Points of View Cancer Prevention

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Minoru Ito, Senior Researcher, Pharmaceutical and Industrial Policy Research Institute

SUMMARY

Although the cancer survival rate and the number of survivors are improving and increasing due to the increase in new drugs and other factors, cancer remains the leading cause of death and national health care expenditure, and is expected to continue to affect the health of the population in the future. Cancer prevention research is ongoing in a wide range of areas, including the environment and lifestyle, and we were able to confirm that this research is being reflected in policy to some extent. A comparison of policies between Japan and the U.S. showed little difference in primary prevention. In secondary prevention, the emphasis on cancer screening was similar in Japan and the U.S., but the U.S. was ahead in terms of communication and education measures, and in setting targets for genetic testing for hereditary cancers. The next report showed that the emphasis on cancer screening was similar in Japan and the U.S. Furthermore, a comparison of cancer prevention research policies in Japan and the U.S. revealed that the two countries share the same general direction of focusing on high-risk groups through risk stratification, but there are differences in research targets (Japanese: cancers common in Asia and rare/refractory cancers vs. U.S.: hereditary cancer syndrome), scope (Japanese: only identifying high-risk groups vs. U.S.: including research on communication and decision-making for high-risk populations), and research methods (Japanese: emphasis on behavioral science vs. U.S.: emphasis on implementation science).

1. Introduction

When looking at next-generation healthcare from the perspective of expanding the scope of healthcare services, it is indisputable that all phases are important for extending healthy life expectancy: "pre-disease/prevention," "diagnosis/treatment," and "prognosis/coexistence. In ^{the "} Policy Research Institute News No. 621 ^," the author focused on cancer survivors and reported on the status of "prognosis and symbiosis" of cancer. In this issue, the author reviews the current status of research on cancer prevention, cancer prevention policies, and the future direction of cancer prevention research. We also compare the current status of cancer prevention in Japan with that in the U.S., with the aim of clarifying the current status of cancer prevention in Japan.

2. the latest status of cancer

First, we would like to review the latest status of cancer. Thanks to the efforts of cancer researchers, medical professionals, and others, the outcome of cancer treatment has continuously improved. In addition, as reported by Tsubakihara in Policy Research Institute News No. 692 ⁾, the increasing number of new drugs with high levels of both treatment satisfaction and drug contribution may have contributed in no small measure to the development of cancer treatment. The latest relative 5-year survival rates and the number of survivors are shown in Figure 1.

According to the All Cancer Association Survival Rate Survey (compiled in August 2023) ³⁾, the number of 5-year survivors has been increasing steadily. The relative 5-year survival rate has also been on a steady upward trend, although the growth has been slower in recent years, reflecting the development of cancer treatment. However, the impact of cancer on the health of the population remains significant. Figure 2 shows the annual trends in the number of deaths by major cause of death from 1960 to 2021. As can be seen from the graph, cancer (malignant neoplasms) has been the leading cause of death since 1981 and has consistently increased since then, recently accounting for about 30% of total deaths. The number of deaths is approximately 1.78 times that of cardiac disease, the second leading cause of death, and its impact on the health of the population is remarkable.

Figure 3 shows the national medical expenditure for cancer (malignant neoplasms) and its share of the national medical expenditure. The national medical expenditure on cancer has been rising steadily and has exceeded 4 trillion yen in recent years. The share of cancer has also been on a steady rise, consistently ranking first since 2008, and will account for 13.4% in 2020, about 1.66 times that of "diseases of the musculoskeletal system and connective tissues," which ranks second. Thus, cancer continues to have a significant impact on the nation's health, both in terms of cause of death and national health care expenditures.

Figure 4 shows the estimated number of cancer cases in Japan by age group, and it is estimated that the number of cases will increase by 2039, mainly among the elderly aged 75 years or older, indicating that cancer will continue to have a significant impact on the health of the nation. This is likely to indicate the need to further strengthen cancer control measures, including cancer prevention.

Research trends in cancer prevention

A search was conducted ^{using the} AMED R&D Proposals ^Database6) of the Japan Agency for Medical Research and Development (JAMED)7) (August 27, 2023) with the aim of obtaining an overview of research trends in cancer prevention. The search ^criteria7) are shown in the footnote. As a result, 164 research projects were HIT. After a close examination of the contents, 149 projects were summarized based on the similarity of their research themes, excluding 15 projects that were judged to have clearly different objectives from those of cancer research. The results are shown in Table 1. The results are presented in two major categories: studies that were considered to be closely related to cancer prevention (83 studies) and studies that were considered to be relatively unrelated to cancer prevention (66 studies), such as those that explored the development of treatments or the basis of disease. The largest number of the studies were on the development of treatments (including development of therapeutic drugs), but when limited to cancer prevention, "Research on cancer-related viruses and preventive vaccines/immunotherapy" (31 studies) was the most common, followed by "Research on genes and gene-environment relationships in cancer prevention" (18 studies), and "Research on screening programs" (13 studies). Research on screening programs" was followed by "Research on the relationship between genes, genes and environment in cancer prevention" (18) and "Research on screening programs" (13).

Looking at individual studies, in "Research on cancer-related viruses and preventive vaccines/immunotherapy," there were many studies on hepatitis C virus and hepatitis B virus related to the development of liver cancer (9 and 6, respectively) and on human papillomavirus related to the development of cervical cancer (6). In "Research on genes and gene-environment relationship in cancer prevention," there were many studies on rare cancers (including AYA cancers) as well as common solid cancers, approaching them from a genomic perspective. In the "Research on Screening Programs," a study on the usefulness of a new screening method combining multiple tests was distinctive.

We continued to utilize PubMed searches and other tools to expand Table 1 by vertically browsing published articles related to cancer prevention, and created a summary of major cancer prevention studies (Table ²⁸⁾ ). Although not all of the studies were identified, and therefore comprehensiveness remains a problem, we believe that we have identified the major trends in cancer prevention research globally. A summary of the published papers referred to is given at the end of this report.

As described above, research related to cancer prevention is being conducted in a wide range of fields, including the environment, lifestyle, individual disposition, diagnosis, intervention, and prediction of recurrence. For these research findings to be implemented in society, it is necessary to carefully consider the usefulness of the research, including cost-effectiveness and social acceptability (ease of acceptance by society), and to establish sufficient evidence. This is by no means an easy task, but we hope that the project will progress steadily in light of the importance of cancer prevention to the health of the nation. In the next chapter, we would like to clarify the characteristics of cancer control in Japan by reviewing cancer control measures in Japan and comparing them with those in the United States, with the aim of understanding how the results of research related to cancer prevention are reflected in policy.

Comparison of cancer prevention policies between Japan and the U.S.

The basis of cancer control in Japan is the Basic Plan for the Promotion of Cancer Control, which was approved by the Cabinet in March 2018 (hereinafter referred to as the "Third Basic Plan") ¹⁰⁾ and, after an interim evaluation in June 2022 (hereinafter referred to as the "Third Interim Evaluation") ¹¹⁾, moved to the Fourth Basic Plan for the Promotion of Cancer Control approved by the Cabinet in March 2023 (hereinafter referred to as the "Fourth Basic Plan")12 ⁾. ^The individual goals and targets in the third interim evaluation are as follows. By looking at the series of steps from the individual goals and results of the third interim evaluation to the enactment of the fourth basic plan in detail, we will confirm the trend of cancer prevention measures in Japan.

In response to the WHO's assertion that "Since about 40% of cancers can be prevented, cancer prevention is the most important and cost-effective long-term measure in all cancer control efforts " ¹³⁾, "enhancement of cancer prevention and cancer screening based on scientific evidence" was stated in the field-specific measures and individual goals of the third basic plan, and "primary cancer Prevention" and "Early detection of cancer and cancer screening (secondary prevention). Table 3 shows the main individual goals of the Third National Strategy and the results of the interim evaluation of the Third National Strategy.

As individual goals for primary prevention of cancer, the following goals were set for smoking: 1) to reduce the adult smoking rate to 12%, 2) to eliminate smoking during pregnancy, and 3) to eliminate smoking among those under 20 years of age. Regarding alcohol consumption, it was decided that by 2022, 13.0% of men and 6.4% of women should be drinking in amounts that increase the risk of lifestyle-related diseases. The target for those who have an exercise habit was set at 36.0% of men and 33.0% of women aged 20 to 64, and 58.0% of men and 48.0% of women aged 65 and over. Regarding the individual targets for early detection of cancer and cancer screening (secondary prevention), the three targets were set at 50% for the cancer screening uptake rate for both men and women, 90% for the uptake rate for a thorough examination, and that "guidelines for cancer screening in the workplace (tentative name)" be established within one year to promote the use of such guidelines in the workplace. ¹⁰⁾

The results of the third interim evaluation for these goals are shown in Table 3. With regard to the individual target for primary cancer prevention, the adult smoking rate showed insufficient improvement, and a further 4.7% reduction was needed to achieve the target. The rates of smoking during pregnancy and smoking among minors showed a decreasing trend. The percentage of high-risk drinkers remained unchanged among men, but increased among women, indicating the need for improvement. The percentage of those with an exercise habit showed a decreasing trend, indicating the need for improvement. With regard to individual targets for early detection of cancer and cancer screening (secondary prevention), the cancer screening uptake rate showed an increasing trend in all screening categories, but the target of 50% was not achieved in all categories except for lung cancer in males. The screening uptake rate for many types of cancer was evaluated as insufficient and in need of improvement. Regarding cancer screening in the workplace, the "Manual on Cancer Screening in the Workplace " ¹⁴⁾ was published in March 2018, and efforts are being made to promote and raise awareness of cancer screening based on scientific evidence, and these efforts are commendable. ¹¹⁾

Based on these results and evaluations, the 4th Basic Plan for Cancer Control Promotion was approved by the Cabinet in March 2023. With regard to cancer prevention, the plan continues from the third basic plan and stipulates primary prevention of cancer and secondary prevention of cancer (cancer screening). As individual goals for primary prevention of cancer, the plan aims to achieve the targets set in the "Next National Health Promotion ^Plan15) " for improvement of lifestyle habits (reduction of risk factors) such as nutrition and diet, physical activity and exercise, alcohol consumption, and smoking. In addition, it was stated that the plan aims to reduce viral and bacterial infections that contribute to carcinogenesis, such as HPV (human papillomavirus), hepatitis virus, and HTLV-1 (human T-cell leukemia virus type 1). The reduction of viral and bacterial infections was mentioned in the Third National Strategy, but was not set as an individual target in the Fourth National Strategy. The individual target for secondary prevention of cancer (cancer screening) is to improve the cancer screening uptake rate, aiming for a 60% uptake rate for all cancer screenings (stomach, cervical, lung, breast, and colorectal cancer) based on the guidelines (Guidelines for Implementation of Priority Health Education and Cancer Screening for Cancer ^{Prevention16)}. It was also established to improve the accuracy management of cancer screening and to aim for a 90% screening uptake rate. Table 4 shows the main individual goals of the 4th Basic Plan.

The fourth basic plan's individual goals for primary prevention of cancer are characterized by the fact that references to exercise and alcohol consumption, which were considered inadequate in the third mid-term evaluation, were given higher rankings, and nutrition and diet were set as the top individual goals. The target for secondary prevention (cancer screening) was set at 60%, which was considered to be an ambitious goal. Figure 5 shows the cancer screening uptake rate in the National Survey of Family ^Life17). The results suggest that there is a possibility of a temporary effect of the new coronavirus infection, and that it is necessary to carefully monitor future trends.

The cancer prevention policy in Japan as described above seemed to incorporate the results of many studies shown in Tables 1 and 2. In particular, the fact that cancer-related virus research, which was the most common research topic in Table 1, was newly reflected in the fourth basic plan and individual goals, and that the improvement of the accuracy of screening was mentioned, seemed to be influenced in no small measure by the results of cancer prevention research.

Meanwhile, Healthy People 2030 ("HP2030") ¹⁸⁾ is playing a major role in cancer prevention measures in the United States. ⁽ Policy Research Institute News No. 6819 ⁾, HP2023 is an initiative launched in 1979 by the United States Department of Health and Human Services (HHS) to identify health concerns facing the U.S. public and to promote health promotion and disease prevention. HP2030 targets multiple diseases and health conditions, one of which is cancer. ²⁰⁾

Cancer is the second leading cause of death in the United States, and although cancer mortality has declined in recent decades, more than 600,000 people still die from cancer each year. ²⁰⁾ Some cancer types and some racial and ethnic minority groups tend to have higher mortality rates, and these disparities can be attributed to social factors such as education, economic status, The goals related to cancer prevention in HP2030 are shown in Table 5-1. In addition, since the individual goals for primary cancer prevention in Japan's 4th National Basic Plan include the general goals of the "Next National Health Promotion Campaign Plan," Table 5-2 shows the general goals that are considered to be almost equivalent in HP2030.

When Table 4, Table 5-1, and Table 5-2 are vertically viewed for the purpose of comparing cancer prevention policies between Japan and the U.S., there are some differences in the granularity of the items regarding primary prevention of cancer between nutrition and diet (nutrition and healthy diet - general), physical activity and exercise (physical activity - general), alcohol consumption (drug and alcohol use - general), and smoking (tobacco use - general). There were some differences in the granularity of the items, but no particular differences were found between them. With regard to viral and bacterial infections involved in carcinogenesis, there were also references to HPV in both Japan and the U.S. Again, no significant differences were found.

However, HP2030 includes an item "increase the proportion of adults who receive preventive care based on scientific evidence" in the "access to and quality of health care" section, and the awareness of overcoming disparities related to the social factors mentioned above is considered to be a distinctive feature. In this respect, the result was reminiscent of Japan's good access to medical care through universal health insurance. On the other hand, the fact that the goal was set for communication and education with health care providers as "the percentage of people who discuss interventions to prevent cancer with health care providers" showed the depth of nostalgia of the U.S. policy.

In the secondary prevention of cancer, the emphasis on cancer screening was similar in both Japan and the U.S. However, the fact that genetic testing is targeted with awareness of hereditary cancers, such as "the percentage of women at high risk of receiving genetic counseling for breast and ovarian cancer" and "the percentage of colorectal cancer patients receiving Lynch syndrome ^testing21), The U.S. policy seemed to have the upper hand. Although it is important to establish evidence and resolve financial issues, it would be desirable to consider the introduction of more advanced and useful cancer tests such as genetic testing for certain cancers in Japan.

Japan-US Comparison of Cancer Prevention Research Policies

The basis of cancer research policy in Japan (including cancer prevention research) is the 10-year strategy for cancer research. The current 10-Year Cancer Research ^Strategy22) was established based on an agreement among the Ministers of Education, Culture, Sports, Science and Technology, Health, Labor and Welfare, and Economy, Trade and Industry, and has been implemented since FY2014. The 10-Year Strategy for Cancer Research presents eight specific research items, one of which is "research on cancer prevention methods and early detection methods. The research is required to develop methods that can be easily and widely implemented, to accurately stratify and individualize cancer risks related to individual factors, including fixed risks such as genetic predisposition and variable risks such as lifestyle, infection, and environmental factors, and to establish methods optimized for each individual so that individual practice can be It was stated that it is required to make this possible. Examples of specific research items listed are shown in Table 6.

In 2019, a report (interim evaluation) ²³⁾ on the promotion of the "Ten-Year Strategy for Cancer Research" was submitted. The report stated that, with regard to "research on cancer prevention methods and early detection methods," it is important to continue to search for unknown carcinogenic factors and to promote more precise individualization of prevention through integrated analysis of carcinogenic risks obtained from genome information and other information to the carcinogenic risks identified so far. He also mentioned the need to develop and disseminate scientifically based preventive practices through intervention trials. He also pointed out the importance of cohort studies and the need to support research from a medium- to long-term perspective. Regarding early detection, it was stated that research should be promoted with emphasis on refractory cancers such as pancreatic cancer, which is difficult to detect in its early stages and for which there are few effective treatments. On the other hand, the need to focus on the detection of cancers that do not affect the prognosis of life, or so-called overdiagnosis, was also pointed out. Table 7 shows the specific research items that should be addressed during the latter half of the 10-year strategy for cancer research (interim report).

Fiscal year 2023 is the last year of the 10-year strategy, and the "Expert Committee on the Future of Cancer Research" is discussing the next 10-year strategy. At the 15th meeting (September 27, 2023), a draft ^report24) on "The Future of Cancer Research" was presented. Although it is subject to change in the future, the specific research items related to cancer prevention are listed in Table 8.

Although it is still considered a draft report, it is particularly noteworthy that the position of risk stratification for both primary and secondary prevention (cancer screening) is more strongly emphasized, that advanced technologies such as genome analysis and multi-omics analysis are mentioned, and that research on screening for rare and refractory cancers is included in the report. The inclusion of research on screening for rare and refractory cancers was considered to be particularly noteworthy.

The basis of cancer research policy in the U.S. (including cancer prevention research) is the Cancer ^Moonshot25). The Cancer Moonshot identifies cancer prevention as one of seven priorities. During the H1N1 pandemic, millions were unable to access recommended cancer screening, and returning screening to previous levels required a multifaceted approach to those whose quality of life could be dramatically improved with early diagnosis. There are significant differences in screening and prevention access by gender, race, ethnicity, region, and socioeconomic status, and approaches (such as telemedicine and direct community involvement) to improve implementation of underutilized proven screening ^methods26) are being studied. In addition, screening identified people at high risk for cancer due to hereditary cancer syndromes as particularly important.Specific research items related to cancer prevention in Cancer Moonshot (Cancer Moonshot Research ^{Initiatives27)} ) are listed in Table Table 9.

A review of Tables 6, 7, 8, and 9 for the purpose of comparing cancer prevention research between Japan and the United States reveals differences in study subjects, scope, and methods. In terms of research targets, while there was a general trend toward stratifying risk and focusing research on high-risk groups, the fact that cancers that are particularly common in Asia and rare/refractory cancers were the main research targets in Japan, while hereditary cancer syndromes were the main research targets in the U.S. was considered characteristic. Another characteristic of the U.S. research subjects, similar to the Japan-U.S. comparison of policies mentioned above, was the inclusion of research on overcoming disparities related to social factors in the U.S. In terms of the scope of research, the U.S. clearly included research on communication and decision-making (support) for individuals with hereditary cancer syndromes, whereas the Japanese research was limited to identifying high-risk groups (e.g., screening for rare and refractory cancers), and in this respect, the U.S. seemed to have the edge.

Furthermore, while both Japan and the U.S. share the general direction of aiming to expand the practice and use of cancer prevention (primary and secondary prevention), there are significant differences in research methods. In Japan, the implementation of cancer prevention is being promoted through research based on behavioral science, whereas in the U.S., implementation science is being promoted through research based on implementation science. Behavioral science is a scientific study of human behavior and attempts to elucidate its laws, focusing on communication between individuals and decision-making mechanisms within a society. Implementation science, on the other hand, is an academic discipline that develops and examines ways to effectively and efficiently incorporate evidence-based interventions into daily activities at medical institutions, health insurers, prefectures, municipalities, etc., and root them in continuity, covering a wide range of topics from disease prevention to early detection, treatment, supportive care, survivorship, and palliative care. A wide range of topics are addressed. However, since implementation science is a new field of study, the methodology and importance of this field are currently little recognized in Japan. ²⁸⁾²⁹⁾ The practice and expanded use of cancer prevention (primary and secondary prevention) is likely to be strongly influenced by national characteristics and social structure, and superiority or inferiority cannot be judged lightly. However, it is meaningful to consider the practice and expansion of cancer prevention in Japan from a broader perspective by incorporating the results of implementation science, a systematic approach to implementing public health programs.

6. summary and discussion

The five-year survival rate and the number of cancer survivors are on an increasing trend, as new drugs with both high treatment satisfaction and drug contribution are on the rise. However, it remains the leading cause of death, the leading cause of national health care expenditure and occupancy rate, and is on an increasing trend, and with the number of cases expected to continue to rise, it will continue to have a significant impact on the health of the population. It is believed that strengthening cancer control measures, including cancer prevention, will be required.

Looking at research trends in cancer prevention, we confirmed that research is being conducted in a wide range of areas, including the environment, lifestyle, individual disposition, diagnosis, intervention, and prediction of recurrence. In the Third Basic Plan for the Promotion of Cancer Control, which has been in effect since 2018, targets were set for smoking, alcohol consumption, and exercise as primary prevention, and for cancer screening uptake rate, screening uptake rate, and establishment and dissemination of guidelines for cancer screening in the workplace as secondary prevention. The targets for secondary prevention are the cancer screening uptake rate, the screening uptake rate, and the formulation and dissemination of guidelines for cancer screening in the workplace. However, in the third interim evaluation in 2022, although the target for the establishment of guidelines was achieved, the targets for alcohol consumption, exercise, and some screening uptake rates showed worsening trends, and although other items showed improvement, the targets were not achieved, and the results were not satisfactory. In response, the Cabinet approved the 4th Basic Plan in 2023. The fact that cancer-related virus research was newly added to the individual targets and the improvement of the accuracy of screening was mentioned seemed to reflect the results of cancer prevention research to no small extent. However, the screening uptake rate for cancer screening, which is important for secondary prevention, has been stagnant in recent years, and further strengthening of efforts is urgently needed.

Healthy People 2030 plays a major role in cancer prevention in the U.S., but there was little difference between Japan and the U.S. in primary prevention. However, in the U.S., there is an awareness of overcoming disparities in access to medical care related to social factors, and Japan, with its universal health insurance system, seems to have an advantage in this respect. In terms of secondary prevention, both Japan and the U.S. tended to emphasize cancer screening, but the U.S. had the advantage in that genetic testing was targeted with hereditary cancer in mind.

We continued with a review of policy trends in cancer prevention research as they relate to future cancer prevention. The direction of cancer prevention research policy in Japan is set forth in the 10-year strategy for cancer research established in 2014, and after an interim report in 2019, the next 10-year strategy for cancer research, scheduled to begin in 2024, is currently under consideration. Although it is still considered a draft report, the following points were considered to be new research directions: the position of risk stratification for both primary and secondary prevention (cancer screening) is more strongly emphasized; advanced technologies such as genome analysis and multi-omics analysis are mentioned; and research on screening for rare and refractory cancers is included. This was thought to be a new direction of research.

On the other hand, the basis of cancer research policy in the U.S. (including cancer prevention research) is the Cancer Moonshot, and a comparison of these research policies between Japan and the U.S. was conducted. Regarding research targets, the general direction to stratify risk and focus on high-risk groups was common in Japan and the U.S. However, it was characteristic that cancers that are particularly common in Asian regions and rare/refractory cancers were the main research targets in Japan, while hereditary cancer syndromes were the main research targets in the U.S. As for the scope of research, while in Japan, research was limited to identifying high-risk groups (e.g., screening for rare and refractory cancers), in the U.S., research on communication and decision-making (support) for individuals with hereditary cancer syndromes was clearly defined, and in this respect, the U.S. was considered to have the advantage. In addition, while the general direction of the research is similar in that it aims to expand the practice and use of cancer prevention, there are significant differences in the research methods used. In Japan, the researchers were trying to advance the practice through research relying on behavioral science, while in the U.S., they were trying to advance the practice through research relying on implementation science. It would be significant for Japan to consider the practice and expansion of cancer prevention from a broader perspective by incorporating the results of implementation science, which is a systematic approach to implementing public health programs.

Conclusion

In next-generation health care, one of the objectives of which is to extend healthy life expectancy, it is very important to expand the perspective from "diagnosis and treatment of diseases" to "prevention of pre-diseases and diseases" and "coexistence with diseases. In particular, about 40% of cancer cases can be prevented, so it is very significant to work on cancer prevention.

The keyword for cancer prevention in the future will be "risk stratification. When considering risk stratification, genome analysis and multi-omics analysis seem to be particularly important, and we look forward to steady progress in Japanese research in these fields. After risk stratification, therapeutic intervention in the stratified population will be necessary. This is a trend that is linked to so-called precision treatment, and the pharmaceutical industry has a great deal of room to contribute in this area.

Furthermore, from the viewpoint of cancer prevention, the pharmaceutical industry could also make a significant contribution in the area of cancer prevention ^vaccines30). The pharmaceutical industry is thought to have made an appropriate contribution to society in the development of vaccines during the pandemic of novel coronavirus infection, and it would be very meaningful to apply this knowledge to cancer prevention.

In order for the results of cancer prevention research to be actually implemented in society, it is necessary to carefully examine the usefulness of the research, including cost-effectiveness and social acceptability, and to establish sufficient evidence. Behavioral science and implementation science mentioned in the Japan-US comparison of cancer prevention research are by no means binary opposites and may be used in an integrated manner. To achieve adequate social implementation, it is desirable to consider cancer prevention from a broader perspective. Considering the importance of cancer prevention to the health of the people, we hope that social implementation efforts will be steadily advanced.

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