From the Department of Epidemiology and Surveillance Research, American Cancer Society, Atlanta, GA.
Received for publication April 12, 2004; accepted for publication June 29, 2004.
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ABSTRACT |
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cohort studies; diabetes mellitus; prostatic neoplasms
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INTRODUCTION |
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The association between diabetes and prostate cancer risk has been studied in several epidemiologic studies. Four (58) of the five largest studies (59) found reductions in risk ranging from approximately 10 to 40 percent. Results from several smaller studies (less than 50 prostate cancer cases among diabetic men), however, have been mixed (1017).
The hypothesis that the relation between diabetes and prostate cancer may differ by time since diabetes diagnosis has been examined with sufficient power in only three studies (79). In the Health Professionals Follow-up Study cohort, prostate cancer incidence was higher immediately after diabetes diagnosis and lower among men with diagnosis of diabetes years earlier (7). The time since diabetes diagnosis did not modify the association between diabetes and prostate cancer in the large Physicians Health Study (8). In contrast, in the Cancer Prevention Study I cohort (9), prostate cancer incidence was significantly increased among men with diagnosis of diabetes for 5 or more years, although this result was based on only 22 cases.
To clarify the potentially complex relation between timing of diabetes mellitus diagnosis and prostate cancer, we examined the association between self-reported diabetes and prostate cancer incidence in the Cancer Prevention Study II Nutrition Cohort. Because participants in this cohort had reported diabetes status at several time points, we were able to examine whether the risk of prostate cancer differed by time since diagnosis of diabetes.
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MATERIALS AND METHODS |
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At enrollment in 1992, participants completed a self-administered mailed questionnaire that included demographic, lifestyle, and medical factors. Follow-up questionnaires were sent to cohort members in 1997, 1999, and again in 2001. The response rate among living participants for all of the follow-up questionnaires (after multiple mailings) was at least 90 percent. For the present study, the follow-up period ended August 31, 2001, just prior to the first mailing of the 2001 questionnaire.
In each Nutrition Cohort questionnaire, participants were asked whether they had ever been diagnosed with diabetes and whether they used insulin. Men were classified as diabetic if they responded yes to either of those questions. In addition, on the 1997 questionnaire, men were asked when they were diagnosed with diabetes (before 1992, 19921993, 19941995, and 1996 or after). Because all Nutrition Cohort participants were also participants in the original CPS-II cohort, information on diabetes was also available from the 1982 CPS-II questionnaire.
We excluded from this analysis men who were lost to follow-up from baseline through August 31, 2001 (n = 3,431), and who reported any prevalent cancer (except nonmelanoma skin cancer) at baseline (n = 9,004). We also excluded men whose reported prostate cancer could not be confirmed (n = 464), men with stage I prostate cancer (n = 48), and men with uninterpretable responses on diabetes status (n = 691). In addition, men with inconsistent information on their diabetes status between 1992, 1997, 1999, and 2001 were censored at the time of their previous report, men with any incident of verified cancer were censored at the date of cancer report, and men lost to follow-up were censored at the time of their last questionnaire. In an attempt to limit the analysis to type 2 diabetes, we excluded men (n = 96) who reported having been diagnosed with diabetes at an age earlier than 30 years. After these exclusions, the analytical cohort consisted of 72,670 men.
There were a total of 5,318 incident cases of fatal or nonfatal prostate cancer. Incident cases of prostate cancer were identified through a self-report of cancer on any of the questionnaires (n = 4,907) and subsequently verified by medical records (n = 4,097) or from linkage with state cancer registries (n = 810). An additional 110 prostate cancer cases were also identified if recorded as the underlying cause of death on a death certificate through December 31, 2000, among cohort members who did not report cancer at enrollment (20). Seventy-six of the 110 deaths were subsequently verified through linkage with cancer registries. Finally, 301 cases of prostate cancer were not reported as prostate cancer but were identified during confirmation of another reported cancer.
For analysis of aggressive prostate cancer, we included prostate cancer cases verified by medical records with stages III and IV, those with a Gleason score of 8 or higher or grade 34, prostate cancer cases verified by the cancer state registry and classified as regional or distant, and prostate cancer deaths. A total of 1,306 aggressive prostate cancer cases were included in this analysis.
We used Cox proportional hazards modeling (21) to examine the association between diabetes and incident prostate cancer while adjusting for other potential confounding factors. Exposure information was calculated as a time-dependent variable based on the diabetes status reported in the 1992, 1997, 1999, or 2001 questionnaire. All Cox models were stratified on single year of age at enrollment and were adjusted for race, education, family history of prostate cancer, body mass index, and quintiles of total energy intake, energy-adjusted total fat intake, lycopene, and total calcium intake. Nondietary variables, other than age, were modeled as dummy variables using the categories shown in table 1. Information on prostate-specific antigen testing was first collected in the 1997 questionnaire and was modeled as a time-dependent variable.
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RESULTS |
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Self-reported diabetes was associated with lower prostate cancer incidence rates after adjustment for age, race, education, and prostate-specific antigen testing (rate ratio (RR) = 0.67, 95 percent confidence interval (CI): 0.60, 0.75) (table 2). The association between diabetes and risk of prostate cancer differed significantly by time since diagnosis (phomogeneity = 0.0002); prostate cancer rates among men diagnosed with diabetes within the last 3 years were higher than among nondiabetic men (RR = 1.23, 95 percent CI: 0.92, 1.65). Men who had had diabetes 4 or more years had a lower rate of prostate cancer than did men without diabetes (RR = 0.63, 95 percent CI: 0.56, 0.71), although no significant trend of decreasing prostate cancer risk with increasing time since diagnosis after the initial 3 years was observed (table 2). Results from models adjusting only for age and race were similar to the multivariate-adjusted rate ratios (data not shown).
Overall, the association between diabetes and prostate cancer was similar in a stratified analysis by stage/grade of prostate cancer at diagnosis (table 3). The pattern of increased prostate cancer risk shortly after diabetes diagnosis and lower risk with long duration of the disease was observed for both aggressive and nonaggressive prostate cancer (table 3).
No significant interactions were observed between diabetes and any of the other potential prostate cancer risk factors included in this analysis. Having a history of prostate-specific antigen testing did not modify the association between diabetes and risk of prostate cancer (data not shown). Because information on prostate-specific antigen testing was not collected until the 1997 questionnaire, we conducted a sensitivity analysis starting with follow-up in 1997. During this follow-up period, diabetes was associated with a 30 percent decreased risk of incident prostate cancer (RR = 0.69, 95 percent CI: 0.58, 0.82). Nearly all men, regardless of diabetes status, were receiving prostate-specific antigen testing during this period.
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DISCUSSION |
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Our results with respect to time since diabetes diagnosis and prostate cancer risk are similar to those observed in the Health Professionals Follow-up Study (7), a cohort of similar design, but they differed from those of the US Physicians Health Study (8) and the CPS-I cohort (9). In the Health Professionals Follow-up Study, risk of prostate cancer was 24 percent higher in the first 5 years after diagnosis of diabetes (RR = 1.24, 95 percent CI: 0.87, 1.77) and was significantly decreased after 10 years (RR = 0.54, 95 percent CI: 0.37, 0.78). It is not clear why our results differed from those for the CPS-I cohort (9), in which men with diabetes for more than 5 years had significantly increased risk of incident prostate cancer. The CPS-I was conducted from 1959 to 1972, a period of time with no early prostate cancer detection practices other than the digital rectal examination. It is possible that, during this time period, prostate cancers would have been more likely to be detected among diabetic men than among nondiabetic men.
Diabetic men in the CPS-II Nutrition Cohort were somewhat less likely to receive prostate-specific antigen testing for prostate cancer than were men with no diabetes. Therefore, we cannot rule out detection bias among nondiabetic men as a possible explanation for the lower prostate cancer rates among diabetic men. However, detection bias seems unlikely to fully account for our results, given that the association between diabetes and prostate cancer was seen for both nonaggressive and aggressive prostate cancer at diagnosis. In addition, we observed reduced risk among diabetics during the 19972001 follow-up period, a time when prostate-specific antigen testing was very prevalent among both diabetic and nondiabetic men in our study cohort. The inverse association between diabetes and prostate cancer observed in this study has also been reported in epidemiologic studies conducted before the advent of widespread prostate-specific antigen testing, including a very large Swedish study (5).
It is plausible that prostate-specific antigen testing could sometimes be conducted as part of diagnostic work-up for diabetic symptoms. In theory, this could have resulted in detection bias, contributing to the increased risk of prostate cancer observed among men with a recent diabetes diagnosis. Such detection bias is unlikely to have strongly influenced our results, because men were not classified as newly diabetic in the proportional hazards model until the date they reported diabetes on a questionnaire, usually many months after the date of diabetes diagnosis.
Metabolic and hormonal changes associated with diabetes could explain the temporal relation observed in this and one previous study (7). First, insulin levels vary dramatically with increasing duration of diabetes; insulin levels are elevated as a result of insulin resistance during the years leading up to a diabetes diagnosis, but they later decrease to levels lower than those of nondiabetic men as a result of damage to pancreatic B cells (22). Insulin has been reported to stimulate the growth of a rat prostate cancer cell line in vitro (23) and has been associated with higher risk of prostate cancer (2) and higher recurrence of the disease (24). Second, insulin downregulates insulin-like growth factor binding protein 1 that controls the free fraction of insulin-like growth factor I (25). Plasma insulin-like growth factor I levels, therefore, are elevated at the beginning of the disease and decrease as the disease progresses (26, 27). Insulin-like growth factor I has been associated with increased prostate cancer risk in several prospective studies (28, 29). Finally, serum levels of insulin correlate negatively with circulating levels of testosterone, dihydrotestosterone, and sex hormone-binding globulin and correlate positively with the testosterone/sex hormone-binding globulin ratio (2, 30). Therefore, serum circulating levels of testosterone are lower in diabetic than nondiabetic men (31, 32), and testosterone has been associated with elevated risk of prostate cancer (33), although not consistently (34).
The reliance on self-report of diabetes is a limitation of this study. We cannot differentiate between type I and type II diabetes, although we excluded men reporting insulin use before the age of 30 years, and the great majority of diabetes diagnoses after this age would be expected to be type II. Second, it is possible that some men reported impaired glucose intolerance as diabetes, which could lead to misclassification of diabetes status. However, this type of misclassification should bias the estimate toward the null. It is noteworthy that the percentage (13.8 percent) of men reporting diabetes in our cohort is in agreement with the prevalence (12.3 percent) of diabetes in the National Health and Nutrition Survey for people 4074 years of age (35).
Results of this study are consistent with the hypothesis that diabetes reduces the risk of prostate cancer starting several years postdiagnosis, and they provide limited support for a role of insulin and testosterone in prostate carcinogenesis.
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NOTES |
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REFERENCES |
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