Dietary factors associated with bladder cancer

Cancers in the bladder is the most common malignancy in the urinary tract and the age adjusted incidence rate is approximately nine per 10,000 for men and 2.2 for women globally [1, 2]. Bladder cancer (BC) is the ninth most common cancer world-wide [2] and is the fifth most common cancer in the United States and represents 4.5% of all new cancer cases. In 2015, it is estimated that there will be 74,000 new cases of BC (56,320 in men and 17,680 in women) and an estimated 16,000 people will die of this disease (~11,510 men and 4,490 in women) [3].

Age, gender, cigarette smoking, exposures to aromatic amines, polycyclic aromatic hydrocarbons or arsenic, certain medications (phenacetin, cyclophosphamide, chlornaphazine), radiation and genetic factors are established risk factors for developing BC while there is suggestive evidence for several other factors, including diet [4]. Since BC is one of the most expensive diseases to treat because of the need for extended courses of treatment coupled with frequent follow-up examinations [5], examination of modifiable risk factors associated with this disease will aid in implementing preventive measures. Even though epidemiological evidence is inconsistent or controversial, diet is believed to be one of the most important modifiable risk factors for cancer prevention [6]. The purpose of this article is to critically review the findings published thus far on the associations between dietary factors and BC focusing on several aspects of diet, including, specific dietary factors such as food groups, intake and circulating concentrations of specific micronutrients.

Several case-control studies have documented that diets high in meat or fat is associated with higher risk of BC [7]. A limitation of these studies is that lack of detailed dietary data to examine the intake of different types of dietary fat or different sources of protein intake in relation to the risk of BC. A study that addressed these limitations showed that a 3% increase in the consumption of energy intake from animal protein was associated with a 15% higher risk of developing BC while a 2% increase in energy from plant protein intake was associated with a 23% lower risk of developing BC [8]. This study also documented that dietary intake of fat or carbohydrate was not associated with BC risk. However, other studies have documented statistically signif icant reduced odds of BC for high intakes of α-linolenic acid and vegetable fat and borderline statistically significant reduced odds for polyunsaturated fat and linoleic acid, indicating the importance of investigating the type, source and the quantities of different dietary fatty acids consumed [9]. Brinkman et al. [10] reported a statistically significant inverse association between olive oil intake and BC consistent with a linear dose-response relationship.

Even though some case-control studies have reported that a higher red meat intake was associated with BC risk [11], a meta-analysis published in 2014 based on 1,558,848 participants documented that red meat intake was not associated with BC, but suggested that high consumption of processed meat was correlated with rising risk of BC, especially in United States [12]. Similar results were observed in a study conducted in the New England region of the United States [13]. These studies indicate the importance of separating red meat and processed meat in evaluating BC risk in relation to meat consumption. Dietary carbohydrate intake does not appear to be associated with BC risk [9], but only limited data is available on this aspect. Two meta-analysis studies published in 2013, however, reported a positive association between diabetes mellitus and risk of BC, indirectly suggesting that control of carbohydrate intake may lower the BC risk [14, 15]. The studies associating macronutrients or macronutrient containing foods and risk of BC have been summarized in Table 1.

Table 1
Summary of the studies associating macronutrient and macronutrient containing foods and risk of bladder cancer

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Even though a large number of studies have investigated the association between fruit and vegetable consumption and BC risk, they have yielded inconsistent results, especially with regard to the types of fruits and vegetables consumed. A male prospective cohort study documented that high cruciferous vegetable consumption may reduce BC risk, but other vegetables and fruits may not confer appreciable benefits against this disease [16]. A cohort of atomic-bomb survivors in Japan reported that consumption of green-yellow vegetables and fruits were protective against the development of BC [17]. A prospective cohort study of male smokers reported that consumption of fruits and vegetables, groups of fruits or vegetables (berries and cruciferous vegetables), specific fruits and vegetables or intakes of alpha-carotene, beta-carotene, lycopene, lutein/zeaxanthin, beta-cryptoxanthin, vitamins A, E, and C, and folate were not related to the risk of BC [18]. In contrast, a population-based case-control study conducted in non-Asians of Los Angeles, California showed a strong inverse associations between smoking-related BC risk and intake of dark-green vegetables, yellow-orange vegetables, citrus fruits/juices, tomato products, total carotenoids and vitamin C [19]. A similar inverse association between fruits and vegetables and risk of BC was observed in a meta-analysis [7]. However, a prospective population-based cohort study of Swedish women and men reported no statistically significant association between intakes of total fruits and vegetables, total fruits, total vegetables, citrus fruits, cruciferous vegetables, or green leafy vegetables and BC risk and these associations did not differ by sex or by smoking status [20]. A population-based case-control study performed in the Belgian province of Limburg showed that total fruit consumption, but not total vegetable intake reduces the effect of smoking on BC risk [21]. The European Prospective Investigation into Cancer and Nutrition (EPIC) study did not support an effect of fruit and vegetable consumption, combined or separately, on BC [22]. The EPIC study also documented that a variety in vegetable and fruit consumption also was not significantly associated with BC risk further providing evidence for the absence of any strong association between fruit and vegetable consumption and aggressive or nonaggressive BC risk [23, 24]. The latest publication from the EPIC study confirmed these observations [25]. A prospective analysis of older adults participating in the US Multiethnic Cohort Study reported that in women, total fruits and vegetables, total vegetables, yellow-orange vegetables, total fruits and citrus fruits were inversely associated with the risk of invasive BC. In addition, this study also reported that women with the highest intakes of vitamins A, C, and E; the carotenoids α-carotene, β-carotene, and β-cryptoxanthin; and folate had a lower risk of BC and for men, no associations for fruits, vegetables, or nutrients were found overall, although inverse associations were observed for vegetable intake among current smokers, and in ethnic-specific analyses, for fruit and vegetable intake among Latinos specifically. These findings suggest that higher consumption of fruits and vegetables may lower the risk of invasive BC among women and highlight the need for gender-specific subgroup analyses in future studies [27].

A hospital-based case-control study reported that consumption of raw, but not cooked cruciferous vegetables was inversely associated with bladder cancer risk [28]. A strong and significant inverse association was also observed between BC mortality and broccoli intake, in particular raw broccoli intake [29]. These studies suggest that cooking may alter the beneficial effects of protective nutrients and this may explain inconsistent results among different studies. In a population-based case-control study of bladder cancer in Maine, New Hampshire, and Vermont no association between fruits and vegetable consumption and risk of bladder cancer was observed [13]. Another US case-control study reported significant inverse associations between intakes of total vegetables, cruciferous vegetables, orange vegetables, dark green vegetables but not intakes of total fruits or citrus fruits and BC risk. Interestingly, this study also showed that the protective effect of vegetable consumption, especially cruciferous vegetables may be modified by genetic variants of GSTM1 and NAT2, suggesting that genetic makeup of individuals may also contribute to inconsistent results reported by different studies [27].

A dose-response meta-analysis of observational studies supported the hypothesis that intakes of fruit and vegetables may reduce the risk of BC [29]. An updated meta-analysis of observational studies published in 2015 also suggested that intake of vegetables and fruits may significantly reduce the risk of BC [30]. A systematic review and meta-analysis published in 2015 as part of the World Cancer Research/American Institute for Cancer Research Continuous Update Project, however, documented that current evidence from cohort studies is not consistent with a role for fruits and vegetables in preventing BC [31]. A preferred reporting items for systematic reviews and meta-analyses (PRISMA Compliant) study that included relevant prospective studies up to 2014 also documented that there is little evidence to support a beneficial effect for total fruits, vegetables or both together and citrus intake against BC [32]. The studies associating fruits and vegetables or micronutrients and risk of BC have been summarized in Table 2.

Table 2
Summary of studies associating fruit and vegetable consumption and risk of bladder cancer

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Studies have suggested a protective role of serum concentrations of selenium on BC risk, but not serum concentrations of retinol or beta-carotene [33]. However, a meta-analysis of epidemiological studies published in 2014 reported that higher serum or plasma concentrations of vitamin A, total carotenoids, α-carotene, β-carotene, lutein and zeaxanthin were associated with lower risk of BC [34]. A case-control study conducted by Liang et al. [35] suggested potential protective effect of plasma concentrations of alpha-tocopherol and retinol on BC risk. A large prospective study conducted among Japanese-American men documented that cigarette smoking, which is a strong risk factor for BC, may explain the apparent protective effect of individual and total carotenoids against this disease [36]. Other studies that investigated joint effect of plasma carotenoids and tobacco smoking suggested that BC may be a preventable disease through nutritional intervention, especially in smokers [37].

Some studies have reported that vitamin D status, as measured by serum 25-hydroxyvitamin D (25(OH) D) concentration, when it is low in male smokers had a nearly two-fold increased risk of BC compared to men with higher levels [38]. In contrast to this earlier report, the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Study observed no association between serum vitamin D status and risk of BC. It is possible that these differences between the 2 studies could be due to the inclusion of women and nonsmokers in the latter study population or due to the differences in the distribution of vitamin D concentrations between the two study populations [39]. The Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study provided additional support for an etiologic role for vitamin D in BC and suggested that free, rather than total, circulating vitamin D may be a more relevant exposure when examining BC risk in relation to vitamin D [40]. Other studies reported that individuals with low levels of plasma 25(OH)D(3) may be at high risk of more aggressive forms of BC, suggesting the importance of investigating the association by the aggressiveness of the disease [41]. A retrospective analysis of data in the Veterans Integrated Service Network-9 (southeastern US) suggested that adequate serum vitamin D levels early in the course of the disease provide the best opportunity to improve outcomes of BC [42]. Finally, a systemic review and meta-analysis published in 2015 documented that serum 25-hydroxyvitamin D concentrations were significantly associated with lower risk of BC [43]. The studies associating circulating concentrations of micronutrients and risk of BC have been summarized in Table 3.

Table 3
Summary of studies associating circulating concentrations of micronutrients and risk of bladder cancer

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US adults in the Cancer Prevention Study II cohort documented that regular use of vitamin E supplements (for ≥10 years), but not vitamin C was associated with a reduced risk of BC mortality [44]. The prospective Health Professionals Follow-Up Study, however, observed a significant dose-response relation not only for vitamin E but also for vitamin C supplement use and BC risk among US men [45]. In contrast, another study reported that the longterm use of commonly consumed supplemental vitamins (multivitamins, beta-carotene, retinol, folic acid, and vitamins B1, B3, B6, B12, C, D and E) have no significant effect on reducing BC risk [46]. The studies associating micronutrient supplements and risk of BC have been summarized in Table 4.

Table 4
Summary of studies associating micronutrient supplements and risk of BC

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A limited number of studies have investigated other food components in relation to BC such as dairy, tea, egg and fish. A study conducted among Swedish men and women reported that the total dairy intake, intake of milk or cheese were not significantly associated with risk of BC, but a statistically significant inverse association was observed for the intake of cultured milk (sour milk and yogurt) [47]. However, The Netherlands Cohort Study on Diet and Cancer only provided weak evidence that BC risk is inversely associated with lower intake of fermented dairy products [48]. With regard to tea, Wang et al. [49] reported that green tea may have a protective effect on BC in Asians while Zhang et al. [50] observed that in Western countries, an increase in tea consumption in general may reduce the risk of BC. A meta-analysis published in 2013 reported that overall, there was no significant association between egg consumption and BC but, increased risk of bladder cancer was detected in North/South America and fried egg intake positively associated with BC risk [51]. The overall current literature on fish consumption and the risk of BC suggested no association. The studies associating other food items and risk of BC have been summarized in Table 5 [52].

Table 5
Summary of studies associating other food items and risk of BC

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In summary, studies that investigated the association between dietary factors and BC risk have largely reported inconsistent results. There is no strong evidence to suggest that specific dietary factors or supplementation with any common micronutrient present in food is effective in reducing BC risk. These limitations in published research however do not totally eclipse the observation that a diet rich in fruits and vegetables and low in processed meat along with especially smoking cessation may convey some protective effects against BC risk.