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Use of selenium in chemoprevention of bladder cancer
Review
Use of selenium in chemoprevention of bladder cancer Maree Brinkman, Frank Buntinx, Erik Muls, Maurice P Zeegers Lancet Oncol 2006; 7: 766–74 Department of General Practice, Katholieke University of Leuven, Leuven, Belgium (M Brinkman MSc, F Buntinx PhD, Prof M P Zeegers PhD); Department of Experimental Medicine and Endocrinology, University Hospital Gasthuisberg, Leuven, Belgium (E Muls PhD); Unit of Genetic Epidemiology, Department of Public Health and Epidemiology, University of Birmingham, Birmingham, UK (Prof M P Zeegers); and Department of General Practice and Research Institute Caphri, Maastricht University, Netherlands (F Buntinx)
Introduction Bladder cancer is a major health problem and ranks the ninth most common cancer for both sexes worldwide.1 In 2002, 357 000 new cases and 145 000 deaths were attributed to the disease.1 About 90% of bladder cancer cases are transitional or urothelial-cell carcinomas, with the remainder comprising adenocarcinomas, small-cell carcinomas, and squamous-cell carcinomas.1 Cancer of the bladder affects mainly elderly people, with a median age at diagnosis of 65–70 years.2 This cancer is more common in men (77% of bladder cancer cases) and 63% of cases are from high-income countries.1 Clinically, two types of bladder cancer are evident: papillary and invasive. Papillary bladder cancer is derived from superficial tumours (stage Ta–T1) and confined to the urothelium (figure 1).3 Although rarely lethal, papillary bladder cancer recurs in up to 75% of patients.3 Only a few of these patients progress to invasive bladder cancer, which develops through carcinoma in situ.3 This type of bladder cancer has the potential to be highly malignant and progressive, and can metastasise and lead to death (figure 2).3
Courtesy of Christopher Luscombe
Correspondence to: Prof Maurice Zeegers, Unit of Genetic Epidemiology, Department of Public Health and Epidemiology, University of Birmingham, Birmingham B15 2TT, UK [email protected]
The anticarcinogenic potential of selenium was first identified nearly 40 years ago in geographical studies that reported lower death rates for cancer in regions with high levels of selenium. Cancer of the bladder was one of the body sites found to share this inverse association. Although many subsequent studies have been done on selenium and cancer, only a few have specifically assessed the relation with bladder cancer. However, the high recurrence rate and ability to monitor bladder urothelial-cell carcinoma make selenium a good candidate for chemoprevention. Evidence suggests that selenium is a biologically plausible, safe, and efficacious potential chemoprevention agent for bladder cancer. Large tertiary chemoprevention trials are needed to further investigate the role of selenium in the prevention of bladder cancer. Future studies should assess the best dose and form of selenium, and whether the protective effect of selenium differs between the sexes. Most cases of bladder cancer are sporadic, and involve no known family history.4 Long-term exposure of the urothelium to carcinogens is thought to cause bladder cancer.4 Cigarette smoking is reported to be the major risk factor for the disease.5 Other factors have also been implicated in its cause, such as radiation, schistosomal infections, and exposure to chemicals (eg, aromatic amines and polycyclic aromatic hydrocarbons).6 Polymorphisms of genes involved in the metabolism of carcinogens—glutathione S transferase (GST), N-acetyltransferase (NAT), and sulphotransferase (SULT)—are thought to modify an individual’s susceptibility to carcinogens and hence their potential risk to cancer.7 From a dietary perspective, high consumption of meat and fat, and high total fluid intake have also been associated with bladder cancer.8 However, results from studies investigating these dietary factors have been inconsistent and inconclusive.8 From existing information on the nutritional factors that are thought to reduce the risk of bladder cancer, several studies8–10 have reported that a diet high in fruit, vegetables, vitamins A, C, and E, and the trace element selenium might be protective. Because geographical studies11,12 done in the 1970s reported a possible inverse association between selenium and cancer mortality, epidemiological studies have focused on investigating the anticarcinogenic properties of this nutrient. Two key findings that emerged from these early studies were the inverse association between selenium and cancer seemed to be both sex and site specific. A larger difference in the reduced death rates was reported for men than for women in regions with high levels of selenium, and mortality was significantly lower for some types of cancer (eg, bladder cancer).11,13 We reviewed the available published work to determine whether selenium is a suitable chemoprevention agent for bladder cancer.
Sources of selenium Figure 1: Endoscopy of three separate lesions of typical low-grade bladder urothelial-cell carcinoma with feeding blood vessels and papillary morphology
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Selenium is an essential trace element that is present in a wide range of foods, including grains, meat, poultry, fish, eggs, and dairy products.14 Large variations in selenium intake exist between populations. The soil http://oncology.thelancet.com Vol 7 September 2006
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Courtesy of Tania Roskams
Selenium biomarkers
Figure 2: Histological presentation of high-grade urothelial-cell carcinoma of the bladder
content of an area generally determines the amount of selenium available in the food supply.15 Regional differences in the soil content of selenium range from 0·1 µg/kg to 1000 mg/kg.16 Areas of China (eg, Sichuan Province), New Zealand, Finland, and the Balkans are reported to be among the countries with the lowest concentrations of selenium.15 However, Venezuela, South Dakota (USA), and Hubei Province, China (adjacent to Sichuan Province) have the highest known selenium concentrations. Other sources of selenium include vitamin supplements, the water supply, and exposure via occupation and the environment.17 The current recommendations for daily selenium intake vary between countries, but generally have a range of 30–85 µg for men and 30–70 µg for women.18
Selenium metabolism Selenium can be classified into two basic chemical forms: organic selenium (selenomethionine and selenocysteine) and inorganic selenium (sodium selenite and selenate). Organic and inorganic selenium are thought to have different bioavailability, anticancer mechanisms of action, and toxic effects.19 Selenium in both its forms and in its reduced states is distributed widely throughout the body. The metabolism of selenium is thought to be involved in many biochemical pathways (figure 3). Hydrogen selenide is a metabolite that is common to both organic and inorganic selenium.20 It plays a central part in selenium metabolism because it is an important intermediary in the biosynthesis of selenoproteins.20 25 selenoproteins have so far been identified out of a possible 50 thought to exist.20 Selenium is incorporated into the selenoproteins as selenocysteine, the 21st aminoacid, via an alternative transcription of the UGA stop codon.20 Another pathway from hydrogen selenide involves methylation of selenium and its excretion from the body as either trimethylselenonium ions in the urine or dimethylselenide ions in the breath.19 http://oncology.thelancet.com Vol 7 September 2006
Exposure to selenium can be determined through dietary intake or the presence of biomarkers.17 Both methods have advantages and disadvantages. Difficulties associated with using only dietary assessment include the wide variation in the selenium concentration in the food supplies in different populations, food import and export between countries, and recall bias leading to underestimation or overestimation of intake.21 Alternatively, selection of the most appropriate biological sample to accurately indicate selenium exposure is one of the challenges of the use of biomarkers.17 The selenium biomarkers most commonly used in epidemiological studies are those taken from the whole blood, serum, plasma, toenails, and urine. Studies comparing dietary intake and biomarkers have provided further information on the metabolism and distribution of selenium throughout the body. In 1978, Schrauzer and White22 assessed the wholeblood concentrations of selenium after supplementation (6 weeks of 150 µg organic selenium per day). They found that although selenium intake seemed to have a linear correlation with blood concentrations, after terminating the supplementation, selenium concentrations in the blood showed an initial fast drop followed by a slow decline for about 40 days.22 The investigators reported that mobilisation of selenium from storage compartments other than the blood might have accounted for this slow decrease in blood concentrations.22 Intake/exposure
Metabolism in the body
Excretion or distribution
Organic selenuim Soil
General proteins
Plants Meat, fish, poultry, grain
Selenomethionine
Methylselenol
Selenocysteine
Hydrogen selenide (H2Se)
Glutathioneselenopersulphide GS-SeH Selenodiglutathione GS-Se-SG
Inorganic selenium
Dimethylselenide (CH3)2Se
Breath
Trimethylselenonium (CH3)3Se
Urine
Selenophosphate Selenoproteins (25 identified, including four glutathione peroxidases) Distributed throughout body
Selenite
Supplements Selenate Water supply
Figure 3: Sources, metabolism, distribution, and excretion of selenium Based on information from Whanger,15 Tingii,19 and Brenneisen and colleagues.20
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According to an early selenium bioavailability study,23 selenium concentrations fall more rapidly in the urine than in plasma. A positive correlation seems to exist between selenium intake and urinary excretion, although the relation is not linear.24 A reduced excretion rate in individuals who have depleted selenium concentrations indicates that the kidneys are involved in regulation.25 Daily urine excretion is estimated to be about half the daily intake, but it has been reported to be as high as 70%.26 The remainder of the selenium is thought to be re-used, incorporated into essential proteins or eliminated via other excretory pathways such as the breath and faeces.27 Excretion levels also depend on the chemical form of selenium. Inorganic selenium is generally thought to be absorbed and retained less efficiently than the organic form of selenium methionine.28 A human metabolic study27 indicated that the peak concentration of selenium in the urine occurred at 6 h after ingestion of selenium methionine compared with 9 h after intake of selenite. After selenite ingestion, the drop in selenium concentration was also slower; however, because only one individual was involved in this study, these results should be interpreted with care. In another human metabolic study,29 11 healthy men were fed either a high (mean 297 [SD 26 µg/day]) or a low (14 [2·6 µg/day]) selenium diet for 17 weeks (first 21 days was a stabilisation period). Excretion increased within 3 days of starting the high selenium diet, but a decrease in selenium excretion was not evident in the lowselenium group until after 18 days.29 A plateau was reached at 70–79 days in the low selenium group.29 This study suggests that homoeostatic control of selenium is slow, limited, and based on selenium intake.29 Lean body mass and previous or usual dietary intake are also thought to be important factors in achieving a selenium balance.30 In a human balance study, Levander and Morris30 noted that although men consumed more dietary selenium than women, selenium plasma concentrations did not differ significantly between the sexes. Swanson and colleagues26 reported that despite higher dietary intakes of selenium, men seem to have similar selenium concentrations in whole blood, serum, and toenail samples to those of women. Although this study found that men did not excrete a proportionately higher concentration of selenium in the urine, two other studies31,32 reported a higher amount per kg body weight of selenium in the urine of women compared with men. Men and women might therefore need different amounts of selenium to minimise the risk of cancer.31 Women have been reported to need only about 71% of the amount of selenium that men need to maintain a selenium balance.30 This potentially higher selenium requirement by men might be because of a greater lean body mass and incorporation of selenium into the sperm.30 Urine measures of selenium provide information on excretion quantities and rates, and evidence of direct 768
contact between selenium and the bladder mucosa. This biomarker, like blood measures such as plasma and serum concentrations of selenium, is thought to provide a more recent indication of intake.17 A reproducibility study measuring toenail concentrations of selenium in 127 women in the USA over 6 years found that these measures were useful biomarkers to determine long-term selenium exposure.33 Other studies26,34 have reported that toenail, whole blood, plasma, and serum measures have correlated well with dietary intake and with each other. The use of toenails has the following advantages: collection is non-invasive, samples are easy to store, and it provides a fairly accurate assessment of selenium intake over the previous 12 months.35 However, there are some temporal issues: toenail measures of selenium might only represent previous exposure and not exposure at time of sampling, and they are slow to reach peak concentrations after selenium supplementation.35
Selenium and bladder cancer Although the actual anticarcinogenic effects of selenium are not fully understood, several explanations have been proposed. The antioxidant role of selenium has been consistently reported. Oxygen reactive species cause damage to DNA and can lead to carcinogenesis.36 Selenium-dependent glutathione peroxidase is a selenoenzyme that protects against oxidative stress to the DNA and cell membrane by removing hydrogen peroxides and lipid hydroperoxides from the cells.37 Selenium metabolites such as selenodiglutathione, methylselenol, selenomethionine, and selenium-methylselenocysteine might affect the metabolism of carcinogens, thus preventing initiation of carcinogenesis.38 These metabolites might also restrict cell proliferation by inhibiting protein kinases and by halting phases of the cell cycle that play a central part in cell growth, tumour promotion, and differentiation.38 A further possible mechanism of action is enhancement of the immune system by stimulating the cytotoxic activities of natural killer cells and lymphokineactivated killer cells to act against cancer cells.37 High doses of selenium might also become prooxidant.16 Lipinski16 presented an hypothesis that sodium selenite in the presence of polythiols has oxidative properties that might have an anticancer effect by increasing the vulnerability of cancer cells to destruction. A review39 stated that selenium, independent of type, can alter several genes to prevent cancer. Selenium might upregulate phase II detoxification enzymes, some selenium-binding proteins, and some apoptotic genes, and downregulate phase I activating enzymes and cell proliferation genes.39 Inhibition of carcinogen–DNA adduct formation and induction of apoptosis by selenium suggests that protection occurs at both the initiation and post-initiation phases of carcinogenesis.39 Because selenium comes into direct contact with bladder mucosa, it is possible that it protects against http://oncology.thelancet.com Vol 7 September 2006
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bladder cancer both directly via the cancer cells and indirectly via the serum by reducing the concentration of carcinogens. Some factors that might affect the duration that selenium is retained in the bladder and concentrations of selenium in the body are consumption of tea, coffee, and alcohol. However, only a few studies have investigated the effect of these diuretics on selenium concentrations. According to one study,32 drinking alcohol or coffee does not significantly affect selenium status. However, alcohol could lead to selenium losses and regular tea consumption might improve selenium concentrations in the serum samples of patients deficient in selenium.40 Age, sex, living environment, and smoking are other factors that might affect selenium concentrations in the body and subsequently alter the risk of bladder cancer.32
In vitro studies Studies done in vitro have focused only on the effects of selenium on cells from body sites other than the urinary bladder. However, results from these studies have underscored the difference in the doses and mechanism of actions between the two types of selenium. Inorganic selenium compounds in cell cultures can induce singlestrand breaks in DNA and necrosis at concentrations of 5–10 µmol/L.38 Alternatively, organic selenium compounds caused apoptosis without DNA breakage at higher concentrations of 10–50 µmol/L.38 Redman and colleagues41 studied the effect of selenium on three tumour cell lines (breast, melanoma, and prostate cancer cells). Results from their study indicated that selenomethionine inhibits growth in tumour and healthy cell lines in a dose-dependent manner.41 Selenomethionine also induced apoptosis at concentrations that inhibited 50% growth in all three cell lines.41 Healthy cells were found to be 1000 times less sensitive than cancer cells to the inhibitory effect of selenomethionine.41 Organic selenium in the form of methylselenocysteine has also been found to decrease cell proliferation and enhance apoptosis of cancer cells.42 Menter and co-workers43 reported that selenite, the inorganic form of selenium, is a more potent inducer of apoptosis in cancer cells than is selenomethionine. Synthetic organoselenium compounds have been suggested to be effective and could be considered as chemoprevention agents.44 A major advantage of these compounds is that they can be modified to have few sideeffects, making them a preferable alternative to inorganic selenium.44 Additional studies in vitro that focus on selenium and bladder cancer cells are needed to determine whether the results seen from other cell lines are relevant to this body site.
Studies done in animals More than 100 studies have been done in animals to investigate selenium and cancer. About two-thirds of these studies have reported a decreased incidence in http://oncology.thelancet.com Vol 7 September 2006
cancer after selenium supplementation, and half of the reductions have involved a decrease of 50% or more.37 One of the few available animal studies45 on selenium and bladder cancer investigated the effect of low glutathione enzymes on the risk of carcinogenesis in the bladder. This comparative study assessed the urinary bladder of rabbits to determine the reasons for susceptibility of the bladder to peroxidase-mediated chemical carcinogenesis. Glutathione peroxidase concentrations and activities were lower in the bladder than in the liver in animals with bladder tumours, suggesting that these selenoenzymes affect carcinogenesis.45 A study done on female rats46 assessed the general metabolic effect of selenium compounds on carcinogenesis. Induction of tumours in the rats by nitrosomethylcy clohexylamine and nitrosomethyl-3-carboxypropylamine was not affected by the concentrations of selenium used.46 The investigators did suggest that the nitrosamines used in this study were unaffected by the selenium because they acted through an unusual mechanism that was not genotoxic or fully known.46 The antioxidant status of mice xenografted with stage III urothelial carcinomas was investigated in another study.36 Significant decreases in the plasma selenium concentrations and glutathione peroxidase activities were found in the mice xenografted with the bladder tumour. This study provided the opportunity to investigate the role of the tumour on the host, and to show that it can induce oxidative stress and a disturbance to the antioxidant defence system.36
Epidemiological studies Only a few epidemiological studies have specifically investigated the association between selenium and bladder cancer. These studies have been heterogeneous in terms of study populations, selenium measures, and study designs (table 1). Prospective designs, such as cohort, nested case-control, and case-cohort studies, in which exposure measures are taken before diagnosis, are preferred for investigating the relation between exposure and disease.21 A large prospective study9 that included 431 cases and 2459 subcohort members done in the Netherlands reported an inverse association between toenail selenium concentrations and the risk of bladder cancer. This association was most pronounced in ex-smokers and in those with invasive transitional-cell carcinomas.9 Results consistent with a dose-response effect were obtained in an early nested case-control study,48 the investigators of which suggested that these results strengthened the case for doing controlled trials. A nested case-control study52 involving data from two large cohorts, the Health Professionals Follow-up Study and the Nurses’ Health Study, found that prediagnostic selenium concentrations were inversely associated with the risk of bladder cancer in women but not in men. However, selenium concentrations of the men in this study52 were 769
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Cases (n)
Controls Results (n)
Ref
431
2459
Rate ratio 0·67 (95% CI 0·46–0·97) highest vs lowest quintile (>0·630 µg/g), p<0·01 (test for trend)
9
Serum
29
293*
Relative risk 3·1 (95% CI not published) lowest (<10·31 µg/dL) vs highest (≥13·31 µg/dL) quintile; 47 p=0·07
Toenail
35
70
OR 2·06 (95% CI 0·67–6·35) lowest vs highest tertile, p=0·03 (test for trend)
48
Serum
15
29
Cases: mean 73·5 µg/L; controls: mean 69·6 µg/L; p=0·62
49
Cases: mean 0·826 µg/g (SD 0·133); controls: mean 0·812 µg/g (SD 0·177); p=0·58
50
Case–cohort study Toenail Nested case-control studies
Toenail
28
28
Toenail
132
132
OR 0·87 (95% CI 0·30–2·52) highest vs lowest quartile, p=0·79 (test for trend)
51
Toenail
338
341
Men: OR 1·17 (95% CI 0·66–2·07) highest vs lowest quartile, p=0·61 (test for trend); women: OR 0·36 (95% CI 0·14–0·91) highest vs lowest quartile, p=0·02 (test for trend)
52
Serum
10
100
Cases: mean 65·7 µg/L (SD 6·5); controls: mean 94·1 µg/L (SD 12·5); p<0·05
53
Plasma
68
23
Plasma
200
386
Case-control studies Selenium lower in cases than controls (p<0·001) for grades II and III, but not grade I
54
OR 0·30 (95% CI 0·17–0·52) highest vs lowest tertile; increase of 10 µg/L plasma selenium: OR 0·76 (95% CI 0·67–0·85), p<0·0001 (test for trend)
55
OR=odds ratio. *The number of controls was determined from power calculations (not individually matched to cases) by the investigators.
Table: Epidemiological studies investigating the association between selenium and bladder cancer, by type of study and sample
substantially higher than those obtained from the Dutch cohort study. An earlier nested case-control study50 done in the USA, also using data from the Nurses’ Health Study cohort and including 28 women with cancer of the urinary tract, found no association between selenium concentrations in toenails and the risk of bladder cancer. This was the only study to assess women exclusively, and found a very weak positive relation between selenium and cancer risk in general.50 No significant results were seen for individuals in the lowest selenium quintile compared with the highest quintile in a study consisting of 29 bladder-cancer cases of Japanese ancestry.47 Two Finnish nested case-control studies found no association between selenium concentration and incidence of bladder cancer.49,51 The soil in Finland was fortified with selenium during the later study and subsequent toenail selenium concentrations might have changed over time, thereby affecting the results.51 Other epidemiological studies that have specifically investigated the association between selenium and bladder cancer incidence are case-control studies. These studies have been retrospective in design with exposure biomarkers (ie, from blood) obtained after cancer diagnosis. Although methodological issues have been associated with this study design,17 case-control studies provide a substantial contribution to the existing epidemiological studies on selenium and bladder cancer. Use of biomarkers avoids potential recall bias in these studies and provides a reliable estimation of exposure for analysis.34 An inverse association between plasma selenium concentrations and bladder cancer was reported in a 770
recent Belgian case-control study55 that included 200 cases and 386 controls. This association was also present in a Turkish study,53 which reported significantly lower selenium concentrations in the ten bladder cancer cases compared with the healthy controls. Selenium concentrations and glutathione peroxidase varied according to stage of the disease in another Turkish case-control study.54 Serum selenium concentrations were lower in patients with transitional-cell carcinoma of grades II and III, but not of grade I. Glutathione peroxidase activity was higher in grade I cases and lower in grade III cases, but was not significant for cases with grade II carcinoma,54 which suggests that selenium is useful for both preventing and treating the disease. Urothelial-cell carcinomas are derived from the urothelium, the epithelium that lines the urinary tract from the renal pelvis to the urethra.3 Hence, some cases occur outside the bladder. In epidemiological studies, bladder-cancer cases have often been grouped into broader categories such as urogenital cancer cases. A Greek study56 that included 17 urogenital cancer cases (including eight bladder and kidney cancer cases) found significantly lower concentrations of selenium in the blood, urine, and hair of cases than in those of controls for all cancers involved in the absorption, metabolism, and excretion of selenium. Other studies involving urogenital cancer have reported no difference in selenium concentrations between cases and controls.57,58 The inconsistent findings from epidemiological studies might be because of the small numbers of cases, resulting in a lack of statistical power. A possible threshold effect might also exist by which selenium must reach a specific http://oncology.thelancet.com Vol 7 September 2006
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concentration to affect carcinogenesis but provides no additional benefit beyond that point.59 Methodological issues associated with study design can also be a problem with epidemiological studies. Causality is difficult to establish from case-control studies, because low concentrations of selenium might be a result of the bladder cancer or altered behaviour associated with the disease.60 An Indian case-control study60 assessed this possibility by checking the nutritional status of patients with cancer by use of haemoglobin and serum protein measures. These measures were not found to be related to selenium concentrations.60 Prospective studies with follow-up adequate to cover the long latency period that leads to clinical development of bladder cancer could provide further information on the role of selenium in its causation.21
Sex differences The potential benefit of selenium to protect against the risk of cancer in men but not women has been reported in some61,62 but not all52 epidemiological studies. A Belgian prospective study61 investigated serum selenium and cancer mortality. Overall findings from this study suggested that selenium is an independent predictor of cancer mortality in men only.61 Two studies,62,63 including one with 12 urogenital cancer cases,63 have reported an increased risk of cancer in men but not women. A Japanese study64 also reported significantly lower selenium concentrations in men but not women with cancer compared with individuals without cancer. The odds ratios of cancer for men and women in the lowest tertiles of selenium concentration were 2·52 (95% CI 2·18–2·90) and 1·32 (1·13–1·53), respectively.64 Possible differences in selenium concentrations and risk of cancer between the sexes have been attributed to different tissue distribution and sex-related factors that affect tumour biology.31 Further assessment of these differences have been limited by the fact that men and women with bladder cancer are often not specified or analysed separately in epidemiological studies because of the small numbers of cases.
Clinical trials Only a few clinical trials have been done to investigate selenium supplementation to reduce cancer incidence in humans. Results from the Nutritional Prevention of Cancer (NPC) trial,65 which investigated the relation between selenium and non-melanoma skin cancer, generated many investigations into selenium as a potential chemoprevention agent. The NPC trial gave 1312 patients either 200 µg selenised yeast or placebo every day for a mean of 4·5 years (SD 2·8) with a mean follow-up of 6·4 years (SD 2·0). Although no association was noted between selenium and the primary outcome of the study (non-melanoma skin cancer), secondary analyses indicated significant decreases in total cancer mortality, incidence, and risk of cancer at other sites, including prostate, lung, and colorectal cancers. A risk ratio of 1·32 (95% CI http://oncology.thelancet.com Vol 7 September 2006
0·40–4·61) was reported for the 14 bladder cancer cases (eight on treatment, six on placebo).65 In addition, 35 patients (21 on treatment, 14 on placebo) were withdrawn from the NPC trial because of adverse sideeffects. These side-effects did not involve known signs of frank selenosis (eg, pathological nail changes, brittle hair, garlic breath, or other illnesses), but included mainly gastrointestinal complaints. The patients reporting adverse effects did not have significantly different plasma selenium concentrations compared with other patients.65 Subsequent clinical trials investigating selenium as a preventive agent against the development of cancer have focused on other body sites, particularly prostate cancer (eg, SELECT; a phase III randomised, double-blind, placebo-controlled, population-based clinical trial designed to test the efficacy of selenium and vitamin E alone and in combination in the prevention of prostate cancer).14 A randomised clinical trial that will specifically investigate the effect of selenium on bladder cancer recurrence and prognosis (the SELENIB trial) will start shortly in the UK. In this study, 1200 patients with nonmuscle invasive bladder cancer will receive a daily supplement of 200 µg high selenium yeast, 154 mg daily α-tocopherol, or placebo (or combinations thereof) for 5 years using a 2 × 2 factorial design. The first results of this study are expected to be reported in 2011.
Chemoprevention Until the SELENIB trial, no chemoprevention trials have been done on bladder cancer. Chemoprevention comprises three types: primary, secondary, and tertiary. Primary chemoprevention refers to the use of agents to prevent the initiation of carcinogenesis.66 Because of the long latency period of bladder cancer, very large studies are needed to evaluate a primary chemoprevention strategy.66 Secondary chemoprevention uses the agent to prevent premalignant lesions from developing into malignant tumours.66 Tertiary chemoprevention is the prevention of a second primary tumour or recurrence. The high risk of recurrence and the ability to assess tumour development with cystoscopy and urine cytology is thought to make patients with bladder cancer an ideal target group for tertiary chemoprevention.67 The European Organisation for Research and Treatment of Cancer has produced tables and software to calculate the risk of recurrence on the basis of six clinical and pathological characteristics, which could enable risk stratification of cases in future chemoprevention trials.68 The safety margin and potential toxic effects of selenium are important considerations for its role in chemoprevention.69 Although toxic effects from selenium have been reported in livestock, reports in human beings have been rare.19 These have involved accidental ingestion of selenic acid (30 g/L) and vitamin tablets containing high quantities of selenium.19 The need for further information about the optimum dose and chemical form of selenium is an important issue for chemoprevention. 771
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A reasonably high safety margin of up to 600 µg per day of selenium was reported as early as 1978.22 Clinical trials are using daily doses of 200–800 µg without obvious toxic effects.70 A chemoprevention study69 on prostate cancer progression gave 1600 µg and 3200 µg selenium per day to individuals for 12 months without reports of any serious adverse effects. Although participants were monitored regularly for signs of toxic effects, this study was discontinued due to a lack of safety information available at these doses.69 Organic selenium in the form of selenised yeast has been used in clinical trials and generally seems to have been well tolerated by participants. Seleniferous regions with high selenium concentrations provide the opportunity to assess both the effect of extended high selenium intake on cancer risk and potential toxic effects. In Venezuela, selenium intake has been reported to be approximately 200–350 µg per day, which is higher than that in other countries such as USA (106 µg/day).18 Total cancer mortality and bladder cancer mortality in Venezuela are substantially lower than those of the USA for both men and women.71 Inhabitants of South Dakota, USA, are another population who have been exposed to high intakes of organic selenium for more than a century without reports of serious toxic effects.72 These findings suggest that organic selenium from food sources is quite safe, even up to four times the upper levels recommended for most populations. However, current intake and recommended daily allowances for most populations are probably lower than the levels necessary to protect against the development of bladder cancer. Vitamin E has also been reported to have anticarcinogenic potential through its antioxidant activity.10 When used in combination with selenium it is thought to have a synergistic effect in cancer chemoprevention.21 A significant inverse association between vitamin E intake and bladder cancer was reported in the Health Professionals Follow-up cohort study.73 This association was strongest among individuals who had been taking vitamin E supplements for many years.73 Another study also found that regular intake of vitamin E supplement for 10 years or more was also associated with a reduction in bladder cancer mortality.74 However, not all studies have found this association.75 Results from the SELENIB trial might help to elucidate this relation.
Conclusions Despite early reports suggesting that selenium concentrations were inversely associated with risk of bladder cancer, only a few studies have assessed this specific relation. Although the exact anticancer mechanism of action of selenium is not fully known, selenium in its various forms might have the potential to act in both the early and late stages of the carcinogenic pathway.21 Further studies in animals and in vitro should help us to understand the role of selenium in the initiation, recurrence, and progression of bladder cancer. 772
Search strategy and selection criteria Material included in this review was identified from computerised searches of PubMed (1966 to March, 2006), EMBASE (1974 to March, 2006) and Current Contents (1998 to March, 2006) using the medical subject headings (MeSH) terms “bladder neoplasms OR carcinoma”, “transitional cell AND selenium”. Free text terms “selen* AND bladder cancer AND chemoprevention” were also used and combined with “clinical trials”, “epidemiologic studies”, “animal studies”, and “in-vitro studies”. Only peer-reviewed English language papers were eligible for inclusion. Additional information and studies were obtained by checking the reference lists from retrieved papers. Epidemiological studies with fewer than five bladder cancer cases were excluded from this review.
Most of the epidemiological studies included in this review have investigated selenium in terms of bladder cancer causes. Results from these studies were equivocal. Generally, the studies included only a few patients and the differences between studies in terms of study design, selenium measures, and populations were underscored. Although some of the larger prospective studies reported an inverse association, most of the studies that included small numbers of cases found no association between selenium concentrations and bladder cancer incidence. Results from all three case-control studies reported an increased risk of bladder cancer associated with lower selenium concentrations. The lower selenium concentrations and glutathione peroxidase activities reported in patients with higher grades of bladder cancer suggest that selenium is suitable for treatment as well as chemoprevention. Large tertiary chemoprevention trials are needed to investigate the association between selenium and bladder cancer, particularly given the high recurrence of superficial bladder cancer. Future investigations should also be directed towards the different responses to selenium observed between men and women. Results from clinical trials will help to provide the necessary information on whether 200 µg selenised yeast (alone and in combination with vitamin E) is the best dose and form of selenium to protect against bladder cancer. Conflicts of interest We declare no conflicts of interest. Acknowledgments We thank K K Cheng from the University of Birmingham, UK, for his opinions on this Review; and Christopher Luscombe from The University Hospital of North Staffordshire, UK, and Prof Tania Roskams from the Katholieke University of Leuven, Belgium, for providing figures 1 and 2. References 1 Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin 2005; 55: 74–108. 2 Kirkali Z, Chan T, Manoharan M, et al. Bladder cancer: epidemiology, staging and grading, and diagnosis. Urology 2005; 66: 4–34. 3 Schulz WA. Understanding urothelial carcinoma through cancer pathways. Int J Cancer 2006; 119: 1513–18.
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Wu XR. Urothelial tumorigenesis: a tale of divergent pathways. Nat Rev Cancer 2005; 5: 713–25. Zeegers MP, Tan FE, Dorant E, van Den Brandt PA. The impact of characteristics of cigarette smoking on urinary tract cancer risk: a meta-analysis of epidemiologic studies. Cancer 2000; 89: 630–39. Zeegers MP, Kellen E, Buntinx F, van den Brandt PA. The association between smoking, beverage consumption, diet and bladder cancer: a systematic literature review. World J Urol 2004; 21: 392–401. Perera FP. Environment and cancer: who are susceptible? Science 1997; 278: 1068–73. Negri E, La Vecchia C. Epidemiology and prevention of bladder cancer. Eur J Cancer Prev 2001; 10: 7–14. Zeegers M, Goldbohm A, Bode P, van den Brandt P. Prediagnostic toenail selenium and risk of bladder cancer. Cancer Epidemiol Biomarkers Prev 2002; 11: 1292–97. Kamat AM, Lamm DL. Chemoprevention of urological cancer. J Urol 1999; 161: 1748–60. Shamberger RJ, Tytko SA, Willis CE. Antioxidants and cancer. Part VI. Selenium and age-adjusted human cancer mortality. Arch Environ Health 1976; 31: 231–35. Schrauzer GN, White DA, Schneider CJ. Cancer mortality correlation studies—III: statistical associations with dietary selenium intakes. Bioinorg Chem 1977; 7: 23–31. Clark LC, Cantor KP, Allaway WH. Selenium in forage crops and cancer mortality in US counties. Arch Environ Health 1991; 46: 37–42. Klein EA, Thompson IM. Update on chemoprevention of prostate cancer. Curr Opin Urol 2004; 14: 143–49. Whanger PD. Selenium and its relationship to cancer: an update dagger. Br J Nutr 2004; 91: 11–28. Lipinski B. Rationale for the treatment of cancer with sodium selenite. Med Hypotheses 2005; 64: 806–10. Vinceti M, Rovesti S, Bergomi M, Vivoli G. The epidemiology of selenium and human cancer. Tumori 2000; 86: 105–18. Rayman MP. The use of high-selenium yeast to raise selenium status: how does it measure up? Br J Nutr 2004; 92: 557–73. Tinggi U. Essentiality and toxicity of selenium and its status in Australia: a review. Toxicol Lett 2003; 137: 103–10. Brenneisen P, Steinbrenner H, Sies H. Selenium, oxidative stress, and health aspects. Mol Aspects Med 2005; 26: 256–67. Platz EA, Helzlsouer KJ. Selenium, zinc, and prostate cancer. Epidemiol Rev 2001; 23: 93–101. Schrauzer GN, White DA. Selenium in human nutrition: dietary intakes and effects of supplementation. Bioinorg Chem 1978; 8: 303–18. Young VR, Nahapetian A, Janghorbani M. Selenium bioavailability with reference to human nutrition. Am J Clin Nutr 1982; 35: 1076–88. Janghorbani M, Xia Y, Ha P, et al. Metabolism of selenite in men with widely varying selenium status. J Am Coll Nutr 1999; 18: 462–69. Robinson JR, Robinson MF, Levander OA, Thompson CD. Urinary excretion of selenium by New Zealand and North American human subjects on differing intakes. Am J Clin Nutr 1985; 41: 1023–31. Swanson CA, Longnecker MP, Veillon C, et al. Selenium intake, age, gender, and smoking in relation to indices of selenium status of adults residing in a seleniferous area. Am J Clin Nutr 1990; 52: 858–62. Kuehnelt D, Kienzl N, Traar P, et al. Selenium metabolites in human urine after ingestion of selenite, L-selenomethionine, or DL-selenomethionine: a quantitative case study by HPLC/ICPMS. Anal Bioanal Chem 2005; 383: 235–46. Swanson CA, Patterson BH, Levander OA, et al. Human [74Se]selenomethionine metabolism: a kinetic model. Am J Clin Nutr 1991; 54: 917–26. Hawkes WC, Alkan FZ, Oehler L. Absorption, distribution and excretion of selenium from beef and rice in healthy North American men. J Nutr 2003; 133: 3434–42. Levander OA, Morris VC. Dietary selenium levels needed to maintain balance in North American adults consuming self-selected diets. Am J Clin Nutr 1984; 39: 809–15.
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Waters DJ, Chiang EC, Cooley DM, Morris JS. Making sense of sex and supplements: differences in the anticarcinogenic effects of selenium in men and women. Mutat Res 2004; 551: 91–107. Rodriguez Rodriguez EM, Sanz Alaejos MT, Diaz RC. Urinary selenium status of healthy people Eur J Clin Chem Clin Biochem 1995; 33: 127–33. Garland M, Morris JS, Rosner BA, et al. Toenail trace element levels as biomarkers: reproducibility over a 6-year period. Cancer Epidemiol Biomarkers Prev 1993; 2: 493–97. Longnecker MP, Stram DO, Taylor PR, et al. Use of selenium concentration in whole blood, serum, toenails, or urine as a surrogate measure of selenium intake. Epidemiology 1996; 7: 384–90. Slotnick MJ, Nriagu JO. Validity of human nails as a biomarker of arsenic and selenium exposure: a review. Environ Res 2006; 102: 125–39. Gauchez AS, Riondel J, Jacrot M, et al. Antioxidant status and lipid peroxidation in athymic mice xenografted with two types of human tumors. Biol Trace Elem Res 1995; 47: 103–09. Combs GF Jr, Gray WP. Chemopreventive agents: selenium. Pharmacol Ther 1998; 79: 179–92. El Bayoumy K. The protective role of selenium on genetic damage and on cancer. Mutat Res 2001; 475: 123–39. El Bayoumy K, Sinha R. Molecular chemoprevention by selenium: a genomic approach. Mutat Res 2005; 591: 224–36. Borawska MH, Witkowska AM, Hukalowicz K, Markiewicz R. Influence of dietary habits on serum selenium concentration. Ann Nutr Metab 2004; 48: 134–40. Redman C, Scott JA, Baines AT, et al. Inhibitory effect of selenomethionine on the growth of three selected human tumor cell lines. Cancer Lett 1998; 125: 103–10. Ip C, Dong Y. Methylselenocysteine modulates proliferation and apoptosis biomarkers in premalignant lesions of the rat mammary gland. Anticancer Res 2001; 21: 863–67. Menter DG, Sabichi AL, Lippman SM. Selenium effects on prostate cell growth. Cancer Epidemiol Biomarkers Prev 2000; 9: 1171–82. El Bayoumy K, Sinha R. Mechanisms of mammary cancer chemoprevention by organoselenium compounds. Mutat Res 2004; 551: 181–97. Mohandas J, Marshall JJ, Duggin GG, et al. Low activities of glutathione-related enzymes as factors in the genesis of urinary bladder cancer. Cancer Res 1984; 44: 5086–91. Lijinsky W, Milner JA, Kovatch RM, Thomas BJ. Lack of effect of selenium on induction of tumors of esophagus and bladder in rats by two nitrosamines. Toxicol Ind Health 1989; 5: 63–72. Nomura A, Heilbrun LK, Morris JS, Stemmermann GN. Serum selenium and the risk of cancer, by specific sites: case-control analysis of prospective data. J Natl Cancer Inst 1987; 79: 103–08. Helzlsouer KJ, Comstock GW, Morris JS. Selenium, lycopene, alpha-tocopherol, beta-carotene, retinol, and subsequent bladder cancer. Cancer Res 1989; 49: 6144–48. Knekt P, Aromaa A, Maatela J, et al. Serum micronutrients and risk of cancers of low incidence in Finland. Am J Epidemiol 1991; 134: 356–61. Garland M, Morris JS, Stampfer MJ, et al. Prospective study of toenail selenium levels and cancer among women. J Natl Cancer Inst 1995; 87: 497–505. Michaud DS, Hartman TJ, Taylor PR, et al. No association between toenail selenium levels and bladder cancer risk. Cancer Epidemiol Biomarkers Prev 2002; 11: 1505–06. Michaud DS, De Vivo I, Morris JS, Giovannucci E. Toenail selenium concentrations and bladder cancer risk in women and men. Br J Cancer 2005; 93: 804–06. Torun M, Aldemir H, Yardim S. Serum selenium levels in various cancer types. Trace Elem Electrolytes 1995; 12: 186–90. Yalcin O, Karatas F, Erulas FA, Ozdemir E. The levels of glutathione peroxidase, vitamin A, E, C and lipid peroxidation in patients with transitional cell carcinoma of the bladder. BJU Int 2004; 93: 863–66. Kellen E, Zeegers M, Buntinx F. Selenium is inversely associated with cancer risk: the Belgian case control study on bladder cancer. Int J Urol 2006 (in press). Bratakos MS, Vouterakos TP, Ioannou PV. Selenium status of cancer patients in Greece. Sci Total Environ 1990; 92: 207–22.
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Salonen JT, Alfthan G, Huttunen JK, Puska P. Association between serum selenium and the risk of cancer. Am J Epidemiol 1984; 120: 342–49. Ringstad J, Jacobsen BK, Tretli S, Thomassen Y. Serum selenium concentration associated with risk of cancer. J Clin Pathol 1988; 41: 454–57. Brooks JD, Metter EJ, Chan DW, et al. Plasma selenium level before diagnosis and the risk of prostate cancer development. J Urol 2001; 166: 2034–38. Gupta S, Narang R, Krishnaswami K, Yadav S. Plasma selenium level in cancer patients. Indian J Cancer 1994; 31: 192–97. Kornitzer M, Valente F, De Bacquer D, et al. Serum selenium and cancer mortality: a nested case-control study within an age- and sexstratified sample of the Belgian adult population. Eur J Clin Nutr 2004; 58: 98–104. Salonen JT, Salonen R, Lappetelainen R, et al. Risk of cancer in relation to serum concentrations of selenium and vitamins A and E: matched case-control analysis of prospective data. Br Med J (Clin Res Ed) 1985; 290: 417–20. Kok FJ, De Bruijn AM, Hofman A, et al. Is serum selenium a risk factor for cancer in men only? Am J Epidemiol 1987; 125: 12–16. Ujiie S, Kikuchi H. The relation between serum selenium value and cancer in Miyagi, Japan: 5-year follow up study. Tohoku J Exp Med 2002; 196: 99–109. Clark LC, Combs GF Jr, Turnbull BW, et al. Effects of selenium supplementation for cancer prevention in patients with carcinoma of the skin. A randomized controlled trial. Nutritional Prevention of Cancer Study Group. JAMA 1996; 276: 1957–63. Grossman HB. Chemoprevention of bladder cancer. Urology 2006; 67: 19–22.
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Gee J, Sabichi AL, Grossman HB. Chemoprevention of superficial bladder cancer. Crit Rev Oncol Hematol 2002; 43: 277–86. Sylvester RJ, van der Meijden AP, Oosterlinck W, et al. Predicting recurrence and progression in individual patients with stage Ta T1 bladder cancer using EORTC risk tables: a combined analysis of 2596 patients from seven EORTC trials. Eur Urol 2006; 49: 466–65. Reid ME, Stratton MS, Lillico AJ, et al. A report of high-dose selenium supplementation: response and toxicities. J Trace Elem Med Biol 2004; 18: 69–74. Clark LC, Marshall JR. Randomized, controlled chemoprevention trials in populations at very high risk for prostate cancer: elevated prostate-specific antigen and high-grade prostatic intraepithelial neoplasia. Urology 2001; 57: 185–87. Bosetti C, La Vecchia C. Cancer mortality in Latin America: implications for prevention. Rev Panam Salud Publica 2005; 18: 1–4. Longnecker MP, Taylor PR, Levander OA, et al. Selenium in diet, blood and toenails in relation to human health in a high seleniferous area. Am J Clin Nutr 1991; 53: 1288–94. Michaud DS, Spiegelman D, Clinton SK, et al. Prospective study of dietary supplements, macronutrients, micronutrients, and risk of bladder cancer in US men. Am J Epidemiol 2000; 152: 1145–53. Jacobs EJ, Henion AK, Briggs PJ, et al. Vitamin C and vitamin E supplement use and bladder cancer mortality in a large cohort of US men and women. Am J Epidemiol 2002; 156: 1002–10. Zeegers MP, Goldbohm RA, van den Brandt PA. Are retinol, vitamin C, vitamin E, folate and carotenoids intake associated with bladder cancer risk? Results from the Netherlands Cohort Study. Br J Cancer 2001; 85: 977–83.
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Use of selenium in chemoprevention of bladder cancer Maree Brinkman, Frank Buntinx, Erik Muls, Maurice P Zeegers Lancet Oncol 2006; 7: 766–74 Department of General Practice, Katholieke University of Leuven, Leuven, Belgium (M Brinkman MSc, F Buntinx PhD, Prof M P Zeegers PhD); Department of Experimental Medicine and Endocrinology, University Hospital Gasthuisberg, Leuven, Belgium (E Muls PhD); Unit of Genetic Epidemiology, Department of Public Health and Epidemiology, University of Birmingham, Birmingham, UK (Prof M P Zeegers); and Department of General Practice and Research Institute Caphri, Maastricht University, Netherlands (F Buntinx)
Introduction Bladder cancer is a major health problem and ranks the ninth most common cancer for both sexes worldwide.1 In 2002, 357 000 new cases and 145 000 deaths were attributed to the disease.1 About 90% of bladder cancer cases are transitional or urothelial-cell carcinomas, with the remainder comprising adenocarcinomas, small-cell carcinomas, and squamous-cell carcinomas.1 Cancer of the bladder affects mainly elderly people, with a median age at diagnosis of 65–70 years.2 This cancer is more common in men (77% of bladder cancer cases) and 63% of cases are from high-income countries.1 Clinically, two types of bladder cancer are evident: papillary and invasive. Papillary bladder cancer is derived from superficial tumours (stage Ta–T1) and confined to the urothelium (figure 1).3 Although rarely lethal, papillary bladder cancer recurs in up to 75% of patients.3 Only a few of these patients progress to invasive bladder cancer, which develops through carcinoma in situ.3 This type of bladder cancer has the potential to be highly malignant and progressive, and can metastasise and lead to death (figure 2).3
Courtesy of Christopher Luscombe
Correspondence to: Prof Maurice Zeegers, Unit of Genetic Epidemiology, Department of Public Health and Epidemiology, University of Birmingham, Birmingham B15 2TT, UK [email protected]
The anticarcinogenic potential of selenium was first identified nearly 40 years ago in geographical studies that reported lower death rates for cancer in regions with high levels of selenium. Cancer of the bladder was one of the body sites found to share this inverse association. Although many subsequent studies have been done on selenium and cancer, only a few have specifically assessed the relation with bladder cancer. However, the high recurrence rate and ability to monitor bladder urothelial-cell carcinoma make selenium a good candidate for chemoprevention. Evidence suggests that selenium is a biologically plausible, safe, and efficacious potential chemoprevention agent for bladder cancer. Large tertiary chemoprevention trials are needed to further investigate the role of selenium in the prevention of bladder cancer. Future studies should assess the best dose and form of selenium, and whether the protective effect of selenium differs between the sexes. Most cases of bladder cancer are sporadic, and involve no known family history.4 Long-term exposure of the urothelium to carcinogens is thought to cause bladder cancer.4 Cigarette smoking is reported to be the major risk factor for the disease.5 Other factors have also been implicated in its cause, such as radiation, schistosomal infections, and exposure to chemicals (eg, aromatic amines and polycyclic aromatic hydrocarbons).6 Polymorphisms of genes involved in the metabolism of carcinogens—glutathione S transferase (GST), N-acetyltransferase (NAT), and sulphotransferase (SULT)—are thought to modify an individual’s susceptibility to carcinogens and hence their potential risk to cancer.7 From a dietary perspective, high consumption of meat and fat, and high total fluid intake have also been associated with bladder cancer.8 However, results from studies investigating these dietary factors have been inconsistent and inconclusive.8 From existing information on the nutritional factors that are thought to reduce the risk of bladder cancer, several studies8–10 have reported that a diet high in fruit, vegetables, vitamins A, C, and E, and the trace element selenium might be protective. Because geographical studies11,12 done in the 1970s reported a possible inverse association between selenium and cancer mortality, epidemiological studies have focused on investigating the anticarcinogenic properties of this nutrient. Two key findings that emerged from these early studies were the inverse association between selenium and cancer seemed to be both sex and site specific. A larger difference in the reduced death rates was reported for men than for women in regions with high levels of selenium, and mortality was significantly lower for some types of cancer (eg, bladder cancer).11,13 We reviewed the available published work to determine whether selenium is a suitable chemoprevention agent for bladder cancer.
Sources of selenium Figure 1: Endoscopy of three separate lesions of typical low-grade bladder urothelial-cell carcinoma with feeding blood vessels and papillary morphology
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Selenium is an essential trace element that is present in a wide range of foods, including grains, meat, poultry, fish, eggs, and dairy products.14 Large variations in selenium intake exist between populations. The soil http://oncology.thelancet.com Vol 7 September 2006
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Courtesy of Tania Roskams
Selenium biomarkers
Figure 2: Histological presentation of high-grade urothelial-cell carcinoma of the bladder
content of an area generally determines the amount of selenium available in the food supply.15 Regional differences in the soil content of selenium range from 0·1 µg/kg to 1000 mg/kg.16 Areas of China (eg, Sichuan Province), New Zealand, Finland, and the Balkans are reported to be among the countries with the lowest concentrations of selenium.15 However, Venezuela, South Dakota (USA), and Hubei Province, China (adjacent to Sichuan Province) have the highest known selenium concentrations. Other sources of selenium include vitamin supplements, the water supply, and exposure via occupation and the environment.17 The current recommendations for daily selenium intake vary between countries, but generally have a range of 30–85 µg for men and 30–70 µg for women.18
Selenium metabolism Selenium can be classified into two basic chemical forms: organic selenium (selenomethionine and selenocysteine) and inorganic selenium (sodium selenite and selenate). Organic and inorganic selenium are thought to have different bioavailability, anticancer mechanisms of action, and toxic effects.19 Selenium in both its forms and in its reduced states is distributed widely throughout the body. The metabolism of selenium is thought to be involved in many biochemical pathways (figure 3). Hydrogen selenide is a metabolite that is common to both organic and inorganic selenium.20 It plays a central part in selenium metabolism because it is an important intermediary in the biosynthesis of selenoproteins.20 25 selenoproteins have so far been identified out of a possible 50 thought to exist.20 Selenium is incorporated into the selenoproteins as selenocysteine, the 21st aminoacid, via an alternative transcription of the UGA stop codon.20 Another pathway from hydrogen selenide involves methylation of selenium and its excretion from the body as either trimethylselenonium ions in the urine or dimethylselenide ions in the breath.19 http://oncology.thelancet.com Vol 7 September 2006
Exposure to selenium can be determined through dietary intake or the presence of biomarkers.17 Both methods have advantages and disadvantages. Difficulties associated with using only dietary assessment include the wide variation in the selenium concentration in the food supplies in different populations, food import and export between countries, and recall bias leading to underestimation or overestimation of intake.21 Alternatively, selection of the most appropriate biological sample to accurately indicate selenium exposure is one of the challenges of the use of biomarkers.17 The selenium biomarkers most commonly used in epidemiological studies are those taken from the whole blood, serum, plasma, toenails, and urine. Studies comparing dietary intake and biomarkers have provided further information on the metabolism and distribution of selenium throughout the body. In 1978, Schrauzer and White22 assessed the wholeblood concentrations of selenium after supplementation (6 weeks of 150 µg organic selenium per day). They found that although selenium intake seemed to have a linear correlation with blood concentrations, after terminating the supplementation, selenium concentrations in the blood showed an initial fast drop followed by a slow decline for about 40 days.22 The investigators reported that mobilisation of selenium from storage compartments other than the blood might have accounted for this slow decrease in blood concentrations.22 Intake/exposure
Metabolism in the body
Excretion or distribution
Organic selenuim Soil
General proteins
Plants Meat, fish, poultry, grain
Selenomethionine
Methylselenol
Selenocysteine
Hydrogen selenide (H2Se)
Glutathioneselenopersulphide GS-SeH Selenodiglutathione GS-Se-SG
Inorganic selenium
Dimethylselenide (CH3)2Se
Breath
Trimethylselenonium (CH3)3Se
Urine
Selenophosphate Selenoproteins (25 identified, including four glutathione peroxidases) Distributed throughout body
Selenite
Supplements Selenate Water supply
Figure 3: Sources, metabolism, distribution, and excretion of selenium Based on information from Whanger,15 Tingii,19 and Brenneisen and colleagues.20
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According to an early selenium bioavailability study,23 selenium concentrations fall more rapidly in the urine than in plasma. A positive correlation seems to exist between selenium intake and urinary excretion, although the relation is not linear.24 A reduced excretion rate in individuals who have depleted selenium concentrations indicates that the kidneys are involved in regulation.25 Daily urine excretion is estimated to be about half the daily intake, but it has been reported to be as high as 70%.26 The remainder of the selenium is thought to be re-used, incorporated into essential proteins or eliminated via other excretory pathways such as the breath and faeces.27 Excretion levels also depend on the chemical form of selenium. Inorganic selenium is generally thought to be absorbed and retained less efficiently than the organic form of selenium methionine.28 A human metabolic study27 indicated that the peak concentration of selenium in the urine occurred at 6 h after ingestion of selenium methionine compared with 9 h after intake of selenite. After selenite ingestion, the drop in selenium concentration was also slower; however, because only one individual was involved in this study, these results should be interpreted with care. In another human metabolic study,29 11 healthy men were fed either a high (mean 297 [SD 26 µg/day]) or a low (14 [2·6 µg/day]) selenium diet for 17 weeks (first 21 days was a stabilisation period). Excretion increased within 3 days of starting the high selenium diet, but a decrease in selenium excretion was not evident in the lowselenium group until after 18 days.29 A plateau was reached at 70–79 days in the low selenium group.29 This study suggests that homoeostatic control of selenium is slow, limited, and based on selenium intake.29 Lean body mass and previous or usual dietary intake are also thought to be important factors in achieving a selenium balance.30 In a human balance study, Levander and Morris30 noted that although men consumed more dietary selenium than women, selenium plasma concentrations did not differ significantly between the sexes. Swanson and colleagues26 reported that despite higher dietary intakes of selenium, men seem to have similar selenium concentrations in whole blood, serum, and toenail samples to those of women. Although this study found that men did not excrete a proportionately higher concentration of selenium in the urine, two other studies31,32 reported a higher amount per kg body weight of selenium in the urine of women compared with men. Men and women might therefore need different amounts of selenium to minimise the risk of cancer.31 Women have been reported to need only about 71% of the amount of selenium that men need to maintain a selenium balance.30 This potentially higher selenium requirement by men might be because of a greater lean body mass and incorporation of selenium into the sperm.30 Urine measures of selenium provide information on excretion quantities and rates, and evidence of direct 768
contact between selenium and the bladder mucosa. This biomarker, like blood measures such as plasma and serum concentrations of selenium, is thought to provide a more recent indication of intake.17 A reproducibility study measuring toenail concentrations of selenium in 127 women in the USA over 6 years found that these measures were useful biomarkers to determine long-term selenium exposure.33 Other studies26,34 have reported that toenail, whole blood, plasma, and serum measures have correlated well with dietary intake and with each other. The use of toenails has the following advantages: collection is non-invasive, samples are easy to store, and it provides a fairly accurate assessment of selenium intake over the previous 12 months.35 However, there are some temporal issues: toenail measures of selenium might only represent previous exposure and not exposure at time of sampling, and they are slow to reach peak concentrations after selenium supplementation.35
Selenium and bladder cancer Although the actual anticarcinogenic effects of selenium are not fully understood, several explanations have been proposed. The antioxidant role of selenium has been consistently reported. Oxygen reactive species cause damage to DNA and can lead to carcinogenesis.36 Selenium-dependent glutathione peroxidase is a selenoenzyme that protects against oxidative stress to the DNA and cell membrane by removing hydrogen peroxides and lipid hydroperoxides from the cells.37 Selenium metabolites such as selenodiglutathione, methylselenol, selenomethionine, and selenium-methylselenocysteine might affect the metabolism of carcinogens, thus preventing initiation of carcinogenesis.38 These metabolites might also restrict cell proliferation by inhibiting protein kinases and by halting phases of the cell cycle that play a central part in cell growth, tumour promotion, and differentiation.38 A further possible mechanism of action is enhancement of the immune system by stimulating the cytotoxic activities of natural killer cells and lymphokineactivated killer cells to act against cancer cells.37 High doses of selenium might also become prooxidant.16 Lipinski16 presented an hypothesis that sodium selenite in the presence of polythiols has oxidative properties that might have an anticancer effect by increasing the vulnerability of cancer cells to destruction. A review39 stated that selenium, independent of type, can alter several genes to prevent cancer. Selenium might upregulate phase II detoxification enzymes, some selenium-binding proteins, and some apoptotic genes, and downregulate phase I activating enzymes and cell proliferation genes.39 Inhibition of carcinogen–DNA adduct formation and induction of apoptosis by selenium suggests that protection occurs at both the initiation and post-initiation phases of carcinogenesis.39 Because selenium comes into direct contact with bladder mucosa, it is possible that it protects against http://oncology.thelancet.com Vol 7 September 2006
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bladder cancer both directly via the cancer cells and indirectly via the serum by reducing the concentration of carcinogens. Some factors that might affect the duration that selenium is retained in the bladder and concentrations of selenium in the body are consumption of tea, coffee, and alcohol. However, only a few studies have investigated the effect of these diuretics on selenium concentrations. According to one study,32 drinking alcohol or coffee does not significantly affect selenium status. However, alcohol could lead to selenium losses and regular tea consumption might improve selenium concentrations in the serum samples of patients deficient in selenium.40 Age, sex, living environment, and smoking are other factors that might affect selenium concentrations in the body and subsequently alter the risk of bladder cancer.32
In vitro studies Studies done in vitro have focused only on the effects of selenium on cells from body sites other than the urinary bladder. However, results from these studies have underscored the difference in the doses and mechanism of actions between the two types of selenium. Inorganic selenium compounds in cell cultures can induce singlestrand breaks in DNA and necrosis at concentrations of 5–10 µmol/L.38 Alternatively, organic selenium compounds caused apoptosis without DNA breakage at higher concentrations of 10–50 µmol/L.38 Redman and colleagues41 studied the effect of selenium on three tumour cell lines (breast, melanoma, and prostate cancer cells). Results from their study indicated that selenomethionine inhibits growth in tumour and healthy cell lines in a dose-dependent manner.41 Selenomethionine also induced apoptosis at concentrations that inhibited 50% growth in all three cell lines.41 Healthy cells were found to be 1000 times less sensitive than cancer cells to the inhibitory effect of selenomethionine.41 Organic selenium in the form of methylselenocysteine has also been found to decrease cell proliferation and enhance apoptosis of cancer cells.42 Menter and co-workers43 reported that selenite, the inorganic form of selenium, is a more potent inducer of apoptosis in cancer cells than is selenomethionine. Synthetic organoselenium compounds have been suggested to be effective and could be considered as chemoprevention agents.44 A major advantage of these compounds is that they can be modified to have few sideeffects, making them a preferable alternative to inorganic selenium.44 Additional studies in vitro that focus on selenium and bladder cancer cells are needed to determine whether the results seen from other cell lines are relevant to this body site.
Studies done in animals More than 100 studies have been done in animals to investigate selenium and cancer. About two-thirds of these studies have reported a decreased incidence in http://oncology.thelancet.com Vol 7 September 2006
cancer after selenium supplementation, and half of the reductions have involved a decrease of 50% or more.37 One of the few available animal studies45 on selenium and bladder cancer investigated the effect of low glutathione enzymes on the risk of carcinogenesis in the bladder. This comparative study assessed the urinary bladder of rabbits to determine the reasons for susceptibility of the bladder to peroxidase-mediated chemical carcinogenesis. Glutathione peroxidase concentrations and activities were lower in the bladder than in the liver in animals with bladder tumours, suggesting that these selenoenzymes affect carcinogenesis.45 A study done on female rats46 assessed the general metabolic effect of selenium compounds on carcinogenesis. Induction of tumours in the rats by nitrosomethylcy clohexylamine and nitrosomethyl-3-carboxypropylamine was not affected by the concentrations of selenium used.46 The investigators did suggest that the nitrosamines used in this study were unaffected by the selenium because they acted through an unusual mechanism that was not genotoxic or fully known.46 The antioxidant status of mice xenografted with stage III urothelial carcinomas was investigated in another study.36 Significant decreases in the plasma selenium concentrations and glutathione peroxidase activities were found in the mice xenografted with the bladder tumour. This study provided the opportunity to investigate the role of the tumour on the host, and to show that it can induce oxidative stress and a disturbance to the antioxidant defence system.36
Epidemiological studies Only a few epidemiological studies have specifically investigated the association between selenium and bladder cancer. These studies have been heterogeneous in terms of study populations, selenium measures, and study designs (table 1). Prospective designs, such as cohort, nested case-control, and case-cohort studies, in which exposure measures are taken before diagnosis, are preferred for investigating the relation between exposure and disease.21 A large prospective study9 that included 431 cases and 2459 subcohort members done in the Netherlands reported an inverse association between toenail selenium concentrations and the risk of bladder cancer. This association was most pronounced in ex-smokers and in those with invasive transitional-cell carcinomas.9 Results consistent with a dose-response effect were obtained in an early nested case-control study,48 the investigators of which suggested that these results strengthened the case for doing controlled trials. A nested case-control study52 involving data from two large cohorts, the Health Professionals Follow-up Study and the Nurses’ Health Study, found that prediagnostic selenium concentrations were inversely associated with the risk of bladder cancer in women but not in men. However, selenium concentrations of the men in this study52 were 769
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Cases (n)
Controls Results (n)
Ref
431
2459
Rate ratio 0·67 (95% CI 0·46–0·97) highest vs lowest quintile (>0·630 µg/g), p<0·01 (test for trend)
9
Serum
29
293*
Relative risk 3·1 (95% CI not published) lowest (<10·31 µg/dL) vs highest (≥13·31 µg/dL) quintile; 47 p=0·07
Toenail
35
70
OR 2·06 (95% CI 0·67–6·35) lowest vs highest tertile, p=0·03 (test for trend)
48
Serum
15
29
Cases: mean 73·5 µg/L; controls: mean 69·6 µg/L; p=0·62
49
Cases: mean 0·826 µg/g (SD 0·133); controls: mean 0·812 µg/g (SD 0·177); p=0·58
50
Case–cohort study Toenail Nested case-control studies
Toenail
28
28
Toenail
132
132
OR 0·87 (95% CI 0·30–2·52) highest vs lowest quartile, p=0·79 (test for trend)
51
Toenail
338
341
Men: OR 1·17 (95% CI 0·66–2·07) highest vs lowest quartile, p=0·61 (test for trend); women: OR 0·36 (95% CI 0·14–0·91) highest vs lowest quartile, p=0·02 (test for trend)
52
Serum
10
100
Cases: mean 65·7 µg/L (SD 6·5); controls: mean 94·1 µg/L (SD 12·5); p<0·05
53
Plasma
68
23
Plasma
200
386
Case-control studies Selenium lower in cases than controls (p<0·001) for grades II and III, but not grade I
54
OR 0·30 (95% CI 0·17–0·52) highest vs lowest tertile; increase of 10 µg/L plasma selenium: OR 0·76 (95% CI 0·67–0·85), p<0·0001 (test for trend)
55
OR=odds ratio. *The number of controls was determined from power calculations (not individually matched to cases) by the investigators.
Table: Epidemiological studies investigating the association between selenium and bladder cancer, by type of study and sample
substantially higher than those obtained from the Dutch cohort study. An earlier nested case-control study50 done in the USA, also using data from the Nurses’ Health Study cohort and including 28 women with cancer of the urinary tract, found no association between selenium concentrations in toenails and the risk of bladder cancer. This was the only study to assess women exclusively, and found a very weak positive relation between selenium and cancer risk in general.50 No significant results were seen for individuals in the lowest selenium quintile compared with the highest quintile in a study consisting of 29 bladder-cancer cases of Japanese ancestry.47 Two Finnish nested case-control studies found no association between selenium concentration and incidence of bladder cancer.49,51 The soil in Finland was fortified with selenium during the later study and subsequent toenail selenium concentrations might have changed over time, thereby affecting the results.51 Other epidemiological studies that have specifically investigated the association between selenium and bladder cancer incidence are case-control studies. These studies have been retrospective in design with exposure biomarkers (ie, from blood) obtained after cancer diagnosis. Although methodological issues have been associated with this study design,17 case-control studies provide a substantial contribution to the existing epidemiological studies on selenium and bladder cancer. Use of biomarkers avoids potential recall bias in these studies and provides a reliable estimation of exposure for analysis.34 An inverse association between plasma selenium concentrations and bladder cancer was reported in a 770
recent Belgian case-control study55 that included 200 cases and 386 controls. This association was also present in a Turkish study,53 which reported significantly lower selenium concentrations in the ten bladder cancer cases compared with the healthy controls. Selenium concentrations and glutathione peroxidase varied according to stage of the disease in another Turkish case-control study.54 Serum selenium concentrations were lower in patients with transitional-cell carcinoma of grades II and III, but not of grade I. Glutathione peroxidase activity was higher in grade I cases and lower in grade III cases, but was not significant for cases with grade II carcinoma,54 which suggests that selenium is useful for both preventing and treating the disease. Urothelial-cell carcinomas are derived from the urothelium, the epithelium that lines the urinary tract from the renal pelvis to the urethra.3 Hence, some cases occur outside the bladder. In epidemiological studies, bladder-cancer cases have often been grouped into broader categories such as urogenital cancer cases. A Greek study56 that included 17 urogenital cancer cases (including eight bladder and kidney cancer cases) found significantly lower concentrations of selenium in the blood, urine, and hair of cases than in those of controls for all cancers involved in the absorption, metabolism, and excretion of selenium. Other studies involving urogenital cancer have reported no difference in selenium concentrations between cases and controls.57,58 The inconsistent findings from epidemiological studies might be because of the small numbers of cases, resulting in a lack of statistical power. A possible threshold effect might also exist by which selenium must reach a specific http://oncology.thelancet.com Vol 7 September 2006
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concentration to affect carcinogenesis but provides no additional benefit beyond that point.59 Methodological issues associated with study design can also be a problem with epidemiological studies. Causality is difficult to establish from case-control studies, because low concentrations of selenium might be a result of the bladder cancer or altered behaviour associated with the disease.60 An Indian case-control study60 assessed this possibility by checking the nutritional status of patients with cancer by use of haemoglobin and serum protein measures. These measures were not found to be related to selenium concentrations.60 Prospective studies with follow-up adequate to cover the long latency period that leads to clinical development of bladder cancer could provide further information on the role of selenium in its causation.21
Sex differences The potential benefit of selenium to protect against the risk of cancer in men but not women has been reported in some61,62 but not all52 epidemiological studies. A Belgian prospective study61 investigated serum selenium and cancer mortality. Overall findings from this study suggested that selenium is an independent predictor of cancer mortality in men only.61 Two studies,62,63 including one with 12 urogenital cancer cases,63 have reported an increased risk of cancer in men but not women. A Japanese study64 also reported significantly lower selenium concentrations in men but not women with cancer compared with individuals without cancer. The odds ratios of cancer for men and women in the lowest tertiles of selenium concentration were 2·52 (95% CI 2·18–2·90) and 1·32 (1·13–1·53), respectively.64 Possible differences in selenium concentrations and risk of cancer between the sexes have been attributed to different tissue distribution and sex-related factors that affect tumour biology.31 Further assessment of these differences have been limited by the fact that men and women with bladder cancer are often not specified or analysed separately in epidemiological studies because of the small numbers of cases.
Clinical trials Only a few clinical trials have been done to investigate selenium supplementation to reduce cancer incidence in humans. Results from the Nutritional Prevention of Cancer (NPC) trial,65 which investigated the relation between selenium and non-melanoma skin cancer, generated many investigations into selenium as a potential chemoprevention agent. The NPC trial gave 1312 patients either 200 µg selenised yeast or placebo every day for a mean of 4·5 years (SD 2·8) with a mean follow-up of 6·4 years (SD 2·0). Although no association was noted between selenium and the primary outcome of the study (non-melanoma skin cancer), secondary analyses indicated significant decreases in total cancer mortality, incidence, and risk of cancer at other sites, including prostate, lung, and colorectal cancers. A risk ratio of 1·32 (95% CI http://oncology.thelancet.com Vol 7 September 2006
0·40–4·61) was reported for the 14 bladder cancer cases (eight on treatment, six on placebo).65 In addition, 35 patients (21 on treatment, 14 on placebo) were withdrawn from the NPC trial because of adverse sideeffects. These side-effects did not involve known signs of frank selenosis (eg, pathological nail changes, brittle hair, garlic breath, or other illnesses), but included mainly gastrointestinal complaints. The patients reporting adverse effects did not have significantly different plasma selenium concentrations compared with other patients.65 Subsequent clinical trials investigating selenium as a preventive agent against the development of cancer have focused on other body sites, particularly prostate cancer (eg, SELECT; a phase III randomised, double-blind, placebo-controlled, population-based clinical trial designed to test the efficacy of selenium and vitamin E alone and in combination in the prevention of prostate cancer).14 A randomised clinical trial that will specifically investigate the effect of selenium on bladder cancer recurrence and prognosis (the SELENIB trial) will start shortly in the UK. In this study, 1200 patients with nonmuscle invasive bladder cancer will receive a daily supplement of 200 µg high selenium yeast, 154 mg daily α-tocopherol, or placebo (or combinations thereof) for 5 years using a 2 × 2 factorial design. The first results of this study are expected to be reported in 2011.
Chemoprevention Until the SELENIB trial, no chemoprevention trials have been done on bladder cancer. Chemoprevention comprises three types: primary, secondary, and tertiary. Primary chemoprevention refers to the use of agents to prevent the initiation of carcinogenesis.66 Because of the long latency period of bladder cancer, very large studies are needed to evaluate a primary chemoprevention strategy.66 Secondary chemoprevention uses the agent to prevent premalignant lesions from developing into malignant tumours.66 Tertiary chemoprevention is the prevention of a second primary tumour or recurrence. The high risk of recurrence and the ability to assess tumour development with cystoscopy and urine cytology is thought to make patients with bladder cancer an ideal target group for tertiary chemoprevention.67 The European Organisation for Research and Treatment of Cancer has produced tables and software to calculate the risk of recurrence on the basis of six clinical and pathological characteristics, which could enable risk stratification of cases in future chemoprevention trials.68 The safety margin and potential toxic effects of selenium are important considerations for its role in chemoprevention.69 Although toxic effects from selenium have been reported in livestock, reports in human beings have been rare.19 These have involved accidental ingestion of selenic acid (30 g/L) and vitamin tablets containing high quantities of selenium.19 The need for further information about the optimum dose and chemical form of selenium is an important issue for chemoprevention. 771
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A reasonably high safety margin of up to 600 µg per day of selenium was reported as early as 1978.22 Clinical trials are using daily doses of 200–800 µg without obvious toxic effects.70 A chemoprevention study69 on prostate cancer progression gave 1600 µg and 3200 µg selenium per day to individuals for 12 months without reports of any serious adverse effects. Although participants were monitored regularly for signs of toxic effects, this study was discontinued due to a lack of safety information available at these doses.69 Organic selenium in the form of selenised yeast has been used in clinical trials and generally seems to have been well tolerated by participants. Seleniferous regions with high selenium concentrations provide the opportunity to assess both the effect of extended high selenium intake on cancer risk and potential toxic effects. In Venezuela, selenium intake has been reported to be approximately 200–350 µg per day, which is higher than that in other countries such as USA (106 µg/day).18 Total cancer mortality and bladder cancer mortality in Venezuela are substantially lower than those of the USA for both men and women.71 Inhabitants of South Dakota, USA, are another population who have been exposed to high intakes of organic selenium for more than a century without reports of serious toxic effects.72 These findings suggest that organic selenium from food sources is quite safe, even up to four times the upper levels recommended for most populations. However, current intake and recommended daily allowances for most populations are probably lower than the levels necessary to protect against the development of bladder cancer. Vitamin E has also been reported to have anticarcinogenic potential through its antioxidant activity.10 When used in combination with selenium it is thought to have a synergistic effect in cancer chemoprevention.21 A significant inverse association between vitamin E intake and bladder cancer was reported in the Health Professionals Follow-up cohort study.73 This association was strongest among individuals who had been taking vitamin E supplements for many years.73 Another study also found that regular intake of vitamin E supplement for 10 years or more was also associated with a reduction in bladder cancer mortality.74 However, not all studies have found this association.75 Results from the SELENIB trial might help to elucidate this relation.
Conclusions Despite early reports suggesting that selenium concentrations were inversely associated with risk of bladder cancer, only a few studies have assessed this specific relation. Although the exact anticancer mechanism of action of selenium is not fully known, selenium in its various forms might have the potential to act in both the early and late stages of the carcinogenic pathway.21 Further studies in animals and in vitro should help us to understand the role of selenium in the initiation, recurrence, and progression of bladder cancer. 772
Search strategy and selection criteria Material included in this review was identified from computerised searches of PubMed (1966 to March, 2006), EMBASE (1974 to March, 2006) and Current Contents (1998 to March, 2006) using the medical subject headings (MeSH) terms “bladder neoplasms OR carcinoma”, “transitional cell AND selenium”. Free text terms “selen* AND bladder cancer AND chemoprevention” were also used and combined with “clinical trials”, “epidemiologic studies”, “animal studies”, and “in-vitro studies”. Only peer-reviewed English language papers were eligible for inclusion. Additional information and studies were obtained by checking the reference lists from retrieved papers. Epidemiological studies with fewer than five bladder cancer cases were excluded from this review.
Most of the epidemiological studies included in this review have investigated selenium in terms of bladder cancer causes. Results from these studies were equivocal. Generally, the studies included only a few patients and the differences between studies in terms of study design, selenium measures, and populations were underscored. Although some of the larger prospective studies reported an inverse association, most of the studies that included small numbers of cases found no association between selenium concentrations and bladder cancer incidence. Results from all three case-control studies reported an increased risk of bladder cancer associated with lower selenium concentrations. The lower selenium concentrations and glutathione peroxidase activities reported in patients with higher grades of bladder cancer suggest that selenium is suitable for treatment as well as chemoprevention. Large tertiary chemoprevention trials are needed to investigate the association between selenium and bladder cancer, particularly given the high recurrence of superficial bladder cancer. Future investigations should also be directed towards the different responses to selenium observed between men and women. Results from clinical trials will help to provide the necessary information on whether 200 µg selenised yeast (alone and in combination with vitamin E) is the best dose and form of selenium to protect against bladder cancer. Conflicts of interest We declare no conflicts of interest. Acknowledgments We thank K K Cheng from the University of Birmingham, UK, for his opinions on this Review; and Christopher Luscombe from The University Hospital of North Staffordshire, UK, and Prof Tania Roskams from the Katholieke University of Leuven, Belgium, for providing figures 1 and 2. References 1 Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin 2005; 55: 74–108. 2 Kirkali Z, Chan T, Manoharan M, et al. Bladder cancer: epidemiology, staging and grading, and diagnosis. Urology 2005; 66: 4–34. 3 Schulz WA. Understanding urothelial carcinoma through cancer pathways. Int J Cancer 2006; 119: 1513–18.
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