1 Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD.
2 Brady Urological Institute, Johns Hopkins Medical Institutions, Baltimore, MD.
3 Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Medical Institutions, Baltimore, MD.
4 Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD.
5 Departments of Nutrition and Epidemiology, Harvard School of Public Health, Boston, MA.
6 Channing Laboratory, Department of Medicine, Harvard Medical School and Brigham and Womens Hospital, Boston, MA.
Received for publication May 16, 2003; accepted for publication September 11, 2003.
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ABSTRACT |
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alcohol drinking; cohort studies; ethanol; prostatic neoplasms; risk
Abbreviations: Abbreviations: CI, confidence interval; HR, hazard ratio.
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INTRODUCTION |
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Because men with liver cirrhosis secondary to excessive alcohol use have lower serum testosterone levels (29), excessive intake might be predicted to be associated with decreased risk of prostate cancer. However, in studies of alcoholics or heavy drinkers, prostate cancer incidence was not reduced (3, 24, 30) or was increased (31).
Some studies have reported that consumption of specific types of alcoholic beveragesbeer (2), wine (22), or liquor (1, 13, 27)may be associated with a higher risk of prostate cancer, but results are not consistent (32). To our knowledge, no studies have examined whether certain drinking patterns, such as consuming the same total weekly amount of alcohol over a period of one or two days as compared with several days, are differently associated with prostate cancer risk.
Despite the large number of published studies, questions remain about the effects of alcohol use at higher intakes, past use, patterns of use, and type of alcoholic beverage consumed. To address these uncertainties, we prospectively evaluated the association of alcohol intake and alcohol drinking patterns with prostate cancer in a large cohort study.
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MATERIALS AND METHODS |
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Ascertainment and classification of prostate cancer cases
For each man who reported a prostate cancer diagnosis on a follow-up questionnaire, we asked for permission to request and review the medical records pertaining to his diagnosis. The response rate for this request was 96 percent. Deaths from prostate cancer were identified as described above for all deaths, and next of kin were asked permission for medical record review. Medical records and pathology reports were obtained for 90 percent of the prostate cancer cases. A study investigator blinded to exposure reviewed the records to confirm the diagnosis. Because the reporting of prostate cancer was found to be accurate, we included in the analysis the remaining 10 percent of cases that were based solely on self-report or a death certificate. We excluded Whitmore-Jewett stage A1 (34) cases, because these cases are susceptible to detection bias due to differential rates of surgery for benign prostatic hyperplasia. From enrollment in 1986 through January 31, 1998, 2,479 cases of incident non-stage-A1 prostate cancer were confirmed in 533,047 person-years of follow-up. Of these cases, 608 were advanced (stage C or D) or fatal.
Assessment of alcohol intake
The semiquantitative food frequency questionnaire that participants completed at baseline consisted of questions on the frequency of consumption of listed portion sizes of 131 food items over the past year, including beer, red wine, white wine, and liquor. This method of assessing alcohol use has been shown to be valid (r = 0.8 in comparison with 2 weeks of diet records; predicts a 0.3-mg/dl increase in serum high density lipoprotein concentration per gram of alcohol intake (r = 0.35)) and reproducible (r = 0.92 for food frequency questionnaires completed 1 year apart) in this cohort (35). We multiplied servings of specified portions of each type of alcoholic beverage by grams of ethanol per serving (beer = 12.8 g, red and white wine = 11.0 g, and liquor = 14.0 g) and summed the data for the different types of alcohol to obtain total alcohol intake in grams per day.
Participants were also asked about the number of days of the week on which they usually consumed alcohol and whether they had changed their level of alcohol intake in the past 10 years. Former drinkers were defined as men who did not currently drink alcohol but who reported that they had decreased their alcohol intake in the past 10 years. We obtained updated information on alcohol intake from the food frequency questionnaires administered 4 and 8 years after baseline. In 1988, we asked participants about the number of drinks they had consumed per week at ages 1822 years.
Statistical analysis
We directly computed age-standardized mean values and proportions for demographic and other factors by category of average daily alcohol intake. We calculated Mantel-Haenszel summary rate ratios and 95 percent confidence intervals for the categories of 0.14.9, 5.014.9, 1529.9, 3049.9, and 50 g/day relative to nondrinking (never drinkers plus former drinkers). Using Cox proportional hazards regression, we estimated multivariable hazard ratios, adjusting for risk factors previously identified in this cohort: body mass index (weight (kg)/height (m)2ordinal) at age 21 years; height (inchesordinal); cumulative cigarette smoking in the past decade (pack-yearsindicator variables for 0, 0.15, 5.110, 10.120, and
20.1 pack-years); family history of prostate cancer; major ancestry (Scandinavian, Southern European, other White, other race); diabetes mellitus; vasectomy; vigorous physical activity (metabolic equivalent-hours/weekordinal); total energy intake (kcal/dayordinal); intakes of tomato sauce, red meat, and fish (servings/dayordinal); energy-adjusted intakes of calcium (mg/dayordinal), fructose (g/dayordinal), and
-linolenic acid (g/dayordinal); and high intake (
15 mg/day) of vitamin E (mostly supplement users). Ordinal variables had five levels, except fish, which had four levels. None of these variables was a strong confounder. To account for any lack of proportionality in the hazards across follow-up, we fitted separate baseline hazards for groups defined by age and calendar period.
We used baseline alcohol intake in the main analysis, and in alternative analyses we used simple updating (i.e., a time-varying covariate) or cumulative average updating (i.e., mean of the reported intakes for all preceding food frequency questionnaires (36)) of alcohol intake. To test for trend, we entered into the model a single ordinal variable, which we evaluated by the Wald test. To limit the likelihood that men without a diagnosis of prostate cancer had an occult prostate tumor during follow-up, in an alternative analysis we included person-time at risk only for noncases who had had a prostate-specific antigen test by 1998.
We evaluated whether prostate cancer risk was associated with drinking patterns by combining reported quantity consumed, using one term for lower intake (<105 g/week, or on average <15 g/day) and a second term for higher intake (105 g/week), with number of days per week on which alcohol was consumed. We examined whether prostate cancer risk differed by type of alcoholic beverage consumed by simultaneously entering into the model terms for wine, beer, or liquor. Beginning follow-up in 1988, we evaluated the weekly number of alcoholic drinks consumed at ages 1822 years with and without adjusting for current alcohol intake.
We created stratified models to assess whether the association between alcohol intake (g/day) and prostate cancer varied by: susceptible subgroupage at diagnosis (60 years vs. >60 years) and family history of prostate cancer; a metabolic pathway inhibited by alcoholfolic acid (<400 µg/day vs.
400 µg/day); sources of pro-oxidantscigarette smoking in the past 10 years and diabetes mellitus; and sources of antioxidantsintakes of vitamin E (<15 mg/day vs.
15 mg/day) and tomato sauce (
0.14 servings/day vs. >0.14 servings/day). To test for multiplicative interaction, we entered main-effect terms along with a cross-product term for alcohol and each factor, the coefficient for which was evaluated by Wald test. Analyses were performed using SAS, release 6.12 (SAS Institute, Inc., Cary, North Carolina).
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RESULTS |
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Alcohol drinking patterns and beverage type
Men who drank alcohol on 56 days per week had a modestly higher risk of prostate cancer (HR = 1.19, 95 percent CI: 1.04, 1.35) than men who did not drink or who drank on less than 1 day per week (table 3). However, the hazard ratio for men who drank on all 7 days of the week was not elevated (HR = 1.05, 95 percent CI: 0.92, 1.20). These patterns were similar for advanced cases and distant metastatic/fatal cases (table 3). Compared with men who did not drink or who drank on less than 1 day per week, men who consumed lower amounts (<15 g/day on days that they drank) on 56 days of the week (<90 g/week) had a suggestive 23 percent higher risk of prostate cancer (figure 1). Men who consumed higher amounts (105 g/week) on 34 or 56 days of the week also had a suggestively higher risk of prostate cancer when compared with nondrinkers (figure 1). In both men who consumed <105 g/week and men who consumed
105 g/week, the hazard ratio was attenuated among those who drank on all 7 days of the week. However, men who consumed greater amounts (
105 g/week) on only 1 or 2 days of the week (i.e., who consumed all 105 g over a period of 1 or 2 days) had a higher risk of prostate cancer (HR = 1.64, 95 percent CI: 1.13, 2.38) (figure 1). Note that this group represents 1 percent of the person-time and prostate cancer cases in the cohort.
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DISCUSSION |
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Our results are compatible with those of two prospective studies (26, 27). In a study of Iowa men (101 cases), the relative risks for 2292 g/week and 92 g/week were 2.1 and 1.5, respectively (26). In a subset of the Harvard Alumni Health Study (366 cases), the relative risks for 1<3 drinks/day (~13<39 g/day) and
3 drinks/day were 1.85 and 1.33, respectively (27). The magnitude of association was lower in our study than in these two studies. A similar risk pattern emerged in the three studies: Risk in the top category was lower than risk in the next-to-highest category. However, the lower cutpoints for the top category were very different in the three studies (13.1 g/day (26), ~39 g/day (27), and 50 g/day in this study). In contrast, in 10 distinct prospective or record-linkage studies (1620, 2225, 37), investigators did not observe associations between total alcohol intake and prostate cancer. Alcohol use in young adulthood was not associated with prostate cancer in our study or elsewhere (27, 38).
Our results are also consistent with those of two meta-analyses (39, 40). Dennis (39) obtained relative risks of 1.15 (95 percent CI: 1.00, 1.32) and 1.21 (95 percent CI: 1.05, 1.39) for consumption of three and four drinks per day, respectively. The relative risks were 1.04 and 1.06 (not statistically significant) for three eligible prospective studies. Bagnardi et al. (40) reported relative risks of 1.09 (95 percent CI: 1.02, 1.17) and 1.19 (95 percent CI: 1.03, 1.37) for 50 g/day (~34 drinks daily) and 100 g/day (~68.5 drinks daily), respectively. Because of the timing of publication, the meta-analyses did not include two of the prospective studies that had positive findings (26, 27).
Ethanol may be predicted to have both adverse and beneficial effects on prostate carcinogenesis. The major metabolic pathway for ethanol is conversion to acetaldehyde by alcohol dehydrogenase, followed by conversion of acetaldehyde to acetate by acetaldehyde dehydrogenase (41). However, with high intake, other metabolic pathways may play a more prominent role. Superoxide and hydroxyethyl radicals are generated from the metabolism of acetaldehyde by xanthine oxidase in the liver (42) and possibly also in the prostate (43). Alcoholics have greater oxidative stress as measured by levels of hydroxyethyl and malondialdehyde protein adducts in circulation (44). In animal models, chronic ethanol intake results in higher lipid peroxidation in the prostate (45). Acetaldehyde inhibits enzymes in the DNA methylation pathway (46, 47). Superoxide generated in the metabolism of acetaldehyde increases folate catabolism, which may explain folate deficiency in alcoholics (42). The greater production of reactive oxygen species and reduced availability of methyl groups for promoter methylation may together contribute to a higher risk of prostate cancer among chronic drinkers or binge drinkers. Although it is plausible, we did not observe effect modification by folic acid intake. Other possible adverse effects of alcohol that might influence prostate cancer risk include enhancement of the solubility and absorption of mutagens and inhibition of cytochrome P-450 detoxification enzymes (48).
Alcohol intake alters sex hormone levels into profiles that would be predicted to decrease risk of prostate cancer. Experimentally, repeated high-dose ethanol intake in nonalcoholic men suppresses testicular production and increases clearance of testosterone (4951), though these effects are transient (51). With sustained alcohol abuse, testicular atrophy may lead to lower concentrations of circulating testosterone (29). Alcohol also increases circulating estrogen levels, possibly through enhanced aromatization of androgens to estrogens in the liver (52). Circulating levels of sex hormone-binding globulin, which is the major carrier of testosterone and estradiol in circulation, are also higher among alcoholics (53). In rodent models, chronic high-dose ethanol ingestion results in reduced prostate weight and atrophy of the prostate epithelium (54), which again would be expected to reduce risk of prostate cancer. Excessive alcohol use (55) and possibly moderate intake (56) may also be associated with lower circulating levels of insulin-like growth factor 1, a purported prostate cancer risk factor (57). If it is causal, the slight positive association between moderate-to-high consumption of alcoholic beverages and prostate cancer observed in our study may reflect a small outweighing of detrimental effects relative to beneficial effects of ethanol on the prostate. At higher levels of alcohol intake, where risk of prostate cancer was not increased, the damage due to reactive oxygen species generated in the metabolism of ethanol may be balanced against the reduced promotional activity of suppressed androgens. However, studies of alcoholics or heavy drinkers have not provided support for an inverse association (3, 24, 30, 31).
The increased oxidative stress hypothesis implies that alcohol would act early in the prostate carcinogenesis pathway, and thus alcohol would affect the overall incidence of prostate cancer. The hormone hypothesis implies that alcohol would reduce hormonal promotion of the growth of prostate tumors. Compatible with these hypotheses, in our study we observed a higher risk of prostate cancer associated with alcohol drinking, and risk was not greater for advanced disease. In our previous studies of prostate cancer in this cohort, risk factors that would be expected to promote the growth of already-initiated prostate tumors, such as fat and red meat intake (58), were more strongly associated with advanced disease. Alternatively, factors that would be expected to influence oxidative burden, like intake of tomato sauce (which contains lycopene), appear to be associated across the spectrum of severity of this disease (59). In Iowa men, a positive association was observed for alcohol intake and local and regional/distant disease (26). In the Netherlands Cohort Study, risk was increased for both local and advanced tumors for specific types of alcohol; however, none of the associations were significantly linearly increasing (22).
We observed that risk of prostate cancer increased with increasing number of days on which alcohol was consumed. However, men who drank alcohol on all days of the week (their mean daily intake was 36.9 g) were not at increased risk. Whether men who drank daily did not have an increased risk because they have sustained depression of testosterone relative to estrogen needs further evaluation. Interestingly, men with a drinking pattern reflecting infrequent intake of a high amount of alcohol had 1.64 times the risk of nondrinkers. These men routinely consumed at least 105 g of alcohol on 1 or 2 days of the week. Their pattern of consumption may result in different metabolic pathways being activated or deactivated or different hormonal profiles (transient vs. sustained) in comparison with men who had a drinking pattern reflecting frequent intake of small amounts. Again, however, we cannot preclude that this was a chance observation due to a small sample size in that subgroup (30 cases in 5,343 person-years).
We did not observe notable differences in risk of prostate cancer by type of alcoholic beverage consumed, with the exception of red wine, for which there was no association. Findings have not been consistent among studies examining different types of alcoholic beverages (1, 2, 13, 22, 27).
Risk of advanced prostate cancer associated with alcohol intake was greater among men who were younger at diagnosis, though age did not modify the association for prostate cancer. If alcohol acts early in prostate carcinogenesis, an association with advanced disease might be more observable in younger men because of a shorter span between the initiation of the tumor and progression. Although we had hypothesized that risk of prostate cancer associated with alcohol intake would be greater among men with a higher oxidative burden, there was no difference in this association by level of intake of vitamin E or tomato sauce. Furthermore, risk of more advanced disease with alcohol intake was greater for those who had not smoked in the past 10 years or who had a higher intake of tomato sauce. It is possible that the findings for more advanced disease are false-positive, given that these analyses contained fewer cases.
The positive association of alcohol intake with prostate cancer appeared to be greater among men with type 2 diabetes mellitus. Men with diabetes exhibit greater oxidative damage (60, 61), which may be worsened by chronic alcohol use (62). In addition, in diabetic rats with low insulin and high glucose levels, liver aldehyde levels are increased and aldehyde dehydrogenase activity is reduced (63). If this is also true in humans with type 2 diabetes, the accumulation of aldehydes such as acetaldehyde may overwhelm primary metabolic enzymes that detoxify aldehydes. Secondary metabolic pathways, such as the xanthine oxidase pathway (42, 43), may be important contributors to a greater abundance of reactive species among persons with diabetes, thus possibly enhancing their prostate cancer risk.
We included in the analysis 3.5 times more cases than the next-largest study on this topic. We adjusted for suspected risk factors for prostate cancer, including cigarette smoking (a risk factor for fatal disease), a strong correlate of alcohol use. Although we cannot rule out confounding by unknown factors that differ between nondrinkers and drinkers, after exclusion of the nondrinkers the results were compatible with the overall findings. We administered a food frequency questionnaire for which alcohol assessment was valid and reliable (35). Because alcohol intake was assessed years prior to diagnosis, it is unlikely that the extent of error in the reporting of alcohol differed by disease status. To account for changing levels of alcohol intake over time and to increase accuracy for long-term intake, in a subanalysis we used simple and cumulative average updating of alcohol intake from three food frequency questionnaires with data collected 4 years apart. The increased risk among men consuming 50 g/day observed when simple updating was used but not when baseline or cumulative average updating was used might indicate that very recent high alcohol intake is important. However, this approach may be more prone to bias due to preclinical disease. It is unlikely that there was bias due to health-conscious mens being those who both moderately drink alcohol and undergo prostate-specific antigen screening, because a high percentage of men had already been screened, and results were unchanged in a subanalysis that included only those men who had had a prostate-specific antigen test.
Overall, alcohol does not appear to be a strong contributor to prostate cancer risk, except possibly in men who consume large amounts infrequently and in men with type 2 diabetes mellitus. Additional study is needed for these groups.
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ACKNOWLEDGMENTS |
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The authors thank Jill Arnold, Stacey De Caro, Elizabeth Frost-Hawes, Mira Kaufman, Laura Sampson, Olga Veysman, Alvin Wing, and Mildred Wolff for their continued help in conducting the Health Professionals Follow-up Study.
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NOTES |
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REFERENCES |
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