This is the first report of a trial in tertiary prevention of selenium for bladder cancer. Other chemopreventive trials have been performed [24
]. High dose vitamins improved significantly the time to tumour recurrence (p = 0.0014) [37
]. Retinoids have been tested with various results [38
]. Neither vitamin B6 (Pyridoxine) [41
] nor difluoromethylornithine reduced the rate of recurrence [43
]. Lactobacillus casei powder significantly reduced the time to recurrence in the intervention group [44
]. Several ongoing trials are investigating cyclooxygenase-2 inhibitors in the recurrence of bladder cancer. Preliminary analysis of the results of the study based at the MD Anderson Cancer Center did not demonstrate a difference in time to tumour recurrence between the two treatment arms [24
]. We are aware of one other selenium and vitamin E factorial trial (SELENIB) that is currently recruiting in the UK [46
]. This chemoprevention study, which is largerly similar to our study (as far as the selenium arm is concerned), aims to include 500 patients with non muscle-invasive bladder cancer. In this trial, patients receive a daily supplement of 200 μg high selenium yeast or placebo and 154 mg daily α-tocopherol or placebo for 5 years using a 2 × 2 factorial design. Two chemopreventive trials on prostate cancer with selenium yeast are currently ongoing [47
Selenized yeast was selected for use in this trial because of its availability and well-characterized safety profile. In both the SELECT trial (prostate cancer prevention) and the NPC trial (basal cell or squamous cell skin cancer prevention), selenium supplementation was not significantly associated with any of the cardiovascular disease endpoints during 7.6 years of follow-up (all cardiovascular diseases, myocardial infarction, stroke, all cardiovascular disease mortality) [48
]. In secondary analyses of data from the NPC study, 58 subjects in the selenium-supplemented group (n = 600) and 39 subjects in the placebo group (n = 602) developed type 2 diabetes (hazard ratio 1.55; 95% CI, 1.03-2.33) [49
]. In the SELECT trial a statistically non-significant increased risk of type 2 diabetes was observed in the selenium group (RR, 1.07; 99% CI, 0.94-1.22) but not in the selenium vitamin E group [21
]. A secondary analysis was carried out using data from a pre-existing randomized clinical trial designed to investigate the effects of selenium yeast on prostate cancer progression (Watchful Waiting Trial) [50
]. There were no statistically significant differences in glucose levels during the course of the trial in men supplemented with selenium as compared with those on placebo. Laclaustra et al. reports that in U.S. adults, high serum selenium concentrations were associated with higher prevalence of diabetes and higher fasting plasma glucose and glycosylated hemoglobin levels. Mean serum selenium level in this trial was 137.1 ng/mL [51
]. In the New England case-control study, independently of the selenium serum level, an increase bladder cancer risk was associated with a history of diabetes (adjusted odds ratio = 2.2, 95% CI, 1.3 to 3.8). The risk may be greater among patients taking oral hypoglycemics and those with diabetes of longer duration [52
]. Total cholesterol, triglycerides, LDL cholesterol, and fasting serum glucose concentrations significantly increased with serum selenium concentration in the Taiwanese elderly. The mean serum selenium concentration was 89.76 ng/mL [53
]. In the UK, the PRECISE Pilot trial randomized 501 elderly volunteers of relatively low selenium status [mean (SD) plasma selenium 88.8 (19.2 ng/mL)] to a six-month treatment with 100, 200 or 300 mg selenium/day as high-selenium yeast or placebo yeast [36
]. Supplementation at 100 and 200 mg selenium/day lowered total serum cholesterol and non-HDL cholesterol [54
]. The effects of a long-term selenium supplement on blood pressure are inconsistent. Laclaustra et al. reported that blood pressure increases if the plasma selenium level is higher than 160 ng/mL [55
]. In a cross-sectional study with selenium in Belgium, the Flemish Study on Environment Genes and Health Outcomes (FLEMENGHO), 20 ng/mL higher plasma selenium level was associated with a clinically not relevant lower blood pressure with an effect sizes of 2.2 mmHg systolic (95% CI -0.57 to -5.05; p = 0.009) and 1.5 mmHg diastolic (95% CI -0.56 to -2.44; p = 0.017) in men, but not in women [56
]. As in Belgium the daily intake of selenium is low, we think that patients taking selenium for three years can only benefit from this treatment, including of blood pressure reduction.
If it is possible to increase the time to recurrence with selenium, patients have to undergo fewer cystopscopies. This means a reduction not only in suffering for the patient, but also in costs for society.
We are aware that the selenium status at baseline and the genetic variation of tested individuals may represent additional reasons for positive or negative results [8
] or risk of disease [54
]. There are 25 selenoproteins and three selenium-containing enzymes (glutathione peroxidases, thioredoxin reductases and iodothyronine deiodinases), the first two being linked with antioxidant activity, and the latter involved with thyroid hormone metabolism. Rayman [57
] suggests that only those persons at risk, those with single nucleotide polymorphisms in selenoproteins, GPx1, GPx4, SEPS1, Sep15, SEPP1 and TXNRD1, should be treated with selenium at doses which optimize the plasma selenium levels in order to activate specific selenoproteins. An intake of 40 μg per day is required to maintain the plasma glutathione peroxidase (GPx) activity at plateau [58
]. We will be investigating those additional genetic analyses in a subsequent sub-project.
The SELEBLAT study is well-designed. Selenium-yeast is a safe and cheap medicine. A computerized program performs our randomization. Neither the investigators, nor the research nurses have access to the randomization numbers. All study personnel is blinded for the medication. Both treatment groups are regularly compared on similarity of prognostic characteristics such as age, gender, smoking, grade of tumour, baseline selenium level and co-morbidity. We will report reasons and numbers of those patients lost to follow up. Both an intention to treat and a per protocol analysis will be performed. For hypothesis building subgroup analyses and analyses of interactions will be performed, as we have demographic and clinical data and questionnaires results on diet and Quality of Life. Standard treatment will be compared between the intervention and the placebo group. Additional intake of selenium by food supplements will be analyzed and compliance will be reported. Our primary outcome measures are both clinical and histologically confirmed recurrences as frequently patients with clinical recurrence are only cauterized without taking a biopsy. Cauterization only reduces the risk of perforation of the bladder. All subsequent patients undergoing TUR operation are included meeting the inclusion criteria. We decided to include both primary and second primary tumours, because the incidence of bladder cancer is low, while the prevalence and the rate of tumour recurrence is high [24
]. Recurrence within the first three months after TUR is considered as residual untreated disease. Although bladder cancer and prostate cancer occur together in 10% of the cases [59
], we decided to exclude patients with prostate cancer too. We deliberately did not exclude any patient for presence of co-morbidity or age aiming for a study population, which represents as far as possible the normal population diagnosed with bladder cancer. We intend to reach the calculated sample size by pooling of our results with the results from the Selenib study (UK), which is similar in design. Progress of the study can be followed on the website: http://www.genepid.bham.ac.uk/Seleblat_Recruitment.shtml.
The first results of our study can be expected for 2014.