Urinary bladder cancer and its associated factors – An epidemiological overview

Incidence and mortality

As per the GLOBOCAN (2018) estimate, there are 18.1 million new cancer cases in the world. Death due to bladder cancer is one of the leading causes of cancer mortality in developed countries and accounts for 3.4% of worldwide cancer burden.^[1] It is seen from the table that with reference to the year 2018, there will be 79.6% increase in India and 80.3% increase in the world in the number of bladder cancer cases by the year 2040 [Table 1].

Regional variations in incidence rates

Bladder cancer incidence rates were more common in men, 4-fold, than in women worldwide. It is seen from Table 2 that the incidence rates, both sexes, were highest in South Europe (male – 26.5 and female – 5.5), followed by West Europe (male – 22.5 and female – 5.1), and lowest in South America (7.0) among males and in East Asia (1.9) among females;^[2] similarly, the mortality rates for men are highest in North Africa (7.5), followed by West Asia (6.5), and lowest in South America (2.5), while in women, highest rates are in North Africa (1.7) and North Europe (1.4) and lowest in East Asia (0.77).^[2]

Global trends

The trend over a period of 15 years (1998–2012) indicated that in males, bladder cancer incidence, in selected registries [Figure 3], showed a significant decline in rates in the UK, France, and Japan, and not in India, China, the USA, and Brazil.^[2] Similarly, among females, the trend shows that there is minimal decline in incidence rates [Figure 4], in all the countries, except in Japan where there is a marginal increase in incidence over the years.^[2]

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Figure 3:

Trends in incidence rates (ASR per 10⁵) in selected registries – world (1998–2012) – males. ^*Source: C15-Vol XI.^[2]

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Figure 4:

Trends in incidence rate (ASR per 10⁵) in selected registries – world (1998–2012) – females. ^*Source: C15-Vol XI.^[2]

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Time trends in Indian PBCR

It is interesting to see the trends of incidence rates of bladder cancer between 1989 and 2014 in major Indian registries [Figure 5]. It is evident that Delhi showed a substantial increase in rates over the years (5.2 in 1989–7.4 in 2014), whereas Mumbai showed a stable increase from 3.5 in 1989 to 4.1 in 2014 in Mumbai but Chennai showed a decline from 3.4 in 1989 to 3.0 in 2014; however, the rates in Bangalore show initially an increase, a plateau and eventually minimal change in incidence rates from 2.3 in 1989 to 2.4 in 2014.^[10,11]

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Figure 5:

Trends in age-adjusted incidence rate (AAR per 10⁵) of bladder cancer in Indian PBCR registries: 1989–2014 – males. ^*Source: NCDIR.^[10,11]

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Trends between 1987 and 2017

Tata memorial hospital is the oldest premier cancer hospital in India and it will be worthwhile to mention the trend of bladder cancer seen over 30-year period. From Figure 7, it is observed that in males, the number of cases increased from 122 in 1987 to 493 in 2012, and in females, from 20 cases in 1987 to 78 cases in 2012, indicating a 4-fold increase in both sexes.^[13-21]

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Figure 7:

Trends in distribution of bladder cancer in Tata Memorial Hospital: 1987–2017. *Source: HBCR TMH Mumbai;^[13-21] figure in () is % of all cancer cases.

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Human Development Index (HDI)

Based on the classification of HDI, it was observed that India belonging to the medium HDI, showed the lowest incidence rates (1.5) and China belonging to countries with very high HDI, also showed lowest incidence rates (3.7), as shown in Table 4.^[1] Further, it is seen that incidence and mortality rates were highest for very high HDI countries and lowest for low HDI countries. The rates were 10.5 and 2.4 in very high HDI and low HDI countries, respectively, indicating 5-fold difference between them.

Diagnosis and treatment

Bladder cancer investigation involves routine investigations such as routine hemogram, biochemistry, urine cytology, imaging, as well as pathology tests. Imaging modalities include computerized tomography, magnetic resonance imaging (MRI), and ultrasonography. Abdominal, transrectal, transvaginal, and transurethral sonography are used specifically to stage bladder cancer. Investigation techniques involve urine tests, cystoscopy, and transurethral resection (TURBT) which are both diagnostic and therapeutic;^[22] in one of the earliest studies, MRI had showed 82% sensitivity, 62% specificity, and 73% accuracy.^[23]

Treatment for bladder cancer and its management depends on extent of disease and guidelines on treatment (TURBT)are already published and available in literature.^[22] Post-TURBT adjuvant intravesical therapy is indicated depending on the risk stratification and staging. Intravesical therapy involves chemotherapy and Bacillus Calmette–Guerin. Radiotherapy is also suggested along with chemotherapy. Muscle invasive bladder cancer may require surgical removing the bladder (cystectomy) and lymphadenectomy (lymph node removal) along with urinary diversion.^[22]

Cancer survival rates

Survival statistics is often used to infer a patient’s prognosis (chance of recovery). However, in cancer usually, a 5-year relative survival rate is considered. The SEER database does not group bladder cancer by AJCC TNM stages (which are used mostly in clinical practices). Instead, it groups cancers into localized, regional, and distant sites; it was reported that patients with localized, in situ, regional spread, and distant disease showed 5-year survival of 70%, 96%, 36%, and 5%, respectively;^[22] for combined stages, survival was 77%.^[22] The 5-year absolute survival in Indian population was lower than other Asian countries as China, Singapore, etc.^[24]

Because of variable representation of in situ tumors, comparison of survival across countries for bladder cancer is difficult to establish. In Europe, the average 5-year survival rate was 69%, ranging from 79% in Malta and 49% in Scotland.^[24] A retrospective audit of all patients registered as urinary bladder cancer in TMH in 2013 was reported recently. The estimated 5-year overall survival and disease-free survival in patients who had RC with PLND were 63% and 57%, respectively (RC – radical cystectomy and PLND – pelvic lymph node dissection).^[25] In Europe, the 5-year age-standardized relative survival rate of all bladder cancer was around 70%, the range between individual countries was approximately 60–70%.^[26]

Treatment costs

The treatment cost increases because of high rates of recurrence and associated intensive surveillance strategies and expensive treatment cost to improve quality of life and combat with the side effects of cancer directed treatment.^[27-29]

Tobacco consumption

Tobacco consumption is a significant risk factor for bladder cancer. Many studies have reported on tobacco consumption and risk of bladder cancer. About 50% of cancers are tobacco-related cancers in India.^[30] Risk for smokers is 3–4-fold higher compared to non-smokers and is estimated to cause 31% of bladder cancer deaths among men and 16% among women.^[31,32] It is reported that 4-aminobiphenyl is the most important carcinogen in cigarette smoke, besides many other carcinogenic substances.^[32] Black tobacco (burnt) is considered more carcinogenic because of a greater concentration of nitrosamines, biphenyls, and aryl amines.^[33] In a meta-analysis from a large cohort study in the USA, smoking of opium showed an elevated risk and so was cannabis;^[34,35] in another cohort study from the USA, the hazard ratio in ex-smokers was 2.22 and 4.06 in current smokers.^[36] The excess risk of bladder cancer in males, observed in a study from Spain, attributed to cigarette smoking, rather than occupational/environmental exposures, and risk increased with years of duration and frequency of smoking.^[33]

Exposures at workplace

Industrial exposure to aromatic amines and carbon black dust, potential carcinogens, used in the dye industry has been linked to incidence of bladder cancer chemicals like aromatic amines.^[37]

It was reported that there was a higher risk for manufacturers of rubber, leather, textiles, steel, metal, paint products and the printing companies,^[38] painters, machinists, printers, hairdressers, construction workers and truck drivers,^[39] benzamine, used in rubber industry and dye production,^[40] hairdressers and barbers, due to the use of dyes^[41,42] and exposure to azo dyes.^[43] Smoking and workplace exposures can act synergistically to cause bladder cancer. Smokers who work with carcinogens chemicals have a significantly higher risk of bladder cancer. The rise in incidence and mortality among women in East Europe region is due to the prevalence of cigarette smoking, while the decrease in mortality rates in some of the Western countries is attributed to the decreasing prevalence of the use of tobacco.^[44]

Arsenic and nitrate in drinking water

It is known that drinking water contains some fraction of arsenic content and poses no threat if it is within the prescribed limits;^[45] however, the risk of bladder cancer gets elevated if arsenic concentration exceeds 300–500 μg/L.^[46] There is an uncertainty of arsenic content at lower levels.^[47,48] A known chemical, nitrate in drinking water showed elevated risk in postmenopausal women.^[49]

Less fluid intake

Although the findings of fluid intake and bladder cancer are inconsistent, still a few studies suggest that drinking a lot of fluids, especially water, every day lowers the risk of bladder cancer. Drinking more water helps to dilute urine and reduces the contact time and simultaneously removing excess toxins through urination.^[50,51]

Age

Although bladder cancer can occur at any age, and many demographic studies have shown that individuals’ aged ≥65 years have 11 times higher incidence than those younger than 65 years.^[22] Despite this, the treatment decisions may not be solely based on age besides other factors that can affect patient survival outcomes.^[52]

Gender

Bladder cancer is more common in men and the possible reason in gender-based disparity in incidence and mortality is the difference in hormonal pathways. The time of diagnosis besides primary care plays an important role in the development of urinary bladder cancer.^[53,54]

Infections and chronic bladder irritation

Urinary infections, bladder and kidney stones, longer placement of bladder catheter, and chronic bladder irritation have been linked to bladder cancer. The association of urinary bladder cancer with recurrent urinary tract infection (UTI) reported in a case–control study from the Netherlands, showed an odds ratio of 6.6 in males and 2.7 in females;^[55] however, another case–control study did not report any association between UTIs and development of BC^[56] though a limited number of episodes of UTI treated with antibiotics were reported to be associated with decreased bladder cancer risk.^[55]

Infection with schistosomiasis hematobium

Schistosomiasis (or bilharziasis), a parasitic infection to bladder, in squamous cell cancers is a risk factor since the carcinogen-metabolizing enzymes were increased soon after infection.^[57,58] In North Africa, high incidence was attributed to the parasite , while in Egypt and Tanzania, it was reported that control of parasite decreased cases of bladder cancer by improving the sanitization and hygiene, respectively.^[59,60]

Genetics and family history

Family history of bladder cancer is considered a higher risk. The cause probably is lower penetrating DNA variants and many such pathways were reported which influences risk through one or more different cancer pathways.^[61-63]

High alcohol consumption was shown to be linked to bladder cancer;^[64,65] smokers with a higher cumulative arsenic intake had elevated risks of bladder cancer.^[66]

Pioglitazone, an antidiabetic agent of the thiazolidinedione class, which is broadly used for glycemic control in patients with type 2 diabetes mellitus, has been reported to increase the risk of bladder cancer as well. The meta-analysis that included 12 studies indicated that pioglitazone was associated with 14% increased risk of bladder cancer.^[67]