Chemoprevention of urothelial carcinoma of the bladder

INTRODUCTION — Urothelial carcinoma of the bladder is a common malignancy of the urinary tract. Most cases of urothelial carcinoma of the bladder can be attributed to smoking and occupational and environmental carcinogen exposures, which cause diffuse changes in the urothelium and eventually result in bladder cancer. The identification of these risk factors provides an opportunity to minimize the incidence of bladder cancer through smoking cessation programs and decreasing exposure to workplace carcinogens [1-3]. (See "Epidemiology and risk factors of urothelial (transitional cell) carcinoma of the bladder", section on 'Risk factors'.)

Other potentially useful approaches include increasing cruciferous vegetable [4-7] and fluid intake [8], decreasing dietary fat [9], and losing weight [10]. Epidemiologic data suggesting that an increased intake of cruciferous vegetables (eg, cabbage, broccoli, and mustard) is associated with a reduced incidence of bladder cancer appear promising, and this is an active area of research [5,6]. However, all of these lifestyle-related factors must be placed in the context of possible predisposing genetic factors, which are poorly understood [11].

Chemoprevention is the use of systemic agents to prevent or reverse these changes. Primary chemoprevention seeks to block the formation of de novo bladder cancers in healthy individuals, while secondary chemoprevention focuses on avoiding the formation of additional tumors in patients who have already been treated for bladder cancer. Although chemoprevention is not routinely recommended in either primary or secondary settings, it is an area of active clinical investigation.

The chemoprevention of bladder cancer with systemic agents is reviewed here, with the focus primarily on agents for which epidemiologic or clinical trial data are available. The use of intravesical agents to prevent the recurrence of non-muscle invasive bladder cancer is discussed separately. (See "Treatment of primary non-muscle invasive urothelial bladder cancer".)

RATIONALE — Premalignant and malignant changes occur in the urothelium of the urinary tract that are chronically exposed to environmental carcinogens in a process referred to as field cancerization. Within this exposed field, chemical carcinogens damage DNA in the urothelial cell epithelium, allowing cancer to develop from multiple clones. These carcinogens are excreted in the urine and stored temporarily in the bladder, where they have an extended opportunity to interact with the urothelium. The gradual accumulation of chromosomal damage in the urothelial cells eventually results in phenotypic expression and transformation into overt neoplasm.

These carcinogens form highly reactive electrophilic species that bind nucleic acid and induce structural mutations within bladder epithelial cells. The observed changes (which may vary in different cells) include allelic deletions, loss of heterozygosity, inactivation of tumor suppressor genes, or activation of proto-oncogenes. The molecular mechanisms and pathways associated with the development of bladder cancer are discussed elsewhere. (See "Epidemiology and risk factors of urothelial (transitional cell) carcinoma of the bladder".)

Effective chemopreventive agents may act by preventing initial damage, enhancing repair, or blocking specific neoplastic processes (such as angiogenesis and invasion) that are involved in the transformation into invasive bladder cancer. In addition, increased urine output (attained by increased fluid intake) works to flush carcinogens out of the bladder, thereby minimizing exposure time.

TARGET POPULATION — Effective bladder cancer chemoprevention is facilitated by the elucidation of appropriate target populations.

The identification of risk factors for bladder cancer identifies populations for whom primary chemoprevention could be of potential utility [12-14]. These risk factors include (see "Epidemiology and risk factors of urothelial (transitional cell) carcinoma of the bladder", section on 'Environmental factors'):

●Tobacco use or heavy second-hand smoke exposure

●Exposure to aniline dyes

●Long-term use of cyclophosphamide

●History of pelvic radiation

●Exposure to chemical carcinogens associated with certain industries (eg, rubber or leather production, aluminum smelting, and exposure to diesel exhaust)

●Genetic factors

The known high rate of relapse after the diagnosis and treatment of early-stage bladder cancer allows the identification of a separate population for whom secondary chemoprevention may be valuable.

CHEMOPREVENTIVE AGENTS — No agent has an established role in either primary or secondary chemoprevention of bladder cancer.

The agents that have been most widely evaluated include vitamins, micronutrients, and various synthetic compounds [15]. The rationale and available data for the most widely clinically or epidemiologically evaluated agents will be reviewed here.

Retinoids — Retinoids (vitamin A analogues) are modulators of differentiation and proliferation in epithelial cells and can serve as potent inhibitors of neoplastic transformation [16]. Laboratory studies demonstrated that rats deficient in vitamin A are more susceptible to environmentally induced bladder carcinogenesis [17] and that retinoid supplements could prevent carcinogen-induced bladder cancer [18-20].

However, clinical data do not support the use of retinoids for primary chemoprevention:

●A meta-analysis published in 2000 that included six case-control studies reported no association between the risk of bladder cancer and low dietary intake of either retinol or beta-carotene [9].

●No benefit was observed using retinoids for primary chemoprevention in the Alpha-Tocopherol, Beta-Carotene (ATBC) Study. The ATBC Study included more than 29,000 male smokers who were randomly assigned to primary prevention using beta-carotene, alpha-tocopherol (a vitamin E precursor), both, or placebo [21,22]. At a median follow-up of 6.1 years, there was no difference in the incidence of bladder cancer regardless of whether patients were or were not taking alpha-tocopherol (81 versus 74 cases) or retinoids (79 versus 76 cases); however, the power of the study to detect a benefit was limited by the low incidence of bladder cancer in both groups.

The use of retinoids for secondary chemoprevention has been assessed in several clinical trials, with conflicting results. Thus, the administration of retinoids should be done only in the context of a well-designed clinical trial.

●Etretinate – Two randomized trials were conducted to evaluate the role of etretinate, a synthetic retinoid, for secondary prevention among patients who had been treated for non-muscle invasive bladder cancer [23,24]. While both trials showed a significant reduction in the rate of recurrence, predominantly in patients with grade 1 or 2 tumors [23] or Ta to T1 tumors [24], the toxicities were significant and included deaths from myocardial infarction in both studies.

●Fenretinide – Two studies evaluated the efficacy of fenretinide for the prevention of a recurrence of non-muscle invasive bladder cancer following transurethral resection of bladder tumors [25,26]. Fenretinide was well tolerated, without serious adverse effects; however, neither study observed a positive impact on the recurrence risk for these patients. In the larger trial, 137 patients with resected non-muscle invasive bladder cancer were randomly assigned to fenretinide or placebo. The risk of recurrence at one year did not differ significantly between both arms (32 percent), and the trial was closed early, before meeting its accrual goal [25].

Side effects have been a concern with chronic prophylactic administration of retinoids. Synthetic retinoids with reduced side effects or retinoids encapsulated into novel delivery systems may improve tolerability and outcomes with these agents [27].

Pyridoxine — Pyridoxine (vitamin B6) has been studied as a means to counteract the abnormalities in tryptophan metabolism that result in the high levels of tryptophan metabolites observed in patients with bladder cancer [28].

Two randomized clinical trials investigating the use of pyridoxine for secondary chemoprevention of bladder cancer have not demonstrated a positive effect:

●In an initial trial conducted by the Veteran's Administration, 121 patients with stage I bladder cancer were randomly assigned to oral pyridoxine, placebo, or intravesical thiotepa [29]. The percentage of patients with a recurrence was not significantly different among the three arms, although pyridoxine was better than placebo if recurrences during the first 10 months were excluded from the analysis, suggesting that pyridoxine may be useful for the prevention of new tumor formation rather than the treatment of existing tumors.

●Based on these results, the European Organisation for Research and Treatment of Cancer (EORTC) organized a larger trial in which 291 men with previously resected non-muscle invasive bladder cancer were randomly assigned to pyridoxine or placebo [30]. The use of pyridoxine had no significant effect on the time to first recurrence or the overall recurrence rate, even after adjusting for urinary levels of tryptophan metabolites.

Ascorbic acid — Ascorbic acid (vitamin C) is a reducing agent that acts as a free radical scavenger; in particular, vitamin C decreases the formation of N-nitroso chemicals that are associated with bladder cancer carcinogenesis. Despite this, high levels of sodium ascorbate were associated with an increased incidence of bladder cancer in rats [31]. Whether these findings are relevant to humans is unclear.

The epidemiologic data are conflicting [32-35], and no randomized prospective trials exist to evaluate the role of vitamin C as a chemopreventative agent.

●In a cohort of 11,580 cancer-free older adult subjects followed over an eight-year period, the use of vitamin C supplements was associated with a decreased incidence of bladder cancer [32]. Two case-control series also suggested that vitamin C might offer some protection against bladder cancer [33,34].

●However, the prospective Cancer Prevention Study II (CPS II) failed to identify any benefit from the use of vitamin C in a cohort of over 990,000 subjects followed for up to 16 years [35]. The use of vitamin C supplements ≥15 times per month was not associated with a decrease in bladder cancer mortality. Similarly, a dietary analysis of patients enrolled in the ATBC Study failed to identify any protective effect associated with increased levels of vitamin C intake [36].

Alpha-tocopherol — Alpha-tocopherol (vitamin E) is an antioxidant and inhibits carcinogenic N-nitroso formation in vitro. These observations provide a rationale for the use of alpha-tocopherol in preventing urothelial transformation.

Epidemiologic data suggest that diets high in alpha-tocopherol are associated with a lower risk of bladder cancer [35,37,38]. In the largest epidemiologic study, over 990,000 United States adults were evaluated as part of the CPS II cohort [35]. The major finding was that regular vitamin E supplementation for more than 10 years was associated with a reduced risk of bladder cancer mortality. This finding was more pronounced in ex-smokers and current smokers than in nonsmokers, suggesting some protection from carcinogens associated with smoking. Use for shorter periods of time was not associated with a reduction in disease-specific mortality.

However, no benefits have been observed in prospective clinical trials [22,39].

●In the ATBC Study, over 29,000 male smokers were randomly assigned to alpha-tocopherol, beta-carotene, both, or placebo [21,22]. There were no statistically significant differences in the incidence of bladder cancer between the groups. However, the dose of alpha-tocopherol used in this trial was lower than that of typical daily supplements (50 versus 200 to 1000 international units).

●In a secondary analysis of the Selenium and Vitamin E Cancer Prevention Trial (SELECT), higher doses (400 international units) of vitamin E, either alone or in combination with selenium, failed to demonstrate a protective effect against bladder cancer in 34,887 men [39].

Multivitamins — The theoretical benefits of vitamin supplementation for cancer prevention led to the idea that a combination of vitamins might prove more powerful than any single nutrient. However, the results of various studies have not been consistent.

●A role in primary prevention was suggested by a case-control study that included 262 patients and 405 controls, which reported that the daily use of multivitamin supplements for more than 10 years was associated with a decrease in the risk of bladder cancer (odds ratio [OR] 0.39, 95% CI 0.24-0.63) [34].

●The potential for multivitamins in secondary chemoprevention was suggested by a prospective trial in which 65 patients treated for non-invasive bladder cancer were given intravesical Bacillus Calmette-Guerin (BCG) [40]. Patients were randomly assigned to a recommended daily allowance multivitamin or to a megadose vitamin (ie, augmented levels of vitamins A, B6, C, E, and zinc). Although there was no difference between the two regimens in the first year, patients receiving the megadose vitamin had a statistically significant lower rate of recurrence at five years (41 versus 91 percent).

●By contrast, in a larger multicenter prospective trial in BCG-naïve patients receiving intravesical BCG (with or without interferon treatment), compared with vitamins dosed at the recommended daily allowance, there was no benefit to the administration of megadose multivitamins [41].

Selenium — Selenium is required for the activity of glutathione peroxidase, which converts lipid hydroperoxides into nontoxic alcohols and hydrogen peroxide into water and oxygen. Glutathione peroxidase may also provide a direct protective effect against carcinogens in the bladder by neutralizing their oxidative potential.

Several large studies correlating the incidence of bladder cancer and serum selenium levels (or toenail concentrations, a surrogate measure of selenium intake during the previous 12 months) have yielded conflicting results:

●Higher selenium concentrations were associated with a decreased risk of bladder cancer in several studies [42-44], with the effect being more pronounced in those with invasive bladder cancer and in ex-smokers [42]. A Belgian case-control study of 178 cases and 362 controls examining serum selenium levels supported these findings [43]. Patients were divided into tertiles by selenium level, and the middle and highest groups demonstrated a significantly decreased incidence of bladder cancer compared with the lowest group. A Turkish case-control study of serum selenium levels showed that those with grade 2 to 3 bladder cancer had lower levels than those with grade 1 cancers or the normal controls [44].

●By contrast, the Nurses' Health Study reported that women who developed bladder cancer actually had higher levels of toenail selenium than the control population [45]. More importantly, a secondary analysis of the SELECT trial did not reveal a role for selenium, alone or in combination with vitamin E, for the primary chemoprevention of bladder cancer in men [39].

The potential role of selenium for secondary chemoprevention was evaluated in the Selenium and Bladder Cancer Trial (SELEBLAT) [46,47]. In this trial, 292 patients who had undergone transurethral resection of a non-muscle invasive urothelial carcinoma were randomly assigned to selenium (200 mcg/day selenium yeast) or placebo. At a median follow-up of 18 months, there was no significant difference in the rate of recurrence (28 versus 32 percent, respectively, for selenium and placebo).

Difluoromethylornithine — Polyamine synthesis is associated with the induction of urothelial cell cancer in experimental models [48]. Difluoromethylornithine (DFMO) irreversibly inhibits ornithine decarboxylase, an enzyme that is required for polyamine synthesis [49].

DFMO was evaluated as a secondary chemopreventive agent in a randomized trial in which 454 patients with newly diagnosed or recurrent, Ta or T1, grade 1 to 2 bladder cancer were randomly assigned to treatment with DFMO or placebo for one year following resection of their bladder cancer [49]. At a median follow-up of 42 months, DFMO did not decrease the incidence of tumor recurrence (46 versus 43 percent with placebo), nor were any benefits observed in terms of the number of patients with progression to carcinoma in situ or grade 3 disease.

Nonsteroidal antiinflammatory drugs — Cyclooxygenases catalyze the synthesis of prostaglandins from arachidonic acid. The effects of prostaglandin synthesis may include increased angiogenesis, inhibition of apoptosis, and decreased immune surveillance, all of which may contribute to carcinogenesis. Although preclinical data suggest a possible benefit [50,51], no clinical trial to date has demonstrated a benefit for secondary chemoprevention.

Celecoxib, a selective cyclooxygenase 2 (COX-2) inhibitor, was evaluated as a secondary chemopreventive agent in a phase IIB clinical trial in which 146 patients with non-muscle invasive bladder cancer who achieved an initial complete response to induction BCG followed by three weeks of maintenance BCG were randomized to celecoxib 200 mg daily or placebo. In this setting, no benefit in time to recurrence or recurrence rate was demonstrated [52]. Although there was hope that the lower incidence of gastrointestinal side effects would indicate a superior therapeutic index in favor of using the selective COX-2 inhibitors, they have been associated with increased cardiovascular risk in some trials. Despite this, there was no increased risk demonstrated in this trial, and celecoxib remains available in some areas of the world.

This study was followed by a phase III clinical trial in London in which 475 patients with non-muscle invasive bladder cancer who achieved a complete response to resection and induction BCG were randomized to celecoxib at a higher dose (400 mg daily or 200 mg twice daily) or placebo. However, the results of this trial have not yet been released [53]. Overall, it seems unlikely that selective COX-2 inhibitors will find widespread use in cancer prevention for an otherwise healthy population. (See "NSAIDs (including aspirin): Role in prevention of colorectal cancer".)

Isoflavones — Isoflavones are natural substances derived from soy protein that are excreted in the urine. A reduced risk of breast, colon, and prostate cancers has been observed in populations with higher levels of soy consumption [54]. In addition, animal experiments indicate that soy protein diets have a protective effect against bladder carcinogenesis, and cell cycle studies show that these agents can induce apoptosis in immortalized bladder cancer cells [55].

However, the limited available clinical evidence does not support a chemoprotective effect from soy protein or isoflavone supplementation on bladder cancer incidence in men. In an epidemiologic study from China involving 18,244 men, a higher risk of bladder cancer was reported in patients consuming more dietary soy daily compared with less frequent intake after adjustment for age, tobacco use, and education level [56].

Polyphenols — Polyphenols are powerful antioxidant compounds that are found in green and black tea. (See "Overview of complementary, alternative, and integrative medicine practices in oncology care, and potential risks and harm".)

Animal studies have shown that green tea leaves inhibit carcinogen-induced bladder tumor formation [57]; however, human epidemiologic studies remain conflicting on the benefit of tea extracts. A 2013 meta-analysis of 17 studies concluded that tea consumption had no impact on bladder cancer risk; however, when the green tea subgroup was analyzed, a protective effect against bladder cancer was observed [58].

Statins — Cholesterol-lowering agents such as hydroxymethylglutaryl-coenzyme A reductase inhibitors (statins) have been shown to decrease the risk of various cancers. No epidemiologic or clinical studies exist to support their use for primary [59-61] or secondary [62] prevention of bladder cancer.

Antiandrogens — Bladder cancer is threefold more common in males, which cannot be explained entirely by differences in exposure to tobacco and other carcinogens between males and females. Data suggest that androgens may promote urothelial carcinogenesis. Enzalutamide, an inhibitor of the androgen axis, was under investigation for secondary chemoprevention in patients with non-muscle invasive bladder cancer; however, the trial was terminated due to poor accrual [63].

SUMMARY

●Rationale – The etiologic risk factors for bladder cancer include smoking and various environmental and occupational carcinogens. These substances are concentrated in the urine, where the urothelial lining is exposed to their carcinogenic effects. (See 'Rationale' above.)

●Chemopreventive agents – Many substances have been assessed for their ability to prevent de novo bladder cancer (primary chemoprevention) or recurrence after an earlier diagnosis (secondary chemoprevention). However, none of these should be used in either of these settings outside of a clinical trial. (See 'Chemopreventive agents' above.)

●Primary prevention – Smoking cessation, increased fluid intake, weight loss, and a healthy diet that is low in fat and high in fruits and vegetables should be recommended to all patients for primary prevention of bladder cancer. (See "Epidemiology and risk factors of urothelial (transitional cell) carcinoma of the bladder", section on 'Risk factors'.)

ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges J Stephen Jones, MD, and Juan Jiménez, MD, PhD, who contributed to an earlier version of this topic review.