Evidence-based cancer prevention recommendations for Japanese

Evidence-based cancer prevention recommendations for Japanese Abstract A comprehensive evidence-based cancer prevention recommendation for Japanese was developed. We evaluated the magnitude of the associations of lifestyle factors and infection with cancer through a systematic review of the literature, meta-analysis of published data, and pooled analysis of cohort studies in Japan. Then, we judged the strength of evidence based on the consistency of the associations between exposure and cancer and biological plausibility. Important factors were extracted and summarized as an evidence-based, current cancer prevention recommendation: ‘Cancer Prevention Recommendation for Japanese’. The recommendation addresses six important domains related to exposure and cancer, including smoking, alcohol drinking, diet, physical activity, body weight and infection. The next step should focus on the development of effective behavior modification programs and their implementation and dissemination. cancer prevention, epidemiology, Japanese Introduction Even though many aspects of cancer etiology are known to be related to lifestyle factors and infection, research findings have tended to be presented individually and have not been comprehensively aggregated to determine which lifestyle habits increase or decrease cancer risk. Among published evaluations or recommendations regarding lifestyle factors and related cancer, the most comprehensive are those from the International Agency for Research on Cancer (IARC) (1), the World Health Organization and Food and Agriculture Organization (WHO/FAO) (2), the World Cancer Research Fund and American Institute for Cancer Research (WCRF/AICR) (3), the WCRF International/ AICR Continuous Update Project (CUP) (4), and the European Code against Cancer fourth Edition (5). However, the research considered in these recommendations was mostly derived from Western countries. Before direct application of such recommendations to Japan, with substantial differences in genetic background and different exposure levels of environment and lifestyle habits, risk assessment in the Japanese population is required. In fact, Japanese have a higher prevalence of the aldehyde dehydrogenase 2*2 null allele (6), which results in slower catalysis in acetaldehyde metabolism (7); a higher prevalence of Helicobacter pylori (HP) infection (8); and a lower prevalence of obesity (9); as well as distinctive dietary habits compared to Western populations such as a high intake of vegetable, fish, soy products, and salt and low intake of meat (10). Accordingly, we have developed a comprehensive recommendation that reflects the characteristics of cancer and related factors for the country since 2003. The objective of this report is to inform the international community of the strength of evidence linking lifestyle factors and infection to the risk of cancer in Japan, and to provide updated evidence-based cancer prevention recommendations applicable for Japanese. Methods To perform risk assessment which defines the health effects of exposure of populations to hazardous agents, evidence from epidemiological studies among the Japanese population was compiled and organized using three processes (systematic review, meta-analysis, and pooled analysis) by the Research Group for the Development and Evaluation of Cancer Prevention Strategies in Japan (Principle investigator: Shoichiro Tsugane, 2003–2011; Shizuka Sasazuki, 2012–2017; and Taichi Shimazu 2017–present). The research group then incorporated the results of the risk assessment with risks of non-cancer diseases and total mortality, as well as social concerns where necessary, and prepared a Cancer Recommendation for Japanese. Literature search and systematic review: qualitative evaluation We searched articles published from 1966 to the date we made a final judgment of the strength of evidence using PubMed and the Japanese Medical Research Database (Igaku-Chuo-Zasshi), and complemented this with manual searches of references from related literature (Table 2). Eligible papers had to be case–control or cohort studies of lifestyle factors, infection and cancer; written in English or Japanese; and based on a Japanese population. The association of each lifestyle factor with infection and site-specific cancer (e.g. lung, liver, stomach, colon, breast, esophagus, pancreas, prostate, cervix, corpus uteri, ovary, head and neck, bladder and blood), as well as total cancer, was evaluated to assess the magnitude of association and strength of evidence. First, the magnitude of association was classified based on the relative risk (RR) estimate and statistical significance as ‘Strong’ RR < 0.5 or RR > 2.0 (statistically significant [SS]); ‘Moderate’, either (i) RR < 0.5 or RR > 2.0 (statistically non-significant [NS]), (ii) RR > 1.5–2.0 (SS) or (iii) 0.5 to <0.67 (SS); ‘Weak’, either (i) RR > 1.5–2.0 (NS), (ii) 0.5 to <0.67 (NS) or (iii) 0.67-1.5 (SS); or ‘No association’, 0.67–1.5 (NS). After this process, the overall strength of evidence was classified into four ranking groups (‘convincing’, ‘probable’, ‘possible’ and ‘insufficient’) based on the method used in the WHO/FAO report (2). In brief, this and the WHO/FAO reports share the following criteria. ‘Convincing’: the results of epidemiological studies are consistent, and there are almost no contradicting results. There are a substantial number of studies. Biological explanations can be used to understand the results. ‘Probable’: the results of epidemiological studies are fairly consistent, but there are inadequacies in the methods (the study period is too short, insufficient number of studies, insufficient number of subjects, follow-up is incomplete, etc.) or there are multiple contradicting results. The association should be biologically plausible. ‘Possible’: evidence based mainly on findings from case–control and cross-sectional studies. ‘Insufficient’: evidence based on findings of a few studies which are suggestive, but are insufficient to establish an association between exposure and disease. Final judgment of the strength of evidence took account of the consistency of the associations between exposure and cancer, the biological mechanism assumption derived from the recent IARC evaluation report (1), evaluations or recommendations of the authoritative reports on exposure and cancer (1–4,11), and quantitative evaluation mentioned in the next section. We briefly described the findings of these reports as ‘international background.’ Notwithstanding the use of this quantitative assessment rule, arbitrary assessment cannot be avoided when there is considerable variation in the magnitude of association between the results of the studies. The final judgment is therefore made based on the consensus of the research group members, and is not necessarily objective. Meta-analysis or pooled analysis: quantitative analysis In general, if the judgment was ‘convincing’ or ‘probable’, meta-analysis of published literature was conducted to obtain summary estimates. Cohort studies or case–control studies reporting RRs or odds ratios (ORs) and 95% confidence intervals (CIs) were included. In the case of multiple publications from one study, the largest or most updated report was selected. We also obtained quantitative summary estimates by conducting pooled analyses of original data from individual studies. Hazard ratios (HRs) of each study were reanalyzed for this project according to a common protocol. Using a random-effects model, we conducted a meta-analysis of the HRs to obtain pooled estimates for the association of lifestyle factors and cancer. This method limits potential sources of heterogeneity because categories of exposure and covariates can be set in an identical manner. To maintain the quality and comparability of data, we set the following a priori criteria: (i) a population-based cohort study started in Japan in the mid-1980s to mid-1990s, (ii) inclusion of more than 30 000 participants and (iii) collection of total mortality and cancer incidence. As of July 2017, 10 cohort studies participate in this pooling project: the Japan Public Health Center-based Prospective Study, Cohort I [JPHC-I] (12); the Japan Public Health Center-Based Prospective Study, Cohort II [JPHC-II] (12); the Japan Collaborative Cohort Study [JACC] (13); the Miyagi Cohort Study [MIYAGI] (14); the Three-Prefecture Miyagi [3-pref MIYAGI] (15); the Ohsaki National Health Insurance Cohort Study [OHSAKI] (16); the Three-Prefecture Aichi [3-pref AICHI] (15); the Takayama Study [TAKAYAMA] (17); the Life Span Study [LSS] (18) and the Three-Prefecture Osaka [3-pref OSAKA] (15) (Table 1). A total of 519 579 subjects were included in the pooled analysis. The pooled analysis provided a large sample size and enabled the detection of a relatively stable estimate and even a small effect. Table 1. Cohort studies in pooling analysis of the Research Group for the Development and Evaluation of Cancer Prevention Strategies in Japan Study  Population  Age (years) at baseline survey  Year(s) of baseline survey  Population size  JPHC-I  Japanese residents of five public health center areas in Japan  40–59  1990  61 595  JPHC-II  Japanese residents of six public health center areas in Japan  40–69  1993–1994  78 825  JACC  Residents from 45 areas throughout Japan  40–79  1988–1990  110 585  MIYAGI  Residents of 14 municipalities in Miyagi Prefecture, Japan  40–64  1990  47 605  OHSAKI  Beneficiaries of National Health Insurance among residents of 14 municipalities in Miyagi Prefecture, Japan  40–79  1994  54 996  3-pref MIYAGI  Residents of three municipalities in Miyagi Prefecture, Japan  40–98  1984  31 345  3-pref AICHI  Residents of two municipalities in Aichi Prefecture, Japan  40–103  1985  33 529  TAKAYAMA  Residents of Takayama, Gifu, Japan  35–  1992  31 552  LSS  Atomic bomb survivors in Hiroshima, Nagasaki, Japan  34–102  1978  33 792 (No. of subjects who participated in at least one survey)      46–104  1991    3-pref OSAKA  Residents of four municipalities in Osaka Prefecture, Japan  40–97  1983–1985  35 755  Total        519 579  Study  Population  Age (years) at baseline survey  Year(s) of baseline survey  Population size  JPHC-I  Japanese residents of five public health center areas in Japan  40–59  1990  61 595  JPHC-II  Japanese residents of six public health center areas in Japan  40–69  1993–1994  78 825  JACC  Residents from 45 areas throughout Japan  40–79  1988–1990  110 585  MIYAGI  Residents of 14 municipalities in Miyagi Prefecture, Japan  40–64  1990  47 605  OHSAKI  Beneficiaries of National Health Insurance among residents of 14 municipalities in Miyagi Prefecture, Japan  40–79  1994  54 996  3-pref MIYAGI  Residents of three municipalities in Miyagi Prefecture, Japan  40–98  1984  31 345  3-pref AICHI  Residents of two municipalities in Aichi Prefecture, Japan  40–103  1985  33 529  TAKAYAMA  Residents of Takayama, Gifu, Japan  35–  1992  31 552  LSS  Atomic bomb survivors in Hiroshima, Nagasaki, Japan  34–102  1978  33 792 (No. of subjects who participated in at least one survey)      46–104  1991    3-pref OSAKA  Residents of four municipalities in Osaka Prefecture, Japan  40–97  1983–1985  35 755  Total        519 579  JPHC-I, Japan Public Health Center-based Prospective Study, Cohort I; JPHC-II, the Japan Public Health Center-Based Prospective Study, Cohort II; JACC, the Japan Collaborative Cohort Study; MIYAGI, the Miyagi Cohort Study; 3-pref MIYAGI, the Three-Prefecture Miyagi; OHSAKI, the Ohsaki National Health Insurance Cohort Study; 3-pref AICHI, the Three-Prefecture Aichi; TAKAYAMA, the Takayama Study; LSS: the Life Span Study; 3-pref OSAKA, the Three-Prefecture Osaka. Table 1. Cohort studies in pooling analysis of the Research Group for the Development and Evaluation of Cancer Prevention Strategies in Japan Study  Population  Age (years) at baseline survey  Year(s) of baseline survey  Population size  JPHC-I  Japanese residents of five public health center areas in Japan  40–59  1990  61 595  JPHC-II  Japanese residents of six public health center areas in Japan  40–69  1993–1994  78 825  JACC  Residents from 45 areas throughout Japan  40–79  1988–1990  110 585  MIYAGI  Residents of 14 municipalities in Miyagi Prefecture, Japan  40–64  1990  47 605  OHSAKI  Beneficiaries of National Health Insurance among residents of 14 municipalities in Miyagi Prefecture, Japan  40–79  1994  54 996  3-pref MIYAGI  Residents of three municipalities in Miyagi Prefecture, Japan  40–98  1984  31 345  3-pref AICHI  Residents of two municipalities in Aichi Prefecture, Japan  40–103  1985  33 529  TAKAYAMA  Residents of Takayama, Gifu, Japan  35–  1992  31 552  LSS  Atomic bomb survivors in Hiroshima, Nagasaki, Japan  34–102  1978  33 792 (No. of subjects who participated in at least one survey)      46–104  1991    3-pref OSAKA  Residents of four municipalities in Osaka Prefecture, Japan  40–97  1983–1985  35 755  Total        519 579  Study  Population  Age (years) at baseline survey  Year(s) of baseline survey  Population size  JPHC-I  Japanese residents of five public health center areas in Japan  40–59  1990  61 595  JPHC-II  Japanese residents of six public health center areas in Japan  40–69  1993–1994  78 825  JACC  Residents from 45 areas throughout Japan  40–79  1988–1990  110 585  MIYAGI  Residents of 14 municipalities in Miyagi Prefecture, Japan  40–64  1990  47 605  OHSAKI  Beneficiaries of National Health Insurance among residents of 14 municipalities in Miyagi Prefecture, Japan  40–79  1994  54 996  3-pref MIYAGI  Residents of three municipalities in Miyagi Prefecture, Japan  40–98  1984  31 345  3-pref AICHI  Residents of two municipalities in Aichi Prefecture, Japan  40–103  1985  33 529  TAKAYAMA  Residents of Takayama, Gifu, Japan  35–  1992  31 552  LSS  Atomic bomb survivors in Hiroshima, Nagasaki, Japan  34–102  1978  33 792 (No. of subjects who participated in at least one survey)      46–104  1991    3-pref OSAKA  Residents of four municipalities in Osaka Prefecture, Japan  40–97  1983–1985  35 755  Total        519 579  JPHC-I, Japan Public Health Center-based Prospective Study, Cohort I; JPHC-II, the Japan Public Health Center-Based Prospective Study, Cohort II; JACC, the Japan Collaborative Cohort Study; MIYAGI, the Miyagi Cohort Study; 3-pref MIYAGI, the Three-Prefecture Miyagi; OHSAKI, the Ohsaki National Health Insurance Cohort Study; 3-pref AICHI, the Three-Prefecture Aichi; TAKAYAMA, the Takayama Study; LSS: the Life Span Study; 3-pref OSAKA, the Three-Prefecture Osaka. Current evaluation and recommendations Evaluation of evidence Judgment of the strength of evidence linking lifestyle factors and infection to total and site-specific cancer risk is summarized in Table 2 (19–46). Regarding cigarette smoking and alcohol drinking, several sites of cancers were evaluated as having ‘convincing’ evidence. Infection was evaluated as having ‘convincing’ evidence for specific types of cancer. Regarding dietary factors, the association with cancer was evaluated for seven food groups; two beverages, hot food and beverages; eight nutrients; highly salted food; and dietary pattern. Most items had ‘insufficient’ data to allow assessment of the strength of evidence based on the currently available evidence. Table 2. The strength of evidence linking lifestyle factors and infection to the risk of total and site-specific cancer among Japanese population (summary), as of 1 August 2017         Conv, convincing; Poss, possible; Insuff, insufficient; AML, acute myeloid leukemia; BMI, body mass index; M, male; F, female; TB, tuberculosis; HBV, hepatitis B virus; HCV, hepatitis C virus; HPV, human papilloma virus; DM, diabetes mellitus; IARC, International Agency for Research on Cancer; exp, exposure; EBV, Epstein-Barr virus. Figures in brackets indicate the decision year of the strength of evidence. *Studies focused on supplement use were not included. Table 2. The strength of evidence linking lifestyle factors and infection to the risk of total and site-specific cancer among Japanese population (summary), as of 1 August 2017         Conv, convincing; Poss, possible; Insuff, insufficient; AML, acute myeloid leukemia; BMI, body mass index; M, male; F, female; TB, tuberculosis; HBV, hepatitis B virus; HCV, hepatitis C virus; HPV, human papilloma virus; DM, diabetes mellitus; IARC, International Agency for Research on Cancer; exp, exposure; EBV, Epstein-Barr virus. Figures in brackets indicate the decision year of the strength of evidence. *Studies focused on supplement use were not included. Cancer prevention recommendation for Japanese Among the results of evaluation of evidence shown in Table 2, important factors were extracted and summarized as an evidence-based, current cancer prevention recommendation: ‘Cancer Prevention Recommendation for Japanese’ (Table 3). Table 3. Cancer Prevention Recommendation for Japanese Current evidence-based Cancer Prevention Recommendations for Japanese  1.  Smoking     Do not smoke cigarettes. Avoid passive smoking.  2.  Drinking     Drink in moderation. Drinking should be kept to within ~23 g alcohol per day. People that usually do not drink, or have alcohol intolerance, should not force themselves to drink.  3.  Diet     Make sure you follow a nutritionally balanced diet.  -Restrict your intake of salt and salt-preserved products. Keep salt consumption to less than 8 g for men and 7 g for women per day for healthy individuals aged 18 years or more. Consumption of foods high in salt should be kept to no more than one time per week.  -Ensure sufficient intake of fruit and vegetables.  -Do not consume too much hot (thermally) food and drinks.  4.  Physical Activity     Be active in daily life. For example, ~60 min of daily physical activity such as walking or more intensive activity as well as vigorous exercise 60 min a week is needed for healthy adults aged between 18 and 64 years old.  5.  Body Weight     Maintain an appropriate weight during adulthood. BMI for middle-aged to elderly men should be between 21 and 27, and between 21 and 25 for middle-aged to elderly women.  6.  Infections     Get tested for hepatitis virus infection and deal with it appropriately. Get tested for Helicobacter pylori infection if there is an opportunity.  Current evidence-based Cancer Prevention Recommendations for Japanese  1.  Smoking     Do not smoke cigarettes. Avoid passive smoking.  2.  Drinking     Drink in moderation. Drinking should be kept to within ~23 g alcohol per day. People that usually do not drink, or have alcohol intolerance, should not force themselves to drink.  3.  Diet     Make sure you follow a nutritionally balanced diet.  -Restrict your intake of salt and salt-preserved products. Keep salt consumption to less than 8 g for men and 7 g for women per day for healthy individuals aged 18 years or more. Consumption of foods high in salt should be kept to no more than one time per week.  -Ensure sufficient intake of fruit and vegetables.  -Do not consume too much hot (thermally) food and drinks.  4.  Physical Activity     Be active in daily life. For example, ~60 min of daily physical activity such as walking or more intensive activity as well as vigorous exercise 60 min a week is needed for healthy adults aged between 18 and 64 years old.  5.  Body Weight     Maintain an appropriate weight during adulthood. BMI for middle-aged to elderly men should be between 21 and 27, and between 21 and 25 for middle-aged to elderly women.  6.  Infections     Get tested for hepatitis virus infection and deal with it appropriately. Get tested for Helicobacter pylori infection if there is an opportunity.  Table 3. Cancer Prevention Recommendation for Japanese Current evidence-based Cancer Prevention Recommendations for Japanese  1.  Smoking     Do not smoke cigarettes. Avoid passive smoking.  2.  Drinking     Drink in moderation. Drinking should be kept to within ~23 g alcohol per day. People that usually do not drink, or have alcohol intolerance, should not force themselves to drink.  3.  Diet     Make sure you follow a nutritionally balanced diet.  -Restrict your intake of salt and salt-preserved products. Keep salt consumption to less than 8 g for men and 7 g for women per day for healthy individuals aged 18 years or more. Consumption of foods high in salt should be kept to no more than one time per week.  -Ensure sufficient intake of fruit and vegetables.  -Do not consume too much hot (thermally) food and drinks.  4.  Physical Activity     Be active in daily life. For example, ~60 min of daily physical activity such as walking or more intensive activity as well as vigorous exercise 60 min a week is needed for healthy adults aged between 18 and 64 years old.  5.  Body Weight     Maintain an appropriate weight during adulthood. BMI for middle-aged to elderly men should be between 21 and 27, and between 21 and 25 for middle-aged to elderly women.  6.  Infections     Get tested for hepatitis virus infection and deal with it appropriately. Get tested for Helicobacter pylori infection if there is an opportunity.  Current evidence-based Cancer Prevention Recommendations for Japanese  1.  Smoking     Do not smoke cigarettes. Avoid passive smoking.  2.  Drinking     Drink in moderation. Drinking should be kept to within ~23 g alcohol per day. People that usually do not drink, or have alcohol intolerance, should not force themselves to drink.  3.  Diet     Make sure you follow a nutritionally balanced diet.  -Restrict your intake of salt and salt-preserved products. Keep salt consumption to less than 8 g for men and 7 g for women per day for healthy individuals aged 18 years or more. Consumption of foods high in salt should be kept to no more than one time per week.  -Ensure sufficient intake of fruit and vegetables.  -Do not consume too much hot (thermally) food and drinks.  4.  Physical Activity     Be active in daily life. For example, ~60 min of daily physical activity such as walking or more intensive activity as well as vigorous exercise 60 min a week is needed for healthy adults aged between 18 and 64 years old.  5.  Body Weight     Maintain an appropriate weight during adulthood. BMI for middle-aged to elderly men should be between 21 and 27, and between 21 and 25 for middle-aged to elderly women.  6.  Infections     Get tested for hepatitis virus infection and deal with it appropriately. Get tested for Helicobacter pylori infection if there is an opportunity.  1. Smoking Do not smoke cigarettes. Avoid passive smoking. Goal Current smokers should stop smoking. Non-smokers should avoid passive smoking. International background Smoking is the single largest cause of cancer worldwide. New sites continue to be added to the list of tobacco-related cancers. IARC reports that 19 sites, including recently added colon and ovary (musinous) cancer, are considered to have sufficient evidence to be related to tobacco smoking (47). For female breast cancer, the evidence is limited. Smoking is also a cause of coronary artery disease (e.g. angina and myocardial infarction), cardiovascular disease (CVD; e.g. stroke), and respiratory disease (e.g. pneumonia and chronic obstructive pulmonary disease). Passive smoking is considered to be a ‘convincing’ risk factor for lung cancer. A meta-analysis of 55 studies on the relationship of passive smoking and lung cancer reported that non-smoking females were at 1.3-fold higher risk from passive smoking from their husbands than females with non-smoking husbands (48). The evidence is sufficient to infer a causal relationship between passive smoking and increased risk of stroke (11). Evidence in Japanese Based on the evaluation of Japanese studies, the ‘Development and Evaluation of Cancer Prevention Strategies in Japan’ Group concluded that there is ‘convincing’ evidence that tobacco smoking increases the risk of total cancer (19). In the report, the risk of total cancer in smokers was 1.5 times as high as that in non-smokers (male: 1.6 times, female: 1.3 times) based on meta-analysis of five cohort studies. Given the above RR and the prevalence of smoking, it was estimated that ~20–23% of cancers in Japanese are caused by smoking (~30–34% for males and 5–6% for females) and could, therefore, have been prevented by not smoking (49). By site, there was ‘convincing’ evidence that smoking increases the risk of cancer of the lung (20), liver (21), stomach (22), esophagus (25), pancreas (26), head and neck (27), bladder (28) and cervix. Our group concluded that passive smoking ‘convincingly’ increases the risk of lung cancer. Based on a cohort study on passive smoking in non-smoking Japanese women, the risk of developing pulmonary adenocarcinoma was approximately doubled in subjects whose husbands were smokers compared to those whose husbands were not smokers (50). Approximately 37% of lung cancer cases in women were estimated to be caused by passive smoking at home. Including this study, a meta-analysis of four cohort studies and five case–control studies was conducted (51). Quantitative synthesis was conducted only for secondhand smoke exposure in the home during adulthood. Of the 12 populations included in the meta-analysis, positive secondhand smoke exposure-lung cancer associations were observed in 11, whereas an inverse association was found in the remaining study. The pooled RR of lung cancer associated with secondhand smoke exposure was 1.28 (95% CI: 1.10–1.48). 2. Drinking Drink in moderation. Goal Drinking should be kept to within ~23 g alcohol per day (equal to ~1 ‘go’ (go = 180 ml) of Japanese sake, 1 large bottle of beer, 2/3 ‘go’ of shochu or awamori, 1 double whiskey or brandy, or two glasses of wine). People who usually do not drink, or have alcohol intolerance, should not force themselves to drink. International background In the report of the WCRF/AICR working group (3) and CUP (4), ‘convincing’ evidence suggest that alcohol drinking increases the risk of oral, pharyngeal, laryngeal, esophageal (squamous cell carcinoma), liver, colorectal (men) and breast (post-menopause) cancers. Furthermore, increases in risk of stomach, colorectal (women) and breast (pre-menopause) cancers were deemed to be ‘probable’. IARC reports that there is sufficient evidence that alcoholic beverages cause these cancers (1). Evidence in Japanese Based on an evaluation of Japanese studies, our group concluded that there is ‘convincing’ evidence that alcohol drinking increases the risk of total cancer (29). By site, the strength of evidence for cancer of the liver (31), colorectum (33) and esophagus (35) was found to be ‘convincing’. A pooled analysis of six cohort studies which included ~310 000 subjects found a J- or U-shaped association for the risk of total and major causes of mortality in men, and for the risk of total and heart disease mortality in women (52). Compared with non-drinkers, there were significantly lower risks of total mortality at an alcohol intake of <69 g/day, cancer mortality at <46 g/day, heart disease mortality at <69 g/day, and cerebrovascular disease mortality at <46 g/day in men, and of total mortality at <23 g/day in women. This means that a small amount of drinking may have the effect of lowering the risk of myocardial infarction or stroke. However, in a pooled analysis, increased risk of cancer was observed for colorectum (53) and female liver (54) sites at the level of more than 23 g/day intake. Therefore, from a general point of view, it is recommended that drinking should be kept within 23 g of alcohol per day. 3. Diet Make sure you follow a nutritionally balanced diet. -Restrict your intake of salt and salt-preserved products. -Ensure sufficient intake of fruit and vegetables. -Do not consume too much hot (thermally) food and drink. Goal -Keep salt consumption to less than 8 g for men and 7 g for women per day for healthy individuals aged 18 years or more. Consumption of foods high in salt should be kept to no more than one time per week. International background Salt may increase the risk of gastric cancer through the destruction of mucus barriers, leading to acid-induced inflammation and persistent infection with HP. Foods preserved by salting are thought to ‘probably’ increase the risk of gastric cancer (4). Limiting consumption of highly salted foods and providing alternatives to salt in food processing or preservation may help mitigate this risk. Fruits and vegetable are considered to lower the risk of cancer via the effects of constituent vitamins, carotenes, folate, fiber, isothiocyanate or other compounds. The WCRF/AICR report concluded that non-starchy vegetables and fruits play a ‘probable’ role in helping to prevent oral, pharyngeal, laryngeal, and lung (fruits only) cancers (3). The joint committee of the WHO/FAO report recommends consumption of at least 400 g of vegetables and fruits per day to prevent lifestyle-related diseases (2). The IARC classified processed and red meat as carcinogenic to humans (Group 1) and probably carcinogenic to humans (Group 2 A), respectively (55). The WCRF International concluded that processed meat ‘convincingly’ and red meat ‘probably’ increases colorectal cancer risk, respectively, and advised limiting red meat and avoiding processed meat (4). A ‘probable’ increase in the risk of esophageal cancer has been noted for mate, a beverage which is customarily drunk at extremely hot temperatures in South America (4). Also, in ‘limited’ cases, some study results have suggested an increase in risk of oral, pharyngeal and laryngeal cancers (3). Evidence in Japanese Based on the evaluation of Japanese studies, our research group concluded that salt and salt-preserved foods ‘probably’ increase the risk of gastric cancer. A cohort study conducted in Japanese subjects indicated that sodium was not associated with increased risk of total cancer but was associated with increased risk of total CVD and stroke (56). In contrast, salted fish roe was associated with increased risk of total cancer. Similar results were seen in the association between salt-preserved foods and the risk of gastric cancer. Limiting salt and salt-preserved food intake would not only be effective for preventing gastric cancer, the most common cancer in Japan, but would also contribute to the prevention of hypertension and decrease the risk of CVD. According to the Dietary Reference Intakes for Japanese (2015), the target level of salt per day is set at under 8 g for men and 7 g for women (57). The evaluation of our group regarding fruits and vegetables revealed that a decrease in risk of esophageal cancer is ‘probable’, while decreased risk of stomach and lung cancer (fruit only) is ‘possible’. In a pooled analysis of four cohort studies conducted in Japanese subjects, a marginally significant decrease in gastric cancer risk in relation to total vegetable intake but not total fruit intake was observed (58). For distal gastric cancer, the association was significant among men. In a prospective cohort study, it was demonstrated that, in the Japanese population, consumption of fruit is associated with lower risk of CVD, whereas intake of fruit or vegetables may not be associated with lower risk of total cancer (59). In the recent pooled analysis from four cohort studies, consumption of fruits or vegetables was not associated with decreased risk of overall cancers (60). Although the impact for overall cancer prevention was undetectable, the results do not contradict the possibly small but protective effect of fruit and vegetable intake on site-specific cancers. It is possible that the aggregation of cancer sites in the analysis might dilute the impact of association; therefore, from a general point of view considering prevention for other chronic diseases, including CVD (61), daily consumption of vegetables and fruits is recommended. Differing from the WCFR International (4), we judged that processed and red meat ‘possibly’ increase colorectal cancer risk. We consider that roughly average levels of processed and red meat intake in Japan (mean 63 g per day) (10), which is much lower than those in Western countries (ranged 50–200 g per day) (55), did not increase colorectal cancer risk. Thus, we did not make any specific recommendation on meat intake. The evaluation of our group regarding hot food and drink concluded that an increase in risk of esophageal cancer is ‘probable’. Many study results have suggested that eating hot food and drinks may lead to esophagitis or esophageal cancer. To avoid damage to the mucosal membrane of the oral cavity and esophagus, hot food and drinks should be allowed to cool before consumption. Consumption of hot tea compared with non-hot tea was associated with increased risk of esophageal cancer mortality (62). In addition, green tea consumption was associated with esophageal cancer risk in men (63). In 2005, the Ministry of Health, Labour and Welfare and the Ministry of Agriculture, Forestry and Fisheries of Japan jointly developed the Japanese Food Guide Spinning Top (64). This guide attempts to illustrate the balance and quantity of food in the usual Japanese diet. Based on a large-scale population-based prospective cohort study, it was shown that closer adherence to Japanese dietary guidelines was associated with a lower risk of total mortality and mortality from CVD, particularly from cerebrovascular disease (65). This study suggested that a balanced diet might contribute to longevity in the Japanese population. 4.Physical activity Be active in daily life. Goal Approximately 60 min of daily physical activity, such as walking or more intensive activity, as well as vigorous exercise 60 min a week, is needed for healthy adults aged between 18 and 64 years old. (‘Exercise and Physical Activity Reference for Health Promotion 2013’) (66) International background An increase in physical activity (exercise) is considered to lead to a ‘convincing’ decrease in risk of colorectal cancer and a ‘probable’ decrease in risk of breast cancer and of endometrial cancer (4). Several mechanisms have been suggested, such as improvement in insulin resistance, obesity, regulation of sex hormones and a beneficial effect on the immune system. Evidence in Japanese Based on the evaluation of Japanese studies, our study group evaluated the risk reduction of colorectal cancer through physical activity as ‘probable’ (67) and the corresponding risk reduction of breast cancer as ‘possible’. A cohort study conducted in Japanese subjects indicated that a high level of physical activity through work or exercise is associated with decreased risk of developing total cancer (68). Further, physical activity reduces the risk of death from not only cancer but also from heart disease, thereby reducing the risk of total mortality (69). Greater total physical activity, either from occupation, daily life, or leisure time, may be of benefit in preventing premature death. 5.Body weight Maintain an appropriate weight during adulthood. Goal Body mass index (BMI) should be between 21 and 27 kg/m2 for middle-aged to elderly men and between 21 and 25 kg/m2 for middle-aged to elderly women. International background Obesity has a ‘convincing’ effect of increasing the risk of colorectal, breast (post-menopause), liver, pancreas, esophageal adenocarcinoma, endometrial and kidney cancers (4). Several mechanisms are involved in the association, such as effects on inflammation and immune response; levels and metabolism of insulin and estradiol; and factors that regulate cell growth (e.g., insulin-like growth factor). Evidence in Japanese Our study group concluded that obesity is a ‘convincing’ and ‘possible’ factor in increasing the risk of breast cancer of post-menopausal and pre-menopausal women, respectively. In addition, the evaluation was ‘probable’ for colorectal and liver cancer and ‘possible’ for total (both high and low BMI) and endometrium cancer. Based on the results of a pooled analysis of eight cohort studies in Japan, a reverse-J pattern was seen for all-cause and cancer mortality (elevated risk only for high BMI in women), and a U- or J-shaped association was seen for heart disease and cerebrovascular disease mortality. The lowest risk of total mortality and mortality from major causes of disease was observed for a BMI of 21–27 kg/m2 in middle-aged and elderly Japanese (70). The association between obesity and cancer in general is not as strong for Japanese as that in Western populations. It is known that under-nutrition, which may lead to low BMI, lowers activity of the immune system, which may facilitate infection, and weakens blood vessel walls, increasing the risk of cerebral hemorrhage. Based on a pooled analysis of eight cohort studies in Japan, a significant positive association between BMI and colorectal cancer was observed; adjusted HRs for a 1 kg/m2 increase in BMI were 1.03 and 1.02 for men and women, respectively (71). For breast cancer, the corresponding values were 1.03 and 1.05 for pre- and post-menopausal women, respectively (72). Based on the significant increase in high BMI and also pre-menopausal breast cancer, the group also concluded that obesity ‘possibly’ increases the risk of cancer among pre-menopausal women. Obesity ‘probably’ increases the risk of liver (36) and colorectum cancer. Summary HRs were also estimated for diabetes mellitus and cancer incidence by pooling study-specific hazard ratios from eight cohort studies (73). Results showed a statistically increased risk for cancers of the colon (HR = 1.40), liver (HR = 1.97), pancreas (HR = 1.85) and bile duct (HR = 1.66; men only). Overall, diabetes mellitus was associated with a 20% increased risk in total cancer incidence in the Japanese population. 6.Infections Get tested for hepatitis virus infection and deal with it appropriately. Get tested for HP infection if there is an opportunity. Goal -Get tested for hepatitis virus infection at a local public health center or medical institution and, if infected, consult a specialist. - Get tested for HP infection if there is an opportunity. And, if infected, make sure you follow healthy lifestyle recommendations to avoid gastric cancer, such as not smoking, restricting salt or salt-preserved products, and ensuring sufficient intake of fruit and vegetables. Receive regular health check-up of the stomach, as well as consulting an attending physician based on detailed inspection of the stomach or gastrointestinal symptoms. International background The percentage of cancers caused by persistent infection with viruses and bacteria is estimated to be ~16.1% worldwide (74). The percentage of cancers caused by infection is fairly low in developed countries, at 7.4%, but is estimated at 22.9% of cancers in developing countries (74). Chronic infection with hepatitis B virus (HBV), hepatitis C virus (HCV) and HP has been evaluated as carcinogenic to humans (a Group 1 carcinogen) (1). Many other types of biological agents are listed as Group 1 carcinogens, including Epstein-Barr virus; human papilloma virus (HPV) types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58 and 59; human T-cell lymphotropic virus type 1; and human immunodeficiency virus type 1 (75). Evidence in Japanese In Japan, due to the high number of cases of gastric and liver cancer, infection with HBV/HCV, HP and HPV is estimated to account for 20% of total cancers (49), a fairly high ratio among developed countries (75). Based on 33 studies of HBV and liver cancer and 10 studies of HCV and liver cancer in Japanese subjects, the Study Group has concluded that HBV and HCV ‘convincingly’ increase the risk of liver cancer. In a retrospective cohort study, interferon therapy significantly reduced the risk for hepatocellular carcinoma, especially among virologic or biochemical responders (76). More recently, in a Phase III trial, antiviral drug use in combination with interferon therapy provided a high sustained virological response (SVR) rate for difficult-to-treat genotype 2 HCV patients who had not achieved SVR during prior interferon treatment (77). Although treatment of HBV remains difficult compared to HCV, progress is remarkable and new medicines are being developed. It is important for middle-aged and elderly people to be tested for hepatitis virus at a local health center or medical institution, because they may be infected without being aware of it (e.g. through past medical practices). Based on 19 studies of the association of HP and gastric cancer conducted in Japanese subjects, the Study Group concluded that it is ‘convincing’ that HP increases the risk of gastric cancer. In a cohort study in which 40 000 middle-aged to elderly (40–69 years old) Japanese were followed-up for 15 years to examine the relationship between HP and gastric cancer, it was reported that HP-positive people have a greater than five times’ higher risk of gastric cancer than those who are HP-negative (78). The preventive effect of gastric cancer by eradication therapy of HP is not conclusive. A meta-analysis of six randomized controlled trials targeting asymptomatic subjects revealed that eradication therapy reduced the risk of gastric cancer (79). However, uncertainties remain about the generalizability of the results and the cost-effectiveness and possible adverse effect of programs applied in community settings. Based on the current situation, the WHO working committee recommends that countries explore the possibility of introducing population-based HP screening and treatment programs, with local considerations of disease burden, other health priorities, and cost-effectiveness (80). Based on seven studies of HPV and cervical cancer conducted in Japanese subjects, the Study Group concluded that it is ‘convincing’ that HPV increases the risk of cervical cancer. It was reported that among 2282 Japanese women with normal cytology, HPV prevalence peaked (35.9%) in women aged 15–19 years, followed by a gradual decline in prevalence through 54 years (28.9% among women aged 20–29 years; 22.3% among women aged 30–39 years; and 11.4% among women aged 40–54 years) (81). In a 4-year follow up of women who were initially seronegative for HPV, no cervical intraepithelial neoplasia (CIN) Grade 1 or greater cases associated with HPV-16/18 were reported from the HPV vaccine group, while five cases were reported in the control group (82). The high vaccine efficacy observed in this report, accompanied by a sustained immune response and a clinically acceptable safety profile, supports results from international clinical trials. The Japanese Ministry of Health, Labour, and Welfare (MHLW) started an HPV vaccination program in April 2013, but suspended all vaccine promotion in June 2013 due to fears of adverse events (83). The MHLW is investigating adverse events associated with HPV vaccines, and still provides access to the routine HPV vaccination program. To determine the impact of adhering to these recommendations on developing cancer, we evaluated whether a combination of five of the healthy lifestyle factors mentioned above (not smoking, moderate drinking, minimizing consumption of salt-preserved foods, being physically active and having appropriate body mass index) is associated with a reduced risk of cancer (84). Compared to 0–1 healthy lifestyle factors, adherence to all five lifestyle factors showed a 43% and 37% risk reduction in developing total cancer for men and women, respectively. Furthermore, a systematic assessment was conducted to estimate the current burden of cancer attributable to known preventable risk factors in Japan in 2005 (49). In men, among the preventable factors, smoking had the highest population attributable fractions (PAFs), at 30% for incidence and 35% for mortality, respectively, followed by infectious agents (23% and 23%, respectively). In women, infectious agents had the highest PAF: 18% and 19% for incidence and mortality, respectively, followed by tobacco smoking (6% and 8%, respectively). Further control of these factors may substantially contribute to a reduction not only in cancer incidence and mortality but also in major non-communicable diseases mortality, to which five lifestyle factors are attributable in Japan (85). Discussion Compared to other international recommendations, there are several points which are distinctive to the present recommendation. First, it is notable that this is a comprehensive recommendation covering many essential lifestyle factors contributing to cancer incidence in our country. As a result, infection was included as one item, which reflects the significant local burden of the related cancers in our country, as well as in other Asian countries. Second, the recommended range of BMI was proposed to be between 21 and 27 kg/m2 and 21 and 25 kg/m2 for middle-aged to elderly men and women, respectively. The recommendations do not focus only on overweight or obesity, but also on low BMI, which was shown to confer elevated risk of all-cause and cancer mortality, especially in men. Third, the items mentioned in the diet recommendation are neither high-calorie nor high-fat items. There was only limited accumulation of evidence from Japanese data, especially for dietary factors. Proposing a systematic dietary recommendation for Japanese awaits additional validated studies that can adequately estimate dietary intake. Although the process of developing the present recommendation is thoroughly evidence-based, the recommended dose for some items was not directly derived from findings in research. For example, the recommended doses for salt and physical activity were derived from other specific reported recommendations (57, 66). Translation of the overall body of science to quantified recommendation is a challenge. The evidence rarely shows clear cut-off points where the risks increase or decrease, and, within any population, people differ from one another. Therefore, as with other recommendations, collective knowledge of reported considerations was also used. As the recommendation is based on currently available epidemiological evidence in Japan, the contents may be amended in the future as more evidence is accumulated. Most of our recommendations may also be applied to other Asian countries, where cancer prevention studies in their own population are nascent. Conclusion We developed evidence-based cancer prevention recommendations for Japanese. Because these recommendations were made based on a systematic review of epidemiologic studies focused on the etiology of cancer, they should be further translated. The next step should focus on the development of effective behavior modification programs and their implementation and dissemination. Funding This study was supported by the National Cancer Center Research and Development Fund (27-A-4). Conflict of interest statement None declared. References 1 International Agency for Research on Cancer. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. http://monographs.iarc.fr/ (10 July 2017, date last accessed). 2 World Health Organization. WHO Technical Reports Series 916. Diet, Nutrition, the Prevention of Chronic Disease. Report of a joint WHO/FAO Expert Consultation . Geneva: WHO, 2003. 3 World Cancer Research Fund/American Institute for Cancer Research. Food, Nutrition and the Prevention of Cancer: A Global Perspective . Washington, DC: American Institute for Cancer Research, 2007. 4 World Cancer Research Fund International/American Institute for Cancer Research. 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Adult mortality attributable to preventable risk factors for non-communicable diseases and injuries in Japan: a comparative risk assessment. PLoS Med  2012; 9: e1001160. Google Scholar CrossRef Search ADS PubMed  Appendix Research group members are listed at the following site (as of July 2017): http://epi.ncc.go.jp/en/can_prev/796/7955.html © The Author(s) 2018. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Japanese Journal of Clinical Oncology Oxford University Press

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Oxford University Press
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© The Author(s) 2018. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
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0368-2811
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1465-3621
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10.1093/jjco/hyy048
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Abstract

Abstract A comprehensive evidence-based cancer prevention recommendation for Japanese was developed. We evaluated the magnitude of the associations of lifestyle factors and infection with cancer through a systematic review of the literature, meta-analysis of published data, and pooled analysis of cohort studies in Japan. Then, we judged the strength of evidence based on the consistency of the associations between exposure and cancer and biological plausibility. Important factors were extracted and summarized as an evidence-based, current cancer prevention recommendation: ‘Cancer Prevention Recommendation for Japanese’. The recommendation addresses six important domains related to exposure and cancer, including smoking, alcohol drinking, diet, physical activity, body weight and infection. The next step should focus on the development of effective behavior modification programs and their implementation and dissemination. cancer prevention, epidemiology, Japanese Introduction Even though many aspects of cancer etiology are known to be related to lifestyle factors and infection, research findings have tended to be presented individually and have not been comprehensively aggregated to determine which lifestyle habits increase or decrease cancer risk. Among published evaluations or recommendations regarding lifestyle factors and related cancer, the most comprehensive are those from the International Agency for Research on Cancer (IARC) (1), the World Health Organization and Food and Agriculture Organization (WHO/FAO) (2), the World Cancer Research Fund and American Institute for Cancer Research (WCRF/AICR) (3), the WCRF International/ AICR Continuous Update Project (CUP) (4), and the European Code against Cancer fourth Edition (5). However, the research considered in these recommendations was mostly derived from Western countries. Before direct application of such recommendations to Japan, with substantial differences in genetic background and different exposure levels of environment and lifestyle habits, risk assessment in the Japanese population is required. In fact, Japanese have a higher prevalence of the aldehyde dehydrogenase 2*2 null allele (6), which results in slower catalysis in acetaldehyde metabolism (7); a higher prevalence of Helicobacter pylori (HP) infection (8); and a lower prevalence of obesity (9); as well as distinctive dietary habits compared to Western populations such as a high intake of vegetable, fish, soy products, and salt and low intake of meat (10). Accordingly, we have developed a comprehensive recommendation that reflects the characteristics of cancer and related factors for the country since 2003. The objective of this report is to inform the international community of the strength of evidence linking lifestyle factors and infection to the risk of cancer in Japan, and to provide updated evidence-based cancer prevention recommendations applicable for Japanese. Methods To perform risk assessment which defines the health effects of exposure of populations to hazardous agents, evidence from epidemiological studies among the Japanese population was compiled and organized using three processes (systematic review, meta-analysis, and pooled analysis) by the Research Group for the Development and Evaluation of Cancer Prevention Strategies in Japan (Principle investigator: Shoichiro Tsugane, 2003–2011; Shizuka Sasazuki, 2012–2017; and Taichi Shimazu 2017–present). The research group then incorporated the results of the risk assessment with risks of non-cancer diseases and total mortality, as well as social concerns where necessary, and prepared a Cancer Recommendation for Japanese. Literature search and systematic review: qualitative evaluation We searched articles published from 1966 to the date we made a final judgment of the strength of evidence using PubMed and the Japanese Medical Research Database (Igaku-Chuo-Zasshi), and complemented this with manual searches of references from related literature (Table 2). Eligible papers had to be case–control or cohort studies of lifestyle factors, infection and cancer; written in English or Japanese; and based on a Japanese population. The association of each lifestyle factor with infection and site-specific cancer (e.g. lung, liver, stomach, colon, breast, esophagus, pancreas, prostate, cervix, corpus uteri, ovary, head and neck, bladder and blood), as well as total cancer, was evaluated to assess the magnitude of association and strength of evidence. First, the magnitude of association was classified based on the relative risk (RR) estimate and statistical significance as ‘Strong’ RR < 0.5 or RR > 2.0 (statistically significant [SS]); ‘Moderate’, either (i) RR < 0.5 or RR > 2.0 (statistically non-significant [NS]), (ii) RR > 1.5–2.0 (SS) or (iii) 0.5 to <0.67 (SS); ‘Weak’, either (i) RR > 1.5–2.0 (NS), (ii) 0.5 to <0.67 (NS) or (iii) 0.67-1.5 (SS); or ‘No association’, 0.67–1.5 (NS). After this process, the overall strength of evidence was classified into four ranking groups (‘convincing’, ‘probable’, ‘possible’ and ‘insufficient’) based on the method used in the WHO/FAO report (2). In brief, this and the WHO/FAO reports share the following criteria. ‘Convincing’: the results of epidemiological studies are consistent, and there are almost no contradicting results. There are a substantial number of studies. Biological explanations can be used to understand the results. ‘Probable’: the results of epidemiological studies are fairly consistent, but there are inadequacies in the methods (the study period is too short, insufficient number of studies, insufficient number of subjects, follow-up is incomplete, etc.) or there are multiple contradicting results. The association should be biologically plausible. ‘Possible’: evidence based mainly on findings from case–control and cross-sectional studies. ‘Insufficient’: evidence based on findings of a few studies which are suggestive, but are insufficient to establish an association between exposure and disease. Final judgment of the strength of evidence took account of the consistency of the associations between exposure and cancer, the biological mechanism assumption derived from the recent IARC evaluation report (1), evaluations or recommendations of the authoritative reports on exposure and cancer (1–4,11), and quantitative evaluation mentioned in the next section. We briefly described the findings of these reports as ‘international background.’ Notwithstanding the use of this quantitative assessment rule, arbitrary assessment cannot be avoided when there is considerable variation in the magnitude of association between the results of the studies. The final judgment is therefore made based on the consensus of the research group members, and is not necessarily objective. Meta-analysis or pooled analysis: quantitative analysis In general, if the judgment was ‘convincing’ or ‘probable’, meta-analysis of published literature was conducted to obtain summary estimates. Cohort studies or case–control studies reporting RRs or odds ratios (ORs) and 95% confidence intervals (CIs) were included. In the case of multiple publications from one study, the largest or most updated report was selected. We also obtained quantitative summary estimates by conducting pooled analyses of original data from individual studies. Hazard ratios (HRs) of each study were reanalyzed for this project according to a common protocol. Using a random-effects model, we conducted a meta-analysis of the HRs to obtain pooled estimates for the association of lifestyle factors and cancer. This method limits potential sources of heterogeneity because categories of exposure and covariates can be set in an identical manner. To maintain the quality and comparability of data, we set the following a priori criteria: (i) a population-based cohort study started in Japan in the mid-1980s to mid-1990s, (ii) inclusion of more than 30 000 participants and (iii) collection of total mortality and cancer incidence. As of July 2017, 10 cohort studies participate in this pooling project: the Japan Public Health Center-based Prospective Study, Cohort I [JPHC-I] (12); the Japan Public Health Center-Based Prospective Study, Cohort II [JPHC-II] (12); the Japan Collaborative Cohort Study [JACC] (13); the Miyagi Cohort Study [MIYAGI] (14); the Three-Prefecture Miyagi [3-pref MIYAGI] (15); the Ohsaki National Health Insurance Cohort Study [OHSAKI] (16); the Three-Prefecture Aichi [3-pref AICHI] (15); the Takayama Study [TAKAYAMA] (17); the Life Span Study [LSS] (18) and the Three-Prefecture Osaka [3-pref OSAKA] (15) (Table 1). A total of 519 579 subjects were included in the pooled analysis. The pooled analysis provided a large sample size and enabled the detection of a relatively stable estimate and even a small effect. Table 1. Cohort studies in pooling analysis of the Research Group for the Development and Evaluation of Cancer Prevention Strategies in Japan Study  Population  Age (years) at baseline survey  Year(s) of baseline survey  Population size  JPHC-I  Japanese residents of five public health center areas in Japan  40–59  1990  61 595  JPHC-II  Japanese residents of six public health center areas in Japan  40–69  1993–1994  78 825  JACC  Residents from 45 areas throughout Japan  40–79  1988–1990  110 585  MIYAGI  Residents of 14 municipalities in Miyagi Prefecture, Japan  40–64  1990  47 605  OHSAKI  Beneficiaries of National Health Insurance among residents of 14 municipalities in Miyagi Prefecture, Japan  40–79  1994  54 996  3-pref MIYAGI  Residents of three municipalities in Miyagi Prefecture, Japan  40–98  1984  31 345  3-pref AICHI  Residents of two municipalities in Aichi Prefecture, Japan  40–103  1985  33 529  TAKAYAMA  Residents of Takayama, Gifu, Japan  35–  1992  31 552  LSS  Atomic bomb survivors in Hiroshima, Nagasaki, Japan  34–102  1978  33 792 (No. of subjects who participated in at least one survey)      46–104  1991    3-pref OSAKA  Residents of four municipalities in Osaka Prefecture, Japan  40–97  1983–1985  35 755  Total        519 579  Study  Population  Age (years) at baseline survey  Year(s) of baseline survey  Population size  JPHC-I  Japanese residents of five public health center areas in Japan  40–59  1990  61 595  JPHC-II  Japanese residents of six public health center areas in Japan  40–69  1993–1994  78 825  JACC  Residents from 45 areas throughout Japan  40–79  1988–1990  110 585  MIYAGI  Residents of 14 municipalities in Miyagi Prefecture, Japan  40–64  1990  47 605  OHSAKI  Beneficiaries of National Health Insurance among residents of 14 municipalities in Miyagi Prefecture, Japan  40–79  1994  54 996  3-pref MIYAGI  Residents of three municipalities in Miyagi Prefecture, Japan  40–98  1984  31 345  3-pref AICHI  Residents of two municipalities in Aichi Prefecture, Japan  40–103  1985  33 529  TAKAYAMA  Residents of Takayama, Gifu, Japan  35–  1992  31 552  LSS  Atomic bomb survivors in Hiroshima, Nagasaki, Japan  34–102  1978  33 792 (No. of subjects who participated in at least one survey)      46–104  1991    3-pref OSAKA  Residents of four municipalities in Osaka Prefecture, Japan  40–97  1983–1985  35 755  Total        519 579  JPHC-I, Japan Public Health Center-based Prospective Study, Cohort I; JPHC-II, the Japan Public Health Center-Based Prospective Study, Cohort II; JACC, the Japan Collaborative Cohort Study; MIYAGI, the Miyagi Cohort Study; 3-pref MIYAGI, the Three-Prefecture Miyagi; OHSAKI, the Ohsaki National Health Insurance Cohort Study; 3-pref AICHI, the Three-Prefecture Aichi; TAKAYAMA, the Takayama Study; LSS: the Life Span Study; 3-pref OSAKA, the Three-Prefecture Osaka. Table 1. Cohort studies in pooling analysis of the Research Group for the Development and Evaluation of Cancer Prevention Strategies in Japan Study  Population  Age (years) at baseline survey  Year(s) of baseline survey  Population size  JPHC-I  Japanese residents of five public health center areas in Japan  40–59  1990  61 595  JPHC-II  Japanese residents of six public health center areas in Japan  40–69  1993–1994  78 825  JACC  Residents from 45 areas throughout Japan  40–79  1988–1990  110 585  MIYAGI  Residents of 14 municipalities in Miyagi Prefecture, Japan  40–64  1990  47 605  OHSAKI  Beneficiaries of National Health Insurance among residents of 14 municipalities in Miyagi Prefecture, Japan  40–79  1994  54 996  3-pref MIYAGI  Residents of three municipalities in Miyagi Prefecture, Japan  40–98  1984  31 345  3-pref AICHI  Residents of two municipalities in Aichi Prefecture, Japan  40–103  1985  33 529  TAKAYAMA  Residents of Takayama, Gifu, Japan  35–  1992  31 552  LSS  Atomic bomb survivors in Hiroshima, Nagasaki, Japan  34–102  1978  33 792 (No. of subjects who participated in at least one survey)      46–104  1991    3-pref OSAKA  Residents of four municipalities in Osaka Prefecture, Japan  40–97  1983–1985  35 755  Total        519 579  Study  Population  Age (years) at baseline survey  Year(s) of baseline survey  Population size  JPHC-I  Japanese residents of five public health center areas in Japan  40–59  1990  61 595  JPHC-II  Japanese residents of six public health center areas in Japan  40–69  1993–1994  78 825  JACC  Residents from 45 areas throughout Japan  40–79  1988–1990  110 585  MIYAGI  Residents of 14 municipalities in Miyagi Prefecture, Japan  40–64  1990  47 605  OHSAKI  Beneficiaries of National Health Insurance among residents of 14 municipalities in Miyagi Prefecture, Japan  40–79  1994  54 996  3-pref MIYAGI  Residents of three municipalities in Miyagi Prefecture, Japan  40–98  1984  31 345  3-pref AICHI  Residents of two municipalities in Aichi Prefecture, Japan  40–103  1985  33 529  TAKAYAMA  Residents of Takayama, Gifu, Japan  35–  1992  31 552  LSS  Atomic bomb survivors in Hiroshima, Nagasaki, Japan  34–102  1978  33 792 (No. of subjects who participated in at least one survey)      46–104  1991    3-pref OSAKA  Residents of four municipalities in Osaka Prefecture, Japan  40–97  1983–1985  35 755  Total        519 579  JPHC-I, Japan Public Health Center-based Prospective Study, Cohort I; JPHC-II, the Japan Public Health Center-Based Prospective Study, Cohort II; JACC, the Japan Collaborative Cohort Study; MIYAGI, the Miyagi Cohort Study; 3-pref MIYAGI, the Three-Prefecture Miyagi; OHSAKI, the Ohsaki National Health Insurance Cohort Study; 3-pref AICHI, the Three-Prefecture Aichi; TAKAYAMA, the Takayama Study; LSS: the Life Span Study; 3-pref OSAKA, the Three-Prefecture Osaka. Current evaluation and recommendations Evaluation of evidence Judgment of the strength of evidence linking lifestyle factors and infection to total and site-specific cancer risk is summarized in Table 2 (19–46). Regarding cigarette smoking and alcohol drinking, several sites of cancers were evaluated as having ‘convincing’ evidence. Infection was evaluated as having ‘convincing’ evidence for specific types of cancer. Regarding dietary factors, the association with cancer was evaluated for seven food groups; two beverages, hot food and beverages; eight nutrients; highly salted food; and dietary pattern. Most items had ‘insufficient’ data to allow assessment of the strength of evidence based on the currently available evidence. Table 2. The strength of evidence linking lifestyle factors and infection to the risk of total and site-specific cancer among Japanese population (summary), as of 1 August 2017         Conv, convincing; Poss, possible; Insuff, insufficient; AML, acute myeloid leukemia; BMI, body mass index; M, male; F, female; TB, tuberculosis; HBV, hepatitis B virus; HCV, hepatitis C virus; HPV, human papilloma virus; DM, diabetes mellitus; IARC, International Agency for Research on Cancer; exp, exposure; EBV, Epstein-Barr virus. Figures in brackets indicate the decision year of the strength of evidence. *Studies focused on supplement use were not included. Table 2. The strength of evidence linking lifestyle factors and infection to the risk of total and site-specific cancer among Japanese population (summary), as of 1 August 2017         Conv, convincing; Poss, possible; Insuff, insufficient; AML, acute myeloid leukemia; BMI, body mass index; M, male; F, female; TB, tuberculosis; HBV, hepatitis B virus; HCV, hepatitis C virus; HPV, human papilloma virus; DM, diabetes mellitus; IARC, International Agency for Research on Cancer; exp, exposure; EBV, Epstein-Barr virus. Figures in brackets indicate the decision year of the strength of evidence. *Studies focused on supplement use were not included. Cancer prevention recommendation for Japanese Among the results of evaluation of evidence shown in Table 2, important factors were extracted and summarized as an evidence-based, current cancer prevention recommendation: ‘Cancer Prevention Recommendation for Japanese’ (Table 3). Table 3. Cancer Prevention Recommendation for Japanese Current evidence-based Cancer Prevention Recommendations for Japanese  1.  Smoking     Do not smoke cigarettes. Avoid passive smoking.  2.  Drinking     Drink in moderation. Drinking should be kept to within ~23 g alcohol per day. People that usually do not drink, or have alcohol intolerance, should not force themselves to drink.  3.  Diet     Make sure you follow a nutritionally balanced diet.  -Restrict your intake of salt and salt-preserved products. Keep salt consumption to less than 8 g for men and 7 g for women per day for healthy individuals aged 18 years or more. Consumption of foods high in salt should be kept to no more than one time per week.  -Ensure sufficient intake of fruit and vegetables.  -Do not consume too much hot (thermally) food and drinks.  4.  Physical Activity     Be active in daily life. For example, ~60 min of daily physical activity such as walking or more intensive activity as well as vigorous exercise 60 min a week is needed for healthy adults aged between 18 and 64 years old.  5.  Body Weight     Maintain an appropriate weight during adulthood. BMI for middle-aged to elderly men should be between 21 and 27, and between 21 and 25 for middle-aged to elderly women.  6.  Infections     Get tested for hepatitis virus infection and deal with it appropriately. Get tested for Helicobacter pylori infection if there is an opportunity.  Current evidence-based Cancer Prevention Recommendations for Japanese  1.  Smoking     Do not smoke cigarettes. Avoid passive smoking.  2.  Drinking     Drink in moderation. Drinking should be kept to within ~23 g alcohol per day. People that usually do not drink, or have alcohol intolerance, should not force themselves to drink.  3.  Diet     Make sure you follow a nutritionally balanced diet.  -Restrict your intake of salt and salt-preserved products. Keep salt consumption to less than 8 g for men and 7 g for women per day for healthy individuals aged 18 years or more. Consumption of foods high in salt should be kept to no more than one time per week.  -Ensure sufficient intake of fruit and vegetables.  -Do not consume too much hot (thermally) food and drinks.  4.  Physical Activity     Be active in daily life. For example, ~60 min of daily physical activity such as walking or more intensive activity as well as vigorous exercise 60 min a week is needed for healthy adults aged between 18 and 64 years old.  5.  Body Weight     Maintain an appropriate weight during adulthood. BMI for middle-aged to elderly men should be between 21 and 27, and between 21 and 25 for middle-aged to elderly women.  6.  Infections     Get tested for hepatitis virus infection and deal with it appropriately. Get tested for Helicobacter pylori infection if there is an opportunity.  Table 3. Cancer Prevention Recommendation for Japanese Current evidence-based Cancer Prevention Recommendations for Japanese  1.  Smoking     Do not smoke cigarettes. Avoid passive smoking.  2.  Drinking     Drink in moderation. Drinking should be kept to within ~23 g alcohol per day. People that usually do not drink, or have alcohol intolerance, should not force themselves to drink.  3.  Diet     Make sure you follow a nutritionally balanced diet.  -Restrict your intake of salt and salt-preserved products. Keep salt consumption to less than 8 g for men and 7 g for women per day for healthy individuals aged 18 years or more. Consumption of foods high in salt should be kept to no more than one time per week.  -Ensure sufficient intake of fruit and vegetables.  -Do not consume too much hot (thermally) food and drinks.  4.  Physical Activity     Be active in daily life. For example, ~60 min of daily physical activity such as walking or more intensive activity as well as vigorous exercise 60 min a week is needed for healthy adults aged between 18 and 64 years old.  5.  Body Weight     Maintain an appropriate weight during adulthood. BMI for middle-aged to elderly men should be between 21 and 27, and between 21 and 25 for middle-aged to elderly women.  6.  Infections     Get tested for hepatitis virus infection and deal with it appropriately. Get tested for Helicobacter pylori infection if there is an opportunity.  Current evidence-based Cancer Prevention Recommendations for Japanese  1.  Smoking     Do not smoke cigarettes. Avoid passive smoking.  2.  Drinking     Drink in moderation. Drinking should be kept to within ~23 g alcohol per day. People that usually do not drink, or have alcohol intolerance, should not force themselves to drink.  3.  Diet     Make sure you follow a nutritionally balanced diet.  -Restrict your intake of salt and salt-preserved products. Keep salt consumption to less than 8 g for men and 7 g for women per day for healthy individuals aged 18 years or more. Consumption of foods high in salt should be kept to no more than one time per week.  -Ensure sufficient intake of fruit and vegetables.  -Do not consume too much hot (thermally) food and drinks.  4.  Physical Activity     Be active in daily life. For example, ~60 min of daily physical activity such as walking or more intensive activity as well as vigorous exercise 60 min a week is needed for healthy adults aged between 18 and 64 years old.  5.  Body Weight     Maintain an appropriate weight during adulthood. BMI for middle-aged to elderly men should be between 21 and 27, and between 21 and 25 for middle-aged to elderly women.  6.  Infections     Get tested for hepatitis virus infection and deal with it appropriately. Get tested for Helicobacter pylori infection if there is an opportunity.  1. Smoking Do not smoke cigarettes. Avoid passive smoking. Goal Current smokers should stop smoking. Non-smokers should avoid passive smoking. International background Smoking is the single largest cause of cancer worldwide. New sites continue to be added to the list of tobacco-related cancers. IARC reports that 19 sites, including recently added colon and ovary (musinous) cancer, are considered to have sufficient evidence to be related to tobacco smoking (47). For female breast cancer, the evidence is limited. Smoking is also a cause of coronary artery disease (e.g. angina and myocardial infarction), cardiovascular disease (CVD; e.g. stroke), and respiratory disease (e.g. pneumonia and chronic obstructive pulmonary disease). Passive smoking is considered to be a ‘convincing’ risk factor for lung cancer. A meta-analysis of 55 studies on the relationship of passive smoking and lung cancer reported that non-smoking females were at 1.3-fold higher risk from passive smoking from their husbands than females with non-smoking husbands (48). The evidence is sufficient to infer a causal relationship between passive smoking and increased risk of stroke (11). Evidence in Japanese Based on the evaluation of Japanese studies, the ‘Development and Evaluation of Cancer Prevention Strategies in Japan’ Group concluded that there is ‘convincing’ evidence that tobacco smoking increases the risk of total cancer (19). In the report, the risk of total cancer in smokers was 1.5 times as high as that in non-smokers (male: 1.6 times, female: 1.3 times) based on meta-analysis of five cohort studies. Given the above RR and the prevalence of smoking, it was estimated that ~20–23% of cancers in Japanese are caused by smoking (~30–34% for males and 5–6% for females) and could, therefore, have been prevented by not smoking (49). By site, there was ‘convincing’ evidence that smoking increases the risk of cancer of the lung (20), liver (21), stomach (22), esophagus (25), pancreas (26), head and neck (27), bladder (28) and cervix. Our group concluded that passive smoking ‘convincingly’ increases the risk of lung cancer. Based on a cohort study on passive smoking in non-smoking Japanese women, the risk of developing pulmonary adenocarcinoma was approximately doubled in subjects whose husbands were smokers compared to those whose husbands were not smokers (50). Approximately 37% of lung cancer cases in women were estimated to be caused by passive smoking at home. Including this study, a meta-analysis of four cohort studies and five case–control studies was conducted (51). Quantitative synthesis was conducted only for secondhand smoke exposure in the home during adulthood. Of the 12 populations included in the meta-analysis, positive secondhand smoke exposure-lung cancer associations were observed in 11, whereas an inverse association was found in the remaining study. The pooled RR of lung cancer associated with secondhand smoke exposure was 1.28 (95% CI: 1.10–1.48). 2. Drinking Drink in moderation. Goal Drinking should be kept to within ~23 g alcohol per day (equal to ~1 ‘go’ (go = 180 ml) of Japanese sake, 1 large bottle of beer, 2/3 ‘go’ of shochu or awamori, 1 double whiskey or brandy, or two glasses of wine). People who usually do not drink, or have alcohol intolerance, should not force themselves to drink. International background In the report of the WCRF/AICR working group (3) and CUP (4), ‘convincing’ evidence suggest that alcohol drinking increases the risk of oral, pharyngeal, laryngeal, esophageal (squamous cell carcinoma), liver, colorectal (men) and breast (post-menopause) cancers. Furthermore, increases in risk of stomach, colorectal (women) and breast (pre-menopause) cancers were deemed to be ‘probable’. IARC reports that there is sufficient evidence that alcoholic beverages cause these cancers (1). Evidence in Japanese Based on an evaluation of Japanese studies, our group concluded that there is ‘convincing’ evidence that alcohol drinking increases the risk of total cancer (29). By site, the strength of evidence for cancer of the liver (31), colorectum (33) and esophagus (35) was found to be ‘convincing’. A pooled analysis of six cohort studies which included ~310 000 subjects found a J- or U-shaped association for the risk of total and major causes of mortality in men, and for the risk of total and heart disease mortality in women (52). Compared with non-drinkers, there were significantly lower risks of total mortality at an alcohol intake of <69 g/day, cancer mortality at <46 g/day, heart disease mortality at <69 g/day, and cerebrovascular disease mortality at <46 g/day in men, and of total mortality at <23 g/day in women. This means that a small amount of drinking may have the effect of lowering the risk of myocardial infarction or stroke. However, in a pooled analysis, increased risk of cancer was observed for colorectum (53) and female liver (54) sites at the level of more than 23 g/day intake. Therefore, from a general point of view, it is recommended that drinking should be kept within 23 g of alcohol per day. 3. Diet Make sure you follow a nutritionally balanced diet. -Restrict your intake of salt and salt-preserved products. -Ensure sufficient intake of fruit and vegetables. -Do not consume too much hot (thermally) food and drink. Goal -Keep salt consumption to less than 8 g for men and 7 g for women per day for healthy individuals aged 18 years or more. Consumption of foods high in salt should be kept to no more than one time per week. International background Salt may increase the risk of gastric cancer through the destruction of mucus barriers, leading to acid-induced inflammation and persistent infection with HP. Foods preserved by salting are thought to ‘probably’ increase the risk of gastric cancer (4). Limiting consumption of highly salted foods and providing alternatives to salt in food processing or preservation may help mitigate this risk. Fruits and vegetable are considered to lower the risk of cancer via the effects of constituent vitamins, carotenes, folate, fiber, isothiocyanate or other compounds. The WCRF/AICR report concluded that non-starchy vegetables and fruits play a ‘probable’ role in helping to prevent oral, pharyngeal, laryngeal, and lung (fruits only) cancers (3). The joint committee of the WHO/FAO report recommends consumption of at least 400 g of vegetables and fruits per day to prevent lifestyle-related diseases (2). The IARC classified processed and red meat as carcinogenic to humans (Group 1) and probably carcinogenic to humans (Group 2 A), respectively (55). The WCRF International concluded that processed meat ‘convincingly’ and red meat ‘probably’ increases colorectal cancer risk, respectively, and advised limiting red meat and avoiding processed meat (4). A ‘probable’ increase in the risk of esophageal cancer has been noted for mate, a beverage which is customarily drunk at extremely hot temperatures in South America (4). Also, in ‘limited’ cases, some study results have suggested an increase in risk of oral, pharyngeal and laryngeal cancers (3). Evidence in Japanese Based on the evaluation of Japanese studies, our research group concluded that salt and salt-preserved foods ‘probably’ increase the risk of gastric cancer. A cohort study conducted in Japanese subjects indicated that sodium was not associated with increased risk of total cancer but was associated with increased risk of total CVD and stroke (56). In contrast, salted fish roe was associated with increased risk of total cancer. Similar results were seen in the association between salt-preserved foods and the risk of gastric cancer. Limiting salt and salt-preserved food intake would not only be effective for preventing gastric cancer, the most common cancer in Japan, but would also contribute to the prevention of hypertension and decrease the risk of CVD. According to the Dietary Reference Intakes for Japanese (2015), the target level of salt per day is set at under 8 g for men and 7 g for women (57). The evaluation of our group regarding fruits and vegetables revealed that a decrease in risk of esophageal cancer is ‘probable’, while decreased risk of stomach and lung cancer (fruit only) is ‘possible’. In a pooled analysis of four cohort studies conducted in Japanese subjects, a marginally significant decrease in gastric cancer risk in relation to total vegetable intake but not total fruit intake was observed (58). For distal gastric cancer, the association was significant among men. In a prospective cohort study, it was demonstrated that, in the Japanese population, consumption of fruit is associated with lower risk of CVD, whereas intake of fruit or vegetables may not be associated with lower risk of total cancer (59). In the recent pooled analysis from four cohort studies, consumption of fruits or vegetables was not associated with decreased risk of overall cancers (60). Although the impact for overall cancer prevention was undetectable, the results do not contradict the possibly small but protective effect of fruit and vegetable intake on site-specific cancers. It is possible that the aggregation of cancer sites in the analysis might dilute the impact of association; therefore, from a general point of view considering prevention for other chronic diseases, including CVD (61), daily consumption of vegetables and fruits is recommended. Differing from the WCFR International (4), we judged that processed and red meat ‘possibly’ increase colorectal cancer risk. We consider that roughly average levels of processed and red meat intake in Japan (mean 63 g per day) (10), which is much lower than those in Western countries (ranged 50–200 g per day) (55), did not increase colorectal cancer risk. Thus, we did not make any specific recommendation on meat intake. The evaluation of our group regarding hot food and drink concluded that an increase in risk of esophageal cancer is ‘probable’. Many study results have suggested that eating hot food and drinks may lead to esophagitis or esophageal cancer. To avoid damage to the mucosal membrane of the oral cavity and esophagus, hot food and drinks should be allowed to cool before consumption. Consumption of hot tea compared with non-hot tea was associated with increased risk of esophageal cancer mortality (62). In addition, green tea consumption was associated with esophageal cancer risk in men (63). In 2005, the Ministry of Health, Labour and Welfare and the Ministry of Agriculture, Forestry and Fisheries of Japan jointly developed the Japanese Food Guide Spinning Top (64). This guide attempts to illustrate the balance and quantity of food in the usual Japanese diet. Based on a large-scale population-based prospective cohort study, it was shown that closer adherence to Japanese dietary guidelines was associated with a lower risk of total mortality and mortality from CVD, particularly from cerebrovascular disease (65). This study suggested that a balanced diet might contribute to longevity in the Japanese population. 4.Physical activity Be active in daily life. Goal Approximately 60 min of daily physical activity, such as walking or more intensive activity, as well as vigorous exercise 60 min a week, is needed for healthy adults aged between 18 and 64 years old. (‘Exercise and Physical Activity Reference for Health Promotion 2013’) (66) International background An increase in physical activity (exercise) is considered to lead to a ‘convincing’ decrease in risk of colorectal cancer and a ‘probable’ decrease in risk of breast cancer and of endometrial cancer (4). Several mechanisms have been suggested, such as improvement in insulin resistance, obesity, regulation of sex hormones and a beneficial effect on the immune system. Evidence in Japanese Based on the evaluation of Japanese studies, our study group evaluated the risk reduction of colorectal cancer through physical activity as ‘probable’ (67) and the corresponding risk reduction of breast cancer as ‘possible’. A cohort study conducted in Japanese subjects indicated that a high level of physical activity through work or exercise is associated with decreased risk of developing total cancer (68). Further, physical activity reduces the risk of death from not only cancer but also from heart disease, thereby reducing the risk of total mortality (69). Greater total physical activity, either from occupation, daily life, or leisure time, may be of benefit in preventing premature death. 5.Body weight Maintain an appropriate weight during adulthood. Goal Body mass index (BMI) should be between 21 and 27 kg/m2 for middle-aged to elderly men and between 21 and 25 kg/m2 for middle-aged to elderly women. International background Obesity has a ‘convincing’ effect of increasing the risk of colorectal, breast (post-menopause), liver, pancreas, esophageal adenocarcinoma, endometrial and kidney cancers (4). Several mechanisms are involved in the association, such as effects on inflammation and immune response; levels and metabolism of insulin and estradiol; and factors that regulate cell growth (e.g., insulin-like growth factor). Evidence in Japanese Our study group concluded that obesity is a ‘convincing’ and ‘possible’ factor in increasing the risk of breast cancer of post-menopausal and pre-menopausal women, respectively. In addition, the evaluation was ‘probable’ for colorectal and liver cancer and ‘possible’ for total (both high and low BMI) and endometrium cancer. Based on the results of a pooled analysis of eight cohort studies in Japan, a reverse-J pattern was seen for all-cause and cancer mortality (elevated risk only for high BMI in women), and a U- or J-shaped association was seen for heart disease and cerebrovascular disease mortality. The lowest risk of total mortality and mortality from major causes of disease was observed for a BMI of 21–27 kg/m2 in middle-aged and elderly Japanese (70). The association between obesity and cancer in general is not as strong for Japanese as that in Western populations. It is known that under-nutrition, which may lead to low BMI, lowers activity of the immune system, which may facilitate infection, and weakens blood vessel walls, increasing the risk of cerebral hemorrhage. Based on a pooled analysis of eight cohort studies in Japan, a significant positive association between BMI and colorectal cancer was observed; adjusted HRs for a 1 kg/m2 increase in BMI were 1.03 and 1.02 for men and women, respectively (71). For breast cancer, the corresponding values were 1.03 and 1.05 for pre- and post-menopausal women, respectively (72). Based on the significant increase in high BMI and also pre-menopausal breast cancer, the group also concluded that obesity ‘possibly’ increases the risk of cancer among pre-menopausal women. Obesity ‘probably’ increases the risk of liver (36) and colorectum cancer. Summary HRs were also estimated for diabetes mellitus and cancer incidence by pooling study-specific hazard ratios from eight cohort studies (73). Results showed a statistically increased risk for cancers of the colon (HR = 1.40), liver (HR = 1.97), pancreas (HR = 1.85) and bile duct (HR = 1.66; men only). Overall, diabetes mellitus was associated with a 20% increased risk in total cancer incidence in the Japanese population. 6.Infections Get tested for hepatitis virus infection and deal with it appropriately. Get tested for HP infection if there is an opportunity. Goal -Get tested for hepatitis virus infection at a local public health center or medical institution and, if infected, consult a specialist. - Get tested for HP infection if there is an opportunity. And, if infected, make sure you follow healthy lifestyle recommendations to avoid gastric cancer, such as not smoking, restricting salt or salt-preserved products, and ensuring sufficient intake of fruit and vegetables. Receive regular health check-up of the stomach, as well as consulting an attending physician based on detailed inspection of the stomach or gastrointestinal symptoms. International background The percentage of cancers caused by persistent infection with viruses and bacteria is estimated to be ~16.1% worldwide (74). The percentage of cancers caused by infection is fairly low in developed countries, at 7.4%, but is estimated at 22.9% of cancers in developing countries (74). Chronic infection with hepatitis B virus (HBV), hepatitis C virus (HCV) and HP has been evaluated as carcinogenic to humans (a Group 1 carcinogen) (1). Many other types of biological agents are listed as Group 1 carcinogens, including Epstein-Barr virus; human papilloma virus (HPV) types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58 and 59; human T-cell lymphotropic virus type 1; and human immunodeficiency virus type 1 (75). Evidence in Japanese In Japan, due to the high number of cases of gastric and liver cancer, infection with HBV/HCV, HP and HPV is estimated to account for 20% of total cancers (49), a fairly high ratio among developed countries (75). Based on 33 studies of HBV and liver cancer and 10 studies of HCV and liver cancer in Japanese subjects, the Study Group has concluded that HBV and HCV ‘convincingly’ increase the risk of liver cancer. In a retrospective cohort study, interferon therapy significantly reduced the risk for hepatocellular carcinoma, especially among virologic or biochemical responders (76). More recently, in a Phase III trial, antiviral drug use in combination with interferon therapy provided a high sustained virological response (SVR) rate for difficult-to-treat genotype 2 HCV patients who had not achieved SVR during prior interferon treatment (77). Although treatment of HBV remains difficult compared to HCV, progress is remarkable and new medicines are being developed. It is important for middle-aged and elderly people to be tested for hepatitis virus at a local health center or medical institution, because they may be infected without being aware of it (e.g. through past medical practices). Based on 19 studies of the association of HP and gastric cancer conducted in Japanese subjects, the Study Group concluded that it is ‘convincing’ that HP increases the risk of gastric cancer. In a cohort study in which 40 000 middle-aged to elderly (40–69 years old) Japanese were followed-up for 15 years to examine the relationship between HP and gastric cancer, it was reported that HP-positive people have a greater than five times’ higher risk of gastric cancer than those who are HP-negative (78). The preventive effect of gastric cancer by eradication therapy of HP is not conclusive. A meta-analysis of six randomized controlled trials targeting asymptomatic subjects revealed that eradication therapy reduced the risk of gastric cancer (79). However, uncertainties remain about the generalizability of the results and the cost-effectiveness and possible adverse effect of programs applied in community settings. Based on the current situation, the WHO working committee recommends that countries explore the possibility of introducing population-based HP screening and treatment programs, with local considerations of disease burden, other health priorities, and cost-effectiveness (80). Based on seven studies of HPV and cervical cancer conducted in Japanese subjects, the Study Group concluded that it is ‘convincing’ that HPV increases the risk of cervical cancer. It was reported that among 2282 Japanese women with normal cytology, HPV prevalence peaked (35.9%) in women aged 15–19 years, followed by a gradual decline in prevalence through 54 years (28.9% among women aged 20–29 years; 22.3% among women aged 30–39 years; and 11.4% among women aged 40–54 years) (81). In a 4-year follow up of women who were initially seronegative for HPV, no cervical intraepithelial neoplasia (CIN) Grade 1 or greater cases associated with HPV-16/18 were reported from the HPV vaccine group, while five cases were reported in the control group (82). The high vaccine efficacy observed in this report, accompanied by a sustained immune response and a clinically acceptable safety profile, supports results from international clinical trials. The Japanese Ministry of Health, Labour, and Welfare (MHLW) started an HPV vaccination program in April 2013, but suspended all vaccine promotion in June 2013 due to fears of adverse events (83). The MHLW is investigating adverse events associated with HPV vaccines, and still provides access to the routine HPV vaccination program. To determine the impact of adhering to these recommendations on developing cancer, we evaluated whether a combination of five of the healthy lifestyle factors mentioned above (not smoking, moderate drinking, minimizing consumption of salt-preserved foods, being physically active and having appropriate body mass index) is associated with a reduced risk of cancer (84). Compared to 0–1 healthy lifestyle factors, adherence to all five lifestyle factors showed a 43% and 37% risk reduction in developing total cancer for men and women, respectively. Furthermore, a systematic assessment was conducted to estimate the current burden of cancer attributable to known preventable risk factors in Japan in 2005 (49). In men, among the preventable factors, smoking had the highest population attributable fractions (PAFs), at 30% for incidence and 35% for mortality, respectively, followed by infectious agents (23% and 23%, respectively). In women, infectious agents had the highest PAF: 18% and 19% for incidence and mortality, respectively, followed by tobacco smoking (6% and 8%, respectively). Further control of these factors may substantially contribute to a reduction not only in cancer incidence and mortality but also in major non-communicable diseases mortality, to which five lifestyle factors are attributable in Japan (85). Discussion Compared to other international recommendations, there are several points which are distinctive to the present recommendation. First, it is notable that this is a comprehensive recommendation covering many essential lifestyle factors contributing to cancer incidence in our country. As a result, infection was included as one item, which reflects the significant local burden of the related cancers in our country, as well as in other Asian countries. Second, the recommended range of BMI was proposed to be between 21 and 27 kg/m2 and 21 and 25 kg/m2 for middle-aged to elderly men and women, respectively. The recommendations do not focus only on overweight or obesity, but also on low BMI, which was shown to confer elevated risk of all-cause and cancer mortality, especially in men. Third, the items mentioned in the diet recommendation are neither high-calorie nor high-fat items. There was only limited accumulation of evidence from Japanese data, especially for dietary factors. Proposing a systematic dietary recommendation for Japanese awaits additional validated studies that can adequately estimate dietary intake. Although the process of developing the present recommendation is thoroughly evidence-based, the recommended dose for some items was not directly derived from findings in research. For example, the recommended doses for salt and physical activity were derived from other specific reported recommendations (57, 66). Translation of the overall body of science to quantified recommendation is a challenge. The evidence rarely shows clear cut-off points where the risks increase or decrease, and, within any population, people differ from one another. Therefore, as with other recommendations, collective knowledge of reported considerations was also used. As the recommendation is based on currently available epidemiological evidence in Japan, the contents may be amended in the future as more evidence is accumulated. Most of our recommendations may also be applied to other Asian countries, where cancer prevention studies in their own population are nascent. Conclusion We developed evidence-based cancer prevention recommendations for Japanese. Because these recommendations were made based on a systematic review of epidemiologic studies focused on the etiology of cancer, they should be further translated. The next step should focus on the development of effective behavior modification programs and their implementation and dissemination. Funding This study was supported by the National Cancer Center Research and Development Fund (27-A-4). Conflict of interest statement None declared. References 1 International Agency for Research on Cancer. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. http://monographs.iarc.fr/ (10 July 2017, date last accessed). 2 World Health Organization. WHO Technical Reports Series 916. Diet, Nutrition, the Prevention of Chronic Disease. Report of a joint WHO/FAO Expert Consultation . Geneva: WHO, 2003. 3 World Cancer Research Fund/American Institute for Cancer Research. Food, Nutrition and the Prevention of Cancer: A Global Perspective . Washington, DC: American Institute for Cancer Research, 2007. 4 World Cancer Research Fund International/American Institute for Cancer Research. 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Journal

Japanese Journal of Clinical OncologyOxford University Press

Published: Apr 12, 2018

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