The association of fish consumption with bladder cancer risk: A meta-analysis
© Li et al; licensee BioMed Central Ltd. 2011
Received: 19 June 2011
Accepted: 19 September 2011
Published: 19 September 2011
The association between fish consumption and risk of bladder cancer has not been established yet. The results from epidemiological studies are inconsistent.
We conducted a meta-analysis of cohort and case-control studies on the relationship between fish intake and bladder cancer. We quantified associations with bladder cancer using meta-analysis of relative risk associated to the highest versus the lowest category of fish intake using random effect models. Heterogeneity among studies was examined using Q and I2 statistics. Publication bias was assessed using the Begg's funnel plot.
Five cohort and 9 case-control studies were eligible for inclusion. The combined relative risk showed that fish consumption was negatively, but not significantly, associated with a decreased risk of bladder cancer (relative risk, 0.86; 95% confidence interval, 0.61-1.12). In subgroup analyses, there was no evidence that study design, geographical region, case sample size, or exposure assessment substantially influenced the estimate of effects.
The overall current literature on fish consumption and the risk of bladder cancer suggested no association. Because of the limited number of studies, further well-designed prospective studies are needed to explore the effect of fish on bladder cancer.
Bladder cancer is the second most common urologic malignancy and the seventh most common cancer in men. It has been estimated that 386,300 patients are newly diagnosed with bladder cancer worldwide in 2008, and approximately 150,200 patients were expected to die of it . Depending on its stage and grade, bladder cancer may be treated with surgery, radiation therapy, chemotherapy, or immunotherapy. Because bladder cancer has the highest lifetime treatment cost of any cancer, and direct exposure to carcinogens is implicated in bladder cancer development and many potentially protective compounds are concentrated in urine, making it an ideal target for preventive therapies .
Smoking, occupational exposure, and chronic infections with schistosoma are the most established risk factors for bladder cancer. At present, evidence on dietary factors is also accumulating. Fish plays an important role in the usual diet worldwide and is an ideal source of n-3 polyunsaturated fatty acids, which may lower cancer risk by suppressing mutations, inhibiting cellular proliferation, and inducing cell apoptosis [3–5]. A report by the World Cancer Research Fund and the American Institute for Cancer Research on the relationship between diet and cancer concluded, based on a comprehensive review of epidemiologic studies, that fish consumption may possibly protect against cancers of the colon, rectum, and ovary . Less attention, however, has been paid to the role of fish consumption on bladder cancer risk. Several epidemiological studies have examined the association between fish intake and the risk of bladder cancer; the majority of results are null, which could possibly be attributable to lack of statistical power in individual studies. Thus, we conducted a meta-analysis of all published studies to evaluate the relationship between fish consumption and bladder cancer.
2. Methods and materials
2.1 Search strategy
We identified studies by a literature search of the PubMed databases up to January 2011 with the following key words: "fish," "meat," or "diet" combined with "bladder cancer," "urothelial cancer," or "urinary tract cancer." In addition, we reviewed the reference lists from all relevant articles to identify additional studies. All searches were conducted independently by two authors. The results were compared, and any questions or discrepancies were resolved through iteration and consensus.
2.2 Study selection
Following criteria were used to identify relevant studies for the meta-analysis. First, they had to be case-control or cohort studies in English language. Second, the studies needed to examine fish consumption as a risk factor for bladder cancer. Last, each study should provide risk estimate together with its corresponding 95% confidence interval (CI) adjusted for at least age, sex and smoking (or sufficient information to calculate it). We also included the articles evaluating the risk of urinary tract cancer with fish consumption, for bladder cancer accounts for the overwhelming majority of tumors, and the renal pelvis and ureter are covered by the same urothelium. The term bladder cancer was used as a synonym for these neoplasms.
2.3 Data extraction
The following data were extracted independently by two authors from each study: the name of the first author, year of publication, the country in which the study was conducted, study design, study period, sample size, exposure of fish consumption, risk estimates with corresponding 95% CIs for highest vs lowest level of fish consumption, covariates controlled for in the analysis and exposure assessment. Because bladder cancer is a rare disease, OR can be interpreted as RR. For simplicity, we report all results as RR.
2.4 Statistical analysis
We estimated a pooled RR with 95% CI based on random-effects models, which incorporates both within and between-study variability . One study reported sex-stratified RRs, we calculated the overall sex-adjusted RR by combining the two estimates with the method of Mantel and Haenszel . Heterogeneity was assessed using Q-test  and I2 score , and statistical significance was considered while P < 0.05. A sensitivity analysis was conducted to test the impact of each study on the pooled estimates by removing each study from the meta-analysis separately. Publication bias was assessed through visual inspection of funnel plots, and tests of Begg . We performed meta-regression analysis to explore the influence of study design, geographical region and publication years in the heterogeneity. All statistical analyses were conducted using Stata (StataCorp, College Station, Texas).
Study characteristics of published cohort and case-control studies on fish intake and bladder cancer
Authors and publication year
RR (95% CI)
Variables of adjustment
Steineck et al.
Ever vs ever
Age, sex and smoking
Steineck et al.
Weekly vs more seldom
Age, sex and smoking
Riboli et al.
The highest vs the first quartile
Age, smoking and total calories
Chyou et al.
≥ 5 times/wk vs ≤ once/wk
Fernandez et al.
≥ 2 servings/wk vs < 1 serving/wk
Age, sex, area of residence, education, smoking, alcohol consumption, and body mass index
Nagano et al.
≥ 5 times/wk vs ≤ once/wk
Age, gender, radiation dose, smoking status, education level, body mass index and calendar time
Wakai et al.
The highest vs the first quartile
Age, sex, smoking and occupational history as a cook.
Balbi et al
The highest vs the first tertile
Age, sex, residence, urban/rural status, education, body mass index, tobacco smoking, 'mate' drinking, and total calories.
Sakauchi et al.
Almost every day vs 1-2 times/month
Age, sex and smoking
Baena et al.
≥ 3 times/wk vs never
Age, smoking, water intake
Holick et al.
≥ 1 serving/day vs 1-3 serving/month
Men 0.71 (0.48-1.04)
Women 1.33 (0.74-2.40)
Age, sex, total caloric intake, pack-years of cigarette smoking, and current smoking
Garcı'a-Closas et al.
The highest vs the first quintile
Age, gender, region, smoking status, duration of smoking and quintiles of fruit and vegetable intake
Hu et al.
The highest vs the first tertile
Age, province, education, body mass index, sex, alcohol, smoking, total of vegetable and fruit intake, and total energy intake
Brinkman et al.
The highest vs the first tertile
Sex, age, smoking status, number of cigarettes smoked per day, number of years smoking, occupational exposure to PAHs or aromatic amines and energy intake.
Summary of pooled risk ratios of bladder cancer for fish consumer by study design, geographical region, and exposure assessment
Number of studies
Q-test for heterogeneity
0.84 (0.42, 1.26)
0.87 (0.54, 1.21)
Hospital-based case-control studies
0.88 (0.40, 1.36)
Population-based case-control studies
0.83 (0.63, 1.03)
0.95 (0.49, 1.42)
0.80 (0.58, 1.02)
0.76 (0.25, 1.27)
0.88 (0.40, 1.36)
0.84 (0.58, 1.09)
Case sample size
0.99 (0.82, 1.17)
0.68 (0.34, 1.02)
Meta-regression analysis was used to explore the influence of publication year, geographical region, study design, case sample size and exposure assessment in the heterogeneity. However, none of them was identified as a possible source of heterogeneity among all the included studies.
Diet is considered to play a very important role in preventing cancer. Fish is an important aspect of diet that has been linked favorably or unfavorably to the risk of several cancers. On the one hand, there are serious concerns about mercury and other environmental impurities that accumulated in fish. On the other hand, fish is regarded as a terrific source of polyunsaturated fatty acids. This present study is the first meta-analysis summarizing the evidence to date regarding the association between fish consumption and bladder cancer risk. Overall, the summary RR for all of the studies suggested no significant association between fish consumption and the bladder cancer risk. There was a significant heterogeneity among the studies. However, the results were also non-significant when the case-control or cohort studies were evaluated individually, or in subgroup analysis by geographical regions, case sample size and exposure assessment. Moreover, we did not identify any potential sources of heterogeneity using meta-regression analysis.
We noted that the associations between fish intake and bladder cancer risk were negative in all studies published after 2000, while the RRs for studies before 2000 tend to be positive (Table 1). This might be explained in part by the improvement of the adjustment for smoking in recent years. Cigarette smoking is one of the most important risk factors for bladder cancer, so it is possible that smoking may confound the fish-bladder cancer association if not properly controlled for, which may be particularly true in older studies, leading to spurious positive associations between fish intake and bladder cancer risk. However, we could not provide the separate meta-analyses for nonsmokers and smokers because of the few studies available.
The association between fish intake and bladder cancer is biologically plausible. Fish and fish oil are a rich source of long-chain, n-3 polyunsaturated fatty acids (PUFA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). The n-3 fatty acids is suggested to reduce cancer risk via several potential mechanisms, including modulation of eicosanoid production and inflammation, angiogenesis, proliferation, susceptibility for apoptosis, and estrogen signaling, which are variables that are key drivers in cancer progression . Using animal models, researchers have found that supplementing the diet of tumor-bearing mice or rats with purified n-3 fatty acids has slowed the growth of various types of cancers [28–30]. In addition, intake of oils containing EPA or DHA has also been shown to suppress cancer growth in animal studies [31–33]. However, no data regarding to the effects of fish ingredients on bladder cancer has been published.
The present study has important limitations which should be considered when interpreting our results. First, fish consumption includes fatty fish, which are much higher in the fatty acids, as well as fish that are lower in marine fatty acids, and many studies have also reported increased cancer risks associated with consumption of salted fish. However, we only assessed total fish consumption because most of these studies were not primarily designed to investigate the effect of fish consumption on bladder cancer risk, and did not specify what type of fish was consumed, providing one explanation for the heterogeneity of the study. Second, only articles published in the English language were included, and we did not search for unpublished studies or original data, although no publication bias was indicated visually or in formal statistical testing. Third, the classification of exposure varied considerably across the included studies, and the different amount of fish consumption may contribute to the heterogeneity among studies in the analysis of the highest versus the lowest intake categories.
In conclusion, in this meta-analysis of 5 cohorts and 9 case-control studies, we did not found fish consumption was associated with reduced risk of bladder cancer. Given the small number of cohort studies included in this meta-analysis, further prospective cohort studies with larger sample size, well-controlled confounding factors, and more accurate assessment of fish consumption are needed to affirm the effect of fish on bladder cancer.
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