Non-muscle-invasive Bladder Cancer

3. EPIDEMIOLOGY and AETIOLOGY

3.1. Epidemiology

Bladder cancer (BC) is the seventh most commonly diagnosed cancer in the male population worldwide, and it is the tenth when both genders are considered [7]. The worldwide age-standardised incidence rate (per 100,000 person/years) is 9.5 in men and 2.4 in women [7]. In the European Union, the age-standardised incidence rate is 20 in men and 4.6 in women [7].

Worldwide, the BC age-standardised mortality rate (per 100,000 person/years) is 3.3 for men vs. 0.86 for women [7]. Bladder cancer incidence and mortality rates vary across countries due to differences in risk factors, detection and diagnostic practices, and variations in access to, and delivery of, healthcare. Additionally, epidemiological variations have been attributed to differing methodologies and the quality of data from individual datasets [8]. The incidence and mortality of BC has decreased in some registries, possibly reflecting the decreased impact of causative factors [9].

Approximately 75% of patients with BC present with a disease confined to the mucosa (stage Ta, CIS) or submucosa (stage T1); in younger patients (< 40 years of age) this percentage is even higher [10]. Patients with TaT1 and CIS have a high disease prevalence due to long-term survival in many cases and lower risk of cancer-specific mortality compared to patients with T2-4 disease [7,8].

3.2. Aetiology

3.2.1. Main risk factors

3.2.1.1. Tobacco

Tobacco smoking is the most important risk factor for BC, accounting for approximately 50% of cases [8,9,11,12]. The aromatic amines and polycyclic aromatic hydrocarbons within the tobacco smoke, which undergo renal excretion, are linked to the development of BC. The risk of BC increases with smoking duration and intensity [18]. Low-tar cigarettes are not associated with a lower risk of developing BC [13]. The risk associated with electronic cigarettes has not been adequately assessed; however, carcinogens have been identified in the urine with electronic cigarettes [14]. Passive exposure to tobacco smoke is also associated with an increased risk of BC [8].

3.2.1.2. Occupational exposure

Occupational exposure to aromatic amines, polycyclic aromatic hydrocarbons and chlorinated hydrocarbons is the second most important risk factor for BC, accounting for about 10% of all cases. This type of occupational exposure occurs mainly in industrial plants which process paint, dye, metal, and petroleum products [8,9,15,16]. In developed industrial settings these risks have been reduced by work-safety guidelines; therefore, chemical workers no longer have a higher incidence of BC compared to the general population [8,15,16]. Recently, greater occupational exposure to diesel exhaust has been suggested as a significant risk factor (odds ratio [OR]: 1.61; 95% confidence interval [CI]: 1.08–2.40) [17]. Additionally, a large registry-based study of over one million people, with a follow up of 21 years, found that residents in the Haifa Bay Area of Israel (which is a centre for petrochemical industry) had a significantly higher incidence of several cancers, including bladder cancer (hazard ratio [HR] 1.11; 95% CI: 1.01–1.23), compared with non-residents [18].

3.2.2. Genetic

Family history seems to have little impact [19]; however, a history of smoking and alcohol consumption seem to significantly increase the risk of BC in patients with a family history of the disease [20]. To date, no clinically relevant genetic alteration has been linked to BC. Genetic predisposition may lead to a higher susceptibility to other risk factors, and thereby explain the familiar clustering of BC in first- and second-degree relatives (HR: 1.69; 95% CI: 1.47−1.95) [8,21-26] that has been confirmed more recently [27]. A recent study identified three single nucleotide polymorphisms related to the development of aggressive NMIBC [28]. Currently, there is insufficient evidence to support genetic screening for BC.

3.2.3. Dietary habits

Dietary habits seem to have limited impact on the risk of developing BC. A protective impact of flavonoids has been suggested [29]. The Mediterranean diet, characterised by a high consumption of vegetables and non- saturated fat (olive oil) with moderate consumption of protein, has been linked to some reduction of BC risk (HR: 0.85; 95% CI: 0.77−0.93) [30-34]. Western diet (high in saturated fats) and organ meat has been shown to increase the risk of BC in a recent meta-analysis [35,36]. The impact of an increased consumption of fruits has been suggested to reduce the risk of BC. This effect has been demonstrated to be significant in women only (HR: 0.92; 95% CI: 0.85–0.99) [37]. This gender discrepancy was also evident in the BLEND study which showed that in men moderate or high intake of vitamins B1, B2 and vitamins related to energy metabolism were found to be associated with an increased BC risk, whereas in women high intake of the same vitamins and vitamin combinations was shown to have a protective effect with the exception of the entire B group vitamin complex [38]. One possible explanation for this gender discrepancies is the difference in the main source of vitamin intake among study participants, being meat in men and fruits/vegetables in women. In addition, higher consumption of tea has also been associated with a reduction in risk of BC in men but through an interaction with tobacco smoking; therefore, making the protective effect of this compound questionable [39]. At present, no supplement has been found to be associated with BC prevention; however, vitamin E supplementation has been associated with an increased risk of recurrence [40]. Considering patients with previous history of BC, preliminary results suggest that a dietary intervention based on cruciferous vegetables, leading to an increased level of isothiocyanates, might be beneficial in reducing risk of recurrence and progression [41]. At present there is no definitive evidence for the impact of diet on BC development or prevention.

3.2.4. Environmental exposure

Although the impact of drinking habits remains uncertain, the chlorination of drinking water and subsequent levels of trihalomethanes are potentially carcinogenic. Additionally, exposure to arsenic in drinking water has been suggested to increase the risk of BC [8,42]. Arsenic intake and smoking have a combined effect [43]. Conversely, chronic exposure to nitrate in drinking water does not seem to be associated with increased risk of BC [44].

The association between personal hair dye use and risk of BC remains uncertain; an increased risk has been suggested in users of permanent hair dyes with a slow NAT2 acetylation phenotype [8] but a large prospective cohort study could not identify an association between hair dye and risk of cancer and cancer-related mortality [45].

3.2.5. Pelvic radiation

Exposure to pelvic ionising radiation is associated with an increased risk of BC [46,47]. In a retrospective analysis of patients with localised prostate cancer, external beam radiotherapy (EBRT) was independently associated with a risk of developing a second primary BC [46]. A single centre study of 583 prostate cancer patients treated with brachytherapy revealed that the risk of developing BC increased in those who received additional EBRT (n=255) (HR 3.29; 95% CI 1.03–10.52). The BC specific mortality was also higher when combination therapy was used [47].

3.2.6. Other

The impact of metabolic factors (body mass index, blood pressure, plasma glucose, cholesterol, and triglycerides) remains uncertain [48]. However, data suggest that high circulating levels of vitamin D and physical exercise are associated with a reduction in the risk of BC [49,50]. Schistosomiasis, which is an infection caused by a parasitic trematode, can lead to BC [8]. A weak association was also suggested for cyclophosphamide and pioglitazone [8,42,51].

3.3. Summary of evidence for epidemiology and aetiology