Common Health Problems | Conditions and treatments

Vitamin E and the Risk of Prostate Cancer. Part 2

With considerable preclinical and epidemiological evidence that selenium and vitamin E may reduce prostate cancer risk, we conducted and reported the results of a prospective randomized trial examining the effect of these 2 agents for prostate cancer prevention. Coordinated by SWOG, a federally funded cancer research cooperative group, the Selenium and Vitamin E Cancer Prevention Trial (SELECT) began accrual on August 22, 2001, and randomized 35 533 men into 4 groups: selenium with matching placebo, vitamin E with matching placebo, both agents, or placebo.

Based on a preplanned interim analysis, the independent data and safety monitoring committee met on September 15, 2008, and recommended the early discontinuation of study supplements because of lack of efficacy for risk reduction and because futility analysis demonstrated no possibility of benefit to the planned degree with additional follow-up.6​

As reported in the initial article,6 with a median follow-up of 5.5 years, the numbers of prostate cancers detected were 473 (hazard ratio [HR], 1.13; 99% CI, 0.95-1.35) for vitamin E; 432 (HR, 1.04; 99% CI, 0.87-1.24) for selenium; 437 (HR, 1.05; 99% CI, 0.88-1.25) for selenium plus vitamin E; and 416 (HR, 1.0) for placebo. Although these results were not statistically significant, the data and safety monitoring committee expressed concern about the increased risk of prostate cancer observed in the vitamin E plus placebo group, which approached statistical significance (P = .06) and a statistically nonsignificant increased risk of type 2 diabetes mellitus in the selenium plus placebo group (P = .16).

Since that time, participant follow-up has continued, allowing observation of additional events. On May 20, 2011, the data and safety monitoring committee reviewed trial data and recommended reporting the finding regarding increased risk of prostate cancer with vitamin E. This recommendation was based on final data collection from the study sites and coincided with the preplanned final analysis at 7 years after the last participant was randomized. Viagra professional Australia

Detailed descriptions of the rationale, design, conduct, and initial results of SELECT have been previously published. The study enrolled healthy men at average risk of prostate cancer based on a baseline prostate-specific antigen (PSA) of ≤4 ng/mL and normal digital rectal examination (DRE) commencing at age 50 years for black men or at age 55 years for all others. Men were randomized into 1 of 4 groups: selenium (200 μg/d from L-selenomethionine) with matching vitamin E placebo, vitamin E (400 IU/d of all rac -α-tocopherol acetate) with matching selenium placebo, both agents, or matching placebo.

Participants without prostate cancer were monitored every 6 months with an annual limited physical examination including blood pressure, weight, and smoking status; participants who developed prostate cancer during the study were monitored annually thereafter. Participants were recommended to undergo PSA and DRE testing and prostate biopsy based on the standard of care in their community and in accordance with the participant's preference. To facilitate adherence, a multivitamin containing no selenium or vitamin E was offered. All participants were required to provide written informed consent and the local institutional review board of each study site approved the study.

Prediction of Erectile Function Following Treatment for Prostate Cancer

Context Sexual function is the health-related quality of life (HRQOL) domain most commonly impaired after prostate cancer treatment; however, validated tools to enable personalized prediction of erectile dysfunction after prostate cancer treatment are lacking.

Objective To predict long-term erectile function following prostate cancer treatment based on individual patient and treatment characteristics.

Design Pretreatment patient characteristics, sexual HRQOL, and treatment details measured in a longitudinal academic multicenter cohort (Prostate Cancer Outcomes and Satisfaction With Treatment Quality Assessment; enrolled from 2003 through 2006), were used to develop models predicting erectile function 2 years after treatment. A community-based cohort (community-based Cancer of the Prostate Strategic Urologic Research Endeavor [CaPSURE]; enrolled 1995 through 2007) externally validated model performance. Patients in US academic and community-based practices whose HRQOL was measured pretreatment (N = 1201) underwent follow-up after prostatectomy, external radiotherapy, or brachytherapy for prostate cancer. Sexual outcomes among men completing 2 years' follow-up (n = 1027) were used to develop models predicting erectile function that were externally validated among 1913 patients in a community-based cohort.

Main Outcome Measures Patient-reported functional erections suitable for intercourse 2 years following prostate cancer treatment.

Results Two years after prostate cancer treatment, 368 (37% [95% CI, 34%-40%]) of all patients and 335 (48% [95% CI, 45%-52%]) of those with functional erections prior to treatment reported functional erections; 531 (53% [95% CI, 50%-56%]) of patients without penile prostheses reported use of medications or other devices for erectile dysfunction. Pretreatment sexual HRQOL score, age, serum prostate-specific antigen level, race/ethnicity, body mass index, and intended treatment details were associated with functional erections 2 years after treatment. Multivariable logistic regression models predicting erectile function estimated 2-year function probabilities from as low as 10% or less to as high as 70% or greater depending on the individual's pretreatment patient characteristics and treatment details. The models performed well in predicting erections in external validation among CaPSURE cohort patients (areas under the receiver operating characteristic curve, 0.77 [95% CI, 0.74-0.80] for prostatectomy; 0.87 [95% CI, 0.80-0.94] for external radiotherapy; and 0.90 for brachytherapy).

Conclusion Stratification by pretreatment patient characteristics and treatment details enables prediction of erectile function 2 years after prostatectomy, external radiotherapy, or brachytherapy for prostate cancer.

Because most patients survive early-stage prostate cancer after treatment,​ health-related quality of life (HRQOL) outcomes have emerged as a major emphasis in treatment decisions. Erectile dysfunction is commonplace after prostate cancer treatment and has significant consequences for HRQOL. Among urinary, bowel, vitality, and sexual HRQOL domains—outcomes commonly impaired by prostate cancer treatment—sexual function in previously potent men is the most commonly impaired and is closely related to outcome satisfaction.

Proximal and Distal Colon Cancer, and Rectal Cancer. Part 4

Our findings add to the limited prospective data on meat consumption in relation to rectal cancer. Consumption of red meat, as reported in 1992/1993, was more strongly associated with rectal than colon cancer in our study, as has been reported in some but not all case-control studies. One recent case-control study found no association between rectal cancer and red meat, poultry and fish, or processed meat consumption but reported increased risk associated with greater doneness of red meat among men.​ In our study, the positive association and significant dose-response relationship was observed mostly with tumors of the rectosigmoid junction rather than the rectum. Taken together with the higher risk of cancer observed in the distal colon, our results suggest that tumors in the distal portion of the large intestine may be particularly associated with meat consumption. It is possible that concentration of stool in the distal portion of the large intestine may contribute to higher cancer risk by increasing exposure to carcinogens as a result of water resorption during transit through the large intestine.

Our study had several limitations in addition to the measurement error inherent in studies based on FFQs. The 1982 questionnaire did not assess the number of servings of meat per day and could not differentiate persons who ate multiple servings from those who ate meat only once per day; we were also unable to estimate total energy intake from the 1982 diet questionnaire. We had no information on meat cooking methods to estimate exposure to heterocyclic amines or other specific carcinogens produced from pyrolysis of meat; our reliance on self-reported data on preference for doneness of meat was likely a crude proxy of the relevant exposures. Although heterocyclic amines are potent mutagens in the Ames assay and are carcinogenic in animal studies, the impact of these compounds on colorectal carcinogenesis in humans is less clear,81​-83 primarily due to the difficulties in measuring exposure and possible interactions between meat and other dietary constituents or genetic susceptibility. We had no information on family history of colorectal cancer from the 1992/1993 questionnaire to update this important variable, which could potentially modify the association between meat intake and risk of colorectal cancer. No information was collected on examination by sigmoidoscopy, colonoscopy, or fecal occult blood test in either the 1982 or 1992/1993 questionnaires. However, in 1997, persons who reported long-term high consumption of red meat were less likely (23%) to have had endoscopy for screening than those persons who reported long-term low intake of red meat (34%). It is difficult to predict the net effect of endoscopy on colorectal cancer incidence. On the one hand, endoscopic removal of precancerous lesions could contribute to lower risk; however, endoscopy could accelerate the diagnosis of some tumors that might not otherwise have been identified during the follow-up period.

Proximal and Distal Colon Cancer, and Rectal Cancer. Part 3

The higher risk associated with prolonged consumption of red meat but not poultry and fish is consistent with other epidemiological studies. The cytotoxic effect of dietary heme has been proposed as a potential mechanism by which red meat increases colorectal cancer risk because of higher heme content in red meat compared with poultry and fish. Heme damages the colonic mucosa and stimulates epithelial proliferation in animal studies.​ Both ingestion of red meat and heme iron supplementation have been shown to increase fecal concentrations of N-nitroso compounds and DNA-adducts in human colonocytes.

We found that consistently high consumption of processed meat was associated with increased risk of distal colon cancer. Results of prospective studies of colorectal cancer and processed meat have been more consistently positive in Europe​ than in the United States. Processed meat includes foods preserved by salting, smoking, or the addition of nitrites or nitrates, and high consumption of these foods can increase exposure to nitrosamines and their precursors. The amount of these substances in processed meat likely varied by region and over time but we had no information to assess the impact of these differences in our study results.

Several prospective studies have reported an inverse association between colon cancer risk and prolonged high consumption of poultry and fish. However, other studies have found either no association​ or increased risk associated with poultry and fish consumption. The lower risk associated with high consumption of poultry and fish or a low ratio of red meat-to-poultry and fish could be attributed to a displacement of red meat in the diet, but in our study high consumption of poultry and fish remained independently associated with lower risk of colon cancer even when controlling for red meat intake. It is also possible that poultry and fish contain factors that may protect against colon cancer. Poultry contains small amounts of nutrients such as selenium and calcium that have been associated with lower risk of colorectal neoplasia, but it is a relatively minor source of these nutrients. Fish is a primary source of omega-3 fatty acids and high intake of fish or fish oil has been inversely associated with colorectal cancer risk in some epidemiological studies.​ In experimental studies, omega-3 fatty acids have been shown to inhibit tumor growth and to modulate the expression of proinflammatory genes.​ However, the poultry and fish consumed by CPS II Nutrition Cohort participants consisted mostly of chicken.

Proximal and Distal Colon Cancer, and Rectal Cancer. Part 2

Red meat consumption was marginally associated with higher risk of rectal cancer (RR, 1.43; 95% CI, 1.00-2.05); this association was somewhat stronger for cancers of the rectosigmoid junction (RR, 1.75; 95% CI, 1.04-2.96) than for cancer of the rectum (RR, 1.31; 95% CI, 0.79-2.15). The relationship between long-term consumption of red meat, poultry and fish, and risk of colon or rectal cancer remained unchanged when all were included in the same model (data not shown).

Effect Modification

No statistically significant interaction was observed between meat consumption and other known risk factors for colon or rectal cancer on a multiplicative scale.

The association between processed meat consumption and colon cancer risk was independent of other covariates only when intake was measured at 2 time points during a 10-year interval. Moreover, the association was observed consistently only for cancers of the distal colon. Prolonged high consumption of red meat was associated with higher risk of rectal cancer, particularly cancers of the rectosigmoid junction. Prolonged high consumption of poultry and fish was marginally associated with lower risk of proximal and distal colon cancer but not rectal cancer.

A strength of our study was the ability to control for several factors known to influence colon cancer risk. Inadequate control for potential confounding may partly explain the inconsistently observed positive associations between red meat and colon cancer risk in other studies, since some positive articles included in the quantitative reviews have adjusted for only age and energy. In our analyses, the association between colon cancer risk and high intake of red (RR, 1.41; 95% CI, 1.12-1.78) and processed meat (RR, 1.33; 95% CI, 1.08-1.64) measured at a single time point is consistent with meta-analysis results,​ adjusting for age and energy intake. However, the association was substantially attenuated with further adjustment for educational attainment, cigarette smoking, physical activity, and other lifestyle factors associated with red meat intake.

To our knowledge, no study has addressed the relationship between long-term meat consumption and risk of colon and rectal cancer. The association with distal colon cancer was stronger among persons who reported greater consumption of processed meat at 2 time points during a 10-year interval, as was the risk of cancer of the rectosigmoid junction among those persons who consistently reported high red meat intake. It is possible that true high consumers of red or processed meat were better defined with less measurement error when assessed twice during a 10-year period. It is also plausible that long-term high consumption of red and processed meat may be more strongly associated with colorectal carcinogenesis than short-term or sporadic consumption of meat. Certain components of red meat may affect both early and late stages in the development of neoplasia. Animal studies show that diets high in red meat tend to affect the early aberrant crypt stage of carcinogenesis. To our knowledge, no study has evaluated the importance of continued high exposure to red meat in animal models.

Proximal and Distal Colon Cancer, and Rectal Cancer

Higher consumption of poultry and fish was inversely associated with colon cancer risk in women but not men. Further adjustment for additional covariates other than energy attenuated the association. Among women, the inverse relationship remained statistically significant (P = .03 for trend). The positive association between colon cancer risk and ratio of red meat-to-poultry and fish intake was also stronger in women than men. The trend test for the ratio of red meat-to-poultry and fish intake was statistically significant in men, women, and both sexes combined. The inverse, marginally significant, association between high consumption of poultry and fish and colon cancer risk in men and women remained unchanged when adjusting simultaneously for red meat (data not shown).

Proximal and Distal Colon Cancer, and Rectal Cancer

After covariate adjustment, no consistent association was observed between consumption of red meat, poultry and fish, or processed meat as reported at a single time point and cancer of either subsite of the colon. Men and women in the second to fifth quintiles of red meat intake had higher risk of rectal cancer compared with those in the lowest quintile, particularly those individuals in the highest quintile (RR, 1.71; 95% CI, 1.15-2.52; P = .007 for trend). This association was observed primarily with cancers of the rectosigmoid junction (RR, 2.40; 95% CI, 1.30-4.43) with risk increasing significantly with the amount of red meat consumed (P = .002 for trend). No significant association was observed between red meat consumption and cancers of the rectum (data not shown). No clear association was observed between rectal cancer risk and other measures of meat consumption reported in 1992/1993.

Energy-Adjusted Meat Intake

Analyses using energy-adjusted meat intake reported in 1992/1993 yielded results similar to those using meat intake (g/wk) with few exceptions. Compared with risk estimates derived from nonenergy-adjusted meat intake, the association between colon cancer and consumption of processed meat (RR, 1.35; 95% CI, 1.04-1.77; highest to lowest quintile, P = .02 for trend) became stronger in men, although the association between rectal cancer and red meat intake (RR, 1.31; 95% CI, 0.96-1.79; P = .03 for trend) was attenuated in men and women combined. Other risk estimates for red meat, poultry and fish, and processed meat remained unchanged.

Long-term Meat Consumption

Prolonged high consumption of red meat was associated with a statistically nonsignificant increased risk of distal colon cancer (RR, 1.29; 95% CI, 0.88-1.89). The most consistent associations were observed between distal colon cancer and prolonged high intake of processed meat (RR, 1.50; 95% CI, 1.04-2.17), and ratio of red meat to poultry and fish (RR, 1.53; 95% CI, 1.08-2.18) compared with persons with prolonged low intake. These associations were not observed with cancer of the proximal colon. The association between distal colon cancer and consumption of processed meat was stronger in analyses based on long-term consumption than on that reported only in 1982 (data not shown). Long-term high intake of poultry and fish was marginally associated with lower risk of proximal (RR, 0.77; 95% CI, 0.59-1.02) and distal (RR, 0.70; 95% CI, 0.50-0.99) colon cancer.

Incident Colon and Rectal Cancer. Part 2

The 1992/1993 FFQ was validated among 441 Nutrition Cohort members who completed four 24-hour dietary recall interviews and a repeat FFQ. For red meat, the correlation coefficient between the FFQ and dietary recall interview was 0.55 among men and 0.78 in women; between the initial FFQ and the repeat FFQ, the correlation coefficient was 0.81 in men and 0.78 in women.

The 1982 questionnaire asked participants to report the average number of days per week they ate each of the 11 meat items. Intake frequencies of red meat, poultry and fish, and processed meat were computed by summing the number of days per week across individual meat items that contributed to each meat group, and categorizing into quintiles. Foods categorized as red meat were beef, pork, ham, liver, smoked meats, frankfurters/sausage, fried bacon, and fried hamburger; poultry and fish included chicken, fish, and fried chicken/fish; and processed meats included ham, smoked meats, frankfurters/sausage, and fried bacon. Turkey was not included on the 1982 questionnaire but was included on the 1992/1993 questionnaire.

We examined long-term meat consumption by considering consumption reported in 1982 and in 1992/1993. Consumption at each time point was categorized into tertiles (low, moderate, high) and participants were classified as low intake in 1982 and 1992/1993 (referent group), high intake in 1982 and 1992/1993, and all other combinations of intake over time.
Statistical Analysis

Colon and rectal cancer incidence rate ratios (RRs) and 95% CIs by meat intake were estimated using Cox proportional hazards regression modeling. P values for linear trend were estimated by modeling meat intake (g/wk) using the median value within quintiles; these results were similar when modeled as continuous variables. This study was observational, not randomized, so P values were interpreted as approximate. To obtain P values and confidence limits, we treated the disease outcome as though it were a random variable that changed over time. Potential confounders were chosen based on a priori considerations and on the observed association with colon or rectal cancer and meat intake.

For each meat variable, we constructed 3 models stratified by single year of age, controlling for other covariates. Model 1 also included total energy (continuous); model 2 included total energy, education (some high school, high school graduate, some college or trade school, college graduate or postgraduate work, or unknown), body mass index calculated as weight in kilograms divided by the square of height in meters in 1992/1993 (<18.5, 18.5-24.9, 25.0-29.9, 30.0-39.9, ≥40.0, or unknown), cigarette smoking in 1992/1993 (never, former, current, ever smoker not specified, or unknown), recreational physical activity in 1992/1993 (none, hours per week of walking, or walking plus other activities), multivitamin use in 1982 (none, current user, or unknown), aspirin use in 1982 and in 1992 (nonuser in 1982 and 1992, ≥15 days per month in 1982 and 1992, <15 days per month in 1982 or 1992, or unknown at either time point), intake of wine (none, any), beer (none, any), and liquor (none, any), and hormone therapy use in 1992/1993 among women (nonuser, former user, current user, ever user not specified, or unknown). Model 3 included all covariates in model 2 plus intake of fruits in 1992/1993 (quintiles), vegetables in 1982 (quintiles), and high-fiber grain foods in 1982 (quintiles). Models of men and women combined also included a term for sex. Family history of colorectal cancer reported in 1982 was examined and excluded as a potential confounder; no information on family history of colorectal cancer was available in 1992/1993. Results of models including age and energy were similar to those from models including only age or age plus energy in quintiles. In a subanalysis of meat consumption reported in 1992/1993, we examined quintiles of energy-adjusted intake of red meat, poultry and fish, and processed meat based on the residual method.​ We also examined how the association with each type of meat was affected when controlling for other types of meat; no substantial difference was observed in these analyses (results not shown).

Meat Consumption and Risk of Colorectal Cancer. Part 2

Study Population

The CPS II Nutrition Cohort has been described in detail elsewhere.54 Briefly, the CPS II Nutrition Cohort comprised 86 404 men and 97 786 women who completed a mailed questionnaire in 1992/1993 and were followed up for cancer incidence and mortality. This cohort is a subset of the CPS II Mortality Cohort in which 1.2 million US adults from all 50 states, Puerto Rico, and the District of Columbia have been followed up for cancer mortality since 1982.54​ In the CPS II Mortality Cohort, participants completed a self-administered questionnaire in 1982 with information on diet, exercise, medical history, and other lifestyle habits. Race was determined on this 1982 questionnaire by multiple choice (white, black, Hispanic, Oriental, and other). Enrollment in the CPS II Nutrition Cohort was limited to men and women aged 50 to 74 years, residing in 21 states with population-based cancer registries that demonstrated at least 90% ascertainment of incident cancers by 1990. The median age at the CPS II Nutrition Cohort enrollment was 63 years.

The 1992/1993 CPS II Nutrition Cohort questionnaire obtained information on diet, physical activity, medical history, and other lifestyle habits. This cohort was recontacted at 2-year intervals between 1997 and 2003 with self-administered questionnaires to update information on newly diagnosed cancers, medical history, and lifestyle factors. Reported cancer diagnoses through 2001 have been verified by clinical information obtained from medical records or linkage with state cancer registries. An earlier study linking CPS II Nutrition Cohort participants to state cancer registries demonstrated that self-report of any cancer could identify incident cancers with a sensitivity of 93%. Mortality follow-up of the entire CPS II Nutrition Cohort​ is ongoing through automated linkage with the National Death Index. Cohort participants on average report higher educational attainment and more behaviors suggesting health consciousness than the general US population. Participants were informed of data linkage activities on each mailed questionnaire and provided written consent by returning the completed questionnaire. All aspects of the CPS II study protocol were approved by the Emory University Institutional Review Board.

This analysis was based on 1667 incident cases of colon or rectal cancer diagnosed from the time of enrollment in 1992/1993 through August 31, 2001. Participants contributed person-years at risk until death or a diagnosis of colon or rectal cancer. Excluded from the analysis were persons who were not known to be deceased but failed to respond to the 1997, 1999, and 2001 questionnaires (3.7%); reported a colon or rectal cancer not verified by pathology report or death certificate (0.3%); reported at baseline a personal history of colon or rectal cancer (1.5%); reported uninterpretable or missing data on meat consumption in 1982 (4.7%); completed less than 85% of the food section of the 1992/1993 questionnaire; or reported implausibly high or low energy intake (9.1%). After exclusions, the analytic cohort included 69 664 men and 78 946 women, representing 81% of the CPS II Nutrition Cohort.

Meat Consumption and Risk of Colorectal Cancer. Part 2

Five​ of 1033-42​ US prospective studies of colorectal cancer reported positive associations with red or processed meat intake, although some associations​ did not reach statistical significance. European prospective studies​ have generally reported no association with fresh or total meat but positive associations with cured or processed meat, sausages,​ or smoked/salted fish. High consumption of poultry or fish has been inconsistently associated with higher​ or lower risk of colorectal cancer; some studies have found no association. Only 2 prospective studies have reported on rectal cancer in relation to meat consumption. The results were conflicting but were limited by the small number of cases.

A meta-analysis​ of case-control and prospective studies estimated the mean relative risk comparing the highest to lowest categories of meat consumption to be 1.35 (95% confidence interval [CI], 1.21-1.51) for red meat and 1.31 (95% CI, 1.13-1.51) for processed meat and colorectal cancer. A review of prospective studies51 concluded that a daily increment of 100 g of red or total meat consumption was associated with a 12% to 17% higher risk of colorectal cancer, and that an increment of 25 g of processed meat was associated with a 49% higher risk. Not all risk estimates included in these review articles were adjusted for potential confounders beyond age and energy intake, so residual confounding may influence the summary risk estimates.

Clarifying the role of meat consumption in colorectal carcinogenesis is important. Meat is an integral component of diet in the United States and many other countries in which colorectal cancer is common. Per capita annual consumption of beef has increased in the United States since 1993, reversing a previous decrease since 1976. Poultry consumption has surpassed beef consumption since the late 1980s.

An earlier analysis of the Cancer Prevention Study II (CPS II) Mortality Cohort, based on deaths from colorectal cancer from 1982 to August 1988, found no association between colorectal cancer mortality and high consumption of red meat, but suggested lower risk associated with higher intake of chicken and fish in women.​ We examined the relationship between meat consumption and incident colon and rectal cancers among 148 610 men and women enrolled in the CPS II Nutrition Cohort in 1992/1993.