Affiliations of authors: Arizona Cancer Center, University of Arizona, Tucson (ETJ, RJ, DSA, MEM); Mel and Enid Zuckerman Arizona College of Public Health, University of Arizona, Tucson (ETJ, MEM); Dartmouth Medical School and the Norris Cotton Cancer Center, Lebanon, NH (ERG, MRK, KW); Centers for Disease Control and Prevention, Atlanta, GA (EWG); National Cancer Institute, Bethesda, MD (EL, AS); Food and Drug Administration, Jefferson, AR (LR); Roswell Park Cancer Institute, Buffalo, NY (MER); Harvard School of Public Health, Boston, MA (SASW)
Correspondence to: Elizabeth T. Jacobs, PhD, Arizona Cancer Center, University of Arizona, P.O. Box 245024, Tucson, AZ 85724-5024 (e-mail: jacobse{at}u.arizona.edu)
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ABSTRACT |
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INTRODUCTION |
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Pooling data from multiple studies is one epidemiologic tool for investigating important public health concerns (18). The availability of blood selenium data from three completed clinical trials of colorectal adenomathe Wheat Bran Fiber Trial, the Polyp Prevention Trial, and the Polyp Prevention Studyprovided an opportunity to assess the relationship between selenium concentrations and adenoma recurrence. Each of the three trials was conducted to assess the effect of a dietary nutrient or intervention on the risk of developing a new colorectal adenoma among participants who recently had an adenoma removed during colonoscopy. The populations of the three trials were similar clinically, and colorectal adenoma endpoints were assessed carefully by follow-up colonoscopy. In this study, individual data from these three trials was pooled to obtain a more precise estimate of the seleniumadenoma association.
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METHODS |
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Wheat Bran Fiber Trial
The Wheat Bran Fiber Trial was conducted at the University of Arizona to compare the effect of a high-fiber cereal supplement and a low-fiber supplement on adenoma recurrence over 3 years among patients who recently had an adenoma removed at colonoscopy (19). Baseline data regarding demographic, medical, and lifestyle characteristics were collected with questionnaires, and dietary habits were assessed using the Arizona Food Frequency Questionnaire (22). A total of 1304 study participants completed the Wheat Bran Fiber Trial by having at least one colonoscopy and/or a diagnosis of colorectal cancer after random assignment to either high-fiber or low-fiber supplement. No statistically significant effect of the high-fiber supplement on adenoma risk was observed (22). For this analysis, we determined plasma selenium concentrations in blood samples from a subset of participants who had completed the Wheat Bran Fiber Trial that were drawn approximately 1 year after random assignment. Five hundred participants were randomly selected for a nested casecontrol design (250 with a recurrence and 250 without recurrence); selenium values were available for 498 of these individuals. The study was approved by the University of Arizona Human Subjects Committee and local hospital committees, and written informed consent was obtained from each participant prior to study enrollment.
Polyp Prevention Trial
The Polyp Prevention Trial was a multicenter study conducted by the National Cancer Institute. Participants with a prior colorectal adenoma were assigned to either a low-fat, high-fiber diet containing fruits and vegetables or a normal diet for 4 years, and subsequent adenoma risk was compared between the two groups (20). Questionnaires were administered at baseline to ascertain demographic information, behavioral, and clinical characteristics and dietary habits (20). A total of 1905 participants completed the trial by having any endoscopic procedure after the year 1 colonoscopy, or for subjects who missed the year 1 colonoscopy, by having any endoscopic procedure performed at least 2 years after random assignment. The dietary intervention was not statistically significantly related to risk of a new adenoma (20). For this analysis, a 40% random sample of the study population was selected. Serum selenium was analyzed in 713 (94%) of the 762 participants who were randomly selected to provide blood samples at baseline. Written informed consent was obtained from all study participants, and the trial was approved by the Institutional Review Board at the National Cancer Institute, as well as by each participating clinic location.
Polyp Prevention Study
The Polyp Prevention Study was a multicenter, randomized, placebo-controlled trial coordinated by investigators at Dartmouth to evaluate the effect of vitamin C, E, and -carotene supplementation on the risk of developing a new colorectal adenoma in participants who had recently had an adenoma resected from their large bowel (21). Usual diet and demographic, lifestyle, and medical characteristics were determined at baseline by questionnaires (21). A total of 751 participants completed the trial by having a colonoscopy both 1 year and 4 years after enrollment. The intervention was not associated with risk of a new adenoma (21). Serum from blood drawn at the time of enrollment (n = 546) or first colonoscopy (n = 6) was analyzed for 552 (74%) of the 751 participants who completed the trial (23). These samples were selected using a nested casecontrol design, as previously described (23). The study protocol was approved by the Internal Review Board at Dartmouth and all other clinic sites, and written informed consent was obtained from all study participants.
Definition of Adenoma Risk
Each of the trials had two time points for follow-up colonoscopies, with the study protocol including a colonoscopy at year 1 followed by another at year 3 (Wheat Bran Fiber) or year 4 (Polyp Prevention Trial and Polyp Prevention Study). For the purpose of the current analyses, any adenoma or colorectal cancer that occurred after randomization in any trial was defined as a recurrence. This endpoint criterion was selected because guidelines for endoscopy surveillance changed during the Wheat Bran Fiber Trial, and therefore not all of the Wheat Bran Fiber Trial participants had both year 1 and year 3 colonoscopies.
Selenium Analysis
For the Polyp Prevention Trial, analyses of serum selenium levels were conducted by atomic absorption spectrometry by the Centers for Disease Control (24) under the direction of one of the coauthors (E.W. Gunter). For the Wheat Bran Fiber Trial, plasma samples were analyzed at the laboratory of Dr. Ivan S. Palmer at South Dakota State University using the fluorometric method (25). For the Polyp Prevention Study, serum selenium concentrations were determined by instrumental neutron activation analysis in the laboratory of Dr. J. Steven Morris at the University of MissouriColumbia Research Reactor Center (23).
Data Pooling
Data for the Polyp Prevention Trial and Polyp Prevention Study were submitted electronically by the National Cancer Institute and Dartmouth, respectively, to the Arizona Cancer Center for pooling with data from the Wheat Bran Fiber Trial. Data from the three trials were checked for accuracy and missing values. Any discrepancies were noted, and the submitting investigators were queried to resolve any outstanding issues. Data from each study site were analyzed individually prior to pooling. Variables were assigned common names and, if necessary, converted to common units of measurement. After the datasets were combined, thorough checks were conducted to ensure that the pooled data for each study site were identical to the original dataset.
Statistical Analyses
All analyses were completed using the Stata statistical software package (version 7.0; Stata, College Station, TX). Summary data for baseline characteristics were calculated using means and standard deviations for continuous variables and by chi-square analysis for categorical variables. To assess whether any baseline characteristics varied by blood selenium values in each trial separately, quartiles were constructed based on the distribution of selenium concentrations of participants in each trial; values for the baseline characteristics were then compared across quartiles. Data from the three trials were then pooled, and quartiles of baseline selenium were created based on the distribution of selenium levels from all participants in the three trials combined to evaluate overall differences in baseline characteristics. The combined analysis of supplemental vitamin E intake included only values from the Wheat Bran Fiber and Polyp Prevention Trials because this information was not collected in the Polyp Prevention Study.
To estimate the association between baseline selenium and adenoma risk, unconditional logistic regression modeling was used for each individual study and for the pooled dataset. First, the models were used to determine which baseline variables were associated with both adenoma and blood selenium. Likelihood ratio tests were performed to assess which variables statistically significantly changed the model, and these variables were included in the multivariable logistic regression analyses of selenium and adenoma risk. These variables were tested within the individual studies and then in the pooled analysis. For the analyses of the individual studies, trend tests were conducted using regression modeling and the quartile-specific category for blood selenium level. For the pooled analysis, regression models based on fractional polynomial functions were used to determine the best transformation for blood selenium. Results indicated a linear fit of the data; thus, we treated blood selenium as a continuous variable for the trend analysis. In addition to analyzing the pooled dataset, the study-specific estimates were combined using a random-effects model to estimate the pooled odds ratios (ORs) (26,27). All statistical tests were two-sided and were considered to be statistically significant if P values were less than .05.
Secondary analyses of adenoma characteristics were also conducted. Individuals were placed into the low-selenium (130 ng/mL) or the high-selenium (>130 ng/mL) category based on the median baseline selenium level. The referent group comprised participants who had no new adenomas and were in the low-selenium category (
130 ng/mL). For analyses by adenoma diameter, the largest adenoma for each participant was classified as either large (
1 cm), or small (<1 cm). In analyses of adenoma location, participants with distal adenomas included those who had at least one adenoma distal to the transverse colon and no adenomas proximal to this region; analysis of proximal polyps included participants with proximal adenomas only. For analyses of adenoma histology, participants were classified as having tubular adenomas only or any adenoma with villous histology (tubulovillous or villous). In addition, categories for nonadvanced (<1 cm in diameter and no villous histology) and advanced (
1 cm in diameter and/or villous histology) adenomas were created.
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RESULTS |
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DISCUSSION |
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Initial interest in selenium as a potential chemopreventive agent was driven by epidemiologic studies that showed a reduced risk for some types of cancer for people living in geographic areas with comparatively high soil selenium levels (3,28). This interest was later enhanced by several studies that indicated at least a modest inverse association between blood levels of selenium and the risk of colorectal adenomas (12,14,23) and cancers (9,14), although no relationship was detected in other studies (16,17). Selenium levels have also been demonstrated to be associated with cancer stage (11) and survival (13). The reasons for the apparent discrepancies in the studies of colorectal neoplasia are unclear; however, the sample sizes tended to be relatively small (12,14,16,17), resulting in greater variability of the association estimates.
The results of one of the component studies of this paper have been published previously (23). For that analysis, the authors defined recurrent adenomas as those detected after the year 1 colonoscopy (23). Compared with the lowest quintile of serum selenium, the odds ratios for increasing quintile of total selenium were 0.78 (95% CI = 0.46 to 1.31); 0.77 (95% CI = 0.45 to 1.34); 0.97 (95% CI = 0.57 to 1.63); and 0.76 (95% CI = 0.44 to 1.30), with a Ptrend of .50 (23). However, as reported in the original article (23), with an odds ratio of 0.57 (95% CI = 0.32 to 1.02) for the highest versus the lowest quintile of selenium, the association between selenium and adenoma recurrence was stronger when all postrandomization recurrent adenomas were included than when the analysis included only polyps occurring after the year 1 exam. The year 1 colonoscopy was intended as a "clean out" colonoscopy to ensure that no adenomas were missed during the screening procedure; therefore, it is possible that adenomas detected at year 1 may represent lesions missed at the index colonoscopy rather than recurrences.
By pooling the study populations of these three large trials, we were able to analyze the effect of selenium on specific adenoma endpoints with greater precision than in the individual studies alone. No statistically significant effects of selenium were detected for adenoma size, location, or histology. The results reported by Wallace et al. (23) for the independent analysis of the Polyp Prevention Study also showed no statistically significant association for adenoma number, size, or location. One study performed in Spain found that selenium levels were statistically significantly lower in study participants with prevalent adenomas at least 1 cm in diameter compared with control subjects (14). However, the mean blood selenium concentration in participants with adenomas was approximately half that observed in participants in this study, and those study participants had prevalent, rather than recurrent, adenomas, as in this study. It is therefore possible that the increased risk of large colorectal adenomas is more pronounced in participants who have an intake of selenium below the 90 µg of selenium per day dose that is adequate for the saturation of selenium-containing enzymes such as glutathione peroxidase (29).
Selecting the optimal selenium compound for chemoprevention is challenging. Potential chemopreventive mechanisms of selenium include protection from oxidative DNA damageinduced apoptosis (4,5) and increased immune system activity (6). Optimization of each of these chemoprotective processes may involve different dosages and different types of selenium; selenocompounds that may exert chemopreventive effects include methylselenol (30), selenodiglutathione (31), glutathione peroxidase, thioredoxin reductase, and other selenoproteins (5).
Another issue is determining the optimal selenium dose for chemoprevention. Because selenium levels of trial participants vary markedly (7,14,17), the effective dose for chemoprevention can be difficult to determine and may also vary widely in a population. For example, in the Nutritional Prevention of Cancer Trial, the reduction in risk of colorectal cancer was observed with supplementation of 200 µg/day of selenium (7). However, later analyses revealed that the protection with selenium supplementation observed in this trial was statistically significant only for those in the lowest tertile of baseline selenium intake (8), suggesting that supplementation may benefit only those with circulating selenium levels of less than 106 ng/mL. In addition, in the same trial, those selenium-supplemented participants in the higher tertiles of baseline selenium levels indeed demonstrated a statistically significantly increased risk of nonmelanoma skin cancer (32). The study population of the Nutritional Prevention of Cancer trial was selected specifically for its high risk for these types of cancers. Nonetheless, future studies should also incorporate cancer type when determining selenium dosage for cancer prevention.
Potential limitations of this work include the different study designs used to select the samples for selenium analysis in each of the original trials. For the Polyp Prevention Study and Wheat Bran Fiber Trial, a nested casecontrol design was used to compare blood selenium levels among subjects; for the Polyp Prevention Trial, the analysis was conducted on a random sample using a prospective design. To reduce the differences between the individual study designs when analyzing and pooling data from the three studies, we tested several baseline characteristics using regression models and likelihood ratio testing, and variables that statistically significantly changed the outcome remained in the final model. Moreover, the individual analyses of selenium and adenoma recurrence for each of these trials yield remarkably similar results across the three trials (Pheterogeneity = .88 for highest quartile of intake). Another possible limitation of the work is that the generalizability of the results may be limited because the participants in these trials were volunteers interested in participating in a long-term clinical trial potentially requiring a diet intervention or supplement, who had at least one previous colorectal polyp, and who, on average, had blood selenium levels higher than the national average of 123 ng/mL (33). Another limitation to this work is that selenoprotein levels and activity could not be assessed. Because the mechanism of action of selenium likely involves these proteins, evaluation of selenoproteins will be an important area of research for future studies.
The strengths of this study include the large sample size that was available by pooling data from three intervention trials. This data pooling technique allowed us to efficiently use previously collected data. The combination of datasets increased the precision of the risk estimates, as exemplified by comparing the individual results with those of the combined analysis. The component studies were all well-conducted clinical intervention trials with similar populations and comprehensive endpoint data collection. Furthermore, all three studies had high follow-up rates, with over 85% of participants randomly assigned having completed each trial, minimizing the possibility of detection bias.
In summary, the results of this report indicate that selenium has a role in reducing the risk of colorectal adenoma recurrence. Because of the metabolic complexity of this nutrient, studies of selenium dose and biologic form that is most effective for chemoprevention are required. Finally, this study provides an excellent example of the advantages of pooling data from large trials to improve the precision of measurements of association.
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NOTES |
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We are indebted to the members of the Phoenix Colon Cancer Prevention Physicians Network for their dedication to the Wheat Bran Fiber Trial, and to Dr. Janine Einspahr for her instrumental role in the biomarkers core. In addition, we would like to thank the investigators for the Polyp Prevention Study, and are particularly grateful for the guidance and insights of Tim Byers, John Baron, Bernard Cole and Steve Morris. Finally, we acknowledge the Polyp Prevention Trial Study Group for their outstanding contribution to this project.
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Manuscript received April 30, 2004; revised September 1, 2004; accepted September 13, 2004.
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