1 Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD.
2 Department of Epidemiology, Michigan State University, East Lansing, MI.
Received for publication October 2, 2002; accepted for publication December 20, 2002.
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ABSTRACT |
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colorectal neoplasms; dietary fats; meat; prospective studies; women
Abbreviations: Abbreviations: BCDDP, Breast Cancer Detection Demonstration Project; CI, confidence interval.
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INTRODUCTION |
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A recent report from the American Institute for Cancer Research (3) specified red meat (but not total meat) as a probable risk factor for colorectal cancer. This report also identified processed meat and highly cooked meat as "possible" risk factors (3). Red meat has been thought to promote colorectal cancer through the effects of fat (see below), iron, protein, and, in the case of processed meat, N-nitroso compounds (35). Additionally, certain cooking practices (e.g., frying or grilling) result in the production of heterocyclic amines in meat, and these compounds have been shown to have high mutagenic activity (6). The role of heterocyclic amines in the diet as causes of specific cancers in humans is not definitively established, but there have been recent reports showing significant positive associations with lung cancer and colonic adenomas (7, 8).
The same American Institute for Cancer Research report also listed both total fat and saturated fat as "possible" risk factors for colorectal cancer (3). As noted in a recent review, the type of fat that has been most strongly associated with colorectal cancer is fat from red meat sources (9). This fat is primarily saturated fat, although fat from dairy foods is also primarily saturated fat, but the association between dairy foods and colorectal cancer is not well established. Numerous investigators have proposed a variety of mechanisms by which dietary fat may increase the risk of colorectal cancer. These include excretion of bile acids into the colon that would have an irritant, proliferative effect on the cells of the lumen. This, however, implies a general fat effect, which would not be consistent with the more pronounced association suggested for fat from red meat. Other investigators have also hypothesized as possible mechanisms specific metabolic changes associated with specific saturated fatty acids, insulin resistance, altered immunologic responses, and changes in the fatty acid composition of cell membranes that, in turn, can affect the binding characteristics of colonic epithelial cells (9). Nonetheless, despite these plausible biologic mechanisms, data from previous prospective studies of diet have generally failed to provide support for an overall association of total fat or saturated fat with colorectal cancer or adenomas (1021).
This study examines the association of prospectively measured dietary meat and fat intake, and various subtypes of each, with colorectal cancer in a large cohort of women.
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MATERIALS AND METHODS |
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Participants subsequently completed a mailed questionnaire during three separate follow-up periods: 19871989, 19921995, and 19951998. Nonresponders to the questionnaires received vigorous follow-up, including repeated mailings and phone calls.
For the purposes of the current analysis, entry into the analytic cohort took place at the completion of the 19871989 questionnaire, the time of the dietary assessment. We excluded from the study women who did not complete a questionnaire at that stage (n = 9,740), women with a diagnosis of colorectal cancer at the time of the 19871989 questionnaire or earlier (n = 479), women whose reported entry date occurred after their exit date (n = 6; see definition of exit dates below), and women who skipped more than 30 items on their food frequency questionnaires or who had a reported total energy intake above 3,800 or below 400 kcal per day (n = 5,647). For this study, we also excluded 65 women with unusually high intakes of meat (reported frequency of consumption exceeding nine times per day), leaving 45,496 women in the final analytic cohort. Including women reporting consumption of meat more often than nine times per day in the analyses did not materially alter the results (data not shown). General descriptive statistics for the analytic cohort appear in table 1.
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In the final analytic cohort, 90 percent (n = 41,073 women) had complete follow-up through 19951998, meaning their exit date corresponded to the date of their first colorectal cancer diagnosis, the date they filled out the 19951998 questionnaire, or their date of death from a cause other than colorectal cancer.
Case ascertainment
We identified colorectal cancer cases from self-reports on the 19921995 and 19951998 questionnaires, from statewide cancer registries, and from the National Death Index (through 1997). We obtained pathology reports for 245 (79 percent) of the 311 women who provided self-reports of a diagnosis of colorectal cancer. The pathology reports confirmed 231 (94 percent) of the cases as adenocarcinoma of the colon or rectum (International Classification of Diseases for Oncology site codes 153.0153.4 and 153.6153.9 for colon cancer and 154.0154.1 for rectal cancer). Because of this high correspondence between the self-reports and medical records, we included the remaining 66 self-reports of colorectal cancer without pathology reports as cases. Exclusion of these 66 cases did not materially affect the results (data not shown). Women with pathology reports contradicting self-reported colorectal cancers were not included as cases, unless they also appeared in a state cancer registry as described below. Pathology reports obtained for self-reported conditions unrelated to colorectal cancer identified 17 more cases of colorectal cancer. A search of the National Death Index identified an additional 107 individuals with death certificates indicating a diagnosis of colorectal cancer. Finally, we used the last-known place of residence for each subject to match against state cancer registries for those states whose registries consented to participate in the study (accounting for 73.5 percent of the analytic cohort). Subjects residing in states with participating registries did not differ in any material way with respect to distribution of risk factors from subjects residing in states whose registries did not consent to participate. This procedure resulted in the identification of a further 66 colorectal cancer cases. Thus, the total number of cases in the analytic cohort over the follow-up period was 487.
Of these 487 colorectal cancer cases, 15.0 percent were located in the rectum, 23.0 percent in the distal colon, and 36.1 percent in the proximal colon; for 25.9 percent, information on the subsite location was unavailable. In terms of grade, 13.2 percent were grade I, 45.5 percent were grade II, 11.9 percent were grade III, 0.3 percent were grade IV, and 29.0 percent were undetermined or were lacking information on grade. More than 96 percent of the cancers on which histology information was available were adenocarcinomas.
Dietary assessment
With the 19871989 questionnaire, respondents completed a 62-item National Cancer Institute/Block food frequency questionnaire to assess usual dietary intake over the previous year. Detailed descriptions of this food frequency questionnaire and its validity have appeared elsewhere (2325). Software designed for this food frequency questionnaire yielded estimates of daily intakes for total energy, macronutrients, and micronutrients (25).
The food frequency questionnaire had 17 line items containing meat. Twelve of these (bacon, beef, fried chicken, fried fish, hamburger, ham or other lunch meat, hot dogs, liver, other chicken, other fish, pork, and sausage) contained primarily meat. The remaining five line items (beef stew, chili, salad, spaghetti, and vegetable soup) were mixed dishes containing meat, and these we apportioned so that only the meat component counted toward the total for meat consumption. Apportionment was based on US Department of Agriculture recipe information indicating grams of meat per 100 g of the mixed food. For meat subtypes, we defined red meat to include bacon, beef, hamburger, ham or other lunch meat, hot dogs, liver, pork, sausage, and the meat components of beef stew, chili, salad, spaghetti, and vegetable soup. White meat included fried chicken, fried fish, other chicken, and other fish, and we defined processed meat as bacon, ham or other lunch meat, hot dogs, and sausage.
Statistical analysis
We used Cox proportional hazards regression (PROC PHREG in SAS version 6.12 software; SAS Institute, Inc., Cary, North Carolina) with age as the underlying time metric to generate rate ratios and 95 percent confidence intervals for dietary fat and meat consumption both separately and in combination. All p values were two sided. To test for trend, we entered grams of meat or percentage of energy from fat into the model as continuous terms and reported the p value associated with the estimated beta coefficient.
We adjusted both meat and fat consumption for energy using the multivariate nutrient density method (grams of meat per 1,000 kcal per day or percentage of total energy from fat, both with total energy also in the model) as described by Willett (26). Other energy adjustment methods yielded similar results as the nutrient density models (data not shown).
We also considered additional variables for inclusion into our models as potential confounders. In evaluating these risk factors, we entered each separately by quintiles into the energy-adjusted models for total meat and total fat. We judged a change of greater than 10 percent in the parameter estimate from the energy-adjusted-only model as evidence for confounding. We tested the following variables in this manner: smoking (ever/never), education (through high school/more than high school), body mass index (weight (kg)/height (m)2), height, weekday physical activity index expressed in units of metabolic equivalent time (as defined by Ainsworth et al. (27)), alcohol, folate, vitamin D, calcium, fiber, fruits, vegetables, grains, and nonsteroidal antiinflammatory drug use (yes/no) that included aspirin, ibuprofen (Advil (Wyeth, Madison, New Jersey); Motrin (McNeill-PPC, Inc., Ft. Washington, Pennsylvania); Nuprin (Bristol-Myers Squibb Company, New York, New York)), Naprosyn (Hoffmann-La Roche, Inc., Nutley, New Jersey), and other pain-relieving drugs but excluded Tylenol (McNeill-PPC, Inc.). We defined women to be users of nonsteroidal antiinflammatory drugs if they had used these drugs at least once a week for at least 1 year. After performing all of these tests, we found that none of the factors listed above generated any material changes in either the meat or the fat model (data not shown) and thus did not include them in any of the final meat or fat models.
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RESULTS |
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Results from the proportional hazards regression analyses for meat and meat subtypes appear in table 4. For total meat, we saw no association between increased consumption and colorectal cancer, with the relative risk in the top quintile being 1.05 (95 percent confidence interval (CI): 0.80, 1.38) and the test for trend having a p value of 0.27.
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The analysis of total fat (table 5) indicated no increase in risk of colorectal cancer with increasing quintile of intake (rate ratio in quintile 5 compared with quintile 1 = 1.14, 95 percent CI: 0.86, 1.53; p for trend = 0.99). In the analysis of subtypes, neither saturated fat nor unsaturated fat had any association with colorectal cancer in either the model controlling only for total energy or the model controlling for total energy and total fat.
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DISCUSSION |
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We also investigated processed meat. Processed meat is high in fat, particularly saturated fat, and is rich in potentially carcinogenic agents. In this cohort, however, we saw no evidence that eating increasing amounts of processed meat conferred any additional risk. Although not high in absolute terms, the consumption of processed meat in the BCDDP cohort (mean = 12.1 g/day in a diet with mean energy = 1,279 kcal) was on a par with that observed among adult women in the United States generally (mean = 15 g/day in a 1,646-kcal diet) (28). Thus, although we cannot rule out the possibility that exceptionally high intakes of processed meat could increase risk, the results from this study suggest that, within the range of consumption typically observed in the United States, processed meat is not associated with colorectal cancer.
Consistent with almost all prior prospective studies of fat and colorectal cancer, this study showed no association between fat or any fat subtype and colorectal cancer. One of these studies did observe an increased risk of colorectal cancer with increasing total fat, fat from animal products, and monounsaturated fat (21), and a similarly designed cohort study found increased risk among men with higher fat intake for adenomas (13), but, interestingly, not for colorectal cancer (14). Outside of these two studies, however, the results have been largely null (1012, 1420).
One explanation for these null results could lie in the method of dietary assessment we used for this cohort. Others have highlighted the complications arising from measurement error in food frequency questionnaire-based dietary assessment in cohort studies, specifically that it could result in serious attenuation of risk estimates (29). The misclassification from this type of measurement error could account for the failure of this study to observe an association if the true effect of meat or fat (or one of the subtypes) is modest.
All food frequency questionnaire-based epidemiologic studies suffer from this important limitation, and the apparent brevity of the BCDDP food frequency questionnaire (62 items) may have exacerbated the problem. In reviewing the published literature on meat intake and colorectal cancer, however, we found that only seven of the 16 prospective studies used substantially larger food frequency questionnaires than we did in the BCDDP: three Harvard studies using a 127-item Willett questionnaire (13, 14, 21), two Iowa Womens Health Study analyses using the same Willett questionnaire (10, 30), one from the Netherlands cohort using its own 150-item food frequency questionnaire (15), and one from the Finnish Alpha-Tocopherol, Beta-Carotene Study cohort that used its own 276-item food frequency questionnaire (18). Interestingly, of these studies with longer food frequency questionnaires, only the three Harvard analyses found an increased risk with higher red meat intake, and only the Netherlands cohort observed a significantly increased risk with processed meat intake. There were no reports of an increased risk with total meat in any of the seven studies that used a longer food frequency questionnaire. Furthermore, despite its shorter length, the BCDDP food frequency questionnaire captured almost identical information as the Willett questionnaire with respect to meat intake. This similarity does not eliminate from the BCDDP study the general problem of possible relative risk attenuation due to misclassification in food frequency questionnaire-based epidemiologic research, but it does suggest that any differences in results between the earlier studies and this one are not likely due to differences in the dietary assessment instruments.
An alternative explanation for the null results may lie in the inability of our dietary instrument to classify people according to exposure to heterocyclic amines. Unfortunately, we did not have direct measures of cooking practices in this cohort, and therefore we could not isolate exposure to these compounds in our analyses. We did attempt to address this question by devising a proxy variable for exposure to heterocyclic amines, but we did not observe any association between increased exposure and colorectal cancer (data not shown). The possibility of misclassification using this proxy variable was substantial, however, and thus a null result does not exclude a true association between heterocyclic amines and colorectal cancer in this cohort. A study with more-precise estimates of exposure to heterocyclic amines might identify an association with meat that we were unable to find in the BCDDP.
The lack of association we observed between meat and colorectal cancer stands in contrast to several (1216, 21, 31), but not all (10, 18, 20, 30, 3236), published results from prospective studies of this dietary risk factor. However, it is important to recognize that, for the vast majority of the prior investigations that did observe an association, the notable associations have not been between total meat and colorectal cancer, but between either red meat or processed meat and either colorectal cancer or adenoma. Among the 16 published studies, there were only two exceptions. The Seventh-day Adventist cohort did observe an elevated risk for total meat, but the "high" exposure group was defined as eating only one or more servings of total meat per week (31). The Finnish Mobile Clinic Health Examination Survey cohort study showed increased risk for poultry, but the comparison was merely between those who did and those who did not report eating this type of meat (16).
The evidence from individual prospective studies to support an association with total meat, and even for red or processed meat, is somewhat less than consistent or persuasive. Definitions or classifications for the subcategories of "red" or "processed" meat, however, are not necessarily straightforward or clearly delineated. The variation in results between those studies that observe subtype associations and those that do not could be due to differences in the cohort populations, measurement error, chance, and so on, but they could also depend critically on how the authors defined their subcategories. The inconsistencies in these results suggest that thoughtful consideration of exactly how we define "red" or "processed" meat could be an important next step in bringing into higher resolution a picture of exactly what type of meat, if any, has an impact on risk of colorectal neoplasia.
Finally, a recent meta-analysis of the data from all published cohort studies of meat and colorectal cancer provided an interesting quantitative assessment of these results. In this paper, Sandhu et al. (37) reported a pooled summary odds ratio of 1.21 (95 percent CI: 1.10, 1.33) for a 100-g/day increase in total meat consumption and of 1.30 (95 percent CI: 1.13, 1.49) for a 100-g/day increase in red meat. Norat et al. (38) also performed a meta-analysis of cohort studies and reported similar findings. Thus, although individual studies typically did not produce notable associations between total meat and colorectal cancer, and only occasionally did so for red meat and colorectal cancer, taken as a whole, the modest positive associations from these studies became statistically significant. If the true association between total meat or red meat and colorectal cancer is of this magnitude (i.e., 1.11.3), the BCDDP cohort did not have adequate power to observe it (lower limit for detectable relative risks was 1.3 given 80 percent power and alpha = 0.05). On the other hand, the confidence intervals for the rate ratios we calculated in the BCDDP cohort include both of these point estimates, suggesting that the findings from our study were not inconsistent with the results from these meta-analyses.
Case-control studies do differ somewhat in their results from the cohort studies described above. In the meta-analysis by Norat et al. (38), the authors reported a summary relative risk of 1.18 (95 percent CI: 0.99, 1.40) for all case-control studies that considered total meat intake, but for red meat and processed meat, the summary relative risks were 1.35 (95 percent CI: 1.21, 1.51) and 1.31 (95 percent CI: 1.13, 1.51), respectively, suggesting a modest but statistically significant relation between the intakes of these types of meat and the risk of colorectal cancer. Case-control studies, however, are subject to specific types of recall bias and selection bias that do not affect prospective studies, and thus they suffer important interpretive limitations relative to cohort studies.
In summary, our results provide no evidence to support an association between total meat, total fat, or any of their subtypes and colorectal cancer, but we cannot rule out the possibility of a real yet modest association of the magnitude described by Sandhu et al. (37) in their meta-analysis of prospective studies of meat and colorectal cancer.
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ACKNOWLEDGMENTS |
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NOTES |
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REFERENCES |
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