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Dietary Fiber Intake Reduces Risk for Gastric Cancer: A Meta-analysis

  • Author Footnotes
    ∗ Authors share co-first authorship.
    Zhizhong Zhang
    Footnotes
    ∗ Authors share co-first authorship.
    Affiliations
    Department of Neurology, Jinling Hospital, Nanjing University School of Medicine, Jiangsu Province, China
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  • Author Footnotes
    ∗ Authors share co-first authorship.
    Gelin Xu
    Footnotes
    ∗ Authors share co-first authorship.
    Affiliations
    Department of Neurology, Jinling Hospital, Nanjing University School of Medicine, Jiangsu Province, China
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  • Minmin Ma
    Affiliations
    Department of Neurology, Jinling Hospital, Nanjing University School of Medicine, Jiangsu Province, China
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  • Jie Yang
    Affiliations
    Department of Neurology, Nanjing First Hospital, Nanjing, China
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  • Xinfeng Liu
    Correspondence
    Reprint requests Address requests for reprints to: Xinfeng Liu, MD, PhD, Department of Neurology, Jinling Hospital, Nanjing University School of Medicine, 305 East Zhongshan Road, Nanjing 210002, Jiangsu Province, China. fax: (86) 25-84664563.
    Affiliations
    Department of Neurology, Jinling Hospital, Nanjing University School of Medicine, Jiangsu Province, China
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  • Author Footnotes
    ∗ Authors share co-first authorship.

      Background & Aims

      The association between dietary fiber intake and gastric cancer risk has been investigated by many studies, with inconclusive results. We conducted a meta-analysis of case-control and cohort studies to analyze this association.

      Methods

      Relevant studies were identified by searching PubMed and Embase through October 2012. We analyzed 21 articles, which included 580,064 subjects. Random-effects models were used to estimate summary relative risks. Dose-response, subgroup, sensitivity, meta-regression, and publication bias analyses were performed.

      Results

      The summary odds ratios of gastric cancer for the highest, compared with the lowest, dietary fiber intake was 0.58 (95% confidence interval, 0.49−0.67) with significant heterogeneity among studies (P < .001, I2 = 62.2%). Stratified analysis for study design, geographic area, source and type of fiber, Lauren’s classification, publication year, sample size, and quality score of study yielded consistent results. Dose-response analysis associated a 10-g/day increment in fiber intake with a significant (44%) reduction in gastric cancer risk. Sensitivity analysis restricted to studies with control for conventional risk factors produced similar results, and omission of any single study had little effect on the combined risk estimate.

      Conclusions

      In a meta-analysis, we show that dietary fiber intake is associated inversely with gastric cancer risk; the effect probably is independent of conventional risk factors. The direction of the protective association of dietary fiber was consistent among all studies, but the absolute magnitude was less certain because of heterogeneity among the studies. Further studies therefore are required to establish this association.

      Keywords

      Abbreviations used in this paper:

      CI (confidence interval), OR (odds ratio), RR (relative risk)
      Gastric cancer is the third most common cause of cancer-related deaths in males and the fifth most common in females worldwide, which is an enormous public health problem.
      • Jemal A.
      • Bray F.
      • Center M.M.
      • et al.
      Global cancer statistics.
      Although the overall incidence is decreasing, gastric cancer remains a serious fatal cancer in the United States, and the survival rate has not improved significantly over the past 2 decades.
      • Lau M.
      • Le A.
      • El-Serag H.B.
      Noncardia gastric adenocarcinoma remains an important and deadly cancer in the United States: secular trends in incidence and survival.
      Thus, there is an urgent need to develop primary prevention strategies for this disease.
      Dietary factors are believed to play an important role in the prevention of gastric cancer, among which dietary fiber has received considerable interest.
      • Gonzalez C.A.
      • Riboli E.
      Diet and cancer prevention: contributions from the European Prospective Investigation into Cancer and Nutrition (EPIC) study.
      In vitro studies suggest that dietary fiber may prevent gastric cancer by acting as a nitrite scavenger, potentially countering the carcinogenic effects of N-nitroso compounds.
      • Moller M.E.
      • Dahl R.
      • Bockman O.C.
      A possible role of the dietary fibre product, wheat bran, as a nitrite scavenger.
      Since the 1980s, many epidemiologic studies have been reported regarding the association between dietary fiber intake and gastric cancer risk, but the results are conflicting. Thus, we performed a meta-analysis of case-control and cohort studies with the following objectives: (1) to summarize the epidemiologic evidence on the association between dietary fiber intake and the risk of gastric cancer; (2) to examine the dietary fiber intake in relation to gastric cancer risk according to study designs, characteristics of study populations, sources and types of fiber, and gastric cancer subtypes; and (3) to evaluate the dose-response relationship between dietary fiber intake and the risk of gastric cancer.

      Materials and Methods

       Search Strategy

      A comprehensive, computerized literature search was performed in PubMed and Embase through October 2012 using the following key words: (dietary fiber) AND (gastric cancer OR stomach cancer). Then, the reference sections of identified publications were searched for further potentially relevant articles. Our study was designed, conducted, and reported according to the standards of quality for reporting meta-analyses.
      • Stroup D.F.
      • Berlin J.A.
      • Morton S.C.
      • et al.
      Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group.

       Study Selection

      Studies included in our meta-analysis had to meet the following criteria: (1) used a case-control or cohort design; (2) the exposure of interest was dietary fiber intake; (3) provided data of gastric cancer occurrence; (4) reported the odds ratio (OR) or relative risk (RR), and the corresponding 95% confidence interval (CI). Three authors (Z.Z., G.X., and X.L.) independently assessed the retrieved studies according to the prespecified criteria and discrepancies were resolved by discussion.

       Data Extraction and Quality Assessment

      For each study, the following information was collected: the last name of the first author, publication year, study design and location, age, sex, study period, sample size, fiber intake assessment and comparison method, OR/RR from the most fully adjusted model for the highest compared with the lowest dietary fiber intake and the corresponding 95% CI, and adjustment for confounders in a multivariate analysis. Data were extracted independently by 2 authors (Z.Z. and G.X.) and then cross-checked. If more than one article was published using the same population, we selected the most recent or most informative report.
      To assess the study quality, an evaluation system based on the Newcastle–Ottawa Scale
      • Stang A.
      Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses.
      was adopted. The included studies were judged on 3 aspects: the selection of study populations, the comparability of the populations, and ascertainment of exposure (including the dietary change) or the outcomes of interest for case-control or cohort studies, respectively. The full score was 10 stars, and a high-quality study was defined as a study with 7 or more stars.

       Statistical Analysis

      ORs or RRs were extracted from the included studies, and their standard errors were calculated from the respective CIs. We quantified the relationship between the dietary fiber intake and the risk of gastric cancer by a random-effects model, which incorporates both within- and between-study variability. The heterogeneity among studies was assessed with the Q and I2 statistics.
      • Higgins J.P.
      • Thompson S.G.
      Quantifying heterogeneity in a meta-analysis.
      To explore the possible heterogeneity among different studies, the variables of study design, geographic area, fiber intake assessment and comparison method were examined further in a meta-regression model. The between-study variance (τ2) was used to quantify the degree of heterogeneity among studies, and the percentage of τ2 was used to show the extent of the explained heterogeneity of the characteristics.
      • Whitehead A.
      • Whitehead J.
      A general parametric approach to the meta-analysis of randomized clinical trials.
      Stratification analyses according to study characteristics were performed to assess the potential effect modification of these variables on outcomes.
      Because the characteristics of the subjects, fiber intake assessment methods, and adjustments for confounding factors were inconsistent among studies, we further conducted a sensitivity analysis to explore the possible explanations for the heterogeneity and to examine the impact of different exclusion criteria on the overall result. We also evaluated the influence of a single study on the entire result by omitting each study in sequence.
      For the dose-response meta-analysis, the method proposed by Greenland and Longnecker
      • Greenland S.
      • Longnecker M.P.
      Methods for trend estimation from summarized dose-response data, with applications to meta-analysis.
      and Orsini et al
      • Orsini N.
      • Bellocco R.
      • Greenland S.
      Generalized least squares for trend estimation of summarized dose-response data.
      was adopted to compute the trend from the correlated log OR estimates across categories of fiber intake. Only the studies that reported the number of cases and control subjects and the OR and its 95% CI for at least 3 quantitative exposure categories were included. For every included study, the median or mean fiber intake for each category was assigned to each corresponding OR.
      Publication bias was evaluated with funnel plots and the Egger linear regression test.
      • Egger M.
      • Davey Smith G.
      • Schneider M.
      • et al.
      Bias in meta-analysis detected by a simple, graphical test.
      All analyses were performed with STATA version 12.0 (StataCorp, College Station, TX). A P value less than .05 was considered significant.

      Results

       Search Results, Study Characteristics, and Quality Assessment

      The search strategy yielded 205 entries, of which 36 were considered to have potential value and the full text was retrieved for detailed evaluation (Figure 1). Among these 36 articles, 17 more were excluded for the following reasons: review or editorial (n = 11); no OR/RR or 95% CI reported (n = 2); or data on the same population (n = 4). Two additional articles were included from the reference review. Thus, 21 articles (26 reports)
      • Risch H.A.
      • Jain M.
      • Choi N.W.
      • et al.
      Dietary factors and the incidence of cancer of the stomach.
      • Buiatti E.
      • Palli D.
      • Decarli A.
      • et al.
      A case-control study of gastric cancer and diet in Italy: II. Association with nutrients.
      • Kabat G.C.
      • Ng S.K.
      • Wynder E.L.
      Tobacco, alcohol intake, and diet in relation to adenocarcinoma of the esophagus and gastric cardia.
      • Ramon J.M.
      • Serra-Majem L.
      • Cerdo C.
      • et al.
      Nutrient intake and gastric cancer risk: a case-control study in Spain.
      • Hansson L.E.
      • Nyren O.
      • Bergstrom R.
      • et al.
      Nutrients and gastric cancer risk. A population-based case-control study in Sweden.
      • Cornee J.
      • Pobel D.
      • Riboli E.
      • et al.
      A case-control study of gastric cancer and nutritional factors in Marseille, France.
      • Harrison L.E.
      • Zhang Z.F.
      • Karpeh M.S.
      • et al.
      The role of dietary factors in the intestinal and diffuse histologic subtypes of gastric adenocarcinoma: a case-control study in the U.S..
      • Ji B.T.
      • Chow W.H.
      • Yang G.
      • et al.
      Dietary habits and stomach cancer in Shanghai, China.
      • Kaaks R.
      • Tuyns A.J.
      • Haelterman M.
      • et al.
      Nutrient intake patterns and gastric cancer risk: a case-control study in Belgium.
      • De Stefani E.
      • Boffetta P.
      • Deneo-Pellegrini H.
      • et al.
      Carbohydrates and risk of stomach cancer in Uruguay.
      • Botterweck A.A.
      • van den Brandt P.A.
      • Goldbohm R.A.
      Vitamins, carotenoids, dietary fiber, and the risk of gastric carcinoma: results from a prospective study after 6.3 years of follow-up.
      • Lopez-Carrillo L.
      • Lopez-Cervantes M.
      • Ward M.H.
      • et al.
      Nutrient intake and gastric cancer in Mexico.
      • Mayne S.T.
      • Risch H.A.
      • Dubrow R.
      • et al.
      Nutrient intake and risk of subtypes of esophageal and gastric cancer.
      • Palli D.
      • Russo A.
      • Decarli A.
      Dietary patterns, nutrient intake and gastric cancer in a high-risk area of Italy.
      • Terry P.
      • Lagergren J.
      • Ye W.
      • et al.
      Inverse association between intake of cereal fiber and risk of gastric cardia cancer.
      • Chen H.
      • Tucker K.L.
      • Graubard B.I.
      • et al.
      Nutrient intakes and adenocarcinoma of the esophagus and distal stomach.
      • Lissowska J.
      • Gail M.H.
      • Pee D.
      • et al.
      Diet and stomach cancer risk in Warsaw, Poland.
      • Qiu J.L.
      • Chen K.
      • Zheng J.N.
      • et al.
      Nutritional factors and gastric cancer in Zhoushan Islands, China.
      • Wu A.H.
      • Tseng C.C.
      • Hankin J.
      • et al.
      Fiber intake and risk of adenocarcinomas of the esophagus and stomach.
      • M AM Pera G.
      • Agudo A.
      • et al.
      Cereal fiber intake may reduce risk of gastric adenocarcinomas: the EPIC-EURGAST study.
      • Bravi F.
      • Scotti L.
      • Bosetti C.
      • et al.
      Dietary fiber and stomach cancer risk: a case-control study from Italy.
      that contained 580,064 subjects, published between 1985 and 2009, were included in this meta-analysis.
      Of the 21 articles, 19 were case-control and 2 were cohort studies. The sample sizes of the included studies ranged from 220 to 435,366. The number of gastric cancer cases varied from 88 to 1124 (Supplementary Table 1).
      The quality scores of each study are summarized in Tables 1 and 2. The quality scores ranged from 5 to 9. The median score was 7 for case-control studies and 8 for cohort studies.
      Table 1Methodologic Quality of Case-Control Studies Included in the Meta-Analysis
      StudyAdequate definition of casesRepresentativeness of casesSelection of controlsDefinition of controlsControl for important factors
      A maximum of 2 stars could be awarded for this item. Studies that controlled for age received 1 star, and studies that controlled for intake of other nutrients received an additional star.
      Exposure ascertainment
      A maximum of 2 stars could be awarded for this item. Studies that ascertained the exposure with a secure record or a structured interview while blind to case/control status received 1 star, and studies that considered the issues related to dietary changes because of disease received an additional star.
      Same method of ascertainment for all subjectsNonresponse rate
      One star was assigned if there was no significant difference in the response rate between case and control subjects by using the chi-square test (P > .05).
      Total quality scores
      Risch et al,
      • Risch H.A.
      • Jain M.
      • Choi N.W.
      • et al.
      Dietary factors and the incidence of cancer of the stomach.
      1985
      6
      Buiatti et al,
      • Buiatti E.
      • Palli D.
      • Decarli A.
      • et al.
      A case-control study of gastric cancer and diet in Italy: II. Association with nutrients.
      1990
      ☆☆7
      Kabat et al,
      • Kabat G.C.
      • Ng S.K.
      • Wynder E.L.
      Tobacco, alcohol intake, and diet in relation to adenocarcinoma of the esophagus and gastric cardia.
      1993
      ☆☆6
      Ramon et al,
      • Ramon J.M.
      • Serra-Majem L.
      • Cerdo C.
      • et al.
      Nutrient intake and gastric cancer risk: a case-control study in Spain.
      1993
      6
      Hansson et al,
      • Hansson L.E.
      • Nyren O.
      • Bergstrom R.
      • et al.
      Nutrients and gastric cancer risk. A population-based case-control study in Sweden.
      1994
      ☆☆☆☆9
      Cornee et al,
      • Cornee J.
      • Pobel D.
      • Riboli E.
      • et al.
      A case-control study of gastric cancer and nutritional factors in Marseille, France.
      1995
      ☆☆6
      Harrison et al,
      • Harrison L.E.
      • Zhang Z.F.
      • Karpeh M.S.
      • et al.
      The role of dietary factors in the intestinal and diffuse histologic subtypes of gastric adenocarcinoma: a case-control study in the U.S..
      1997
      ☆☆6
      Ji et al,
      • Ji B.T.
      • Chow W.H.
      • Yang G.
      • et al.
      Dietary habits and stomach cancer in Shanghai, China.
      1998
      ☆☆7
      Kaaks et al,
      • Kaaks R.
      • Tuyns A.J.
      • Haelterman M.
      • et al.
      Nutrient intake patterns and gastric cancer risk: a case-control study in Belgium.
      1998
      ☆☆6
      De Stefani et al,
      • De Stefani E.
      • Boffetta P.
      • Deneo-Pellegrini H.
      • et al.
      Carbohydrates and risk of stomach cancer in Uruguay.
      1999
      ☆☆7
      López-Carrillo et al,
      • Lopez-Carrillo L.
      • Lopez-Cervantes M.
      • Ward M.H.
      • et al.
      Nutrient intake and gastric cancer in Mexico.
       1999
      ☆☆7
      Palli et al,
      • Palli D.
      • Russo A.
      • Decarli A.
      Dietary patterns, nutrient intake and gastric cancer in a high-risk area of Italy.
      2001
      ☆☆5
      Terry et al,
      • Terry P.
      • Lagergren J.
      • Ye W.
      • et al.
      Inverse association between intake of cereal fiber and risk of gastric cardia cancer.
      2001
      ☆☆☆☆8
      Mayne et al,
      • Mayne S.T.
      • Risch H.A.
      • Dubrow R.
      • et al.
      Nutrient intake and risk of subtypes of esophageal and gastric cancer.
      2001
      ☆☆7
      Chen et al,
      • Chen H.
      • Tucker K.L.
      • Graubard B.I.
      • et al.
      Nutrient intakes and adenocarcinoma of the esophagus and distal stomach.
      2002
      ☆☆☆☆9
      Lissowska et al,
      • Lissowska J.
      • Gail M.H.
      • Pee D.
      • et al.
      Diet and stomach cancer risk in Warsaw, Poland.
      2004
      ☆☆7
      Qiu et al,
      • Qiu J.L.
      • Chen K.
      • Zheng J.N.
      • et al.
      Nutritional factors and gastric cancer in Zhoushan Islands, China.
      2005
      ☆☆7
      Wu et al,
      • Wu A.H.
      • Tseng C.C.
      • Hankin J.
      • et al.
      Fiber intake and risk of adenocarcinomas of the esophagus and stomach.
      2007
      ☆☆8
      Bravi et al,
      • Bravi F.
      • Scotti L.
      • Bosetti C.
      • et al.
      Dietary fiber and stomach cancer risk: a case-control study from Italy.
      2009
      ☆☆7
      a A maximum of 2 stars could be awarded for this item. Studies that controlled for age received 1 star, and studies that controlled for intake of other nutrients received an additional star.
      b A maximum of 2 stars could be awarded for this item. Studies that ascertained the exposure with a secure record or a structured interview while blind to case/control status received 1 star, and studies that considered the issues related to dietary changes because of disease received an additional star.
      c One star was assigned if there was no significant difference in the response rate between case and control subjects by using the chi-square test (P > .05).
      Table 2Methodologic Quality of Cohort Studies Included in the Meta-analysis
      StudyRepresentativeness of the exposed cohortSelection of the nonexposed cohortAscertainment of exposureOutcome of interest not present at start of studyControl for important factors
      A maximum of 2 stars could be awarded for this item. Studies that controlled for age received 1 star, and studies that controlled for intake of other nutrients received an additional star.
      Assessment of outcomeFollow-up period long enough for outcomes to occur
      A cohort study with a follow-up time longer than 5 years was assigned 1 star.
      Adequacy of follow-up evaluation of cohorts
      A cohort study with a follow-up rate greater than 80% was assigned 1 star.
      Total quality scores
      Botterweck et al,
      • Botterweck A.A.
      • van den Brandt P.A.
      • Goldbohm R.A.
      Vitamins, carotenoids, dietary fiber, and the risk of gastric carcinoma: results from a prospective study after 6.3 years of follow-up.
      2000
      8
      MA et al,
      • M AM Pera G.
      • Agudo A.
      • et al.
      Cereal fiber intake may reduce risk of gastric adenocarcinomas: the EPIC-EURGAST study.
      2007
      8
      a A maximum of 2 stars could be awarded for this item. Studies that controlled for age received 1 star, and studies that controlled for intake of other nutrients received an additional star.
      b A cohort study with a follow-up time longer than 5 years was assigned 1 star.
      c A cohort study with a follow-up rate greater than 80% was assigned 1 star.

       Fiber Intake and Gastric Cancer Risk

      The multivariable-adjusted ORs for each study and the combined OR for the highest vs the lowest categories of dietary fiber intake are shown in Figure 2. Of the 26 reports, 24 showed an inverse association between the dietary fiber intake and the gastric cancer risk, 14 of which were statistically significant. Overall, the pooled OR for the highest compared with the lowest dietary fiber intake was 0.58 (95% CI, 0.49–0.67) with significant heterogeneity among studies (P < .001, I2 = 62.2%).
      Figure thumbnail gr2
      Figure 2Forest plot of dietary fiber intake and risk of gastric cancer. C, cardia; N, noncardia; D, diffuse; I, intestinal; M, male; F, female; HCC, hospital-based case-control; PCC, population-based case-control.

       Dose-Response Meta-Analysis

      Two case-control studies
      • Lopez-Carrillo L.
      • Lopez-Cervantes M.
      • Ward M.H.
      • et al.
      Nutrient intake and gastric cancer in Mexico.
      • Terry P.
      • Lagergren J.
      • Ye W.
      • et al.
      Inverse association between intake of cereal fiber and risk of gastric cardia cancer.
      that reported the number of cases and control subjects and the OR and its 95% CI for at least 3 quantitative exposure categories were included for the dose-response meta-analysis. The summary OR for an increment of 10 g/d of dietary fiber intake was 0.56 (95% CI, 0.45–0.71) without heterogeneity (P = .941, I2 = 0.0%).

       Subgroup Analysis

      Subgroup analysis was by study design, and significant inverse associations were observed in population-based case-control studies (OR, 0.56; 95% CI, 0.46–0.67) and hospital-based case-control studies (OR, 0.52; 95% CI, 0.41–0.66) (Table 3). When stratifying by geographic area the ORs were 0.48 (95% CI, 0.40–0.58) for studies conducted in North America, 0.66 (95% CI, 0.52–0.84) for studies conducted in Europe, and 0.63 (95% CI, 0.47–0.84) for studies conducted in China. In the subgroup analyses by fiber source and fiber type, the ORs were 0.58 (95% CI, 0.41–0.82) for cereal fiber, 0.67 (95% CI, 0.46–0.99) for fruit fiber, 0.72 (95% CI, 0.57–0.90) for vegetable fiber, 0.42 (95% CI, 0.34–0.52) for insoluble fiber, and 0.41 (95% CI, 0.32–0.52) for soluble fiber. Stratifying by Lauren’s classification, the association was similar in diffuse-type gastric cancer (OR, 0.62; 95% CI, 0.42–0.92) and in intestinal-type gastric cancer (OR, 0.63; 95% CI, 0.45–0.89). Moreover, significant associations also were observed in the subgroup analysis by publication year (before and after 2000), sample size (<1000 and ≥1000), and quality score (<7 stars and ≥7 stars) (Table 3).
      Table 3Stratified Analyses of Dietary Fiber Intake and Gastric Cancer Risk
      GroupReports, nOR (95% CI)Heterogeneity test
      χ2PI2, %
      Total260.58 (0.49–0.67)66.16<.00162.2
      Design
       Cohort20.89 (0.68–1.17)0.00.9680.0
       Case-control240.53 (0.45–0.62)48.74.00156.9
       Population based180.56 (0.46–0.67)51.46<.00167.0
       Hospital based60.52 (0.41–0.66)3.38.6420.0
      Geographic area
       China40.63 (0.47–0.84)2.96.3970.0
       Europe110.66 (0.52-0.84)32.93<.00169.6
       North America100.48 (0.40-0.58)14.07.12036.0
      Fiber source
       Cereal fiber40.58 (0.41-0.82)10.82.01372.3
       Fruit fiber60.67 (0.46–0.99)22.45<.00177.7
       Vegetable fiber50.72 (0.57–0.90)5.85.21131.6
      Fiber type
       Insoluble fiber30.42 (0.34–0.52)0.31.8550.0
       Soluble fiber20.41 (0.32–0.52)0.04.8370.0
      Lauren’s classification
       Diffuse30.62 (0.42–0.92)1.91.3850.0
       Intestinal30.63 (0.45–0.89)5.55.06263.9
      Location
       Cardia30.66 (0.37–1.15)9.34.00978.6
       Noncardia30.55 (0.36–0.83)7.08.02971.7
      Publication year
       Before 2000130.55 (0.44–0.69)34.95<.00165.7
       2000 or later130.60 (0.49–0.74)30.97.00261.2
      Sample size
       <1000150.54 (0.45–0.66)24.70.03843.3
       ≥1000110.61 (0.48–0.77)39.38<.00174.6
      Quality score
       <7 stars80.56 (0.41–0.77)20.64.00466.1
       ≥7 stars180.58 (0.49–0.70)43.80<.00161.2

       Sensitivity Analyses

      Sensitivity analyses were performed to explore potential sources of heterogeneity and to examine the influence of various exclusion criteria on the overall result. Exclusion of 4 studies
      • Risch H.A.
      • Jain M.
      • Choi N.W.
      • et al.
      Dietary factors and the incidence of cancer of the stomach.
      • Ramon J.M.
      • Serra-Majem L.
      • Cerdo C.
      • et al.
      Nutrient intake and gastric cancer risk: a case-control study in Spain.
      • Botterweck A.A.
      • van den Brandt P.A.
      • Goldbohm R.A.
      Vitamins, carotenoids, dietary fiber, and the risk of gastric carcinoma: results from a prospective study after 6.3 years of follow-up.
      • M AM Pera G.
      • Agudo A.
      • et al.
      Cereal fiber intake may reduce risk of gastric adenocarcinomas: the EPIC-EURGAST study.
      that were not adjusted for total energy intake or dietary factors yielded an OR of 0.55 (95% CI, 0.47–0.64), with substantial evidence of heterogeneity (P = .001, I2 = 56.2%). Restricting analysis to studies that were controlled for smoking yielded similar results (OR, 0.59, 95% CI, 0.50–0.69; n = 19), yet heterogeneity still was present (P = .004, I2 = 52.0%). Further exclusion of any single study did not materially alter the overall result, with a range from 0.56 (95% CI, 0.48–0.65) to 0.60 (95% CI, 0.51–0.69).

       Meta-regression

      Meta-regression analysis indicated that geographic area (P = .039) and fiber intake assessment method (P = .042), but not the study design and fiber intake comparison method, were significant sources of heterogeneity (Table 4). The estimated between-study variance (τ2) was reduced from 0.088 to 0.067 (geographic area) and 0.066 (fiber intake assessment method). Moreover, we found that geographic area alone could explain 23.86% of the τ2 in the meta-regression analyses, and fiber intake assessment could explain 24.54% of the τ2.
      Table 4Meta-regression Analysis
      VariableCoefficientStandard errorP value95% CI
      Study design-0.1550.097.125-0.356 to 0.046
      Geographic area-0.2240.102.039-0.435 to -0.012
      Fiber intake assessment method-0.4710.217.042-0.922 to -0.019
      Fiber intake comparison method0.0320.061.612-0.096 to 0.159
      NOTE. Values in bold are statistically significant in meta-regression analysis.

       Publication Bias

      The funnel plot did not show any obvious asymmetry. The Egger test also indicated no evidence of publication bias (P = .931).

      Discussion

      In the past 2 decades, the role of dietary fiber in the development of gastric cancer increasingly has been recognized. In this meta-analysis, we found that high dietary fiber intake was associated significantly with a reduced risk of gastric cancer. Stratified analysis for study design, geographic area, source and type of fiber, Lauren’s classification, publication year, sample size, and quality score of the study yielded similar results. Moreover, the dose-response meta-analysis indicated that an increase in dietary fiber intake of 10 g/day was associated with a statistically significant 44% decreased risk of gastric cancer.
      The mechanism by which a high intake of dietary fiber may reduce the risk of gastric cancer has been investigated in many studies. Nitrite is a precursor for the endogenous formation of N-nitroso compounds, which are potentially carcinogenic in human beings.
      • Grosse Y.
      • Baan R.
      • Straif K.
      • et al.
      Carcinogenicity of nitrate, nitrite, and cyanobacterial peptide toxins.
      In acid conditions, dietary fiber has been shown to scavenge nitrites and has similar efficacy as vitamin C in reducing the concentration of nitrite in the stomach.
      • Moller M.E.
      • Dahl R.
      • Bockman O.C.
      A possible role of the dietary fibre product, wheat bran, as a nitrite scavenger.
      Dietary fiber is a rich source of ferulic acid and p-coumaric acid, which could delay the progression of the cell cycle and produce anticancer effects.
      • Janicke B.
      • Hegardt C.
      • Krogh M.
      • et al.
      The antiproliferative effect of dietary fiber phenolic compounds ferulic acid and p-coumaric acid on the cell cycle of Caco-2 cells.
      Also, short-chain fatty acids, mainly produced by the fermentation of dietary fiber, can induce differentiation, growth arrest, and apoptosis in the gastrointestinal tract.
      • Augenlicht L.H.
      • Anthony G.M.
      • Church T.L.
      • et al.
      Short-chain fatty acid metabolism, apoptosis, and Apc-initiated tumorigenesis in the mouse gastrointestinal mucosa.
      Furthermore, high dietary fiber intake could simply indicate a diet rich in vegetables and fruit, and a variety of nutrients, which have been shown to prevent gastric cancer.
      • Gonzalez C.A.
      • Pera G.
      • Agudo A.
      • et al.
      Fruit and vegetable intake and the risk of stomach and oesophagus adenocarcinoma in the European Prospective Investigation into Cancer and Nutrition (EPIC-EURGAST).
      For instance, studies have shown that Allium vegetables, a source of dietary fiber, have an antibacterial effect against Helicobacter pylori, which is a pivotal risk factor for gastric cancer.
      • Jonkers D.
      • van den Broek E.
      • van Dooren I.
      • et al.
      Antibacterial effect of garlic and omeprazole on Helicobacter pylori.
      • Canizares P.
      • Gracia I.
      • Gomez L.A.
      • et al.
      Thermal degradation of allicin in garlic extracts and its implication on the inhibition of the in-vitro growth of Helicobacter pylori.
      Prior meta-analysis and review also indicated that high intake of fiber-rich foods such as whole grains,
      • Jacobs Jr., D.R.
      • Marquart L.
      • Slavin J.
      • et al.
      Whole-grain intake and cancer: an expanded review and meta-analysis.
      vegetables, and fruit
      • Ogimoto I.
      • Shibata A.
      • Fukuda K.
      World Cancer Research Fund/American Institute of Cancer Research 1997 recommendations: applicability to digestive tract cancer in Japan.
      was associated with a decreased risk of gastric cancer. These studies support our finding that increased intake of dietary fiber is associated with a decreased gastric cancer risk.
      There are only 3 studies that investigated whether the association between the dietary fiber intake and the gastric cancer risk differed by Lauren’s classification (intestinal or diffuse). Another 3 studies examined the risk by location (cardia or noncardia) (Table 3). Therefore, whether the association differs according to histologic subtype or location warrants further study.

       Study Strengths and Limitations

      A meta-analysis is an important method for revealing trends that might not be evident in a single study. A strength of this meta-analysis was that the number of total subjects (580,064) was substantial, which significantly increased the statistical power of the analysis. Moreover, we observed a significant dose-response relation between the dietary fiber intake and the gastric cancer risk, which further strengthened this association.
      Our study also had several limitations. First, because of the observational design, the possibility that other factors may account for the observed association could not be ruled out. Nevertheless, most studies in this meta-analysis adjusted for potential confounders, including age, sex, total energy intake, smoking, and drinking. The inverse association between the fiber intake and the gastric cancer risk persisted when we restricted the analysis to studies that adjusted for these confounders. Second, the range between the lowest and highest categories for dietary fiber intake was much different among the studies, which may have contributed to the heterogeneity in the pooled analysis. Third, our meta-analysis contained a small number of observational cohort studies and only 2 case-control studies were eligible for the dose-response meta-analysis. Therefore, more observational studies with standardized fiber intake collection strategies are needed to answer this question more completely. Fourth, a problem with dietary assessments in case-control studies of gastric cancer is that dietary habits may have changed because of symptoms related to the cancer. However, most articles (20 of 21) in our meta-analysis asked about dietary habits 1 year or more before diagnosis/interview (eg, 1, 2, 4, 5, 10, or 20 years) and none of the studies asked about current diet (ie, right before diagnosis). The studies chose to ask about dietary habits 1 year or more before diagnosis/interview to evaluate the potential risk factors with a rational latency period before the onset of gastric cancer. In contrast, very recent dietary habits (ie, right before diagnosis) would be past the window of time relevant to the development of gastric cancer and thus would be less valid. Although the symptoms of gastric cancer experienced by the patients may have resulted in recent dietary changes, they would not have affected dietary habits many years ago. Fifth, many studies only provided the results without showing detailed calculation methods or the raw data (eg, the number of case and control subjects at different levels of consumption). To do this, the investigators of all the published studies were encouraged to share their raw data. Sixth, most of the included studies lacked the information concerning H pylori infection. Only 2 studies
      • Lissowska J.
      • Gail M.H.
      • Pee D.
      • et al.
      Diet and stomach cancer risk in Warsaw, Poland.
      • Wu A.H.
      • Tseng C.C.
      • Hankin J.
      • et al.
      Fiber intake and risk of adenocarcinomas of the esophagus and stomach.
      examined whether the association between dietary fiber intake and gastric cancer risk was modified by H pylori infection. Because H pylori infection is a key risk factor for gastric cancer, our result should be considered with caution because of potential confounding. Future studies should consider H pylori infection in the analysis.

       Implications

      Gastric cancer is a major cause of death worldwide. The association between the dietary fiber intake and the risk of gastric cancer remains controversial. According to the result of our meta-analysis, a 10-g/day increment in fiber intake was associated with a reduction in the risk of gastric cancer of 44%. This risk reduction could be translated into a reduction of as many as 324,720 gastric cancer deaths per year on a worldwide scale.
      • Jemal A.
      • Bray F.
      • Center M.M.
      • et al.
      Global cancer statistics.
      Dietary fiber intake in the United States is around 15 g/day, which is only half the recommended amount.
      • Marlett J.A.
      • McBurney M.I.
      • Slavin J.L.
      Position of the American Dietetic Association: health implications of dietary fiber.
      Fiber intake may be increased by well-described dietary changes such as increases in cereal, fruit, and vegetable consumption.

      Conclusions

      This meta-analysis shows that dietary fiber intake is associated inversely with the risk of gastric cancer. However, because of potential bias and confounding, these results should be considered with caution. Further well-designed large prospective studies and randomized clinical trials for dietary fiber supplementation are warranted to confirm this association and to establish the potential dose-response relationship. Future studies should use standardized fiber intake collection strategy and consider H pylori infection in the analysis, which should lead to a better comprehensive understanding of the association between dietary fiber intake and the risk of gastric cancer.

      Acknowledgments

      The authors thank Jian Xu (Molecular Oncology Research Institute, Tufts Medical Center, Tufts University, Boston, MA) for critical review and language editing of the manuscript.

      Supplemental Material

      Supplementary Table 1Characteristics of the Included Studies
      StudyDesignCountryAge, y/sexStudy periodCases/controlsAssessment of intake/food item number/fiber intake calculation/ nutrient databaseTime period of dietary questionsAverage intake (case, control)/ comparison cut-off pointOR/RR (95% CI)Adjusted or matched variables
      Risch et al,
      • Risch H.A.
      • Jain M.
      • Choi N.W.
      • et al.
      Dietary factors and the incidence of cancer of the stomach.
      1985
      PCCCanada35–79

      M/F
      1979–1982246/246FFQ/—/amount × frequency/USDA's food composition tables1 year before interview19.2, 19.8 g/d/Continuous variable0.40 (0.28–0.58)Age, sex, and area of residence
      Buiatti et al,
      • Buiatti E.
      • Palli D.
      • Decarli A.
      • et al.
      A case-control study of gastric cancer and diet in Italy: II. Association with nutrients.
      1990
      PCCItaly≤ 75

      M/F
      1985–19871016/1159FFQ/146/portion size× frequency/Italian food tables12-month period 2 years before interviewControl, 35 g/d/quintile

      50 vs 23 g/d
      0.90 (0.70, 1.30)Age, sex, area, place of residence, migration from south, socioeconomic status, familial GC history, Quetelet index and kilocalories
      Kabat et al,
      • Kabat G.C.
      • Ng S.K.
      • Wynder E.L.
      Tobacco, alcohol intake, and diet in relation to adenocarcinoma of the esophagus and gastric cardia.
      1993
      HCCUnited States60–70

      M/F
      1981–1990122/4544FFQ/30/fiber value/USDA's food composition tables5 years before diagnosis—/Quartile (IV vs I)0.91 (0.32–2.50)Age, smoking, alcohol, education, hospital, and dietary factors
      Ramon et al,
      • Ramon J.M.
      • Serra-Majem L.
      • Cerdo C.
      • et al.
      Nutrient intake and gastric cancer risk: a case-control study in Spain.
      1993
      PCCSpain30–80

      M/F
      1986–1989117/234FFQ/89/amount × frequency/French and US food composition tables6 months before symptom/

      interview
      —/Quartile (IV vs I)1.04 (0.62–2.11)Age, sex, education years, cigarettes/day, and alcohol g/day
      Hansson et al,
      • Hansson L.E.
      • Nyren O.
      • Bergstrom R.
      • et al.
      Nutrients and gastric cancer risk. A population-based case-control study in Sweden.
      1994
      PCCSweden40–79

      M/F
      1989–1992338/679FFQ/45/portion size × frequency/Swedish food composition databaseAdolescence and 20 years

      before interview
      11.9, 12.4 g/d/quartile

      18.2 vs 7.5 g/d
      0.71 (0.49–1.03)Age, sex, and energy intake
      Cornee et al,
      • Cornee J.
      • Pobel D.
      • Riboli E.
      • et al.
      A case-control study of gastric cancer and nutritional factors in Marseille, France.
      1995
      HCCFrance66.6

      M/F
      1985–198892/128Dietary history questionnaire/—/ portion size × frequency/French and English food tables1 year before symptom/interview24, 22 g/d/tertile

      27 vs 19 g/d
      0.59 (0.29–1.21)Age, sex, occupation, and total energy intake
      Harrison et al,
      • Harrison L.E.
      • Zhang Z.F.
      • Karpeh M.S.
      • et al.
      The role of dietary factors in the intestinal and diffuse histologic subtypes of gastric adenocarcinoma: a case-control study in the U.S..
      1997
      HCCUnited States54–62

      M/F
      1992–199491/132FFQ/60/frequency × portion size/USDA's food composition data tape1 year before interview—/quartile (IV vs I)0.60 (0.40–0.96)
      Intestinal.
      Age, sex, race, caloric intake, education, pack-years of smoking, alcohol drinking, and BMI
      0.50 (0.30–0.90)
      Diffuse.
      Ji et al,
      • Ji B.T.
      • Chow W.H.
      • Yang G.
      • et al.
      Dietary habits and stomach cancer in Shanghai, China.
      1998
      PCCChina20–69

      M/F
      1988–19891124/1451FFQ/84/amount × frequency/Chinese food composition tables10 years before symptom/

      interview
      —/quartile

      ≥12.3 vs ≤7.7 g/d (men)

      ≥9.9 vs ≤6.3 g/d (women)
      0.60 (0.40–0.80)
      Male.
      Age, income, education, smoking, alcohol drinking, and total calories intake
      0.60 (0.30–0.90)
      Female.
      Kaaks et al,
      • Kaaks R.
      • Tuyns A.J.
      • Haelterman M.
      • et al.
      Nutrient intake patterns and gastric cancer risk: a case-control study in Belgium.
      1998
      PCCBelgium35–74

      M/F
      1979–1983301/2851Dietary history questionnaire/>150/portion size × frequency/British food composition tables1 year before symptom/interview22.5, 22.7

      g/d for men

      18.1, 20 g/d for women/quartile (IV vs I)
      0.30 (0.20–0.44)Age, sex, province, and total energy intake
      De Stefani et al,
      • De Stefani E.
      • Boffetta P.
      • Deneo-Pellegrini H.
      • et al.
      Carbohydrates and risk of stomach cancer in Uruguay.
      1999
      HCCUruguay30–89

      M/F
      1997–199888/351FFQ/64/portion size × frequency/Spanish food composition tables2 years before symptom/interview—/Tertile (III vs I)0.34 (0.17–0.65)Age, sex, residence, urban/rural status, total energy, sugar-rich foods, and starch intakes
      Lopez-Carrillo et al,
      • Lopez-Carrillo L.
      • Lopez-Cervantes M.
      • Ward M.H.
      • et al.
      Nutrient intake and gastric cancer in Mexico.
      1999
      PCCMexico20–98

      M/F
      1989–1990220/752FFQ/70/portion size × frequency/USDA's food intake analysis system1 year before symptom/interview24.4, 27.0

      g/d/quartile

      ≥33.36 vs ≤18.27 g/d
      0.22 (0.09–0.55)Age, sex, total calories, chili-pepper consumption, socioeconomic status, cigarette smoking, salt consumption, history of peptic ulcer, type of interview, duration of interview, place of interview
      Botterweck et al,
      • Botterweck A.A.
      • van den Brandt P.A.
      • Goldbohm R.A.
      Vitamins, carotenoids, dietary fiber, and the risk of gastric carcinoma: results from a prospective study after 6.3 years of follow-up.
      2000
      CohortThe Netherlands55–69

      M/F
      1986–1992282/120, 852FFQ/150/—/Dutch food composition table1 year before study26.2 g/d/quintile

      37.6 vs 17.8 g/d
      0.90 (0.60–1.40)Age, sex, smoking status, education, stomach disorders, and family history of stomach carcinoma
      Palli et al,
      • Palli D.
      • Russo A.
      • Decarli A.
      Dietary patterns, nutrient intake and gastric cancer in a high-risk area of Italy.
      2001
      PCCItaly50–64

      M/F
      1985–1987382/561FFQ/181/portion size × frequency/Italian food composition tables1 year before interviewControl,

      22 g/d/tertile

      29.4 vs 16.7 g/d
      0.80 (0.50–1.10)Age, sex, social class, family history of gastric cancer, area of rural residence, BMI tertiles, total energy and tertiles of the residuals of each nutrient of interest
      Terry et al,
      • Terry P.
      • Lagergren J.
      • Ye W.
      • et al.
      Inverse association between intake of cereal fiber and risk of gastric cardia cancer.
      2001
      PCCSweden66

      M/F
      1995–1997258/815FFQ/63/frequency × nutrient content/Swedish food composition database20 years before interview12.9, 15.5 g/d/quartile

      21.3 vs 8.0 g/d
      0.40 (0.30–0.80)Age, sex, BMI, cigarette smoking, alcohol consumption, antioxidant intake, total energy consumption, socioeconomic status, and symptoms of gastroesophageal reflux
      Mayne et al,
      • Mayne S.T.
      • Risch H.A.
      • Dubrow R.
      • et al.
      Nutrient intake and risk of subtypes of esophageal and gastric cancer.
      2001
      PCCUnited States30–79

      M/F
      1993–1995607/687FFQ/104/portion size × frequency/US nutrition coding center nutrient data system3–5 y before symptom/interview—/Quartile (IV vs I)0.43 (0.30–0.61)
      Cardia.
      Age, sex, site, race, proxy status, income, education, BMI, cigarettes/day, years of consuming beer, wine, and liquor, and energy intake
      0.38 (0.28–0.53)
      Noncardia.
      Chen et al,
      • Chen H.
      • Tucker K.L.
      • Graubard B.I.
      • et al.
      Nutrient intakes and adenocarcinoma of the esophagus and distal stomach.
      2002
      PCCUnited States70.3

      M/F
      1986–1994124/449Health habits and history questionnaire/60/portion size × frequency/US Dietsys database1 year before interview11, 11 g/d/quartile (IV vs I)0.40 (0.20–0.80)Age, sex, respondent type, alcohol use, tobacco use, education level, family history of respective cancers, and vitamin supplement use
      Lissowska et al,
      • Lissowska J.
      • Gail M.H.
      • Pee D.
      • et al.
      Diet and stomach cancer risk in Warsaw, Poland.
      2004
      PCCPoland50–70

      M/F
      1994–1996274/463FFQ/118/portion size × frequency/US and Polish food tables4 years before interview20.6, 21.1

      g/d for men

      17.1, 17 g/d for women

      /quartile (IV vs I)
      0.73 (0.46–1.17)Age, sex, education, smoking, and calories from foods
      Qiu et al,
      • Qiu J.L.
      • Chen K.
      • Zheng J.N.
      • et al.
      Nutritional factors and gastric cancer in Zhoushan Islands, China.
      2005
      PCCChina28–85

      M/F
      2000-2001103/133FFQ/>60/portion size × frequency/Chinese food composition tables1 year before interview10.1, 10.3

      g/d/quartile (IV vs I)
      2.41 (0.51–11.5)
      Male.
      Age, present residence, education, economic status, smoking, alcohol, and total calories intake
      0.72 (0.06–8.97)
      Female.
      Wu et al,
      • Wu A.H.
      • Tseng C.C.
      • Hankin J.
      • et al.
      Fiber intake and risk of adenocarcinomas of the esophagus and stomach.
      2007
      PCCUnited States30–74

      M/F
      1992–1997623/1308FFQ/124/portion size × frequency/USDA's nutrient database for standard reference1 year before symptom10.2, 12,

      11.8 g/d
      10.2 g/d is for gastric cardia, 12 g/d is for distal gastric cancer, and 11.8 g/d is for controls.
      /quartile (IV vs I)
      0.58 (0.40–0.90)
      Cardia.
      Age, sex, race, birthplace, education, smoking, BMI, reflux, use of vitamins, and total calories
      0.69 (0.50–1.00)
      Noncardia.
      MA et al,
      • M AM Pera G.
      • Agudo A.
      • et al.
      Cereal fiber intake may reduce risk of gastric adenocarcinomas: the EPIC-EURGAST study.
      2007
      CohortEuropean countries25–70

      M/F
      1992–1998312/435, 366FFQ/—/—/ country-specific food composition tables1 year before study24.4 g/d for men, 23 g/d for women/quartile (IV vs I)0.89 (0.63–1.26)Age, sex, height, weight, education level, smoking status
      Bravi et al,
      • Bravi F.
      • Scotti L.
      • Bosetti C.
      • et al.
      Dietary fiber and stomach cancer risk: a case-control study from Italy.
      2009
      HCCItaly22–80

      M/F
      1997–2007230/547FFQ/78/Englyst procedure/Italian food composition database2 years before diagnosis/ hospitalizationControl, 15.8 g/d/quintile

      >20.1 vs 11.37 g/d
      0.47 (0.28–0.79)Age, sex, year of interview, years of education, BMI, tobacco smoking, family history of stomach cancer, and total energy intake
      BMI, body mass index; F, female; FFQ, food frequency questionnaire; HCC, hospital-based case-control; PCC, population-based case-control; M, male; USDA, US Department of Agriculture.
      a Intestinal.
      b Diffuse.
      c Male.
      d Female.
      e Cardia.
      f Noncardia.
      g 10.2 g/d is for gastric cardia, 12 g/d is for distal gastric cancer, and 11.8 g/d is for controls.

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