Cancer Causes Control DOI 10.1007/s10552-014-0469-0
ORIGINAL PAPER
Intake of fruit and vegetables and risk of bladder cancer: a dose–response meta-analysis of observational studies Baodong Yao • Yujie Yan • Xianwu Ye Hong Fang • Huilin Xu • Yinan Liu • Sheran Li • Yanping Zhao
•
Received: 2 February 2014 / Accepted: 9 September 2014 Ó Springer International Publishing Switzerland 2014
Abstract Background Observational studies suggest an association between fruit and vegetables intake and risk of bladder cancer, but the results are controversial. Methods We therefore summarized the evidence from observational studies in categorical, linear, and nonlinear, dose–response meta-analysis. Pertinent studies were identified by searching EMBASE and PubMed from their inception to August 2013. Results Thirty-one observational studies involving 12,610 cases and 1,121,649 participants were included. The combined rate ratio (RR, 95 % CI) of bladder cancer for the highest versus lowest intake was 0.83 (0.69–0.99) for total fruit and vegetables, 0.81 (0.70–0.93) for total vegetables, 0.77 (0.69–0.87) for total fruit, 0.84 (0.77–0.91) for cruciferous vegetables, 0.79 (0.68–0.91) for citrus fruits, and 0.74 (0.66–0.84) for yellow–orange vegetables. Subgroup analysis showed study design and gender as possible sources of heterogeneity. A nonlinear relationship was found of citrus fruits intake with risk of bladder cancer (Pfor nonlinearity = 0.018), and the RRs (95 % CI) of bladder cancer were 0.87 (0.78–0.96), 0.80 (0.67–0.94), 0.79 (0.66–0.94), 0.79 (0.65–0.96), and 0.79 (0.64–0.99) for 30, 60, 90, 120, and 150 g/day. A nonlinear relationship was Electronic supplementary material The online version of this article (doi:10.1007/s10552-014-0469-0) contains supplementary material, which is available to authorized users. B. Yao Y. Yan H. Fang H. Xu Y. Liu Y. Zhao (&) Shanghai Minhang Center for Disease Control and Prevention, 965 Zhongyi Road, Shanghai 201101, China e-mail: [email protected] X. Ye S. Li The Fifth People’s Hospital of Shanghai, Fudan University, Shanghai, China
also found of yellow–orange vegetable intake with risk of bladder cancer risk (Pfor nonlinearity = 0.033). Some evidence of publication bias was observed for fruit, citrus fruits, and yellow–orange vegetables. Conclusion This meta-analysis supports the hypothesis that intakes of fruit and vegetables may reduce the risk of bladder cancer. Future well-designed studies are required to confirm this finding. Keywords Bladder cancer Bladder neoplasms Meta-analysis Fruit Vegetable
Introduction Bladder cancer, the 10th most common cancer worldwide, represents an important health problem [1]. Around 350, 000 cases were recorded in 2002, accounting for around three per cent of all cancers. In the USA, an estimated 72, 570 cases were newly diagnosed with bladder and 15, 210 will die from this disease in 2013 [2]. Tobacco smoking is the well-established behavioral risk factor for bladder cancer [3], with 50 % of newly diagnosed cases estimated to be attributable to the effects of smoking [3]. In addition, occupational exposure to aromatic amines (AAs) [4] and schistosomal infections [5] is known to cause bladder cancer. The established causal risk factors for bladder cancer do not fully explain bladder cancer incidence. Intake of fruit and vegetables has been hypothesized to protect against several cancers, including bladder cancer [6]. Several epidemiological studies investigated associations between fruit and vegetables intake and bladder cancer risk [7–9]. The report from the World Cancer Research Fund and the American Institute for Cancer
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Research (WCRF/AICR) in 2007 stated that no conclusions could be reached for associations between fruit and vegetables intake and bladder cancer risk [1]. Since this report was published, other relevant studies on this association have been published [10–13], but the results were inconsistent. A review by Brinkman and Zeegers published in 2008 [14] concluded that fruit, citrus fruits, cruciferous vegetables, and yellow–orange vegetables were identified as having a possible protective effect. But the exact shape of the dose–response relationship between the intake of fruit and vegetables and bladder cancer risk has not been clearly defined. Therefore, to better characterize this issue, we conducted a dose–response meta-analysis of observational studies to summarize the epidemiologic evidence on the association between fruit and vegetables intake and bladder cancer risk.
Methods Literature search We systematically identified articles through searching EMBASE and PubMed from their inception to August 2013 using the following keywords vegetable or fruit combined with bladder cancer or neoplasm. No language restrictions were imposed. We also manually reviewed the reference lists of relevant publications to search for additional articles. Two researchers independently reviewed all potentially relevant articles to determine whether an article met the general inclusion criteria, and disagreement was resolved by discussion between the researchers. All studies were included, if they met the following criteria: (1) a case– control or cohort study; (2) the exposure of interest was fruit or vegetables intake (total fruit and vegetables, fruit, vegetables, or their subgroups); (3) the outcome of interest was bladder cancer, and (4) multivariate adjusted odds ratios (OR), rate ratios (RR), or hazard ratios (HR) with 95 % confidence interval (CI). When multiple publications from the same study were available, we used the most recent studies or studies with the largest number of cases. Data extraction The following data were collected from all studies: the first author’s name, study design, year of publication, country where the study was performed, the number of cases and controls or participants, type of controls, the methods used for collection of data on exposure, years of follow-up in cohort study, sex, participant age at baseline, variables adjusted for in the multivariable analysis, as well as multivariate adjusted RRs with their 95 % CIs for each
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category of fruit and vegetables intake. We extracted the RRs that reflected the greatest degree of adjustment for potentially confounding variables. Data extraction was conducted by two investigators, with disagreements being resolved by consensus. For every study, the median or mean fruit and vegetables intake for each category were assigned to each corresponding RR. When the levels of fruit and vegetables intake were given by a range, the value of exposure was assigned as the midpoints of the ranges of the reported categories of fruit and vegetables intake. If the upper boundary of the highest category was not provided, we assumed that the boundary had the same amplitude as the adjacent category. When the lowest category was openended, we set the lower boundary to zero. Some studies included in this meta-analysis reported fruit and vegetables intake with different measurement units (e.g., g/day, servings/month, or times/week). We standardized all data into g/day. If the intakes were reported in densities (i.e., g/d/1,000 kcal), we recalculated the reported intakes to absolute intakes using the mean or median energy intake. In studies that report intakes as frequency, we converted a serving size as 80 g according to other meta-analysis [15, 16]. When fruit and vegetable intake was expressed in portions/day, the exposure level was transformed into g/d by multiplying this quantity by 106 g according to study from Dauchet et al. [17]. Statistical analysis A combined measure was calculated as the inverse variance-weighted mean of the natural logarithm of multivariate adjusted RRs with 95 % CI to assess the association of fruit and vegetables intake with bladder cancer risk for the highest versus lowest levels. The I2 of Higgins and Thompson was used to assess heterogeneity among studies [18]. I2 describes the proportion of total variation attributable to between-study heterogeneity as opposed to random error or chance. In the presence of substantial heterogeneity (I2 [ 50 %) [19], the DerSimonian and Laird random-effect model was adopted as the combining method; otherwise, the fixed-effect model was used as the combining method. In an attempt to evaluate the possible publication bias, Egger’s test (linear regression method) was used [20]. An analysis of influence was conducted [21], which describes how robust the combined estimator is to the removal of individual study. An individual study is suspected of excessive influence, if the point estimate of its omitted analysis lies outside the 95 % CI of the combined analysis. Subgroup analyses were carried out to investigate potential sources of between-study heterogeneity. For the dose–response analysis, studies included must provide the following information: the number of cases and
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were case–control studies, and 11 were cohort studies. The main characteristics of these articles are presented in Tables 1 and 2. The articles combined had a total of 1,121,649 individuals with 12,610 bladder cancer events. Fourteen articles were conducted in Europe, five in Asia, eleven in North America, and one in South America. The study population in 22 articles consisted of both sexes, seven articles included men only, and two articles included women only. Most articles provided RR estimates that were adjusted for age (30 articles) and smoking (30 articles). Total fruit and vegetables High versus low analyses
Fig. 1 Selection of articles in the meta-analysis
participants (person-years) or controls, and RR with 95 % CI for each category of fruit and vegetables intake. A twostage random-effects dose–response meta-analysis was performed proposed by Orsini et al. [22] to compute the trend from the correlated log RR estimates across categories of fruit and vegetables intake taking into account the between-study heterogeneity. Briefly, a restricted cubic spline model, with three knots at the 25th, 50th, and 75th percentiles [23] of fruit and vegetables intake levels, was estimated using generalized least square regression taking into account the correlation within each set of published RRs [24]. Then, the restricted maximum likelihood method in a multivariate random-effect meta-analysis was [25] used to combine the study-specific estimates. A p value for nonlinearity was calculated by testing the null hypothesis that the coefficient of the second spline is equal to 0 [26]. All statistical analyses were performed with STATA version 12 (Stata Corporation, College Station, TX, USA). p value \ 0.05 was considered statistically significant.
Results Study characteristic Figure 1 shows a flow diagram of how we selected relevant articles. We identified 33 potentially relevant articles [7–13, 27–52]. Two articles were excluded because of overlapping publications from the same study population [43, 52]. Thus, a total of 31 case–control and cohort articles met our inclusion criteria. Among these 31 publications, 20
Data from 10 articles (two case–control publications and eight cohort publications) [7, 13, 38, 44, 45, 47–51] with 11 studies investigated the association between total fruit and vegetable intake and bladder cancer risk, because one publication [13] provided two separate results (for men and women) (please see Supplementary Table 1 for detailed information on the intake distribution of total fruit and vegetables in the subgroups of studies). The data included 3,715 cases among 583,117 participants. The combined RR for high versus low intake was 0.83 (95 % CI 0.69–0.99) with moderate between-study heterogeneity (Pheterogeneity = 0.014, I2 = 55.0 %) (Fig. 2a). We conducted subgroup analyses to explore the sources of heterogeneity (Table 3). An inverse association was observed in case–control studies (RR 0.76, 95 % CI 0.59–0.99) but not in cohort studies (RR 0.85, 95 % CI 0.68–1.06). Analyses stratified by gender showed that there were inverse associations between total fruit and vegetables intake with bladder cancer risk in studies including both male and female participants (RR 0.82, 95 % CI 0.70–0.97). But the associations were not statistically significant in studies including only male or female participants (RR 0.94, 95 % CI 0.77–1.14; RR 0.62, 95 % CI 0.20–1.86). Results were consistent for studies conducted in the USA (RR 0.74, 95 % CI 0.51–1.06) and in Europe (RR 0.92, 95 % CI 0.78–1.07). Total fruit and vegetables intake was not associated with bladder cancer risk across categories of different smoking status. Sensitivity analysis excluding one study at a time did not substantially modify the findings. No significant publication bias was found according to Egger’s test (p = 0. 714). Dose–response analysis Five articles [38, 47, 48, 50, 51] were available to evaluate the dose–response association of total fruit and vegetables
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123
Finland
USA
Sweden
Europe
USA
Michaud et al. [49]
Holick et al. [51]
Larsson et al. [50]
Ros et al. [12]
Park et al. [13]
M/F
M/F
M/F
F
M
M/F
M/F
M/F
45–75
25–70
–
30–55
50–69
55–69
40–75
–
74.9(M)/ 73.8(F)
–
Age (year)
185,885
468,656
82,002
88,796
27,111
120,852
38,540
47,909
7,995
11,580
16,477
Cohort size
12.5
8.9
9.4
20
11
6.3
1979–1993
1986–1996
22
1981–1989
14
Years of follow-up
M male, F female, FFQ food-frequency questionnaire, BMI body mass index
Netherlands
Zeegers et al. [48]
USA
Japan
M
USA
Chyou et al. [46] Michaud et al. [47]
Nagano et al. [9]
M
USA
Shibataet al. [45]
M/F
Sweden
Steineck et al. [44]
Sex
Country and study Period
References
581
947
485
237
344
619
114
252
96
71
70
No. of cases
Cancer registry/ health insurance records/ pathology hospital registries Cancer registry/ death certificate files
Cancer registry
Medical records/ self-reported
Cancer registry
Cancer registry
Cancer registry
Hospital/cancer registry Medical records/ self-reported
Hospital records
Cancer registry
Case assessment
A quantitative FFQ
A validated FFQ
A validated FFQ
FFQ
A 276-food item dietary questionnaire
A 150-item semiquantitative FFQ
FFQ
FFQ/A 24-h diet recall history A 131-item FFQ
A detailed health questionnaire
A questionnaire
Exposure measurement
Table 1 Main characteristics of cohort articles included in the meta-analysis, ranked by year of publication
Quartiles
Tertiles
Quartiles
Quintiles
Quintiles
Quintiles
Tertiles
Quintiles
Tertiles
Tertiles
–
Exposure categories
Age at cohort entry, ethnicity, total energy intake, first-degree family history of bladder cancer, employment in a high-risk industry, smoking, and interactions of ethnicity with smoking status
Age at entry, sex, center, smoking status, duration of smoking, lifetime intensity of smoking, energy intake from fat, and nonfat sources
Age, sex, education, smoking status, pack-years of smoking, and total energy intake
Age, pack-years of cigarette smoking, current smoking, and total caloric intake
Age, duration of smoking, smoking dose, total energy, and trial interventions
Age, sex, smoking, and total vegetable consumption (for fruits items) or total fruit consumption (for vegetable consumption)
Age, gender, radiation exposure, smoking status, educational level, BMI, and calendar time
Age, smoking status, geographic region, total fluid intake, and caloric intake
Age and smoking
Age and smoking
Age and gender
Adjustments
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Italy
USA
China
Germany
Japan
Italy
Uruguay
Italy
USA
Japan
USA
Belgium
Spain
Italy
USA
Negri et al. [28]
Bruemmer et al. [29]
Yu et al. [30]
Pohlabeln et al. [31]
Wakai et al. [32]
Peluso et al. [33]
Balbi et al. [7]
Pelucchi et al. [34]
Castelao et al. [8]
Wakai et al. [35]
Schabath et al. [36]
Kellen et al. [37]
Garcı´a-Closas et al. [38]
Sacerdote et al. [39]
Tang et al. [40]
USA
Spain
Riboli et al. [27]
Lin et al. [41]
Country
References
M/F
M/F
M
M/F
M/F
M/F
M/F
M/F
F
M/F
M
M/F
M/F
M/F
M/F
M/F
M
Sex
64.47(case)/ 64.99(control)
21–92
40–75
65.3(case)/ 64.0(control)
67.67(case)/ 64.26(control)
63.4(case)/ 62.4(control)
20–79
25–64
30–79
40–89
45–74
20–99
65.6
C20
884
275
266
912
200
409
124
1,592
110
144
162
297
300
217
262
365
\75 45–65
432
No. of cases
\80
Age (year)
(H)
878
(H)
825
(H)
193
(H)
873
(P)
385
(H)
451
(H)
620
(P)
1592
(H)
298
(H)
576
(H)
104
(P)
295
(H)
300
(H)
254
(P)
405
(H)
6,147
(H and P)
789
No. of control method)
A 45-min FFQ
A 44-itemfood FFQ
A 22-item FFQ
FFQ
A standardized FFQ
FFQ
FFQ
A structured FFQ
A structured FFQ
A detailed FFQ
A 24 h recall interview
A well-validated FFQ
A standardized FFQ
FFQ
FFQ
FFQ
FFQ
Exposure measurement
Table 2 Main characteristics of case–control articles included in the meta-analysis, ranked by year of publication
Quartiles
Quartiles
–
Quintiles
Tertiles
Tertiles
Quartiles
Quintiles
Tertiles
Tertiles
–
Quartiles
–
Quartiles
Quartiles
Tertiles
Quartiles
Exposure Categories
Age, sex, ethnicity, smoking, total energy intake, and alcohol consumption
Age, education level, gender, total meat intake, smoking status, and pack-years
Age, smoking status, and maximum number of cigarettes
Age, gender, region, and smoking
Age, sex, smoking, and occupational exposure to PAHs or AAs
Age, gender, ethnicity, smoking, and total energy
Age, sex, year of first visit and cumulative consumption of cigarettes
Age, sex, race, education, nonsteroidal anti-inflammatory drugs, number of years employed as a hairdresser/barber and smoking
Age, study center, education, BMI, coffee and alcohol consumption, and smoking
Age, sex, residence, urban/rural status, education, BMI, smoking, drinking, and total calories
Age and smoking
Age, gender, hospital, smoking, occupational history, and energy intake
Age, sex, area of residence, and smoking
Age, sex, residence, income, education, occupation, pack-years, saccharine use, taking analgesics, and urinary disease
Age, sex, smoking, and county
Age, sex, residence, education, and smoking
Age, sex, residence, total calories and smoking
Adjustments
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Age, sex, smoking status, smoking duration, smoking amount, and other food groups
Age, gender, region, race, Hispanic status, smoking status, usual BMI, and total energy
Smoking, exposure to AAs and/or PAHs, coffee drinking
FFQ (H)
469 487 63.5 M/F Isa et al. [11]
China
(P)
M male, F female, FFQ food-frequency questionnaire, H hospital-based, P population-based, BMI body mass index, PAHs polycyclic aromatic hydrocarbons, AAs aromatic amines
Quartiles
Quartiles 1,171 M/F Wu et al. [10]
USA
[30
1,418
A self-administered FFQ
Quartiles FFQ 180
(H)
185 20–80 M Italy Pavanello et al. [42]
Sex Country
Table 2 continued
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intake with bladder cancer risk. The data included 2,419 cases among 222,521 participants. The departure from nonlinear relationship was not significant (Pfor nonlinearity = 0.454), and the risk of bladder cancer decreased by 3 % (RR 0.97, 95 % CI 0.95–0.99) for 100 g/day increment in total fruit and vegetables intake. The RRs (95 % CI) of bladder cancer were 1.00 (0.99–1.00), 0.96 (0.92–1.00), 0.92 (0.86–0.99), 0.90 (0.83–0.98), and 0.89 (0.80–0.99) for 100, 200, 300, 400, and 500 g/day. Total vegetables
References
Age (year)
No. of cases
No. of control method)
Exposure measurement
Exposure Categories
Adjustments
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High versus low analyses Data from 20 articles [7, 10, 12, 13, 27–30, 33, 37–41, 45, 47–51] (12 case–control publications and eight cohort publications) with 21 studies investigated the association between total vegetables intake and bladder cancer risk, because one publication [13] provided two separate results (for men and women) (please see Supplementary Table 1 for detailed information on the intake distribution of total vegetables in the subgroups of studies). The data included 8,826 cases among 1,050,928 participants. The combined RR for high versus low intake was 0.81 (95 % CI 0.70–0.93) with moderate between-study heterogeneity (Pheterogeneity \ 0.001, I2 = 66.0 %) (Fig. 2b). We then conducted subgroup analyses by study design, gender, geographic locations, number of cases, and smoking status (Table 3). Analyses stratified by study design showed that there were inverse associations between total vegetables intake with bladder cancer risk in case–control studies (RR 0.73, 95 % CI 0.59–0.92), not in cohort studies (RR 0.91, 95 % CI 0.82–1.02). An inverse association was observed in studies including both male and female participants (RR 0.76, 95 % CI 0.63–0.92). In stratified analysis by geographic locations, the RRs were 0.84 (95 % CI 0.74–0.95) for studies in USA and 0.81 (95 % CI 0.64–1.03) for studies in Europe. The associations between total vegetables intake with bladder cancer risk were not statistically significant in each subgroup analysis that was stratified by smoking status. In the sensitivity analysis in which one study at a time was excluded and the rest were analyzed, we detected significantly inverse association between total vegetable intakes and bladder cancer risk (range of summary RRs 0.69–0.95 with the largest limit of the 95 % CI never crossing 1.0). No significant publication bias was found according to Egger’s test (p = 0. 389). Dose–response analysis Eleven articles [10, 28, 30, 37, 38, 40, 41, 47, 48, 50, 51] were available to evaluate the dose–response association of
Cancer Causes Control Fig. 2 Forest plot of relative risk of high versus low analysis for fruit and vegetables intake with bladder cancer risk. ES effect size, IV inverse variance, D ? L DerSimonian and Laird, Ref. reference number. a Forest plot for total fruit and vegetables, b forest plot for total vegetables, c forest plot for total fruit
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123
4
2
M
F
5
1
0
USA
South America
Asia
5
C300
1
10
Yes
No
Adjustment for BMI or obesity
6
\300
Number of cases
5
Europe
Geographic locations
5
9
2
Number of studies
(0.70–1.02)
0.84
(0.41–1.09)
0.67
(0.74–0.94)
0.84
(0.53–1.03)
0.74
–
(0.41–1.09)
0.67
(0.51–1.06)
0.74
0.92 (0.78–1.07)
(0.21–1.86)
0.617
(0.77–1.14)
0.94
(0.70–0.97)
0.82
(0.68–1.06)
0.85
(0.59–0.99)
0.76
Summary estimate (95 % CI)
Total vegetables and fruit
Both M and F
Gender
Cohort
Case–control
Design
Sub-groups
0.011
–
0.284
0.012
–
–
0.007
0.275
\0.001
0.237
0.765
0.007
0.546
Pheterogeneity
57.9
–
20.6
65.9
–
–
71.6
21.9
91.8
29.1
0.0
62.3
0.0
I (%)
2
19
2
10
11
1
1
9
10
2
7
12
9
12
Number of studies
Vegetables
(0.69–0.95)
0.81
(0.68–1.06)
0.85
(0.67–0.99)
0.815
(0.72–0.96)
0.83
(0.3–1.2)
0.6
(0.40–1.09)
0.66
(0.74–0.95)
0.84
0.81 (0.64–1.03)
(0.31–2.09)
0.81
(0.79–1.06)
0.92
(0.63–0.92)
0.76
(0.82–1.02)
0.91
(0.59–0.92)
0.73
Summary estimate (95 % CI)
Table 3 Subgroup analyses of vegetables and fruit intake and bladder cancer risk, high versus low analyses
\0.001
0.279
\0.001
0.079
–
–
0.114
\0.001
0.004
0.224
\0.001
0.148
\0.001
Pheterogeneity
68.7
14.8
78.6
40.4
–
–
38.1
79.6
88.0
26.8
71.5
33.8
72.9
I (%)
2
23
4
11
16
4
1
10
12
3
10
14
11
16
Number of studies
Fruit
(0.67–0.86)
0.76
(0.76–1.12)
0.92
(0.73–1.01)
0.86
(0.62–0.79)
0.70
(0.56–0.92)
0.72
(0.77–0.98)
0.86
0.75 (0.62–0.92)
(0.58–1.03)
0.78
(0.62–0.95)
0.77
(0.65–0.89)
0.76
(0.79–0.98)
0.88
(0.60–0.85)
0.72
Summary estimate (95 % CI)
0.001
0.059
0.001
0.196
0.761
0.061
\0.001
0.140
0.024
0.001
0.127
0.001
Pheterogeneity
54.6
59.6
65.5
22.7
0.0
44.8
70.6
49.1
52.9
62.3
34.0
61.6
I2 (%)
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(0.432–0.773)
0.578
0.841
0.296 (0.819–1.231)
1.004
total vegetables intake with bladder cancer risk. The data included 5,315 cases among 232,215 participants. The departure from nonlinear relationship was not significant (Pfor nonlinearity = 0.513), and the risk of bladder cancer decreased by 6 % (RR 0.94, 95 % CI 0.89–0.99) for 100 g/day increment in total vegetables intake (Fig. 3a). The RRs (95 % CI) of bladder cancer were 0.96 (0.90–1.01), 0.92 (0.84–1.00), 0.85 (0.78–0.93), 0.77 (0.67–0.89), and 0.73(0.60–0.88), for 100, 200, 300, 400, and 500 g/day.
0.0
18.7
41.1 0.131 (0.589–1.040)
0.783
54.9 \0.001 0.77
(0.69–0.87)
I2 (%) Pheterogeneity Summary estimate (95 % CI)
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Number of studies
32.9 0.787 4
(0.584–1.062)
0.202
0.303
CI confidence interval, M male, F female, BMI body mass index
0.0 0.835 0.775 4 Current smokers
(0.567–1.061)
0.821
(0.666–1.012)
4 0.0 0.841 0.906
(0.719–1.142)
4 Former smokers
0.828
(0.623–1.101)
5 13.7 0.324 (0.586–1.171)
(0.60–1.60)
0.828 4 Smoking status Never smokers
4
4 17.5
48.3 0.101
– – (0.70–0.93)
– – 1 No
0.010 0.81 10 Yes
Adjustment for smoking
–
58.4
21
0 1.00
0.81
(0.67–0.99)
66.0 \0.001
27
I2 (%) Pheterogeneity Number of studies Pheterogeneity Number of studies
Summary estimate (95 % CI)
I2 (%)
Vegetables Total vegetables and fruit Sub-groups
Table 3 continued
6
High versus low analyses
Summary estimate (95 % CI)
Fruit
Total fruit
Data from 26 articles [7, 9, 10, 12, 13, 27–35, 37–41, 45–51] (16 case–control publications and 10 cohort publications) with 27 studies investigated the association between total fruit intakes and bladder cancer risk, because one publication [13] provided two separate results (for men and women) (please see Supplementary Table 1 for detailed information on the intake distribution of total fruit in the subgroups of studies). The data included 9,867 cases among 1,099,807 participants. The combined RR for high versus low intake was 0.77 (95 % CI 0.69–0.87) with moderate between-study heterogeneity (Pheterogeneity \ 0.001, I2 = 54.9 %) (Fig. 2c). We conducted subgroup analyses according to study design, gender, geographic locations, and number of cases (Table 3). The association between total fruit intake and bladder cancer was somewhat stronger among case–control studies than cohort studies and among studies including \300 cases than studies including 300 or more cases. The protective effect of fruit consumption was only found in current smoker, and the combined RR for high versus low intake was 0.58 (95 % CI 0.43–0.77) without between-study heterogeneity (Pheterogeneity = 0.841, I2 = 0.0 %). Sensitivity analysis excluding one study at a time did not substantially modify the findings. Egger’s test for publication bias was statistically significant (p = 0.003). Dose–response analysis Fifteen articles [9, 10, 28, 30, 34, 35, 37, 38, 40, 41, 46–48, 50, 51] were available to evaluate the dose–response association of total fruit intake with bladder cancer risk. The data included 5,792 cases among 279,593 participants. The departure from nonlinear relationship was not significant (Pfor nonlinearity = 0.068), and the risk of bladder cancer decreased by 7 % (RR 0.93, 95 % CI 0.88–0.98) for 100 g/day increment in total fruit intake (Fig. 3b). The RRs (95 % CI) of bladder cancer were 0.91 (0.85–0.98), 0.87
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Cancer Causes Control Fig. 3 The dose–response analysis between total fruit and vegetables intake and risk of bladder cancer in observational studies with restricted cubic splines in a multivariate random-effects dose–response model. The solid line and the long dash line represent the estimated relative risk and its 95 % confidence interval of the nonlinear relationship. Short dash line represents the linear relationship. a For total vegetables, b for total fruit, c for cruciferous vegetables, d for citrus fruits
(0.80–0.95), 0.87 (0.79–0.94), 0.86 (0.78–0.94), and 0.85 (0.76–0.88) for 100, 200, 300, 400, and 500 g/day.
publication bias was found according to Egger’s test (p = 0. 443).
Cruciferous vegetables
Dose–response analysis
High versus low analyses
Eight articles [8, 10, 36, 40, 41, 47, 50, 51] were available to evaluate the dose–response association of cruciferous vegetables intake with bladder cancer risk. The data included 5,189 cases among 223,675 participants. The departure from nonlinear relationship was not significant (Pfor nonlinearity = 0.924), and the risk of bladder cancer decreased by 32 % (RR 0.68, 95 % CI 0.56–0.81) for 100 g/day increment in total fruit intake (Fig. 3c). The RRs (95 % CI) of bladder cancer were 0.94 (0.91–0.97), 0.87 (0.82–0.93), 0.82 (0.74–0.90), 0.74 (0.65–0.86), and 0.70 (0.60–0.83) for 20, 40, 60, 80, and 100 g/day.
Data from 11 articles [8, 10, 13, 36, 39–41, 47, 49–51] (six case–control publications and five cohort publications) with 12 studies investigated the association between cruciferous vegetables intake and bladder cancer risk, because one publication [13] provided two separate results (for men and women) (please see Supplementary Table 1 for detailed information on the intake distribution of cruciferous vegetables in the subgroups of studies). The data included 6,496 cases among 441,657 participants. The combined RR for high versus low intake was 0.84 (95 % CI 0.77–0.91) with moderate between-study heterogeneity (Pheterogeneity = 0.146, I2 = 30.7 %). In the subgroup analysis, an inverse association was observed in case–control studies (RR 0.81, 95 % CI 0.73–0.90), but not in cohort studies (RR 0.86, 95 % CI 0.68–1.08). By geographic locations, an inverse association was observed in studies conducted in USA (RR 0.80, 95 % CI 0.73–0.88), but not in studies in Europe (RR 0.99, 95 % CI 0.81–1.20). Sensitivity analysis excluding one study at a time did not substantially modify the findings. No significant
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Yellow–orange vegetables High versus low analyses Data from five articles [8, 10, 13, 38, 41] (four case– control publications and one cohort publications) with six studies investigated the association between yellow and orange vegetables intake and bladder cancer risk, because one publication [13] provided two separate results (for men and women) (please see Supplementary Table 1 for detailed information on the intake
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distribution of yellow–orange vegetables in the subgroups of studies). The data included 5,140 cases among 190,646 participants. The combined RR for high versus low intake was 0.74 (95 % CI 0.66–0.84) with moderate between-study heterogeneity (Pheterogeneity = 0.402, I2 = 2.2 %). In the subgroup analysis, four articles were cohort studies and inverse association was observed (RR 0.75, 95 % CI 0.65–0.86). By geographic locations, four articles were conducted in USA and an inverse association was observed (RR 0.75, 95 % CI 0.66–0.85). Sensitivity analysis excluding one study at a time did not substantially modify the findings. Publication bias was found according to Egger’s test (p \ 0.05).
Dose–response analysis Eight articles [8, 11, 37, 38, 41, 48, 50, 51] were available to evaluate the dose–response association of citrus fruits intake with bladder cancer risk. The data included 5,355 cases among 177,956 participants. A nonlinear relationship was found of citrus fruits intake with risk of bladder cancer (Pfor nonlinearity = 0.018) with the greatest reduction for an intake of 90 g/day, and the RRs (95 % CI) of bladder cancer were 0.87 (0.78–0.96), 0.80 (0.67–0.94), 0.79 (0.66–0.94), 0.79 (0.65–0.96), and 0.79 (0.64–0.99) for 30, 60, 90, 120, and 150 g/day (Fig. 3d).
Discussion Dose–response analysis Four articles [8, 10, 38, 41] were available to evaluate the dose–response association of yellow–orange vegetables with bladder cancer risk. The data included 4,456 cases. A nonlinear relationship was found of yellow– orange vegetables intake with risk of bladder cancer risk (Pfor nonlinearity = 0.033). The RRs (95 % CI) of bladder cancer were 0.87 (0.80–0.95), 0.80 (0.70–0.90), 0.78 (0.69–0.88), 0.76 (0.68–0.86), and 0.74 (0.64–0.83) for 10, 20, 30, 40, and 50 g/day. Citrus fruits High versus low analyses Data from 11 articles [7, 8, 11, 13, 37–39, 41, 48, 50, 51] (seven case–control publications and four cohort publications) with 12 studies investigated the association between citrus fruits intake and bladder cancer risk, because one publication [13] provided two separate results (for men and women) (please see Supplementary Table 1 for detailed information on the intake distribution of citrus fruits in the subgroups of studies). The data included 6,407 cases among 486,986 participants. The combined RR for high versus low intake was 0.79 (95 % CI 0.68–0.91) with moderate between-study heterogeneity (Pheterogeneity = 0.015, I2 = 53.2 %). We then conducted subgroup analyses. An inverse association was observed in case–control studies (RR 0.73, 95 % CI 0.58–0.91) but not in cohort studies (RR 0.87, 95 % CI 0.676–1.01). By geographic locations, an inverse association was observed in studies conducted in USA (RR 0.83, 95 % CI 0.72–0.95), but not in studies in Europe (RR 0.88, 95 % CI 0.76–1.02). Sensitivity analysis excluding one study at a time did not substantially modify the findings. Egger’s test for publication bias was statistically significant (p = 0.034).
In this meta-analysis, the increasing intake of fruit, vegetables, cruciferous vegetables, yellow–orange vegetables, citrus fruits, and fruit and vegetables combined were associated with statistically significant reductions in bladder cancer risk. Similar results were observed in a linear dose–response analysis. In the nonlinear dose–response analysis, we found for the first time in a meta-analysis, to our knowledge, evidence of a nonlinear inverse association between citrus fruits and yellow–orange vegetables and bladder cancer risk. We found a nonlinear inverse association between citrus fruits intake and bladder cancer risk among studies with the greatest reduction in risk at the lower range of intake. Although some caution is needed in interpreting the exact quantities and size of the risk estimates because of the measurement errors associated with use of the dietary assessment methods, our results indicate that there is a low threshold level of 90 g/day intake of citrus fruits that can reduce risk about 21.2 %. Above that level, there seems to be no additional benefit of increasing citrus fruits intake in terms of bladder cancer risk. Thus, it is important for public health recommendations. Thus, from a public health perspective, targeting individuals and populations with a low citrus fruits intake might be most effective for bladder cancer prevention. We also found a nonlinear inverse association between yellow and orange vegetables intake and bladder cancer risk. And there was a sharper decrease in bladder cancer risk, when yellow–orange vegetables intake increased from 0 g/day to about 20 g/day. The risk of bladder cancer decreased slower thereafter, with yellow– orange vegetables intake up to 20 g/day. Within the subgroup analysis, we found study design as a possible source of heterogeneity. We found inverse association between intake of vegetables, cruciferous vegetables, citrus fruits, and fruit and vegetables combined with bladder cancer risk in case–control studies but not in cohort studies. The potential bias of case–control studies,
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such as selection bias and recall bias, might contribute to the discrepancy between case–control and cohort studies. As for recall bias, considering that fruit and vegetables are generally considered to be good for health, patients might tend to overestimate the past fruit and vegetables consumption than controls. This recall bias could affect the association toward a much positive association between fruit and vegetables consumption and bladder cancer risk. Thus, considering the discrepancy between the findings from the case–control and cohort studies, caution is needed in interpreting the results from the case–control studies. However, we found inverse association between intake of fruit and bladder cancer risk in both case–control studies and cohort studies. We found a consistent pattern of difference or heterogeneity about the association between fruit and vegetables intake and bladder cancer risk in the results by gender, except for fruit. The inverse associations were found among studies including both male and female participants, but there was no evidence of a protective effect of fruit and vegetables in studies including only male or female participants. One prospective study reported no sex difference in the associations between fruit or vegetables and bladder cancer risk and, accordingly, combined men and women in the analysis [52]. Another study found an inverse association between fruits, vegetables, and bladder cancer risk that was largely confined to women [13]. It is not clear whether the difference in our study is a chance finding, because there were few studies in these subgroup including only male or female participants. Our meta-analysis has several strengths. This is the first comprehensive meta-analysis of a large number of studies on the association between the intake of vegetables and fruit and bladder cancer risk, including several prospective studies. We also used linear and nonlinear meta-analytic methods and conducted several subgroup analyses. As a meta-analysis of observational studies, our findings have several potential limitations. First, because of the observational design, exclusion of potential confounding from other bladder cancer risk factors cannot be ruled out. A meta-analysis is not able to address problems with confounding factors that could be inherent in the original studies. In most studies included in this meta-analysis, the investigators had adjusted for age and smoking. However, only few studies adjusted for AAs, which has been shown to increase the incidence of bladder cancer [4]. Second, our results are likely to be affected by some degree of misclassification of exposure, which was inevitable given that the intake of fruit and vegetables was self-reported. Most of the original articles included in our meta-analysis used a validated food-frequency questionnaire, but only two reports updated the information on fruit and vegetables intake during follow-up [47, 51]. Third, incomparability of results between studies may also occur because study design, study
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populations, geographic locations, and intake category vary across studies. Moderate heterogeneity was detected in high versus low analyses, except cruciferous vegetables. Though we conducted several subgroup analyses, there was almost moderate heterogeneity in all strata. In addition, there were many differences among studies, including dietary assessment methods, the variety of fruit or vegetables investigated, the choice of exposure categories, and the portion sizes specified. These differences could affect the estimation of the true relation. As in any meta-analysis, the possibility of publication bias is of concern because small studies with negative results tend not to be published. Some evidence of publication bias was observed for total fruit, citrus fruits, and yellow–orange vegetables. In conclusion, our results suggest that there is a weak inverse association between intake of fruit and vegetables and bladder cancer risk. Also, there is a nonlinear inverse association between citrus fruits intake and bladder cancer risk. However, the possibility that the association may be due to bias or confounding cannot be completely excluded. We, therefore, believe that future well-designed studies are required to confirm this finding. Conflict of interest No conflict of interest existed for any of the authors.
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ORIGINAL PAPER
Intake of fruit and vegetables and risk of bladder cancer: a dose–response meta-analysis of observational studies Baodong Yao • Yujie Yan • Xianwu Ye Hong Fang • Huilin Xu • Yinan Liu • Sheran Li • Yanping Zhao
•
Received: 2 February 2014 / Accepted: 9 September 2014 Ó Springer International Publishing Switzerland 2014
Abstract Background Observational studies suggest an association between fruit and vegetables intake and risk of bladder cancer, but the results are controversial. Methods We therefore summarized the evidence from observational studies in categorical, linear, and nonlinear, dose–response meta-analysis. Pertinent studies were identified by searching EMBASE and PubMed from their inception to August 2013. Results Thirty-one observational studies involving 12,610 cases and 1,121,649 participants were included. The combined rate ratio (RR, 95 % CI) of bladder cancer for the highest versus lowest intake was 0.83 (0.69–0.99) for total fruit and vegetables, 0.81 (0.70–0.93) for total vegetables, 0.77 (0.69–0.87) for total fruit, 0.84 (0.77–0.91) for cruciferous vegetables, 0.79 (0.68–0.91) for citrus fruits, and 0.74 (0.66–0.84) for yellow–orange vegetables. Subgroup analysis showed study design and gender as possible sources of heterogeneity. A nonlinear relationship was found of citrus fruits intake with risk of bladder cancer (Pfor nonlinearity = 0.018), and the RRs (95 % CI) of bladder cancer were 0.87 (0.78–0.96), 0.80 (0.67–0.94), 0.79 (0.66–0.94), 0.79 (0.65–0.96), and 0.79 (0.64–0.99) for 30, 60, 90, 120, and 150 g/day. A nonlinear relationship was Electronic supplementary material The online version of this article (doi:10.1007/s10552-014-0469-0) contains supplementary material, which is available to authorized users. B. Yao Y. Yan H. Fang H. Xu Y. Liu Y. Zhao (&) Shanghai Minhang Center for Disease Control and Prevention, 965 Zhongyi Road, Shanghai 201101, China e-mail: [email protected] X. Ye S. Li The Fifth People’s Hospital of Shanghai, Fudan University, Shanghai, China
also found of yellow–orange vegetable intake with risk of bladder cancer risk (Pfor nonlinearity = 0.033). Some evidence of publication bias was observed for fruit, citrus fruits, and yellow–orange vegetables. Conclusion This meta-analysis supports the hypothesis that intakes of fruit and vegetables may reduce the risk of bladder cancer. Future well-designed studies are required to confirm this finding. Keywords Bladder cancer Bladder neoplasms Meta-analysis Fruit Vegetable
Introduction Bladder cancer, the 10th most common cancer worldwide, represents an important health problem [1]. Around 350, 000 cases were recorded in 2002, accounting for around three per cent of all cancers. In the USA, an estimated 72, 570 cases were newly diagnosed with bladder and 15, 210 will die from this disease in 2013 [2]. Tobacco smoking is the well-established behavioral risk factor for bladder cancer [3], with 50 % of newly diagnosed cases estimated to be attributable to the effects of smoking [3]. In addition, occupational exposure to aromatic amines (AAs) [4] and schistosomal infections [5] is known to cause bladder cancer. The established causal risk factors for bladder cancer do not fully explain bladder cancer incidence. Intake of fruit and vegetables has been hypothesized to protect against several cancers, including bladder cancer [6]. Several epidemiological studies investigated associations between fruit and vegetables intake and bladder cancer risk [7–9]. The report from the World Cancer Research Fund and the American Institute for Cancer
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Research (WCRF/AICR) in 2007 stated that no conclusions could be reached for associations between fruit and vegetables intake and bladder cancer risk [1]. Since this report was published, other relevant studies on this association have been published [10–13], but the results were inconsistent. A review by Brinkman and Zeegers published in 2008 [14] concluded that fruit, citrus fruits, cruciferous vegetables, and yellow–orange vegetables were identified as having a possible protective effect. But the exact shape of the dose–response relationship between the intake of fruit and vegetables and bladder cancer risk has not been clearly defined. Therefore, to better characterize this issue, we conducted a dose–response meta-analysis of observational studies to summarize the epidemiologic evidence on the association between fruit and vegetables intake and bladder cancer risk.
Methods Literature search We systematically identified articles through searching EMBASE and PubMed from their inception to August 2013 using the following keywords vegetable or fruit combined with bladder cancer or neoplasm. No language restrictions were imposed. We also manually reviewed the reference lists of relevant publications to search for additional articles. Two researchers independently reviewed all potentially relevant articles to determine whether an article met the general inclusion criteria, and disagreement was resolved by discussion between the researchers. All studies were included, if they met the following criteria: (1) a case– control or cohort study; (2) the exposure of interest was fruit or vegetables intake (total fruit and vegetables, fruit, vegetables, or their subgroups); (3) the outcome of interest was bladder cancer, and (4) multivariate adjusted odds ratios (OR), rate ratios (RR), or hazard ratios (HR) with 95 % confidence interval (CI). When multiple publications from the same study were available, we used the most recent studies or studies with the largest number of cases. Data extraction The following data were collected from all studies: the first author’s name, study design, year of publication, country where the study was performed, the number of cases and controls or participants, type of controls, the methods used for collection of data on exposure, years of follow-up in cohort study, sex, participant age at baseline, variables adjusted for in the multivariable analysis, as well as multivariate adjusted RRs with their 95 % CIs for each
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category of fruit and vegetables intake. We extracted the RRs that reflected the greatest degree of adjustment for potentially confounding variables. Data extraction was conducted by two investigators, with disagreements being resolved by consensus. For every study, the median or mean fruit and vegetables intake for each category were assigned to each corresponding RR. When the levels of fruit and vegetables intake were given by a range, the value of exposure was assigned as the midpoints of the ranges of the reported categories of fruit and vegetables intake. If the upper boundary of the highest category was not provided, we assumed that the boundary had the same amplitude as the adjacent category. When the lowest category was openended, we set the lower boundary to zero. Some studies included in this meta-analysis reported fruit and vegetables intake with different measurement units (e.g., g/day, servings/month, or times/week). We standardized all data into g/day. If the intakes were reported in densities (i.e., g/d/1,000 kcal), we recalculated the reported intakes to absolute intakes using the mean or median energy intake. In studies that report intakes as frequency, we converted a serving size as 80 g according to other meta-analysis [15, 16]. When fruit and vegetable intake was expressed in portions/day, the exposure level was transformed into g/d by multiplying this quantity by 106 g according to study from Dauchet et al. [17]. Statistical analysis A combined measure was calculated as the inverse variance-weighted mean of the natural logarithm of multivariate adjusted RRs with 95 % CI to assess the association of fruit and vegetables intake with bladder cancer risk for the highest versus lowest levels. The I2 of Higgins and Thompson was used to assess heterogeneity among studies [18]. I2 describes the proportion of total variation attributable to between-study heterogeneity as opposed to random error or chance. In the presence of substantial heterogeneity (I2 [ 50 %) [19], the DerSimonian and Laird random-effect model was adopted as the combining method; otherwise, the fixed-effect model was used as the combining method. In an attempt to evaluate the possible publication bias, Egger’s test (linear regression method) was used [20]. An analysis of influence was conducted [21], which describes how robust the combined estimator is to the removal of individual study. An individual study is suspected of excessive influence, if the point estimate of its omitted analysis lies outside the 95 % CI of the combined analysis. Subgroup analyses were carried out to investigate potential sources of between-study heterogeneity. For the dose–response analysis, studies included must provide the following information: the number of cases and
Cancer Causes Control
were case–control studies, and 11 were cohort studies. The main characteristics of these articles are presented in Tables 1 and 2. The articles combined had a total of 1,121,649 individuals with 12,610 bladder cancer events. Fourteen articles were conducted in Europe, five in Asia, eleven in North America, and one in South America. The study population in 22 articles consisted of both sexes, seven articles included men only, and two articles included women only. Most articles provided RR estimates that were adjusted for age (30 articles) and smoking (30 articles). Total fruit and vegetables High versus low analyses
Fig. 1 Selection of articles in the meta-analysis
participants (person-years) or controls, and RR with 95 % CI for each category of fruit and vegetables intake. A twostage random-effects dose–response meta-analysis was performed proposed by Orsini et al. [22] to compute the trend from the correlated log RR estimates across categories of fruit and vegetables intake taking into account the between-study heterogeneity. Briefly, a restricted cubic spline model, with three knots at the 25th, 50th, and 75th percentiles [23] of fruit and vegetables intake levels, was estimated using generalized least square regression taking into account the correlation within each set of published RRs [24]. Then, the restricted maximum likelihood method in a multivariate random-effect meta-analysis was [25] used to combine the study-specific estimates. A p value for nonlinearity was calculated by testing the null hypothesis that the coefficient of the second spline is equal to 0 [26]. All statistical analyses were performed with STATA version 12 (Stata Corporation, College Station, TX, USA). p value \ 0.05 was considered statistically significant.
Results Study characteristic Figure 1 shows a flow diagram of how we selected relevant articles. We identified 33 potentially relevant articles [7–13, 27–52]. Two articles were excluded because of overlapping publications from the same study population [43, 52]. Thus, a total of 31 case–control and cohort articles met our inclusion criteria. Among these 31 publications, 20
Data from 10 articles (two case–control publications and eight cohort publications) [7, 13, 38, 44, 45, 47–51] with 11 studies investigated the association between total fruit and vegetable intake and bladder cancer risk, because one publication [13] provided two separate results (for men and women) (please see Supplementary Table 1 for detailed information on the intake distribution of total fruit and vegetables in the subgroups of studies). The data included 3,715 cases among 583,117 participants. The combined RR for high versus low intake was 0.83 (95 % CI 0.69–0.99) with moderate between-study heterogeneity (Pheterogeneity = 0.014, I2 = 55.0 %) (Fig. 2a). We conducted subgroup analyses to explore the sources of heterogeneity (Table 3). An inverse association was observed in case–control studies (RR 0.76, 95 % CI 0.59–0.99) but not in cohort studies (RR 0.85, 95 % CI 0.68–1.06). Analyses stratified by gender showed that there were inverse associations between total fruit and vegetables intake with bladder cancer risk in studies including both male and female participants (RR 0.82, 95 % CI 0.70–0.97). But the associations were not statistically significant in studies including only male or female participants (RR 0.94, 95 % CI 0.77–1.14; RR 0.62, 95 % CI 0.20–1.86). Results were consistent for studies conducted in the USA (RR 0.74, 95 % CI 0.51–1.06) and in Europe (RR 0.92, 95 % CI 0.78–1.07). Total fruit and vegetables intake was not associated with bladder cancer risk across categories of different smoking status. Sensitivity analysis excluding one study at a time did not substantially modify the findings. No significant publication bias was found according to Egger’s test (p = 0. 714). Dose–response analysis Five articles [38, 47, 48, 50, 51] were available to evaluate the dose–response association of total fruit and vegetables
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123
Finland
USA
Sweden
Europe
USA
Michaud et al. [49]
Holick et al. [51]
Larsson et al. [50]
Ros et al. [12]
Park et al. [13]
M/F
M/F
M/F
F
M
M/F
M/F
M/F
45–75
25–70
–
30–55
50–69
55–69
40–75
–
74.9(M)/ 73.8(F)
–
Age (year)
185,885
468,656
82,002
88,796
27,111
120,852
38,540
47,909
7,995
11,580
16,477
Cohort size
12.5
8.9
9.4
20
11
6.3
1979–1993
1986–1996
22
1981–1989
14
Years of follow-up
M male, F female, FFQ food-frequency questionnaire, BMI body mass index
Netherlands
Zeegers et al. [48]
USA
Japan
M
USA
Chyou et al. [46] Michaud et al. [47]
Nagano et al. [9]
M
USA
Shibataet al. [45]
M/F
Sweden
Steineck et al. [44]
Sex
Country and study Period
References
581
947
485
237
344
619
114
252
96
71
70
No. of cases
Cancer registry/ health insurance records/ pathology hospital registries Cancer registry/ death certificate files
Cancer registry
Medical records/ self-reported
Cancer registry
Cancer registry
Cancer registry
Hospital/cancer registry Medical records/ self-reported
Hospital records
Cancer registry
Case assessment
A quantitative FFQ
A validated FFQ
A validated FFQ
FFQ
A 276-food item dietary questionnaire
A 150-item semiquantitative FFQ
FFQ
FFQ/A 24-h diet recall history A 131-item FFQ
A detailed health questionnaire
A questionnaire
Exposure measurement
Table 1 Main characteristics of cohort articles included in the meta-analysis, ranked by year of publication
Quartiles
Tertiles
Quartiles
Quintiles
Quintiles
Quintiles
Tertiles
Quintiles
Tertiles
Tertiles
–
Exposure categories
Age at cohort entry, ethnicity, total energy intake, first-degree family history of bladder cancer, employment in a high-risk industry, smoking, and interactions of ethnicity with smoking status
Age at entry, sex, center, smoking status, duration of smoking, lifetime intensity of smoking, energy intake from fat, and nonfat sources
Age, sex, education, smoking status, pack-years of smoking, and total energy intake
Age, pack-years of cigarette smoking, current smoking, and total caloric intake
Age, duration of smoking, smoking dose, total energy, and trial interventions
Age, sex, smoking, and total vegetable consumption (for fruits items) or total fruit consumption (for vegetable consumption)
Age, gender, radiation exposure, smoking status, educational level, BMI, and calendar time
Age, smoking status, geographic region, total fluid intake, and caloric intake
Age and smoking
Age and smoking
Age and gender
Adjustments
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Italy
USA
China
Germany
Japan
Italy
Uruguay
Italy
USA
Japan
USA
Belgium
Spain
Italy
USA
Negri et al. [28]
Bruemmer et al. [29]
Yu et al. [30]
Pohlabeln et al. [31]
Wakai et al. [32]
Peluso et al. [33]
Balbi et al. [7]
Pelucchi et al. [34]
Castelao et al. [8]
Wakai et al. [35]
Schabath et al. [36]
Kellen et al. [37]
Garcı´a-Closas et al. [38]
Sacerdote et al. [39]
Tang et al. [40]
USA
Spain
Riboli et al. [27]
Lin et al. [41]
Country
References
M/F
M/F
M
M/F
M/F
M/F
M/F
M/F
F
M/F
M
M/F
M/F
M/F
M/F
M/F
M
Sex
64.47(case)/ 64.99(control)
21–92
40–75
65.3(case)/ 64.0(control)
67.67(case)/ 64.26(control)
63.4(case)/ 62.4(control)
20–79
25–64
30–79
40–89
45–74
20–99
65.6
C20
884
275
266
912
200
409
124
1,592
110
144
162
297
300
217
262
365
\75 45–65
432
No. of cases
\80
Age (year)
(H)
878
(H)
825
(H)
193
(H)
873
(P)
385
(H)
451
(H)
620
(P)
1592
(H)
298
(H)
576
(H)
104
(P)
295
(H)
300
(H)
254
(P)
405
(H)
6,147
(H and P)
789
No. of control method)
A 45-min FFQ
A 44-itemfood FFQ
A 22-item FFQ
FFQ
A standardized FFQ
FFQ
FFQ
A structured FFQ
A structured FFQ
A detailed FFQ
A 24 h recall interview
A well-validated FFQ
A standardized FFQ
FFQ
FFQ
FFQ
FFQ
Exposure measurement
Table 2 Main characteristics of case–control articles included in the meta-analysis, ranked by year of publication
Quartiles
Quartiles
–
Quintiles
Tertiles
Tertiles
Quartiles
Quintiles
Tertiles
Tertiles
–
Quartiles
–
Quartiles
Quartiles
Tertiles
Quartiles
Exposure Categories
Age, sex, ethnicity, smoking, total energy intake, and alcohol consumption
Age, education level, gender, total meat intake, smoking status, and pack-years
Age, smoking status, and maximum number of cigarettes
Age, gender, region, and smoking
Age, sex, smoking, and occupational exposure to PAHs or AAs
Age, gender, ethnicity, smoking, and total energy
Age, sex, year of first visit and cumulative consumption of cigarettes
Age, sex, race, education, nonsteroidal anti-inflammatory drugs, number of years employed as a hairdresser/barber and smoking
Age, study center, education, BMI, coffee and alcohol consumption, and smoking
Age, sex, residence, urban/rural status, education, BMI, smoking, drinking, and total calories
Age and smoking
Age, gender, hospital, smoking, occupational history, and energy intake
Age, sex, area of residence, and smoking
Age, sex, residence, income, education, occupation, pack-years, saccharine use, taking analgesics, and urinary disease
Age, sex, smoking, and county
Age, sex, residence, education, and smoking
Age, sex, residence, total calories and smoking
Adjustments
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Age, sex, smoking status, smoking duration, smoking amount, and other food groups
Age, gender, region, race, Hispanic status, smoking status, usual BMI, and total energy
Smoking, exposure to AAs and/or PAHs, coffee drinking
FFQ (H)
469 487 63.5 M/F Isa et al. [11]
China
(P)
M male, F female, FFQ food-frequency questionnaire, H hospital-based, P population-based, BMI body mass index, PAHs polycyclic aromatic hydrocarbons, AAs aromatic amines
Quartiles
Quartiles 1,171 M/F Wu et al. [10]
USA
[30
1,418
A self-administered FFQ
Quartiles FFQ 180
(H)
185 20–80 M Italy Pavanello et al. [42]
Sex Country
Table 2 continued
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intake with bladder cancer risk. The data included 2,419 cases among 222,521 participants. The departure from nonlinear relationship was not significant (Pfor nonlinearity = 0.454), and the risk of bladder cancer decreased by 3 % (RR 0.97, 95 % CI 0.95–0.99) for 100 g/day increment in total fruit and vegetables intake. The RRs (95 % CI) of bladder cancer were 1.00 (0.99–1.00), 0.96 (0.92–1.00), 0.92 (0.86–0.99), 0.90 (0.83–0.98), and 0.89 (0.80–0.99) for 100, 200, 300, 400, and 500 g/day. Total vegetables
References
Age (year)
No. of cases
No. of control method)
Exposure measurement
Exposure Categories
Adjustments
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High versus low analyses Data from 20 articles [7, 10, 12, 13, 27–30, 33, 37–41, 45, 47–51] (12 case–control publications and eight cohort publications) with 21 studies investigated the association between total vegetables intake and bladder cancer risk, because one publication [13] provided two separate results (for men and women) (please see Supplementary Table 1 for detailed information on the intake distribution of total vegetables in the subgroups of studies). The data included 8,826 cases among 1,050,928 participants. The combined RR for high versus low intake was 0.81 (95 % CI 0.70–0.93) with moderate between-study heterogeneity (Pheterogeneity \ 0.001, I2 = 66.0 %) (Fig. 2b). We then conducted subgroup analyses by study design, gender, geographic locations, number of cases, and smoking status (Table 3). Analyses stratified by study design showed that there were inverse associations between total vegetables intake with bladder cancer risk in case–control studies (RR 0.73, 95 % CI 0.59–0.92), not in cohort studies (RR 0.91, 95 % CI 0.82–1.02). An inverse association was observed in studies including both male and female participants (RR 0.76, 95 % CI 0.63–0.92). In stratified analysis by geographic locations, the RRs were 0.84 (95 % CI 0.74–0.95) for studies in USA and 0.81 (95 % CI 0.64–1.03) for studies in Europe. The associations between total vegetables intake with bladder cancer risk were not statistically significant in each subgroup analysis that was stratified by smoking status. In the sensitivity analysis in which one study at a time was excluded and the rest were analyzed, we detected significantly inverse association between total vegetable intakes and bladder cancer risk (range of summary RRs 0.69–0.95 with the largest limit of the 95 % CI never crossing 1.0). No significant publication bias was found according to Egger’s test (p = 0. 389). Dose–response analysis Eleven articles [10, 28, 30, 37, 38, 40, 41, 47, 48, 50, 51] were available to evaluate the dose–response association of
Cancer Causes Control Fig. 2 Forest plot of relative risk of high versus low analysis for fruit and vegetables intake with bladder cancer risk. ES effect size, IV inverse variance, D ? L DerSimonian and Laird, Ref. reference number. a Forest plot for total fruit and vegetables, b forest plot for total vegetables, c forest plot for total fruit
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123
4
2
M
F
5
1
0
USA
South America
Asia
5
C300
1
10
Yes
No
Adjustment for BMI or obesity
6
\300
Number of cases
5
Europe
Geographic locations
5
9
2
Number of studies
(0.70–1.02)
0.84
(0.41–1.09)
0.67
(0.74–0.94)
0.84
(0.53–1.03)
0.74
–
(0.41–1.09)
0.67
(0.51–1.06)
0.74
0.92 (0.78–1.07)
(0.21–1.86)
0.617
(0.77–1.14)
0.94
(0.70–0.97)
0.82
(0.68–1.06)
0.85
(0.59–0.99)
0.76
Summary estimate (95 % CI)
Total vegetables and fruit
Both M and F
Gender
Cohort
Case–control
Design
Sub-groups
0.011
–
0.284
0.012
–
–
0.007
0.275
\0.001
0.237
0.765
0.007
0.546
Pheterogeneity
57.9
–
20.6
65.9
–
–
71.6
21.9
91.8
29.1
0.0
62.3
0.0
I (%)
2
19
2
10
11
1
1
9
10
2
7
12
9
12
Number of studies
Vegetables
(0.69–0.95)
0.81
(0.68–1.06)
0.85
(0.67–0.99)
0.815
(0.72–0.96)
0.83
(0.3–1.2)
0.6
(0.40–1.09)
0.66
(0.74–0.95)
0.84
0.81 (0.64–1.03)
(0.31–2.09)
0.81
(0.79–1.06)
0.92
(0.63–0.92)
0.76
(0.82–1.02)
0.91
(0.59–0.92)
0.73
Summary estimate (95 % CI)
Table 3 Subgroup analyses of vegetables and fruit intake and bladder cancer risk, high versus low analyses
\0.001
0.279
\0.001
0.079
–
–
0.114
\0.001
0.004
0.224
\0.001
0.148
\0.001
Pheterogeneity
68.7
14.8
78.6
40.4
–
–
38.1
79.6
88.0
26.8
71.5
33.8
72.9
I (%)
2
23
4
11
16
4
1
10
12
3
10
14
11
16
Number of studies
Fruit
(0.67–0.86)
0.76
(0.76–1.12)
0.92
(0.73–1.01)
0.86
(0.62–0.79)
0.70
(0.56–0.92)
0.72
(0.77–0.98)
0.86
0.75 (0.62–0.92)
(0.58–1.03)
0.78
(0.62–0.95)
0.77
(0.65–0.89)
0.76
(0.79–0.98)
0.88
(0.60–0.85)
0.72
Summary estimate (95 % CI)
0.001
0.059
0.001
0.196
0.761
0.061
\0.001
0.140
0.024
0.001
0.127
0.001
Pheterogeneity
54.6
59.6
65.5
22.7
0.0
44.8
70.6
49.1
52.9
62.3
34.0
61.6
I2 (%)
Cancer Causes Control
(0.432–0.773)
0.578
0.841
0.296 (0.819–1.231)
1.004
total vegetables intake with bladder cancer risk. The data included 5,315 cases among 232,215 participants. The departure from nonlinear relationship was not significant (Pfor nonlinearity = 0.513), and the risk of bladder cancer decreased by 6 % (RR 0.94, 95 % CI 0.89–0.99) for 100 g/day increment in total vegetables intake (Fig. 3a). The RRs (95 % CI) of bladder cancer were 0.96 (0.90–1.01), 0.92 (0.84–1.00), 0.85 (0.78–0.93), 0.77 (0.67–0.89), and 0.73(0.60–0.88), for 100, 200, 300, 400, and 500 g/day.
0.0
18.7
41.1 0.131 (0.589–1.040)
0.783
54.9 \0.001 0.77
(0.69–0.87)
I2 (%) Pheterogeneity Summary estimate (95 % CI)
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Number of studies
32.9 0.787 4
(0.584–1.062)
0.202
0.303
CI confidence interval, M male, F female, BMI body mass index
0.0 0.835 0.775 4 Current smokers
(0.567–1.061)
0.821
(0.666–1.012)
4 0.0 0.841 0.906
(0.719–1.142)
4 Former smokers
0.828
(0.623–1.101)
5 13.7 0.324 (0.586–1.171)
(0.60–1.60)
0.828 4 Smoking status Never smokers
4
4 17.5
48.3 0.101
– – (0.70–0.93)
– – 1 No
0.010 0.81 10 Yes
Adjustment for smoking
–
58.4
21
0 1.00
0.81
(0.67–0.99)
66.0 \0.001
27
I2 (%) Pheterogeneity Number of studies Pheterogeneity Number of studies
Summary estimate (95 % CI)
I2 (%)
Vegetables Total vegetables and fruit Sub-groups
Table 3 continued
6
High versus low analyses
Summary estimate (95 % CI)
Fruit
Total fruit
Data from 26 articles [7, 9, 10, 12, 13, 27–35, 37–41, 45–51] (16 case–control publications and 10 cohort publications) with 27 studies investigated the association between total fruit intakes and bladder cancer risk, because one publication [13] provided two separate results (for men and women) (please see Supplementary Table 1 for detailed information on the intake distribution of total fruit in the subgroups of studies). The data included 9,867 cases among 1,099,807 participants. The combined RR for high versus low intake was 0.77 (95 % CI 0.69–0.87) with moderate between-study heterogeneity (Pheterogeneity \ 0.001, I2 = 54.9 %) (Fig. 2c). We conducted subgroup analyses according to study design, gender, geographic locations, and number of cases (Table 3). The association between total fruit intake and bladder cancer was somewhat stronger among case–control studies than cohort studies and among studies including \300 cases than studies including 300 or more cases. The protective effect of fruit consumption was only found in current smoker, and the combined RR for high versus low intake was 0.58 (95 % CI 0.43–0.77) without between-study heterogeneity (Pheterogeneity = 0.841, I2 = 0.0 %). Sensitivity analysis excluding one study at a time did not substantially modify the findings. Egger’s test for publication bias was statistically significant (p = 0.003). Dose–response analysis Fifteen articles [9, 10, 28, 30, 34, 35, 37, 38, 40, 41, 46–48, 50, 51] were available to evaluate the dose–response association of total fruit intake with bladder cancer risk. The data included 5,792 cases among 279,593 participants. The departure from nonlinear relationship was not significant (Pfor nonlinearity = 0.068), and the risk of bladder cancer decreased by 7 % (RR 0.93, 95 % CI 0.88–0.98) for 100 g/day increment in total fruit intake (Fig. 3b). The RRs (95 % CI) of bladder cancer were 0.91 (0.85–0.98), 0.87
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Cancer Causes Control Fig. 3 The dose–response analysis between total fruit and vegetables intake and risk of bladder cancer in observational studies with restricted cubic splines in a multivariate random-effects dose–response model. The solid line and the long dash line represent the estimated relative risk and its 95 % confidence interval of the nonlinear relationship. Short dash line represents the linear relationship. a For total vegetables, b for total fruit, c for cruciferous vegetables, d for citrus fruits
(0.80–0.95), 0.87 (0.79–0.94), 0.86 (0.78–0.94), and 0.85 (0.76–0.88) for 100, 200, 300, 400, and 500 g/day.
publication bias was found according to Egger’s test (p = 0. 443).
Cruciferous vegetables
Dose–response analysis
High versus low analyses
Eight articles [8, 10, 36, 40, 41, 47, 50, 51] were available to evaluate the dose–response association of cruciferous vegetables intake with bladder cancer risk. The data included 5,189 cases among 223,675 participants. The departure from nonlinear relationship was not significant (Pfor nonlinearity = 0.924), and the risk of bladder cancer decreased by 32 % (RR 0.68, 95 % CI 0.56–0.81) for 100 g/day increment in total fruit intake (Fig. 3c). The RRs (95 % CI) of bladder cancer were 0.94 (0.91–0.97), 0.87 (0.82–0.93), 0.82 (0.74–0.90), 0.74 (0.65–0.86), and 0.70 (0.60–0.83) for 20, 40, 60, 80, and 100 g/day.
Data from 11 articles [8, 10, 13, 36, 39–41, 47, 49–51] (six case–control publications and five cohort publications) with 12 studies investigated the association between cruciferous vegetables intake and bladder cancer risk, because one publication [13] provided two separate results (for men and women) (please see Supplementary Table 1 for detailed information on the intake distribution of cruciferous vegetables in the subgroups of studies). The data included 6,496 cases among 441,657 participants. The combined RR for high versus low intake was 0.84 (95 % CI 0.77–0.91) with moderate between-study heterogeneity (Pheterogeneity = 0.146, I2 = 30.7 %). In the subgroup analysis, an inverse association was observed in case–control studies (RR 0.81, 95 % CI 0.73–0.90), but not in cohort studies (RR 0.86, 95 % CI 0.68–1.08). By geographic locations, an inverse association was observed in studies conducted in USA (RR 0.80, 95 % CI 0.73–0.88), but not in studies in Europe (RR 0.99, 95 % CI 0.81–1.20). Sensitivity analysis excluding one study at a time did not substantially modify the findings. No significant
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Yellow–orange vegetables High versus low analyses Data from five articles [8, 10, 13, 38, 41] (four case– control publications and one cohort publications) with six studies investigated the association between yellow and orange vegetables intake and bladder cancer risk, because one publication [13] provided two separate results (for men and women) (please see Supplementary Table 1 for detailed information on the intake
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distribution of yellow–orange vegetables in the subgroups of studies). The data included 5,140 cases among 190,646 participants. The combined RR for high versus low intake was 0.74 (95 % CI 0.66–0.84) with moderate between-study heterogeneity (Pheterogeneity = 0.402, I2 = 2.2 %). In the subgroup analysis, four articles were cohort studies and inverse association was observed (RR 0.75, 95 % CI 0.65–0.86). By geographic locations, four articles were conducted in USA and an inverse association was observed (RR 0.75, 95 % CI 0.66–0.85). Sensitivity analysis excluding one study at a time did not substantially modify the findings. Publication bias was found according to Egger’s test (p \ 0.05).
Dose–response analysis Eight articles [8, 11, 37, 38, 41, 48, 50, 51] were available to evaluate the dose–response association of citrus fruits intake with bladder cancer risk. The data included 5,355 cases among 177,956 participants. A nonlinear relationship was found of citrus fruits intake with risk of bladder cancer (Pfor nonlinearity = 0.018) with the greatest reduction for an intake of 90 g/day, and the RRs (95 % CI) of bladder cancer were 0.87 (0.78–0.96), 0.80 (0.67–0.94), 0.79 (0.66–0.94), 0.79 (0.65–0.96), and 0.79 (0.64–0.99) for 30, 60, 90, 120, and 150 g/day (Fig. 3d).
Discussion Dose–response analysis Four articles [8, 10, 38, 41] were available to evaluate the dose–response association of yellow–orange vegetables with bladder cancer risk. The data included 4,456 cases. A nonlinear relationship was found of yellow– orange vegetables intake with risk of bladder cancer risk (Pfor nonlinearity = 0.033). The RRs (95 % CI) of bladder cancer were 0.87 (0.80–0.95), 0.80 (0.70–0.90), 0.78 (0.69–0.88), 0.76 (0.68–0.86), and 0.74 (0.64–0.83) for 10, 20, 30, 40, and 50 g/day. Citrus fruits High versus low analyses Data from 11 articles [7, 8, 11, 13, 37–39, 41, 48, 50, 51] (seven case–control publications and four cohort publications) with 12 studies investigated the association between citrus fruits intake and bladder cancer risk, because one publication [13] provided two separate results (for men and women) (please see Supplementary Table 1 for detailed information on the intake distribution of citrus fruits in the subgroups of studies). The data included 6,407 cases among 486,986 participants. The combined RR for high versus low intake was 0.79 (95 % CI 0.68–0.91) with moderate between-study heterogeneity (Pheterogeneity = 0.015, I2 = 53.2 %). We then conducted subgroup analyses. An inverse association was observed in case–control studies (RR 0.73, 95 % CI 0.58–0.91) but not in cohort studies (RR 0.87, 95 % CI 0.676–1.01). By geographic locations, an inverse association was observed in studies conducted in USA (RR 0.83, 95 % CI 0.72–0.95), but not in studies in Europe (RR 0.88, 95 % CI 0.76–1.02). Sensitivity analysis excluding one study at a time did not substantially modify the findings. Egger’s test for publication bias was statistically significant (p = 0.034).
In this meta-analysis, the increasing intake of fruit, vegetables, cruciferous vegetables, yellow–orange vegetables, citrus fruits, and fruit and vegetables combined were associated with statistically significant reductions in bladder cancer risk. Similar results were observed in a linear dose–response analysis. In the nonlinear dose–response analysis, we found for the first time in a meta-analysis, to our knowledge, evidence of a nonlinear inverse association between citrus fruits and yellow–orange vegetables and bladder cancer risk. We found a nonlinear inverse association between citrus fruits intake and bladder cancer risk among studies with the greatest reduction in risk at the lower range of intake. Although some caution is needed in interpreting the exact quantities and size of the risk estimates because of the measurement errors associated with use of the dietary assessment methods, our results indicate that there is a low threshold level of 90 g/day intake of citrus fruits that can reduce risk about 21.2 %. Above that level, there seems to be no additional benefit of increasing citrus fruits intake in terms of bladder cancer risk. Thus, it is important for public health recommendations. Thus, from a public health perspective, targeting individuals and populations with a low citrus fruits intake might be most effective for bladder cancer prevention. We also found a nonlinear inverse association between yellow and orange vegetables intake and bladder cancer risk. And there was a sharper decrease in bladder cancer risk, when yellow–orange vegetables intake increased from 0 g/day to about 20 g/day. The risk of bladder cancer decreased slower thereafter, with yellow– orange vegetables intake up to 20 g/day. Within the subgroup analysis, we found study design as a possible source of heterogeneity. We found inverse association between intake of vegetables, cruciferous vegetables, citrus fruits, and fruit and vegetables combined with bladder cancer risk in case–control studies but not in cohort studies. The potential bias of case–control studies,
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such as selection bias and recall bias, might contribute to the discrepancy between case–control and cohort studies. As for recall bias, considering that fruit and vegetables are generally considered to be good for health, patients might tend to overestimate the past fruit and vegetables consumption than controls. This recall bias could affect the association toward a much positive association between fruit and vegetables consumption and bladder cancer risk. Thus, considering the discrepancy between the findings from the case–control and cohort studies, caution is needed in interpreting the results from the case–control studies. However, we found inverse association between intake of fruit and bladder cancer risk in both case–control studies and cohort studies. We found a consistent pattern of difference or heterogeneity about the association between fruit and vegetables intake and bladder cancer risk in the results by gender, except for fruit. The inverse associations were found among studies including both male and female participants, but there was no evidence of a protective effect of fruit and vegetables in studies including only male or female participants. One prospective study reported no sex difference in the associations between fruit or vegetables and bladder cancer risk and, accordingly, combined men and women in the analysis [52]. Another study found an inverse association between fruits, vegetables, and bladder cancer risk that was largely confined to women [13]. It is not clear whether the difference in our study is a chance finding, because there were few studies in these subgroup including only male or female participants. Our meta-analysis has several strengths. This is the first comprehensive meta-analysis of a large number of studies on the association between the intake of vegetables and fruit and bladder cancer risk, including several prospective studies. We also used linear and nonlinear meta-analytic methods and conducted several subgroup analyses. As a meta-analysis of observational studies, our findings have several potential limitations. First, because of the observational design, exclusion of potential confounding from other bladder cancer risk factors cannot be ruled out. A meta-analysis is not able to address problems with confounding factors that could be inherent in the original studies. In most studies included in this meta-analysis, the investigators had adjusted for age and smoking. However, only few studies adjusted for AAs, which has been shown to increase the incidence of bladder cancer [4]. Second, our results are likely to be affected by some degree of misclassification of exposure, which was inevitable given that the intake of fruit and vegetables was self-reported. Most of the original articles included in our meta-analysis used a validated food-frequency questionnaire, but only two reports updated the information on fruit and vegetables intake during follow-up [47, 51]. Third, incomparability of results between studies may also occur because study design, study
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populations, geographic locations, and intake category vary across studies. Moderate heterogeneity was detected in high versus low analyses, except cruciferous vegetables. Though we conducted several subgroup analyses, there was almost moderate heterogeneity in all strata. In addition, there were many differences among studies, including dietary assessment methods, the variety of fruit or vegetables investigated, the choice of exposure categories, and the portion sizes specified. These differences could affect the estimation of the true relation. As in any meta-analysis, the possibility of publication bias is of concern because small studies with negative results tend not to be published. Some evidence of publication bias was observed for total fruit, citrus fruits, and yellow–orange vegetables. In conclusion, our results suggest that there is a weak inverse association between intake of fruit and vegetables and bladder cancer risk. Also, there is a nonlinear inverse association between citrus fruits intake and bladder cancer risk. However, the possibility that the association may be due to bias or confounding cannot be completely excluded. We, therefore, believe that future well-designed studies are required to confirm this finding. Conflict of interest No conflict of interest existed for any of the authors.
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