Abstract and Figures The purpose of this chapter is to provide a literature survey through an overview of the research...

  18. (PDF) cancer: an overview

    cancer: an overview Academic Journal of Cancer Research 8 (1):01-09 Authors: Garima Mathur Galgotias University Abstract Now a day's cancer is the most prevalent life threatening disease...

  19. Anastrozole for the prevention of breast cancer in high-risk

    The effectiveness of anastrozole for breast cancer prevention has been demonstrated. The objective of this study was to evaluate the cost-effectiveness of anastrozole for the prevention of breast cancer in women with a high risk of breast cancer and to determine whether anastrozole for the primary prevention of breast cancer can improve the quality of life of women and save health-care resources.

  20. Media coverage of cancer therapeutics: A review of literature

    Methods: This literature review included peer-reviewed primary research articles that reported how cancer treatments are portrayed in the lay media. A structured literature search of Medline, EMBASE and Google Scholar was performed. Potentially eligible articles were reviewed by three authors for inclusion. Three reviewers, each independently ...

  21. A literature review on the imaging methods for breast cancer

    In a literature review, Leonard Fass (2008) and Safarpour Lima and colleagues (2019) found that cancer care is dependent on imaging through screening [ 11, 14 ].

  22. Cancer Research

    About the Journal. Cancer Research publishes impactful original studies, reviews, and opinion pieces of high significance to the broad cancer research community.Cancer Research seeks manuscripts that offer conceptual or technological advances leading to basic and translational insights into cancer biology.Read More About the Journal

  23. A review of literature about involving people affected by cancer in

    Objective: To systematically review the literature on involving people affected by cancer in healthcare research, policy and planning and practice. Methods: Database searches, cited author, and grey literature searches were conducted. Results: 131 documents were included. Rationales for the agenda of involvement represent two polar characteristics of modernity: individualism and collectivism.

  24. Frontiers

    3.2 Clinical use and research ... and factors associated with mortality among patients with SARS-CoV-2 infection and cancer compared with those without cancer: A systematic review and meta-analysis. ... a case report and literature review. Front. Immunol. 15:1321236. doi: ...

  25. New Insights into Oral Cancer—Risk Factors and Prevention: A Review of

    In this review, a relevant English Literature search in PubMed, ScienceDirect, and Google Scholar from 2000 to mid-2018 was performed. All published articles related to oral cancer and its prevention were included. The risk factors of oral cancer and strategies of oral cancer prevention will be discussed.

  26. Volunteer Needed for Grief Literature Review

    We are looking for a volunteer to help us with data extraction for our literature review on Prolonged Grief in African Americans. As a volunteer, you would read research articles to extract relevant data in Covidence. The position could expand to include title and abstract screening, full-text review, and article writing. We are looking for someone who is: If you are interested or if you have ...