Global colorectal cancer research, 2007‐2021: Outputs and funding

Abstract The purpose of this study was to provide an evidence base for colorectal cancer research activity that might influence policy, mainly at the national level. Improvements in healthcare delivery have lengthened life expectancy, but within a situation of increased cancer incidence. The disease burden of CRC has risen significantly, particularly in Africa, Asia and Latin America. Research is key to its control and reduction, but few studies have delineated the volume and funding of global research on CRC. We identified research papers in the Web of Science (WoS) from 2007 to 2021, and determined the contributions of the leading countries, the research domains studied, and their sources of funding. We identified 62 716 papers, representing 5.7% of all cancer papers. This percentage was somewhat disproportionate to the disease burden (7.7% in 2015), especially in Eastern Europe. International collaboration increased over the time period in almost all countries except in China. Genetics, surgery and prognosis were the leading research domains. However, research on palliative care and quality‐of‐life in CRC was lacking. In Western Europe, the main funding source was the charity sector, particularly in the UK, but in most other countries government played the leading role, especially in China and the USA. There was little support from industry. Several Asian countries provided minimal contestable funding, which may have reduced the impact of their CRC research. Certain countries must perform more CRC research overall, especially in domains such as screening, palliative care and quality‐of‐life. The private‐non‐profit sector should be an alternative source of support.

relative contribution of different countries. CRC accounted for 5.7% of all cancer papers, slightly less than its share of the disease burden. Some regions, such as Eastern Europe, are underperforming in CRC research relative to their economic status. Leading areas of research included genetics and surgery, and more research is needed on palliative care and quality-of-life. Some countries, including China and the US, provide substantial government funding for CRC research, while others rely on the charity sector. Overall, the private sector provided little funding.

| INTRODUCTION
Between 2000 and 2015, major improvements were achieved in global health, leading to increases in life expectancy. [1][2][3] These improvements were particularly significant in low-and lowermiddle income countries (LMICs). 4,5 But as populations age, their cancer burden increases 6 and cancers such as colorectal cancer (CRC) cause significant morbidity and mortality. 7,8 Thus, in 2000, CRC accounted for 0.51% of the world total disease burden, but in 2015 this had increased to 0.70%, according to the World Health Organization. 9 The impact of CRC is measured in Disability Adjusted Life Years (DALYs), which take account both of early death and of time spent living with a disease. The increase in DALYs was 56% in Asia and in Latin America, and as much as 67% in Africa. CRC also increased its share of the overall cancer burden, with a rise of 9%, but with percentage increases of 27% in Latin America and 23% in Asia. 9 Research is an essential aspect of high quality CRC care systems. 10 Patients treated at research-active hospitals have better outcomes than those who are not. 11 However, to date there has been little systematic consideration of the state of global CRC research.
The only publication that focused on the disease by itself was a list of the 100 most influential papers. 12 However, this did not address the geographical spread of the total output, or its variation with time. No previous study has determined if CRC research was performed in the research domains most important for the understanding, control and treatment of the disease.
Some bibliometric studies of overall cancer research in selected geographical areas have shown that CRC is neglected by researchers relative to its burden of disease. As a proportion of all cancer research, CRC research appeared to be only 50% of what would be expected, based on the percentage of deaths in India in 2004. 13 16 ). The time difference was designed to allow for the time taken for the research to be conducted and published. We grouped the countries by continent, and then compared these outputs relative to all cancer research with their collective burden in DALYs from CRC, and their overall cancer disease burden. This was performed in order to determine if CRC research was receiving sufficient attention, relative to that on other cancer anatomical sites. We also listed the leading individual organizations that published CRC research papers, and determined for each of them the corresponding total for all cancer research (ONCOL) and the ratio between them, which shows whether or not they placed additional focus on CRC research.
A second macro was employed to characterize the papers by their research domain (such as genetics, surgery, quality-of-life), based on words in their title or the journals in which they were published. We determined the relative commitment of the leading countries to each type of research, in order to show which research domains predominated and also which might benefit from more international collaboration. We also subdivided the domain of genetics into four subject areas: heritability, sporadic CRC, genomic signatures and animal models.
Finally, we analyzed the funding sources for the papers published from 2009 to 2016. Since late 2008, the WoS has included explicit funding acknowledgement data as three searchable fields. However, it is also necessary to take account of implicit acknowledgements from paper addresses for government laboratories, those of commercial companies, and collecting charities (but not foundations). Because the names of financial sponsors are given in many different formats, we coded them with a three-part code 17 6,13,14 This focus on surgical research reflects its primacy as the major treat- increased its share to 22% of the total, but surgery declined to 18%.
Palliative care also increased, to 1.0% of the total in these 3 years.    for successful men and their wives (see Table 4), 17 and a few large ones, such as Lundbeck and Novo Nordisk.
There was also a big variation in the governmental sector, between departments (under direct ministerial control) and agencies (intended to be independent). In some countries, notably Sweden (SE; 70%), Canada (CA; 61%), China (CN; 47%), Belgium (BE; 46%), Brazil (BR; 45%) and Norway (NO; 45%), local or regional authorities were substantial funders of this research ( Table 4). The percentage contribution of government agencies, which usually have a contestable grant funding system with peer review, is particularly strong in France (FR; 90%), the USA (86%) and Switzerland (CH; 77%).
Industry funded only 4.9% of the research. This is much less than for lung cancer, which was reaching 8% in 2009 to 2013. 18 Figure 3 shows that commercial funding is not a major contributor to CRC research, except in Belgium (BE; 13%) and Germany (DE; 10%). Overall, pharma companies contributed 46% of the total, and biotech companies, 15% (although the distinction between them is often not clear), and nonpharma The quality of the research must also be considered.
The needs of CRC research in the individual countries will vary, because there are substantial differences in the impact of the disease. 19 Our study reveals that certain countries, especially in Eastern Europe, are underperforming in CRC research relative to their GDP and need to do more to address the rising burden of this cancer. Countries such as Brazil and Switzerland may also need to change their research portfolios, to respond to the specific CRC-related challenges they face.  Table 1 Although CRC morbidity and mortality can be mitigated through appropriate screening and surveillance approaches, these research areas appear to be neglected in many countries, especially in Asia.
This may be due to a shortage of human and financial resources, but also a lack of awareness of the need for these types of research.
Tumor heterogeneity in CRC has been identified, and many approaches have been developed to determine patient prognosis based on the biology of individual tumors and personal characteristics. 29 Thus, research on the prognosis of CRC has attracted more and more attention, and its output recently overtook that in genetics.
Palliative care research has been severely neglected, perhaps because it requires more collaboration from workers from several different disciplines who provide support to patients. However, recently it has received more attention, although it still represents barely 1% of the total research output.
Alternative sources of funding are evidently needed and should be actively sought by governments and societies. This will involve fiscal encouragement to the charitable sector, and the formation and support of medical research charities in geographical areas where they do not currently exist. However, this is particularly difficult in LMICs, where medical research and science are usually low on the list of national priorities. In this context, international collaboration can be an important source of additional funding, and can also provide a level of peer review for national funding bodies. For example, in the Czech Republic international collaborative proposals that are deemed fundable by say an EU funding scheme, but fall just below the overall budget threshold, may be funded at national level following the positive peer review.
The study has some limitations. We used a single database of research outputs (the WoS). This has some language biases, omitting a proportion of clinical papers in national languages, especially from East Asia. For example, the papers from China are in much more basic/discovery research on average than those from the rest of the world, so it is likely that a number of clinical papers will have been omitted from the WoS. A few funding sources could not be coded, as no information about them was available on the Web, or they were given in the acknowledgements only as initials. There were also some funding references where their name was not given, only the grant number, and not all of these sources could be identified. Nonetheless, the data accumulated and evaluated in this study provide crucial T A B L E 4 The funding sub-sectors contributing to the total government and private-non-profit sectoral contributions to CRC research in 23 leading countries, 2007 to 2016 intelligence to help guide our collective research efforts to understand CRC and deliver research-informed insights that will help reduce its global burden.