Clinical Gastroenterology and Hepatology 2014;-:-–-
Allium Vegetables and Garlic Supplements Do Not Reduce Risk of Colorectal Cancer, Based on Meta-analysis of Prospective Studies Beibei Zhu,* Li Zou,* Lu Qi,‡ Rong Zhong,* and Xiaoping Miao* *State Key Laboratory of Environment Health (Incubation), Ministry of Education Key Laboratory of Environment and Health, Ministry of Environmental Protection Key Laboratory of Environment and Health, and Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; ‡ Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts BACKGROUND & AIMS:
Laboratory studies have provided evidence that allium vegetables and garlic supplements might protect against colorectal cancer (CRC), but epidemiologic studies have produced inconsistent findings.
METHODS:
We conducted a meta-analysis of prospective studies evaluating the associations between allium vegetables, garlic supplements, and CRC risk. We pooled effect measures using fixed- or random-effect models, assessing the highest vs the lowest intakes. We used a dose-response regression model to evaluate the relationship between allium vegetable intake and CRC risk.
RESULTS:
Our analysis included 8 studies with 20 reports of the effects of allium vegetables (5458 patients with CRC including 7,125,067 person-years) and 5 studies with 11 reports of the effects of garlic supplements (2685 patients with CRC including 2,304,439 person-years). We found no association between higher intake of allium vegetables and CRC risk (relative risk [RR], 1.06; 95% confidence interval [CI], 0.96–1.17; P [ .26). Intake of allium vegetables did not correspond to CRC risk (P for nonlinear [ .24, P for linear [ .20). In subgroup analysis, a higher consumption of allium vegetables was associated marginally with increased risk of colon cancer among women (RR, 1.23; 95% CI, 1.01–1.50; P [ .05). Use of garlic supplements was associated significantly with an increased risk of CRC (RR, 1.18; 95% CI, 1.02–1.36; P [ .03).
CONCLUSIONS:
In a meta-analysis, we found no evidence that higher intake of allium vegetables reduced the risk for CRC. We observed that garlic supplements increased the risk for CRC, but this finding requires external validation.
Keywords: Diet; Cancer Risk Factor; Prevention; Review.
olorectal cancer (CRC) ranks as the third most common cancer worldwide,1 and the incidence of CRC varies 10-fold in both sexes across countries, but almost 60% of the cases occur in developed countries.1 The considerable geographic difference in CRC incidence rates suggests that environmental factors such as diet may play an important role in the development of CRC. Allium genus is characterized by a high content of organosulfur compounds and flavonoids, which have shown beneficial effects against various cancers including CRC.2–4 The most widely used allium vegetables are garlic, onion, and leeks. A body of laboratory studies5–8 has indicated that allium vegetables and related supplements have protective effects against CRC, however, epidemiologic studies have yielded inconsistent results. An expert review panel organized by the World Cancer Research Fund and the American Institute for Cancer Research concluded that garlic intake was a “probable” protective factor against CRC.9 A
C
meta-analysis10 of 7 studies showed that high intake of garlic might have a protective effect against CRC. However, 2 recent prospective studies11,12 including 3 large cohorts found no significant association between garlic intake and risk of CRC. Similarly, data on the associations of onion and leek intakes with CRC also have been inconsistent.13–15 Among allium vegetable-related supplements, the most widely used is a garlic supplement, which was combined with garlic intake in the previous meta-analysis. Nevertheless, some studies11,16 found that garlic supplements were associated significantly with an increased risk of CRC. Given the widespread use of garlic
Abbreviations used in this paper: CI, confidence interval; CRC, colorectal cancer; RR, relative risk. © 2014 by the AGA Institute 1542-3565/$36.00 http://dx.doi.org/10.1016/j.cgh.2014.03.019
2
Zhu et al
supplements,17 it is important to assess its long-term effects. Therefore, we conducted a meta-analysis (including a dose-response approach) based on prospective studies to comprehensively and precisely assess associations between intake of allium vegetables, garlic supplement use, and risk of CRC.
Clinical Gastroenterology and Hepatology Vol.
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No.
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provided the intake frequency of allium vegetables, when the study provided the amount of intake, we transformed it into frequency. The individual authors were contacted via e-mail if the data of interest were not provided in the publication. We also checked the references of all retrieved articles to identify additional studies.
Statistical Analysis
Methods Literature Search and Eligibility Criteria We searched the Medline and Embase databases from inception to October 2013, targeting the studies investigating the relationship between allium vegetables, garlic supplements, and CRC risk. To perform a comprehensive literature search, we used the following combined terms: the MeSH headings and keywords relating to “colorectal neoplasms,” the MeSH heading “allium” and the keywords regarding exposure (garlic, onion, leeks, scallion, chive, garlic supplement, vegetables, food, and diet), restricting our search to Englishlanguage articles. Reference lists of eligible studies and relevant review articles also were scanned to identify further pertinent studies. Studies were considered eligible if they met the following criteria: (1) the design of the study was prospective such as a cohort or casecohort study; (2) the study investigated the relationship of allium vegetables or garlic supplements and CRC risk; and (3) the study provided or allowed the calculation of relative risk (RR) with 95% confidence intervals (CIs). We excluded nonhuman studies, case reports, comparative studies not using an analytic epidemiologic design, or studies that did not report analyses of primary data (eg, letters, editorials, or narrative reviews), and studies that did not provide sufficient data. When multiple studies pertained to the same or partially overlapping populations, we used the results with the longest follow-up time or largest sample size.
Data Extraction All data were extracted independently and crosschecked by 2 reviewers. For eligible studies, the following data were extracted by 2 authors independently: the first author, publication year, geographic region, demographics of participants, sample size (number of case and total participants), duration of follow-up evaluation, covariates adjusted in the multivariable analysis, allium vegetables, garlic supplement consumption categories, and the RR (with the 95% CI) with the corresponding number of cases and person-years for each category. If the person-years were not presented, they were estimated as a product of the number of subjects times the mean follow-up duration. We extracted the RRs that represented the greatest degree control of potential confounders. For comparability, for most studies that
The RRs and 95% CI were considered as the effect size for all studies, and we extracted the maximally adjusted RR (95% CI). Any results stratified by sex or tumor site were treated as separate reports. We quantified the relationship between allium vegetables, garlic supplements, and CRC risk by pooling the RRs for the highest vs the lowest category in a random-effects model as described by DerSimonian and Laird18 when the between-study heterogeneity was significant (P < .05), otherwise a fixed-effect model was used. To precisely evaluate the association between allium vegetable intake and risk of CRC, a random-effects doseresponse meta-analysis was performed according to the method described by Greenland and Longnecker19 and Orsini et al.20 Furthermore, a potential curve-linear relationship between allium vegetables and CRC risk was assessed using restricted cubic splines with 3 knots at fixed percentiles (10%, 50%, and 90%) of the distribution.21 A P value for curve linearity or nonlinearity was calculated by testing the null hypothesis that the coefficient of the second spline is equal to zero. We quantified the extent of heterogeneity using the Q test22 and the I2 score.23 Stratified analyses were performed, if feasible, according to allium vegetable species, sex and site, geographic region, number of cases, and duration of follow-up evaluation. A sensitivity analysis also was performed. Funnel plots and the Egger test24 were applied to examine the publication bias. All statistical analyses were performed with Stata version 10.0 (STATA Corp, College Station, TX). All statistical tests were 2-sided.
Results Study Characteristics The main characteristics of the studies included in this meta-analysis are summarized in Tables 1 and 2. Eight studies on allium vegetables11,12,15,25–27 involved a total of 5458 CRC patients and 7,125,067 person-years of follow-up. The articles by Meng et al12 and Lin et al26 each included 2 studies. Five eligible cohort studies11,12,15,16 on garlic supplements, involving a total of 2685 patients and 2,304,439 person-years of followup, were finally included in this study. The article by Meng et al12 included 2 studies. The follow-up duration varied from 3.3 years to 10 years. The literature search and selection procedures are shown in Supplementary
Sellers et al,25 1998, United States
Source of participants Iowa Women’s Health Study
McCullough Cancer et al,11 2012, Prevention United States Study II Nutrition Cohort
Nurses’ Health Study
1130
1339
35,216
99,700
76,208
10
7
24
55–69
69
30–55
Site Colon
Colorectal
Sex F
Exposure Garlic 0 serving/wk 1 serving/wk >1 serving/wk
0 serving/wk 1 serving/wk >1 serving/wk M (579) Garlic F (551)
Allium Vegetables and Garlic Supplements Do Not Reduce Risk of Colorectal Cancer, Based on Meta-analysis of Prospective Studies Beibei Zhu,* Li Zou,* Lu Qi,‡ Rong Zhong,* and Xiaoping Miao* *State Key Laboratory of Environment Health (Incubation), Ministry of Education Key Laboratory of Environment and Health, Ministry of Environmental Protection Key Laboratory of Environment and Health, and Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; ‡ Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts BACKGROUND & AIMS:
Laboratory studies have provided evidence that allium vegetables and garlic supplements might protect against colorectal cancer (CRC), but epidemiologic studies have produced inconsistent findings.
METHODS:
We conducted a meta-analysis of prospective studies evaluating the associations between allium vegetables, garlic supplements, and CRC risk. We pooled effect measures using fixed- or random-effect models, assessing the highest vs the lowest intakes. We used a dose-response regression model to evaluate the relationship between allium vegetable intake and CRC risk.
RESULTS:
Our analysis included 8 studies with 20 reports of the effects of allium vegetables (5458 patients with CRC including 7,125,067 person-years) and 5 studies with 11 reports of the effects of garlic supplements (2685 patients with CRC including 2,304,439 person-years). We found no association between higher intake of allium vegetables and CRC risk (relative risk [RR], 1.06; 95% confidence interval [CI], 0.96–1.17; P [ .26). Intake of allium vegetables did not correspond to CRC risk (P for nonlinear [ .24, P for linear [ .20). In subgroup analysis, a higher consumption of allium vegetables was associated marginally with increased risk of colon cancer among women (RR, 1.23; 95% CI, 1.01–1.50; P [ .05). Use of garlic supplements was associated significantly with an increased risk of CRC (RR, 1.18; 95% CI, 1.02–1.36; P [ .03).
CONCLUSIONS:
In a meta-analysis, we found no evidence that higher intake of allium vegetables reduced the risk for CRC. We observed that garlic supplements increased the risk for CRC, but this finding requires external validation.
Keywords: Diet; Cancer Risk Factor; Prevention; Review.
olorectal cancer (CRC) ranks as the third most common cancer worldwide,1 and the incidence of CRC varies 10-fold in both sexes across countries, but almost 60% of the cases occur in developed countries.1 The considerable geographic difference in CRC incidence rates suggests that environmental factors such as diet may play an important role in the development of CRC. Allium genus is characterized by a high content of organosulfur compounds and flavonoids, which have shown beneficial effects against various cancers including CRC.2–4 The most widely used allium vegetables are garlic, onion, and leeks. A body of laboratory studies5–8 has indicated that allium vegetables and related supplements have protective effects against CRC, however, epidemiologic studies have yielded inconsistent results. An expert review panel organized by the World Cancer Research Fund and the American Institute for Cancer Research concluded that garlic intake was a “probable” protective factor against CRC.9 A
C
meta-analysis10 of 7 studies showed that high intake of garlic might have a protective effect against CRC. However, 2 recent prospective studies11,12 including 3 large cohorts found no significant association between garlic intake and risk of CRC. Similarly, data on the associations of onion and leek intakes with CRC also have been inconsistent.13–15 Among allium vegetable-related supplements, the most widely used is a garlic supplement, which was combined with garlic intake in the previous meta-analysis. Nevertheless, some studies11,16 found that garlic supplements were associated significantly with an increased risk of CRC. Given the widespread use of garlic
Abbreviations used in this paper: CI, confidence interval; CRC, colorectal cancer; RR, relative risk. © 2014 by the AGA Institute 1542-3565/$36.00 http://dx.doi.org/10.1016/j.cgh.2014.03.019
2
Zhu et al
supplements,17 it is important to assess its long-term effects. Therefore, we conducted a meta-analysis (including a dose-response approach) based on prospective studies to comprehensively and precisely assess associations between intake of allium vegetables, garlic supplement use, and risk of CRC.
Clinical Gastroenterology and Hepatology Vol.
-,
No.
-
provided the intake frequency of allium vegetables, when the study provided the amount of intake, we transformed it into frequency. The individual authors were contacted via e-mail if the data of interest were not provided in the publication. We also checked the references of all retrieved articles to identify additional studies.
Statistical Analysis
Methods Literature Search and Eligibility Criteria We searched the Medline and Embase databases from inception to October 2013, targeting the studies investigating the relationship between allium vegetables, garlic supplements, and CRC risk. To perform a comprehensive literature search, we used the following combined terms: the MeSH headings and keywords relating to “colorectal neoplasms,” the MeSH heading “allium” and the keywords regarding exposure (garlic, onion, leeks, scallion, chive, garlic supplement, vegetables, food, and diet), restricting our search to Englishlanguage articles. Reference lists of eligible studies and relevant review articles also were scanned to identify further pertinent studies. Studies were considered eligible if they met the following criteria: (1) the design of the study was prospective such as a cohort or casecohort study; (2) the study investigated the relationship of allium vegetables or garlic supplements and CRC risk; and (3) the study provided or allowed the calculation of relative risk (RR) with 95% confidence intervals (CIs). We excluded nonhuman studies, case reports, comparative studies not using an analytic epidemiologic design, or studies that did not report analyses of primary data (eg, letters, editorials, or narrative reviews), and studies that did not provide sufficient data. When multiple studies pertained to the same or partially overlapping populations, we used the results with the longest follow-up time or largest sample size.
Data Extraction All data were extracted independently and crosschecked by 2 reviewers. For eligible studies, the following data were extracted by 2 authors independently: the first author, publication year, geographic region, demographics of participants, sample size (number of case and total participants), duration of follow-up evaluation, covariates adjusted in the multivariable analysis, allium vegetables, garlic supplement consumption categories, and the RR (with the 95% CI) with the corresponding number of cases and person-years for each category. If the person-years were not presented, they were estimated as a product of the number of subjects times the mean follow-up duration. We extracted the RRs that represented the greatest degree control of potential confounders. For comparability, for most studies that
The RRs and 95% CI were considered as the effect size for all studies, and we extracted the maximally adjusted RR (95% CI). Any results stratified by sex or tumor site were treated as separate reports. We quantified the relationship between allium vegetables, garlic supplements, and CRC risk by pooling the RRs for the highest vs the lowest category in a random-effects model as described by DerSimonian and Laird18 when the between-study heterogeneity was significant (P < .05), otherwise a fixed-effect model was used. To precisely evaluate the association between allium vegetable intake and risk of CRC, a random-effects doseresponse meta-analysis was performed according to the method described by Greenland and Longnecker19 and Orsini et al.20 Furthermore, a potential curve-linear relationship between allium vegetables and CRC risk was assessed using restricted cubic splines with 3 knots at fixed percentiles (10%, 50%, and 90%) of the distribution.21 A P value for curve linearity or nonlinearity was calculated by testing the null hypothesis that the coefficient of the second spline is equal to zero. We quantified the extent of heterogeneity using the Q test22 and the I2 score.23 Stratified analyses were performed, if feasible, according to allium vegetable species, sex and site, geographic region, number of cases, and duration of follow-up evaluation. A sensitivity analysis also was performed. Funnel plots and the Egger test24 were applied to examine the publication bias. All statistical analyses were performed with Stata version 10.0 (STATA Corp, College Station, TX). All statistical tests were 2-sided.
Results Study Characteristics The main characteristics of the studies included in this meta-analysis are summarized in Tables 1 and 2. Eight studies on allium vegetables11,12,15,25–27 involved a total of 5458 CRC patients and 7,125,067 person-years of follow-up. The articles by Meng et al12 and Lin et al26 each included 2 studies. Five eligible cohort studies11,12,15,16 on garlic supplements, involving a total of 2685 patients and 2,304,439 person-years of followup, were finally included in this study. The article by Meng et al12 included 2 studies. The follow-up duration varied from 3.3 years to 10 years. The literature search and selection procedures are shown in Supplementary
Sellers et al,25 1998, United States
Source of participants Iowa Women’s Health Study
McCullough Cancer et al,11 2012, Prevention United States Study II Nutrition Cohort
Nurses’ Health Study
1130
1339
35,216
99,700
76,208
10
7
24
55–69
69
30–55
Site Colon
Colorectal
Sex F
Exposure Garlic 0 serving/wk 1 serving/wk >1 serving/wk
0 serving/wk 1 serving/wk >1 serving/wk M (579) Garlic F (551)
