IJC International Journal of Cancer

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1 IJC International Journal of Cancer Alcohol and smoking and subsequent risk of prostate cancer in Japanese men: The Japan Public Health Center-based prospective study Norie Sawada 1, Manami Inoue 1,2, Motoki Iwasaki 1, Shizuka Sasazuki 1, Taiki Yamaji 1, Taichi Shimazu 1 and Shoichiro Tsugane 1 1 and Prevention Division, Research Center for Cancer Prevention and Screening, National Cancer Center, Tokyo, Japan 2 Graduate School of Medicine, The University of Tokyo, Tokyo, Japan Although alcohol and smoking have not been established as risk factors for prostate cancer, they are important risk factors for other human cancers and potentially major avoidable factors. Alcohol drinkers and smokers might be less likely to get screening, which might lead to attenuation of the positive association. Here, we investigated the association of alcohol drinking and smoking and prostate cancer according to stage, as well as prostate cancer detected by subjective symptoms, in a large prospective study among Japanese men. The Japan Public Health Center-based prospective study (JPHC study) was established in 1990 for Cohort I and in 1993 for Cohort II. Subjects were 48,218 men aged years who completed a questionnaire, which included their alcohol and smoking habits at baseline, and who were followed until the end of During 16 years of follow-up, 913 men were newly diagnosed with prostate cancer; of whom 248 had advanced cases, 635 were organlocalized and 30 were of an undetermined stage. Alcohol consumption was dose-dependently associated with advanced prostate cancer [nondrinkers: reference, g=week: hazard ratio (HR) , 95% confidence interval (CI) ; g=week: HR , 95% CI ; 300 g=week: HR , 95% CI , p for trend ]. The positive association was not substantially changed among cancers detected by subjective symptoms. Smoking was inversely associated with prostate cancer among total subjects, but tended to increase the risk of advanced prostate cancer detected by subjective symptoms. In conclusion, abstinence from alcohol and prohibition of smoking might be important factors in the prevention of advanced prostate cancer. Alcohol and smoking are important risk factors for human cancers and potentially major avoidable factors. The report by the World Cancer Research Fund=American Institute for Cancer Research (WCRF=AICR) on nutrition, physical activity and cancer concluded that the data were too limited to determine an association between alcohol and prostate cancer. 1 Further, a recent meta-analysis of 50 case control and 22 cohort studies concluded that there was no evidence of a material association between alcohol drinking and prostate cancer. 2 However, questions remain about the effects of alcohol use at higher intake. Given that the proportion of heavy Key words: prostate cancer, alcohol, smoking, prospective, JPHC study Grant sponsors: National Cancer Center Research and Development Fund (Since 2011), A Grant-in-Aid for Cancer Research (from 1989 to 2010) DOI: /ijc History: Received 23 May 2013; Accepted 22 July 2013; Online 9 Aug 2013 Correspondence to: N. Sawada, and Prevention Division, Research Center for Cancer Prevention and Screening, National Cancer Center, Tsukiji, Chuo-ku, Tokyo , Japan, Tel.: , nsawada@ncc.go.jp drinkers has been increasing for decades in Japan, 3 research in Japan might help answer these unsolved questions. Moreover, the effects of alcohol in different histological grades of prostate cancer are also controversial. It is possible that previous studies were affected by detection bias associated with screening, such as prostate-specific antigen (PSA) screening, which would mask an association if alcohol drinkers were less likely to get screening. With regard to tobacco, the International Agency for Research on Cancer does not consider prostate cancer to be tobacco-related. 4 A recent meta-analysis of 24 prospective cohort studies showed no increased risk of incident prostate cancer for current smokers, but a statistically significant increase in risk for amount and pack-years of smoking. 5 Epidemiological research suggests that the results of studies examining incidence may differ from those studying prostate cancer mortality. 6 Interestingly, five studies found no positive association between smoking and prostate cancer incidence in Japan, albeit that analysis was not done according to stage However, one report showed that smoking of 35 or more cigarettes per day increased the risk of prostate cancer mortality, 12 while a meta-analysis also showed that current smokers had an increased risk of fatal prostate cancer. 5 These findings suggest that the effects of smoking might differ according to stage. Moreover, the lower rates of PSA Int. J. Cancer: 134, (2014) VC 2013 UICC

2 972 Alcohol and smoking and risk of prostate cancer What s new? The impact of alcohol consumption or smoking on prostate-cancer risk has been unclear. Using a large, prospective study, the authors investigated the association between these activities and prostate cancer according to stage at diagnosis. They found that alcohol was associated with advanced disease. Both alcohol and smoking were also associated with advanced prostate cancers that were detected by subjective symptoms. These results suggest that abstinence from alcohol and prohibition of smoking might play an important role in the prevention of advanced prostate cancer. screening among smokers than nonsmokers might lead to attenuation of a positive association, as it does in alcohol drinkers. Here, we investigated the association of alcohol drinking and smoking and prostate cancer according to stage in a large prospective study among Japanese men. To avoid detection bias, we particularly focused on the association in cancers detected by subjective symptoms. Methods Study population The study cohort was part of the Japan Public Health Center-based prospective study (JPHC study), which was launched in 1990 for Cohort I and in 1993 for Cohort II. The study design has been described in detail previously. 13 Cohort I consisted of all registered Japanese residents aged years of five Public Health Center (PCH) areas, and Cohort II of all residents aged years of six PHC areas across Japan. In our analysis, one PHC area was excluded as incidence data were not available. Thus, we defined a population-based cohort of 65,803 men. After initiation of the study, 148 subjects were found to be ineligible and were excluded because of non-japanese nationality (n 5 31), late report of migration occurring before the start of the followup period (n 5 113), incorrect birth data (n 5 2) and duplicate registration (n 5 2), leaving 65,655 men eligible for participation. This study was approved by the institutional review board of the National Cancer Center, Tokyo, Japan. Baseline survey At baseline, participants completed a self-administered questionnaire that assessed information on alcohol consumption, smoking history, medical history and other lifestyle factors. Among eligible subjects, 50,437 men (77%) returned valid responses. Information on alcohol intake was obtained for frequency and amount using validated questions. Average frequency was reported in six categories for Cohort I: <1 day per month, 1 3 days per month, 1 2 days per week, 3 4 days per week, 5 6 days per week and everyday. Subjects consuming alcoholic beverages at least once a week were also asked about the type of drink consumed and the average consumption. Subjects in Cohort II were also asked about their drinking status as never-, ex- or current drinkers. Ex- and current drinkers provided information on average frequency, type of drink consumed and average daily consumption. Subjects were classified for alcohol consumption into the five groups of nondrinkers (<1 day=month in Cohort I and II or exdrinkers in Cohort II), occasional drinkers (1 3 days=month) and three groups of regular drinkers (1 149 g=week ethanol, g=week and 300 g=week or more). The method used to calculate ethanol intake from the questionnaire and its validity have been detailed elsewhere. 14,15 Information on smoking habit was also collected. Subjects were categorized as never-, ex- or current smokers. Smoking intensity for current smokers was evaluated by pack-years, defined by multiplying the number of years of smoking times the number of cigarettes per day divided by 20. We classified current smokers by the three smoking intensity categories of <20 pack-years, pack-years and 40 pack-years. Follow-up Subjects were followed from the baseline survey until December 31, Changes in residence status including survival were identified annually through the residential registry of each area or, for those who had moved out of the study area, through the municipal office of the area to which they had moved. Among questionnaire respondents at baseline, 10,056 (19.9%) died, 5,213 (10.3%) moved out of a study area and 421 (0.8%) were lost to follow-up during the study period. The occurrence of cancer was identified by active patient notification from major local hospitals in the study area and data linkage with population-based cancer registries, with permission from the local governments responsible for the registries. Cases were coded using the International Classification of Diseases for Oncology, Third Edition (ICD-O-3). Death certificate information was used as a supplementary information source, with 2.1% of cases of prostate cancer ascertained by death certificate only (DCO). These ratios were considered satisfactory for our study. We excluded subjects with self-reported prostate cancer at baseline (nine persons) and incomplete information for alcohol and=or smoking items (2,219 men). A total of 913 newly diagnosed prostate cancer cases were identified by December 31, Advanced cases were defined by a diagnosis of extraprostatic or metastatic cancer involving lymph nodes or other organs. If this information was not available, advanced cases were defined as those with a high Gleason score (8 10) or poor differentiation. These criteria were selected to allow the identification of advanced cases with a high likelihood of

3 Sawada et al. 973 Table 1. Baseline characteristics of study subjects by alcohol consumption and smoking status Alcohol consumption Smoking status Non-drinkers Occasional Never Past Current Number of subjects Proportion (%) Age (years) 6 SD Body mass index 6 SD Current smoker (%) Heavy drinker ( ethanol g=week) (%) Marital status, yes (%) History of diabetes mellitus (%) Japanese tea consumption, daily (%) Miso soup consumption, daily (%) poor prognosis. The remaining cases were organ-localized. In this study, there were 248 (27.1%) advanced cases, 635 (69.6%) localized cases and 30 (3.3%) cases of undetermined stage. Finally, a total of 48,218 men, including prostate cancer patients, were used in the analysis. Statistical analysis Person-years of follow-up were calculated for each person from the date of completion to the date of prostate cancer diagnosis, date of emigration from the study area or date of death, whichever came first, or if none of these occurred, follow-up was through to the end of the study period (December 31, 2010). Subjects who were lost to follow-up were censored on the last confirmed date of presence in the study area. Hazard ratio (HR) and 95% confidence interval (CI) for alcohol consumption and smoking were calculated by the Cox proportional hazards model according to the SAS PHREG procedure (SAS Institute, Cary, NC). Covariates used in the model were age at enrollment (continuous), study area (ten PHC areas), body mass index (continuous), marital status (yes=no), past history of diabetes mellitus (yes=no), smoking status [when calculating HR for alcohol consumption: never-, ex- and pack-years in current smokers (1 19, and 40)], alcohol consumption (when calculating HR for smoking status and intensity: nondrinkers, occasional drinkers, g=week, g=week and 300 g=week), Japanese tea consumption (<1 cup=day, 1 2 cups=day, 3 4 cups=day and 5 cups=day) and miso soup consumption (<1 cup=day, 1 cups=day, 2 cups=day and 3 cups=day). These variables are either known or suspected risk factors for cancer or were previously associated with the risk of prostate cancer. p-values for trends were assessed by assignment of ordinal variables in each category. All p-values are two-sided, and statistical significance was determined at the p < 0.05 level. Results During 769,715 person-years of follow-up (average follow-up, 16.0 years) for 48,218 men, a total of 913 cases of prostate cancer were newly diagnosed and included in the analyses. Baseline characteristics of subjects according to alcohol consumption and smoking status are shown in Table 1. Subjects with higher alcohol consumption tended to be younger, smoke more and drink less Japanese tea and more miso soup. Never smokers tended to drink less alcohol, Japanese tea and miso soup. The proportion of men with a history of diabetes mellitus was higher in nondrinkers and lower in never smokers. The proportion of men who lived with their wife was lower in nondrinkers and current smokers. Table 2 shows the characteristic of prostate cancer according to the method of detection, although this was not known for 191 cases (20.9%). A total of 85.3% of prostate cancers detected by screening were localized cancers, whereas 44.4% of prostate cancers detected by subjective symptoms were advanced cancers. Subjects with cancers detected by subjective symptoms tended to be older and to smoke more. The proportion of heavy drinkers among those with cancers detected by subjective symptoms was similar to that among those detected by screening. Table 3 shows age- and area-adjusted and multivariable HRs and 95% CIs for prostate cancer by alcohol consumption. Alcohol consumption was not associated with total prostate cancer. On stratification by stage, in contrast, alcohol consumption was dose-dependently associated with advanced prostate cancer (nondrinkers: reference, g=week: HR , 95% CI ; g=week: HR , 95% CI ; 300 g=week: HR , 95% CI 5

4 974 Alcohol and smoking and risk of prostate cancer Table 2. Characteristic of the prostate cancer by method of detection Subjective symptons (n 5 232) Screening (n 5 312) Detection method Incidentally during attendance at hospital for another condition (n 5 178) Unknown (n 5 191) Localized prostate cancer (%) Advanced prostate cancer (%) Age (years) 6 SD Body mass index 6 SD Current smoker (%) Heavy drinker (300 ethanol g=week)(%) Marital status, yes (%) History of diabetes mellitus (%) Japanese tea consumption, daily (%) Miso soup consumption, daily (%) , p for trend ). No statistically significant association was seen between alcohol consumption and localized prostate cancer risk. To exclude the influence of screening, we next analyzed the association between prostate cancer and alcohol consumption in subjects whose cancer was detected by subjective symptoms. Results showed that the positive association of alcohol consumption in subjects with advanced prostate cancer was similar to that among total subjects, but slightly stronger (nondrinkers: reference, g=week: HR , 95% CI ; g=week: HR , 95% CI ; 300 g=week: HR , 95% CI , p for trend ). We performed a sensitivity analysis excluding ex-drinkers in the reference category in Cohort II. Similarly, the positive association between alcohol consumption and prostate cancer was detected by subjective symptoms (never-drinkers: reference, ex-drinkers: HR , 95% CI , occasional drinkers; HR , 95% CI , g=week: HR , 95% CI , g=week: HR , 95% CI , 300 g=week: HR , 95% CI , p for trend ). We also analyzed the associations of specific types of alcoholic beverages with advanced prostate cancer risk in subjects whose cancer was detected by subjective symptoms (data not shown). Although beer showed a stronger positive association with advanced cancer, the multivariable HRs for types of alcohol (sake, liquor and beer) all showed positive but not statistically significant associations with prostate cancer risk (nondrinkers: reference, 150 g=week: HR , 95% CI , HR , 95% CI , HR , 95% CI , respectively). Table 4 shows adjusted HRs and 95% CIs for prostate cancer by pack-years. Smoking was related to a decreased risk of total and localized prostate cancer. A linear decrease in HRs with increasing pack-years was seen in current smokers (p for trend in total prostate cancer, p for trend in localized prostate cancer). The association between prostate cancer and smoking was attenuated when analysis was restricted to subjects whose cancer was detected by subjective symptoms. Smoking tended to be associated with an increased risk of advanced prostate cancer (never smokers: reference, 0 20 pack-years: HR , 95% CI , pack-years: HR , 95% CI , 40 pack-years: HR , 95% CI , p for trend ). Discussion Here, we investigated the relationship between alcohol consumption and smoking and the risk of prostate cancer in a population-based prospective study in Japan. Results showed that increasing alcohol intake was positively associated with advanced prostate cancer. A positive association was similarly seen among cancers detected by subjective symptoms. In contrast, an inverse association between smoking and prostate cancer was found among total subjects, whereas smoking tended to be associated with an increased risk of advanced prostate cancers detected by subjective symptoms. Results of previous epidemiological studies of the relationship between alcohol drinking and prostate cancer have been inconsistent. A meta-analysis by Middleton Fillmore et al. reported a positive linear association with alcohol drinking, with an RR of 1.16 (95% CI: ) per unit increase in the number of alcoholic drinks consumed daily. As stated by the authors, this association warrants further investigation, particularly in relation to heavy drinking. 16 In contrast, a more recent analysis of 50 case control and 22 cohort studies reported that there was no evidence of any substantial effect of alcohol on prostate cancer, even at high doses, although they found a significant pooled RR for any drinking vs. no drinking of 1.06 (95% CI: ). 2 However, they did not consider the role of alcohol in different histological grades of prostate cancer. Our study showed a positive association between alcohol consumption and advanced prostate cancer. This result is

5 Sawada et al. 975 Table 3. Hazard ratios (HRs) and 95% confidence intervals (CIs) of prostate cancer by alcohol consumption Occasional Alcohol consumption (g=week) Non-drinkers (1 3 times= month) Ptrend Total No. of cases Person-years of follow-up 173,225 72, , , ,826 HR 1 (95%CI) 1.00 (reference) 0.97 ( ) 1.07 ( ) 1.12 ( ) 0.94 ( ) 0.68 HR 2 (95%CI) 1.00 (reference) 0.94 ( ) 1.07 ( ) 1.13 ( ) 1.02 ( ) 0.49 Localized No. of cases Person-years of follow-up 172,499 72, , , ,938 HR 1 (95%CI) 1.00 (reference) 0.99 ( ) 1.03 ( ) 1.00 ( ) 0.88 ( ) 0.31 HR 2 (95%CI) 1.00 (reference) 0.96 ( ) 1.03 ( ) 1.00 ( ) 0.91 ( ) 0.54 Advanced No. of cases Person-years of follow-up 173,127 72, , , ,770 HR 1 (95%CI) 1.00 (reference) 0.89 ( ) 1.25 ( ) 1.47 ( ) 1.39 ( ) 0.02 HR 2 (95%CI) 1.00 (reference) 0.84 ( ) 1.23 ( ) 1.51 ( ) 1.41 ( ) 0.02 Cases detected by subjective symptoms Total No. of cases Person-years of follow-up 171,072 72, , , ,535 HR 1 (95%CI) 1.00 (reference) 0.93 ( ) 1.23 ( ) 1.11 ( ) 1.23 ( ) 0.25 HR 2 (95%CI) 1.00 (reference) 0.86 ( ) 1.23 ( ) 1.13 ( ) 1.23 ( ) 0.24 Localized No. of cases Person-years of follow-up 170,819 71, , , ,141 HR 1 (95%CI) 1.00 (reference) 1.00 ( ) 0.99 ( ) 0.70 ( ) 0.82 ( ) 0.27 HR 2 (95%CI) 1.00 (reference) 0.96 ( ) 1.00 ( ) 0.72 ( ) 0.90 ( ) 0.46 Advanced No. of cases Person-years of follow-up 171,043 72, , , ,520 HR 1 (95%CI) 1.00 (reference) 0.87 ( ) 1.90 ( ) 1.87 ( ) 2.07 ( ) HR 2 (95%CI) 1.00 (reference) 0.70 ( ) 1.82 ( ) 1.84 ( ) 1.86 ( ) Adjusted for age and public health center area. 2 Adjusted for age, public health center area, smoking status, body mass index, marital status, history of diabetes mellitus, and intake of miso soup and Japanese tea. consistent with several previous reports. With regard to the association between alcohol and prostate cancer by stage, alcohol consumption increased the risk of advanced or fatal prostate cancer, although a recent prospective US cohort study reported a nonsignificant association between alcohol and advanced cancers and an increased risk of nonadvanced cases. 21 Other studies that showed no association between alcohol and prostate cancer might have been affected by detection bias of screening, which would mask an association if heavy drinkers were less likely to get PSA screening. 22 Given that PSA screening rate is lower in Japan than in Western countries, 23 and that the results between total subjects and those whose cancer was detected by subjective symptoms were similar, our results might not be affected by screening. Indeed, the proportion of heavy drinkers among those whose cancer was detected by screening (24.4%) was similar to that among those whose cancers were detected by subjective symptoms (24.6%). Alcohol consumption might influence prostate carcinogenesis by any of several possible mechanisms. Ethanol or

6 976 Alcohol and smoking and risk of prostate cancer Table 4. Hazard ratios (HRs) and 95% confidence intervals (CIs) of prostate cancer by smoking status Smoking status Pack-years in current smokers Never Past Ptrend Total No. of cases Person-years of follow-up 186, ,861 72, , ,222 HR 1 (95%CI) 1.00 (reference) 0.88 ( ) 0.70 ( ) 0.83 ( ) 0.79 ( ) 0.02 HR 2 (95%CI) 1.00 (reference) 0.84 ( ) 0.67 ( ) 0.84 ( ) 0.80 ( ) 0.05 Localized No. of cases Person-years of follow-up 185, ,088 72, , ,696 HR 1 (95%CI) 1.00 (reference) 0.92 ( ) 0.57 ( ) 0.79 ( ) 0.70 ( ) HR 2 (95%CI) 1.00 (reference) 0.90 ( ) 0.53 ( ) 0.81 ( ) 0.72 ( ) Advanced No. of cases Person-years of follow-up 186, ,773 72, , ,135 HR 1 (95%CI) 1.00 (reference) 0.73 ( ) 0.92 ( ) 0.86 ( ) 0.87 ( ) 0.77 HR 2 (95%CI) 1.00 (reference) 0.66 ( ) 0.90 ( ) 0.84 ( ) 0.84 ( ) 0.79 Cases detected by subjective symptoms Total No. of cases Person-years of follow-up 183, ,375 72, , ,099 HR 1 (95%CI) 1.00 (reference) 0.95 ( ) 0.85 ( ) 0.96 ( ) 1.11 ( ) 0.69 HR 2 (95%CI) 1.00 (reference) 0.89 ( ) 0.82 ( ) 0.95 ( ) 1.12 ( ) 0.56 Localized No. of cases Person-years of follow-up 183, ,078 72, , ,874 HR 1 (95%CI) 1.00 (reference) 0.89 ( ) 0.31 ( ) 0.65 ( ) 0.77 ( ) 0.13 HR 2 (95%CI) 1.00 (reference) 0.84 ( ) 0.23 ( ) 0.65 ( ) 0.83 ( ) 0.24 Advanced No. of cases Person-years of follow-up 183, ,358 72, , ,051 HR 1 (95%CI) 1.00 (reference) 1.07 ( ) 1.60 ( ) 1.44 ( ) 1.37 ( ) 0.16 HR 2 (95%CI) 1.00 (reference) 0.97 ( ) 1.54 ( ) 1.43 ( ) 1.31 ( ) Adjusted for age and public health center area. 2 Adjusted for age, public health center area, alcohol drinking, body mass index, marital status, history of diabetes mellitus, and intakeof miso soup and Japanese tea. acetaldehyde, which is a carcinogen, 24 affects cell proliferation and induces DNA damage, which may lead to malignant changes. 25,26 Furthermore, accumulating evidence suggests that prostate carcinogenesis by alcohol is mediated through increased estrogens and decreased androgens and sex hormone-biding globulin Results regarding the effect of smoking on prostate cancer have been inconsistent. Our present results showed that smoking decreased the risk of prostate cancer in total subjects, but that this negative association might have been impaired in subjects whose cancer was detected by subjective symptoms. Greater health consciousness in subjects who undergo screening might lead to increased diagnoses of prostate cancer, particularly localized cancer, and thereby obscure any association with smoking. In fact, the proportion of current smokers among those whose cancers were detected by screening (38.8%) was lower than that among those with detection by subjective symptoms (45.3%). Therefore, it is plausible that our results show that smoking is associated with an increase risk of advanced prostate cancer detected by subjective symptoms.

7 Sawada et al. 977 This result is supported by a more recent meta-analysis of 24 cohorts, which showed that smoking increased the risk of fatal prostate cancer. 5 The adverse effects of smoking on advanced or fatal prostate cancer may reflect its effect on tumor progression. For example, smoking may increase serum estrogen metabolites, which have been postulated to induce a more aggressive tumor and thereby increase prostate cancer death. 33 However, the possibility that smokers did not go to hospital until their cancer had progressed to an advanced stage cannot be ruled out. The major strengths of our study were its prospective design, high response rate (80%) and negligible proportion of losses to follow-up (0.8%). Information on alcohol consumption and smoking status were collected before the diagnosis of prostate cancer, thereby avoiding the probability of recall bias, which is inherent to case control studies. On the other hand, our study had several limitations. Because we used information on alcohol and smoking obtained at a single time-point only (baseline), misclassification of exposure due to changes in alcohol drinking or smoking behavior during the study period might have occurred. A recent Canadian case control study reported that although current alcohol intake did not increase prostate cancer risk, lifetime intake increased risk for prostate cancer without consideration to stage, 34 indicating that such misclassification would underestimate the true relative risk, if present. Second, our results might be explained by an increase in PSA screening during the follow-up period if drinkers tended to be screened more frequently, and thus had an increased frequency of prostate cancer diagnosis. This is unlikely, however, as PSA screening is associated with healthier behaviors. 35 Third, we were unable to analyze the relation between PSA screening and healthy behavior among all subjects. Unfortunately, we did not collect information from PSA screening for all subjects, because the diffusion of PSA screening began after the initiation of this study. In conclusion, we found that alcohol drinking increases the risk of advanced prostate cancer. Although the positive association between smoking and advanced prostate cancer was not statistically significant, our results support previous meta-analyses. Abstinence from alcohol and prohibition of smoking might be an important factor in the prevention of advanced prostate cancer. Acknowledgements The authors are indebted to the Aomori, Iwate, Ibaraki, Niigata, Osaka, Kochi, Nagasaki and Okinawa Cancer Registries for providing their incidence data. References 1. World Cancer Research Fund=American Institute for Cancer Research. Food, nutrition, physical activity, and the prevention of cancer: a global perspective. 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