Muscle-invasive and Metastatic Bladder Cancer

3. EPIDEMIOLOGY AND AETIOLOGY

3.1 Clinical presentation

Painless visible haematuria is the most common presenting complaint. Other presenting symptoms and clinical signs include non-visable haematuria, urgency, dysuria, increased frequency and - in more advanced tumours - pelvic pain and symptoms related to urinary tract obstruction.

3.2. Epidemiology

Bladder cancer (BC) is the sixth most commonly diagnosed cancer in males, and it is the ninth when both sexes are considered [7]. The worldwide age-standardised incidence rate (per 100,000 person/years) is 9.3 for males and 2.4 for females [7]. In the European Union, the age-standardised incidence rate is 23.2 for males and 5.9 for females [7]. In Europe, the highest age-standardised incidence rate has been reported in Spain (32.4 in males and 7.8 in females) and the lowest in Luxembourg (10.3 in males and 4.4 in females) [7].

Worldwide, the BC age-standardised mortality rate (per 100,000 person/years) in 2022 was 3.1 for males versus 0.80 for females [7]. Bladder cancer incidence and mortality rates vary across countries due to differences in risk factors, detection and diagnostic practices, and availability of treatments. The variations are, however, also partly caused by the various methodologies used in the studies and the quality of data collection [8]. The incidence and mortality of BC have decreased in some registries, possibly reflecting the decreased impact of causative agents [9-11].

Approximately 25% of patients with BC present with muscle invasive disease. In younger patients (< 40 years) this percentage is lower [12]. Patients with T2-4 tumours have a higher risk of cancer-specific mortality (CSM) compared with TaT1 and carcinoma in situ (CIS) [7,8].

3.3. Aetiology

3.3.1. Tobacco smoking

Tobacco smoking is the most well-established risk factor for BC, causing 50-65% of male cases and 20-30% of female cases [13]. A meta-analysis of 89 studies that comprised data from 57,145 BC cases calculated summary odds ratios (ORs). Dose-response meta-analyses were used to examine the relationships between smoking intensity, duration, pack-years and cessation with BC risk. The sources of heterogeneity were explored, and sensitivity analyses were conducted to test the robustness of findings. Former smokers (hazard ratio [HR]: 2.2) and current smokers (HR: 4.1) had higher risks of BC than never smokers [14]. In studies in which chance, bias and confounding can be discounted with reasonable confidence, a causal relationship has been established between exposure to tobacco and cancer [13,15].

An increase in risk estimates for current smokers relative to never-smokers has been described, suggesting this could be due to changes in cigarette composition [13]. Starting to smoke at a younger age increased the risk of death from BC [16]. An immediate decrease in the risk of BC has been observed in those who stopped smoking. The reduction was approximately 40% within one to four years of quitting smoking, and 60% after 25 years of cessation [17]. Encouraging people to stop smoking would result in the incidence of BC decreasing equally in males and females [13].

3.3.2. Occupational exposure to chemicals

Occupational exposure is the second-most important risk factor for BC. Work-related cases accounted for 20-25% of all BC cases in several series and it is likely to occur in occupations in which dyes (except hair dyes [18]), rubbers, textiles, paints, leathers and chemicals are used [19]. The risk of BC due to occupational exposure to carcinogenic aromatic amines is significantly greater after ten years or more of exposure; the mean latency period usually exceeds 30 years [20]. Population-based studies established the occupational attribution for BC in males to be 7.1%, while no such attribution was discernible for females [21].

3.3.3. Radiotherapy

Increased rates of secondary bladder malignancies have been reported after external-beam radiotherapy (EBRT) for gynaecological malignancies, with relative risks of 2 to 4 [22].

A recent study analysed 583 patients with prostate cancer who underwent brachytherapy, with or without EBRT, and assessed disease-free survival (DFS) for BC in this cohort. Of these patients, 2.4% developed BC after brachytherapy with or without EBRT. The percentage of high-grade urothelial carcinoma (UC) was 63.6%. A total of 85.7% of the patients had NMIBC, and 14.3% of patients had MIBC. Disease-free survival was longer in brachytherapy monotherapy than in combination therapy (brachytherapy + EBRT). The study showed that most cases of BC after brachytherapy with or without EBRT are high grade and invasive. External-beam radiotherapy in combination might be a risk factor for BC in patients with prostate cancer who underwent brachytherapy [23].

It has been proposed that patients who have received EBRT for prostate cancer with modern modalities such as intensity-modulated radiotherapy (IMRT) may have lower rates of in-field bladder- and rectal secondary malignancies [24]. Nevertheless, since longer follow-up data are not yet available, and as BC requires a long period to develop, further studies are required [24].

3.3.4. Dietary factors

It is biologically plausible for dietary factors to influence BC risk, considering that beneficial as well as harmful components of a diet are excreted through the urinary tract and in direct contact with the epithelium of the bladder. However, studies that investigated the association between dietary factors and BC risk have largely reported inconsistent results. Dietary carbohydrate intake does not appear to be directly associated with BC risk. Even though a large number of studies have investigated the association between fruit and vegetable consumption, their micronutrient content, and BC risk, these have yielded inconsistent results. No strong evidence is available to suggest that supplementation with any common micronutrient is effective in reducing BC risk. However, the limitations in published research do not totally eclipse the observation that a diet rich in fruits and vegetables and low in processed meat - especially along with smoking cessation - may convey some protective effects against BC risk [25].

3.3.5. Metabolic disorders

In a large prospective study pooling six cohorts from Norway, Sweden and Austria (the Metabolic syndrome and Cancer project, Me-Can 2.0), metabolic aberrations, especially elevated blood pressure and triglycerides, were associated with increased risks of BC among males, whereas high body mass index (BMI) was associated with decreased BC risk. The associations between BMI, blood pressure and BC risk significantly differed between males and females [26].

The association of diabetes mellitus with the risk of BC has been evaluated in numerous meta-analyses with inconsistent results. When analysing specific subpopulations, diabetes mellitus was associated with BC or CSM risk, especially in males [27]. The FDA recommends that healthcare professionals should not prescribe pioglitazone in patients with active BC [28]. Several countries in Europe have removed this agent from the market or included warnings for prescription. However, a recent systematic review emphasised the importance of cautious interpretation regarding the safety profile of pioglitazone in relation to BC risk. Of the included studies, two suggested a potential association between pioglitazone use and an increased risk of BC, whereas four reported no statistically significant correlation [29]. Moreover, the benefits of glycaemic control versus unknown risks for cancer recurrence with pioglitazone should be considered in patients with a prior history of BC.

3.3.6. Bladder schistosomiasis and chronic urinary tract infection

Bladder schistosomiasis (bilharzia) is the second most common parasitic infection after malaria, with approximately 250 million people infected annually [30]. There is a clear relationship between schistosomiasis and UC of the bladder, which can develop into BC and, if not treated, squamous cell carcinoma (SCC). Better control of the disease reduces the incidence of SCC of the bladder in endemic areas, such as Egypt [31].

Invasive SCC has been linked to the presence of chronic urinary tract infection (UTI) distinct from schistosomiasis. A direct association between BC and UTIs has been observed in several case-control studies, which have reported a twofold increased risk of BC in patients with recurrent UTIs in some series [31]. However, a meta-analysis found no statistical association when pooling data from the most recent and highest quality studies. This highlights the need for better quality data to be able to draw conclusions [32].

Urinary calculi and chronic irritation or inflammation of the urothelium have been described as possible risk factors for BC. A meta-analysis of case-control and cohort studies suggests a positive association between history of urinary calculi and BC [33].

3.3.7. Sex

Although males are more likely to develop BC than females, females present with more advanced disease and have worse survival rates. A meta-analysis including nearly 28,000 patients showed that female sex was associated with a worse survival outcome (HR: 1.20; 95% confidence interval [CI]: 1.09-1.32) compared to male sex after radical cystectomy (RC) [34]. This finding had already been presented in a descriptive nationwide analysis based on 27,773 Austrian patients. After analysis, it was found that cancer-specific survival (CSS) was identical for pT1 tumours in both sexes, while females had a worse CSS in both age cohorts (< 70 years and ≥ 70 years) with higher tumour stages [35]. However, treatment patterns are unlikely to explain the differences in OS [36]. In a population-based study from the Ontario Cancer Registry analysing all patients with BC treated with cystectomy or radical radiotherapy (RT) between 1994 and 2008, no differences in OS, mortality and outcomes were found between males and females following radical therapy [37]. The sex-specific difference in survival for patients with BC was also analysed in the Norwegian population. Survival was inferior for females, but only within the first two years after diagnosis. This discrepancy was partly attributed to a more severe T-stage in female patients at initial diagnoses [38].

A population-based study from the MarketScan databases suggests that possible reasons for worse survival in the female population may include longer delays in diagnosis than males, as the differential diagnosis in females include diseases that are more prevalent than BC, such as UTIs [39]. Furthermore, differences in the sex prevalence of BC may be due to other factors besides tobacco and chemical exposure. In a large prospective cohort study, postmenopausal status was associated with an increased risk of BC, even after adjustment for smoking status. This finding suggests that the differences in oestrogen and androgen levels between males and females may be responsible for some of the difference in the sex prevalence of BC [40-42]. Moreover, a population study assessing impact of hormones on BC suggested that younger age at menopause (≤ 45 years) is associated with an increased risk of BC [43].

3.3.8. Genetic factors

There is growing evidence that genetic susceptibility factors and family association may influence the incidence of BC. A population-based study of cancer risk in relatives and spouses of UC patients showed an increased risk for first- and second-degree relatives and suggests genetic or environmental roots independent of smoking-related behaviour [44]. Shared environmental exposure was recognised as a potentially confounding factor [45]. Studies have detected genetic susceptibility with independent loci, which are associated with BC risk [46]. Genome-wide association studies of BC identified several susceptibility loci associated with BC risk [47].

3.4. Summary of evidence and recommendations for epidemiology and risk factors