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Prospective Study of Dietary Fiber, Whole Grain Foods, and Small Intestinal Cancer

      Background & Aims: Although a number of epidemiologic studies have found dietary fiber and whole grains to be inversely associated with colorectal cancer incidence, studies of dietary and other risk factors for small intestinal cancer have been sparse and all of a case-control design. We conducted a prospective cohort study to determine the relationship between intake of dietary fiber/whole grains and the incidence of small intestinal cancer. Methods: We analyzed dietary data collected in 1995 and 1996 from 293,703 men and 198,618 women in the National Institutes of Health–AARP Diet and Health Study. We used multivariate Cox proportional hazards models to estimate relative risk (RR) and 2-sided 95% confidence intervals (CIs) for quintiles of dietary fiber and whole grain intake. Results: Through 2003, 165 individuals developed small intestinal cancers. Dietary fiber/whole grain intake was generally associated with a lower risk of small intestinal cancer. The multivariate RRs (95% CIs; 5th vs 1st intake quintile) were 0.79 (0.43–1.44; P trend, .41) for total dietary fiber, 0.51 (0.29–0.89; P trend, .01) for fiber from grains, and 0.59 (0.33–1.05; P trend, .06) for whole grain foods. Conclusions: Intake of fiber from grains and whole-grain foods was inversely associated with small intestinal cancer incidence; the RR values were consistent with those from the same dietary factors for large bowel cancer in this cohort. In conjunction with the anatomic and physiologic commonalities of the large and small bowel, as well as the mutually increased risks for second cancer for both organs, grain fiber and whole grain foods seem to protect against lower gastrointestinal cancers.

      Abbreviations used in this paper:

      AARP (American Association of Retired Persons), CI (confidence interval), FFQ (Food-Frequency Questionnaire), RR (relative risk)
      Cancer of the small intestine remains rare; incidence rates in the United States among men and women, respectively, are 2.2 and 1.5 per 100,000.
      • Ries L.A.G.
      • Melbert D.
      • Krapcho M.
      • et al.
      SEER Cancer statistics review, 1975–2004.
      In contrast, the comparable figures for colorectal cancer are 61 and 45 per 100,000. This enormous incidence disparity occurs despite the fact that the small intestine comprises 75% of the human alimentary tract and 90% of its mucosal area.
      • Beebe-Dimmer J.L.
      • Schottenfeld D.
      Cancers of the small intestine.
      A number of epidemiologic studies have found dietary fiber, and more recently whole grains, to be inversely associated with colorectal cancer, although the evidence is inconsistent.
      • Bingham S.A.
      • Day N.E.
      • Luben R.
      • et al.
      Dietary fibre in food and protection against colorectal cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC): an observational study.
      • Park Y.
      • Hunter D.J.
      • Spiegelman D.
      • et al.
      Dietary fiber intake and risk of colorectal cancer: a pooled analysis of prospective cohort studies.
      • Jacobs D.R.
      • Marquart L.
      • Slavin J.
      • et al.
      Whole-grain intake and cancer: an expanded review and meta-analysis.
      • Larsson S.C.
      • Giovannucci E.
      • Bergkvist L.
      • et al.
      Whole grain consumption and risk of colorectal cancer: a population-based cohort of 60,000 women.
      Studies of dietary and other risk factors for small intestinal cancer are sparse and all have been of the case-control design.
      • Negri E.
      • Bosetti C.
      • La Vecchia C.
      • et al.
      Risk factors for adenocarcinoma of the small intestine.
      • Chow W.H.
      • Linet M.S.
      • McLaughlin J.K.
      • et al.
      Risk factors for small intestine cancer.
      • Wu A.H.
      • Yu M.C.
      • Mack T.M.
      Smoking, alcohol use, dietary factors and risk of small intestinal adenocarcinoma.
      • Chen C.C.
      • Neugut A.I.
      • Rotterdam H.
      Risk factors for adenocarcinomas and malignant carcinoids of the small intestine: preliminary findings.
      None of these previous studies has focused on fiber and whole grain intake. Prospective cohort studies of the role of dietary factors in small intestinal cancer are desirable—the possibility of recall bias is largely precluded
      • Willett W.
      Nutritional epidemiology.
      —but need to be large given the relative rarity of the disease.

      Methods

      The National Institutes of Health–AARP Diet and Health Study has been described previously.
      • Schatzkin A.
      • Subar A.F.
      • Thompson F.E.
      Oxford University Press
      Design and serendipity in establishing a large cohort with wide dietary intake distributions: the National Institutes of Health-American Association of Retired Persons Diet and Health Study.
      • Schatzkin A.
      • Mouw T.
      • Park Y.
      Oxford University Press
      Dietary fiber and whole-grain consumption in relation to colorectal cancer in the NIH–AARP Diet and Health Study.
      Of the 567,169 men and women AARP members who were 50–71 years old and returned satisfactorily completed questionnaires in 1995–1996, we excluded individuals who provided duplicate questionnaires (n = 179), indicated they were proxies for the intended respondents (n = 15,760), requested to be withdrawn (n = 6), had moved out of the study area or died at baseline (n = 617), had prevalent cancer except nonmelanoma skin cancer at baseline (n = 51,193), reported end-stage renal disease at baseline (n = 997), or had extreme intakes of fiber or total energy (values >2 times the interquartile range of gender-specific Box-Cox log-transformed intake of total energy or fiber, n = 6,096). Our analytic cohort comprised 293,703 men and 198,618 women.

       Dietary Assessment

      At baseline, we assessed diet with a self-administered 124-item food-frequency questionnaire (FFQ) and also collected information on lifestyle and medical history. Participants were asked to report their usual frequency of intake and portion size over the last 12 months, using 10 predefined frequency categories ranging from “never” to “6+ times per day” for beverages, from “never” to “2+ times per day” for solid foods, and 3 categories of portion size. The food items, portion sizes, and nutrient database were based on Subar et al's method
      • Subar A.F.
      • Midthune D.
      • Kulldorff M.
      Oxford University Press
      Evaluation of alternative approaches to assign nutrient values to food groups in food frequency questionnaires.
      using the United States Department of Agriculture's 1994–1996 Continuing Survey of Food Intake by Individuals.
      • Tippett K.S.
      • Cypel Y.S.
      Design and operation: the continuing survey of food intakes by individuals and diet and health knowledge survey, 1994–1996. Continuing survey of food intakes by individuals, nationwide food surveys.
      The nutrient database for dietary fiber was informed by the Association of Official Analytical Chemists method.
      • Prosky L.
      • Asp N.G.
      • Furda I.
      • et al.
      Determination of total dietary fiber in foods and food products: collaborative study.
      In addition, food groups and their serving sizes were defined by the Pyramid Servings Database corresponding to the 1994–1996 Continuing Survey of Food Intake by Individuals, which utilizes a recipe file to disaggregate food mixtures into their component ingredients and assigns them to food groups. One serving of whole grains was defined based on standard portion sizes developed by the US Department of Agriculture, such as 1 slice of whole grain bread, 1 cup of ready-to-eat whole grain cereal, or 1/2 cup of cooked whole grains.
      US Department of Agriculture
      The food guide pyramid.
      The FFQ used in the study was validated using 2 nonconsecutive 24-hour dietary recalls in 1,953 participants. The energy-adjusted correlation coefficients for dietary fiber intake assessed by FFQ and two 24-hour recalls was 0.72 in men and 0.66 in women.
      • Thompson F.E.
      • Kipnis V.
      • Midthune D.
      • et al.
      Performance of a food-frequency questionnaire in the US NIH–AARP (National Institutes of Health–American Association of Retired Persons) Diet and Health Study.

       Case Ascertainment

      We identified cancer cases through probabilistic linkage with 11 state cancer registry databases through December 31, 2003.
      • Michaud D.S.
      • Midthune D.
      • Hermansen S.
      • et al.
      Comparison of cancer registry case ascertainment with SEER estimates and self-reporting in a subset of the NIH–AARP Diet and Health Study.
      Small intestinal cancer was defined as a first primary malignancy with the International Classification of Diseases for Oncology, 3rd edition (ICD-O) codes C170–C179. Information on small intestinal cancer tumor site and histology was also obtained through linkage with state cancer registries. We ascertained vital status through annual linkage of the cohort to the Social Security Administration Death Master File in the United States, follow-up searches of the National Death Index Plus for participants who matched to the Social Security Administration Death Master File, cancer registry linkage, questionnaire responses, and responses to other mailings.

       Statistical Analysis

      We used multivariate Cox proportional hazards models, after verifying that the proportional hazards assumption was met, to estimate relative risks (RRs) and 2-sided 95% confidence intervals (CIs) for quintiles of dietary fiber and whole grain intakes; age was the underlying time metric.
      • Cox D.R.
      Regression models and life-tables.
      We calculated person-years of follow-up time from the date of the baseline questionnaire until the date of cancer diagnosis, death, moving out of the registry areas, or end of follow-up, whichever occurred first. Dietary fiber intake was energy adjusted using a residual method
      • Willett W.
      • Stampfer M.J.
      Total energy intake: implications for epidemiologic analyses.
      and whole grain intake was expressed as servings per 1,000 kcal of total energy.
      The study was approved by the National Cancer Institute Special Studies Institutional Review Board.

      Results

      During an average of 7 years of follow-up, we identified 165 small intestinal cancers (51 in duodenum, 70 in jejunum or ileum, and 44 in overlapping or unknown sites; 60 adenocarcinoma, 80 carcinoids, and 25 others). The 10th and 90th percentile values were 12 and 28 g/d for dietary fiber and 0.2 and 1.3 servings/1,000 kcal for whole grains. The correlation between intakes of dietary fiber and whole grains was 0.6. The participants who consumed more fiber or whole grains were more likely to be educated, slightly less overweight, nonsmokers, more physically active, and consumers of less red meat and total fat (Table 1).
      Table 1Selected Characteristics of Study Participants by Quintiles of Dietary Fiber and Whole Grain Intakes
      Total populationQuintiles of dietary fiber intakeQuintiles of whole grain intake
      Q1Q2Q3Q4Q5Q1Q2Q3Q4Q5
      Participants (n)492,32198,46498,46498,46598,46498,46498,46498,46598,46498,46498,464
      Dietary fiber (g/d)
      Mean values.
      19.511161922301517192124
      Whole grain (servings/1,000 kcal)
      Mean values.
      0.70.40.50.70.81.00.20.40.60.81.4
      Age (y)6261626262636262626263
      Men (%)6045546066736359585960
      College/post college (%)6254606265685661636565
      BMI (kg/m2)27.127.327.327.327.026.527.327.427.227.026.6
      Current smoking (%)122414107520131187
      Physical activity, ≥3 times/week (%)4631394652623743475053
      Current menopausal hormone therapy (%)4441454546453943454747
      Family history of cancer (yes, %)4948494949484748494949
      Red meat (g/1,000 kcal)
      Mean values.
      3542393632244138353227
      Total fat (% energy/d)
      Mean values.
      3033323129263232313028
      Energy (kcal/d)
      Mean values.
      1,8311,7581,8221,8611,8711,8441,9701,9061,8531,7741,654
      low asterisk Mean values.
      Total dietary fiber was significantly associated with a lower risk of small intestinal cancer in the age- and gender-adjusted model (RR for the highest vs the lowest quintile [RRQ5vsQ1], 0.57; 95% CI, 0.34–0.97; P trend, .02; Table 2). After adjustment for other risk factors, however, the association was attenuated and no longer statistically significant (multivariate RRQ5vsQ1, 0.79; 95% CI, 0.43–1.44; P trend, .41). Fiber from grains was significantly inversely associated with small intestinal cancer (multivariate RRQ5vsQ1, 0.51; 95% CI, 0.29–0.89; P trend, .01). The associations of fiber from grains did not differ by gender. For a 5 g/d increment of fiber from grains, the multivariate RR was 0.76 (95% CI, 0.56–1.05) in men (111 cases) and 0.60 (95% CI, 0.32–1.12) in women (54 cases). The association for fiber from beans was similar to that for fiber from grains, although the trend was not significant. Neither fruit nor vegetable fiber was associated with this malignancy. Intake of whole grains was marginally inversely related to small intestinal cancer (multivariate RRQ5vsQ1, 0.59; 95% CI, 0.33–1.05; P trend, .06). After exclusion of small intestinal cancer cases diagnosed during the first 2 years of follow-up, the results were essentially unchanged. The observed associations with small intestinal cancer did not differ by cigarette smoking status (never vs former vs current): P values for interactions were .54, .74, and .59, respectively for total dietary fiber, fiber from grains, and intake of whole grains.
      Table 2Relative Risks and 95% Confidence Intervals of Small Intestinal Cancer by Quintiles of Dietary Fiber and Whole Grain Intakes
      QuintileP trend
      Linear trends were tested by including in regression models variables constructed from the medians of the intake quintiles.
      12345
      Total fiber (g/d)
      Intake ranges.
      <1414–<1717–<2020–<24.5≥24.5
       Cases/person years35/673,84537/676,59935/676,11333/676,01625/677,395
       Age, gender adjusted1.000.98 (0.61–1.55)0.88 (0.55–1.41)0.79 (0.49–1.28)0.57 (0.34–0.97).02
       Multivariate
      Adjusted for age, gender, education (less than high school, high school graduate, and college graduate/postgraduate), family history of cancer (no, yes), smoking (never, past, current), body mass index (continuous), physical activity (never/rarely, ≤3 times/month, 1–2, and ≥3 times/week), menopausal hormone therapy use in women (never, past, and current), and intakes of red meat (quintiles), total fat (quintiles), and total energy (continuous). In analyses of total fiber and whole grains, these variables were mutually adjusted one for the other.
      1.000.99 (0.62–1.60)0.95 (0.57–1.56)0.92 (0.54–1.56)0.79 (0.43–1.44).41
      Fiber from grains (g/d)<3.73.7–<55–<6.46.4–<8.4≥8.4
       Cases/person years34/675,07741/677,59932/676,86137/675,22121/675,209
       Age, gender adjusted1.001.13 (0.72–1.78)0.83 (0.51–1.36)0.92 (0.52–1.48)0.49 (0.28–0.85).01
       Multivariate
      Adjusted for age, gender, education (less than high school, high school graduate, and college graduate/postgraduate), family history of cancer (no, yes), smoking (never, past, current), body mass index (continuous), physical activity (never/rarely, ≤3 times/month, 1–2, and ≥3 times/week), menopausal hormone therapy use in women (never, past, and current), and intakes of red meat (quintiles), total fat (quintiles), and total energy (continuous). In analyses of total fiber and whole grains, these variables were mutually adjusted one for the other.
      1.001.10 (0.70–1.74)0.81 (0.50–1.33)0.91 (0.56–1.47)0.51 (0.29–0.89).01
      Fiber from fruits (g/d)<1.61.6–<2.92.9–<4.24.2–<6.3≥6.3
       Cases/person years30/662,13639/675,44835/675,97931/678,31930/678,085
       Age, gender adjusted1.001.23 (0.76–1.97)1.07 (0.66–1.74)0.93 (0.56–1.53)0.88 (0.53–1.46).29
       Multivariate
      Adjusted for age, gender, education (less than high school, high school graduate, and college graduate/postgraduate), family history of cancer (no, yes), smoking (never, past, current), body mass index (continuous), physical activity (never/rarely, ≤3 times/month, 1–2, and ≥3 times/week), menopausal hormone therapy use in women (never, past, and current), and intakes of red meat (quintiles), total fat (quintiles), and total energy (continuous). In analyses of total fiber and whole grains, these variables were mutually adjusted one for the other.
      1.001.21 (0.75–1.95)1.08 (0.65–1.78)0.97 (0.57–1.64)1.03 (0.60–1.78).76
      Fiber from vegetables (g/d)<6.56.5–<8.78.7–<1111–<14.2≥14.2
       Cases/person years33/662,24746/675,01225/677,41529/677,28832/678,005
       Age, gender adjusted1.001.35 (0.86–2.11)0.71 (0.42–1.20)0.81 (0.49–1.34)0.88 (0.54–1.44).21
       Multivariate
      Adjusted for age, gender, education (less than high school, high school graduate, and college graduate/postgraduate), family history of cancer (no, yes), smoking (never, past, current), body mass index (continuous), physical activity (never/rarely, ≤3 times/month, 1–2, and ≥3 times/week), menopausal hormone therapy use in women (never, past, and current), and intakes of red meat (quintiles), total fat (quintiles), and total energy (continuous). In analyses of total fiber and whole grains, these variables were mutually adjusted one for the other.
      1.001.31 (0.83–2.05)0.70 (0.41–1.18)0.82 (0.49–1.37)0.99 (0.60–1.66).50
      Fiber from beans (g/d)<0.70.7–<1.31.3–<1.91.9–<3.0≥3.0
       Cases/person years45/676,90827/677,76025/675,72742/664,66026/674,912
       Age, gender adjusted1.000.59 (0.36–0.93)0.52 (0.32–0.85)0.84 (0.55–1.29)0.51 (0.31–0.84).09
       Multivariate
      Adjusted for age, gender, education (less than high school, high school graduate, and college graduate/postgraduate), family history of cancer (no, yes), smoking (never, past, current), body mass index (continuous), physical activity (never/rarely, ≤3 times/month, 1–2, and ≥3 times/week), menopausal hormone therapy use in women (never, past, and current), and intakes of red meat (quintiles), total fat (quintiles), and total energy (continuous). In analyses of total fiber and whole grains, these variables were mutually adjusted one for the other.
      1.000.54 (0.34–0.88)0.48 (0.29–0.78)0.77 (0.50–1.19)0.49 (0.30–0.81).08
      Whole grain (servings/1,000 kcal)<0.30.3–<0.50.5–<0.70.7–<1.0≥1.0
       Cases/person years39/670,28934/675,90241/677,44829/677,89722/678,431
       Age, gender adjusted1.000.86 (0.54–1.36)1.01 (0.65–1.57)0.70 (0.43–1.13)0.52 (0.31–0.88).01
       Multivariate
      Adjusted for age, gender, education (less than high school, high school graduate, and college graduate/postgraduate), family history of cancer (no, yes), smoking (never, past, current), body mass index (continuous), physical activity (never/rarely, ≤3 times/month, 1–2, and ≥3 times/week), menopausal hormone therapy use in women (never, past, and current), and intakes of red meat (quintiles), total fat (quintiles), and total energy (continuous). In analyses of total fiber and whole grains, these variables were mutually adjusted one for the other.
      1.000.86 (0.54–1.37)1.03 (0.65–1.63)0.73 (0.44–1.22)0.59 (0.33–1.05).06
      low asterisk Intake ranges.
      Adjusted for age, gender, education (less than high school, high school graduate, and college graduate/postgraduate), family history of cancer (no, yes), smoking (never, past, current), body mass index (continuous), physical activity (never/rarely, ≤3 times/month, 1–2, and ≥3 times/week), menopausal hormone therapy use in women (never, past, and current), and intakes of red meat (quintiles), total fat (quintiles), and total energy (continuous). In analyses of total fiber and whole grains, these variables were mutually adjusted one for the other.
      Linear trends were tested by including in regression models variables constructed from the medians of the intake quintiles.
      Associations for total dietary fiber, fiber from specific sources, and whole grain foods were not significantly different among small intestinal subsites (Table 3). The inverse associations for fiber from grains, fiber from beans, and whole grain foods did not differ significantly between adenocarcinomas and carcinoid tumors. The associations for fiber from fruits (P = .03) and fiber from vegetables (P = .02) did differ according to histotype. The numbers of anatomic subsite- and histology-specific cases were small.
      Table 3Multivariate Relative Risks
      The relative risk is for an increment of 10 g/d of total fiber, 5 g/d of fiber from grains, fruits, and vegetables, 2 g/d of fiber from beans and 1 serving/1,000 kcal of whole grains. The models adjusted for age, gender, education, family history of cancer, smoking, body mass index, physical activity, hormone replacement therapy use in women, and intakes of red meat, total fat, and total energy. Total fiber and whole grains were mutually adjusted. Results were essentially unchanged when the jejunum was combined with the duodenum rather than the ileum.
      and 95% Confidence Intervals of Subtypes of Small Intestinal Cancer by Sites and Histology
      TotalSubsite
      Tumor subsites were defined by International Classification of Diseases for Oncology, 3rd ed. (ICD-O-3) codes: Duodenum (C170, n = 51), jejunum (C171, n = 21), and ileum (C172, n = 49).
      ,
      Differences in results among tumor sites and histologic types were evaluated with the Wald test.
      Histologic type
      Adenocarcinomas were tumors with histologic codes 8140, 8144, 8145, 8210, 8260, 8261, 8263, 8480, 8481, and 8490 and carcinoids were tumors with histologic codes 8240, 8241, 8246, and 8249.
      ,
      Differences in results among tumor sites and histologic types were evaluated with the Wald test.
      Duodenum (n = 51)Jejunum/ileum (n = 70)Adenocarcinomas (n = 60)Carcinoids (n = 80)
      Total fiber0.91 (0.68–1.23)0.68 (0.39–1.19)0.81 (0.49–1.33)0.65 (0.38–1.12)1.19 (0.79–1.79)
      Fiber from grains0.73 (0.55–0.97)0.78 (0.31–1.42)0.74 (0.47–1.16)0.78 (0.49–1.10)0.62 (0.40–0.96)
      Fiber from fruits1.01 (0.76–1.34)0.75 (0.43–1.30)0.99 (0.63–1.56)0.62 (0.35–1.10)1.34 (0.94–1.91)
      P < .05.
      Fiber from vegetables1.02 (0.87–1.21)0.87 (0.64–1.20)0.92 (0.69–1.22)0.78 (0.56–1.07)1.25 (1.01–1.55)
      P < .05.
      Fiber from beans0.81 (0.66–0.99)0.72 (0.48–1.08)0.86 (0.64–1.17)0.81 (0.58–1.13)0.76 (0.56–1.03)
      Whole grains0.67 (0.43–1.03)1.04 (0.52–2.09)0.54 (0.27–1.10)0.77 (0.38–1.57)0.53 (0.28–1.01)
      low asterisk The relative risk is for an increment of 10 g/d of total fiber, 5 g/d of fiber from grains, fruits, and vegetables, 2 g/d of fiber from beans and 1 serving/1,000 kcal of whole grains. The models adjusted for age, gender, education, family history of cancer, smoking, body mass index, physical activity, hormone replacement therapy use in women, and intakes of red meat, total fat, and total energy. Total fiber and whole grains were mutually adjusted. Results were essentially unchanged when the jejunum was combined with the duodenum rather than the ileum.
      Tumor subsites were defined by International Classification of Diseases for Oncology, 3rd ed. (ICD-O-3) codes: Duodenum (C170, n = 51), jejunum (C171, n = 21), and ileum (C172, n = 49).
      Adenocarcinomas were tumors with histologic codes 8140, 8144, 8145, 8210, 8260, 8261, 8263, 8480, 8481, and 8490 and carcinoids were tumors with histologic codes 8240, 8241, 8246, and 8249.
      § Differences in results among tumor sites and histologic types were evaluated with the Wald test.
      low asterisklow asterisk P < .05.

      Discussion

      Intakes of fiber from grains and whole grain foods were inversely associated with small as well as large intestinal cancers
      • Schatzkin A.
      • Mouw T.
      • Park Y.
      Oxford University Press
      Dietary fiber and whole-grain consumption in relation to colorectal cancer in the NIH–AARP Diet and Health Study.
      in this cohort. No other prospective study has examined these dietary factors in relation to small intestinal cancer. Our previous analysis of fiber and whole grains in relation to colorectal cancer in this cohort yielded similar results, namely, inverse associations for intakes of fiber from grains and whole grain foods.
      • Schatzkin A.
      • Mouw T.
      • Park Y.
      Oxford University Press
      Dietary fiber and whole-grain consumption in relation to colorectal cancer in the NIH–AARP Diet and Health Study.
      Grain fiber and whole grain foods could affect pathophysiologic processes common to carcinogenesis within both the small and large intestines. Investigators have proposed several mechanisms by which dietary fiber can protect against colorectal cancer. These include (a) stool bulking; (b) decreased transit time (both a and b result in less contact between potential carcinogens and mucosal surface); (c) bile acid and carcinogen binding; and (d) short chain fatty acid, especially butyrate, production via fermentation (butyrate has anticarcinogenic properties
      • Young G.P.
      • Hu Y.
      • Le Leu R.K.
      • et al.
      Dietary fibre and colorectal cancer: a model for environment—gene interactions.
      ). Moreover, whole grain components other than fiber—vitamins (including B vitamins), minerals, phenols, and phytoestrogens—could affect intestinal (both small and large) carcinogenesis.
      • Schatzkin A.
      • Mouw T.
      • Park Y.
      Oxford University Press
      Dietary fiber and whole-grain consumption in relation to colorectal cancer in the NIH–AARP Diet and Health Study.
      Some of these mechanisms, however—stool bulking and fermentation, for example—are not likely relevant to carcinogenesis in the small intestine. It is also conceivable that grain fiber and whole grains protect against cancer in the small intestine via processes not operative in the large bowel.
      We found no statistically significant difference in the relations between grain fiber/whole grain foods and small intestinal cancer according to histology. We recognize, however, that the limited number of cases within each histologic category makes it difficult to rule out such differences. If the inverse relation and its constancy across histotypes is confirmed, that would suggest that the cancer-protective processes engendered by grain fiber and whole grain foods operate similarly for columnar and enteroendocrine cells in the small intestinal epithelium.
      The prospective nature of this study is a strength, but even in a cohort of this size the relatively small number of cases through up to 8 years of follow-up remains a limitation. This is particularly true for anatomic subsite- and histology-specific analyses. It would be desirable to confirm our findings in other large cohorts, pooling projects, or consortial efforts, especially those studies attempting to reduce measurement error by incorporating more intensive dietary assessment instruments such as multiple recalls or records. Excluding the first 2 years of follow-up did not alter the inverse grain fiber and whole grain associations, which provides some evidence that these findings were not due to reverse causation, that is, the effect of preclinical disease on diet. As with any observational study, even our careful adjustment for behavioral and socioeconomic covariates cannot entirely rule out confounding factors associated with grain fiber or whole grain foods as well as small intestinal cancer.
      The small and large intestines have substantial anatomic and physiologic commonalities. Moreover, persons with a cancer at 1 of these 2 sites have an increased risk of malignancy at the other.
      • Curtis R.E.
      • Freedman D.M.
      • Ron E.
      New malignancies among cancer survivors: SEER cancer registries, 1973–2000.
      The similar protective associations in our cohort for grain fiber and whole grain foods vis-à-vis small as well as large intestinal cancer support a causal role for these dietary factors in both organs. The discovery of common causes for small and large intestinal cancers, coupled with greater insight into the factors conferring relative resistance to malignant change in the small bowel,
      • Neugut A.I.
      • Jacobson J.S.
      • Suh S.
      • et al.
      The epidemiology of cancer of the small bowel.
      can help to clarify the nature of—and suggest preventive strategies for—lower gastrointestinal carcinogenesis.

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