Epidemiology of Bladder Cancer in the Arab World: 2019 Global Burden of Disease Data.

Introduction

Urinary bladder cancer (UBC) ranks the 9 th most commonly diagnosed cancer globally; 7 th most common cancer in men and the 17th most common cancer in women (Ploeg et al., 2009). Most cases of UBC are associated with schistosomiasis are squamous cell carcinoma (SCC), while those associated with smoking are transitional cell carcinoma (TCC) (Jemal et al., 2011).

Data on the incidence of UBC are difficult to interpret because of the changing classifications among different sources (Parkin, 2008). UBC incidence is three to four times more common in developed countries relative to developing countries (Ploeg et al., 2009). However, the incidence is decreasing in developed countries, and increasing in developing countries (Pakzad et al., 2015). Similarly, mortality rates are, for the most part, decreasing in developed countries whereas trends in developing countries are more variable (Parkin, 2008).

A study investigating cancer incidence, mortality rates, and their relationship with the Human Development Index (HDI) in the world illustrated the five countries with the highest age-standardized incidence rate (ASIR) per 100,000 were Belgium (17.5), Lebanon (16.6) Malta (15.8), Turkey (15.2), and Denmark (14.4). In general, there was a positive linear relationship between the standardized incidence rate and income (r=0.653, P<0.001). Notably, the five countries that had the highest age-standardized death rates (ASDR) per 100,000 were Turkey (6.6), Egypt (6.5), Iraq (6.3), Lebanon (6.3), and Mali (5.2) (Mahdavifar et al., 2016).

There is paucity of data regarding the burden of UBC in the Arab world. More data is needed to provide up-to-date information for further research on the topic. In this study, we systematically reviewed the data provided by the Global Burden of Disease (GBD) online database to calculate the most recent epidemiological metrics and compare them with those in the literature, thus setting ground for future research which would improve the management of UBC.

Materials and Methods

Arab countries were selected based on membership to the Arab League (2013). They included the following countries: Jordan, Syria, Lebanon, Palestine, Saudi Arabia, Iraq, Kuwait, Qatar, Bahrain, United Arab Emirates (UAE), Oman, Yemen, Egypt, Sudan, Libya, Algeria, Tunisia, Morocco, Djibouti, Somalia, Mauritania, and Comoros. The literature was thoroughly reviewed for papers containing any of these countries and the phrase “bladder cancer”.

We queried the GBD results tool for bladder cancer data in Arab countries for the year 2019 (Network, 2017).

The resulting Table was uploaded to a Microsoft Excel spreadsheet and R program (v.3.6.0) for further analysis. Of note, we used the GBD sociodemographic index (SDI) to categorize Arab countries. This index reflects average income, fertility and level of education of each country.

Similar to other global databases, the GBD uses modelling to estimate the incidence and mortality of different diseases. Regions with similar geography, demographics and income are used to impute unavailable data, the estimated mortality-to-incidence ratio (MIR) is used to predict incidence using causes of death as provided by death certificate. The Disability-Adjusted Life Years (DALY) is an important metric that reflects years lost because of death and/or disability. To calculate DALYs, cancer-related disability is spread over 4 sequalae of equal weight that reflect disease diagnosis, treatment, metastasis and relapse.

The prevalence of smoking was obtained from the World Development Indicators Data published by the World Health Organization . The population numbers were obtained from the World Bank Open Data .

To compare the ASIR, ASDR, and ASDALYs of bladder cancer in Arab countries to the global values, a one-sample student t-test was used, with global ASIR, ASDR, and ASDALYs as the reference values respectively. Spearman correlation was used to analyze the relation between smoking prevalence and bladder cancer incidence which is illustrated in the Figures.

To obtain ASIR, ASDR and ASDALYs for Arab countries as a group, the corresponding value was multiplied by each country population and the sum was divided by the total Arab population. Mortality-to-incidence ratio (MIR) was obtained by dividing the number of deaths attributed to bladder cancer by the number of patients diagnosed.

Results

Incidence

It is estimated that 524,304 patients were diagnosed with UBC in 2019 globally, of those, 27,503 (5.2%) were diagnosed in Arab countries making it the 4th most common neoplasm in the Arab World ( Table 1 and 2 ). Globally, UBC has an ASIR of 6.52/100,000, whereas ASIR for developing UBC in Arab countries was (9.9/100,000); with males (16/100,000) having much higher incidence than females (3.6/100,000) ( Table 2 , 3 ). There was no significant difference in the ASIR between the Arab World and the Global ASIR (p=0.1) ( Figure 4 A ). Lebanon had the highest ASIR in the Arab world (30.1/100,000), which was followed by Egypt (19.1/100,000), Iraq (13.8/100,000), United Arab Emirates and Qatar (12.2/100,000), Libya (11.4/100,000), Bahrain (11.3/100,000), Kuwait (10.7/100,000), Tunisia (10.6/100,000), Jordan (8.7/100,000), and Palestine (7.5/100,000). These 11 countries had an ASIR higher than the global value (6.5/100,000). Lowest ASIRs were recorded in Somalia (2.4/100,000), Comoros (2.7/100,000) and Mauritania (3.1/100,000) ( Table 2 ). Similar to global statistics, males had higher ASIR than females in all Arab countries. Average male: female ratio in Arab countries is (4.4:1) and ranged from 1.6:1 in Somalia to 9.3:1 in Tunisia.

In general, the incidence of UBC increases with age in all Arab countries. It is noteworthy that the incidence rate of UBC in Egypt and Morocco declines in individuals 75-79 years old then continues to rise in older individuals. Egypt has the highest incidence for individuals 20-64 years old showing unique epidemiology where young patients are highly affected unlike other Arab countries. For individuals between 65-79 years, Iraq takes the lead in the incidence rate. After the age of 80, Qatar takes the lead, followed by Bahrain, Kuwait, Iraq and Tunisia ( Figure 1 ).

Deaths

The number of patients dying with UBC in Arab countries was estimated to be 10,532 in 2019 making it the 8th most common cause of death due to neoplasms in the Arab World ( Table 1 ). Countries with the highest number of UBC-related deaths were Egypt (4844), Iraq (1265), Morocco (630), Algeria (600), Lebanon (536). The ASDR of UBC in the Arab countries was greater than that of the Global ASDR (4.7 and 2.9 per 100,000 respectively). There was a significant difference in the ASDR between the Arab World and the Global ASDR (p=0.02) ( Figure 4 B ). The highest ASDR was seen in Lebanon (10.4 per 100,000), followed by Egypt (7.8 per 100,000), and Iraq (6.8 per 100,000). Saudi Arabia and Syria had the lowest ASDR (1.66 and 2.08 per 100,000, respectively) ( Table 4 ). Similar to ASIR, ASDR for males was higher than that of females in all Arab countries ( Table 3 ).

DALYs

The total number of annual DALYs related to UBC in Arab countries was estimated to be 272,976 which makes it the 10th most common cause of DALYs due to neoplasm ( Table 1 ). Since the global DALYs were found to be 4,392,583, this means Arab countries represent 6.21% of the global DALYs. Egypt and Lebanon had the highest ASDALYs amongst all Arab countries (201.7 and 192.7 per 100,000, respectively), almost 4 folds that of Global ASDALYs (54.2 per 100,000). On the other hand, Saudi Arabia and Algeria recorded the lowest ASDALYs (33 and 39.4 per 100,000, respectively). There was a significant difference between the ASDALYs in the Arab World (99.2) and the Global ASDALYs (54.2), (p=0.03) ( Table 4 ).

MIR

Mortality-Incidence Ratio (MIR) of bladder cancer globally is 0.436, compared to 0.448 which is the average MIR of Arab countries. Seven of the Arab countries had a MIR higher than the global value. These include Somalia, Comoros, Mauritania, Djibouti, Yemen, Sudan and Morocco which had MIR values ranging from 0.5 to 0.85. There was an inversely proportional relationship between SDI and MIR, (correlation coefficient = -0.9, p<0.0001). ( Table 4 , 5 ). Overall, MIR was higher in females in all Arab Countries. Three countries recorded the highest MIR values for both males and females: Somalia (0.83 and 0.86, respectively), followed by Comoros (0.81 and 0.82, respectively), and Mauritania (0.73 and 0.76, respectively). The lowest MIR was recorded in Saudi Arabia for both males and females (0.23 and 0.34, respectively) ( Table 5 ).

Discussion

Results and Findings

Historically, UBC has an interesting epidemiology in the Arab world, particularly in North Africa. It is a very common malignancy in Egyptian males, which was previously attributed to Schistosomiasis, a major risk factor for squamous cell carcinoma (SCC). However, recent data shows a rise in transitional cell carcinoma (TCC) incidence attributed to smoking and a decline in the incidence of (SCC) owing to schistosomiasis among Egyptian males (Fedewa et al., 2009). According to a study by Bergmans et al which was done by collecting data from the SEER registry in the USA, it was found that in Arab males that migrated to America bladder cancer incidence was higher than in Hispanics and Blacks. This suggests that genetics may play a role in the etiology of the disease and its prevalence in the Arab world. (Bergmans et al., 2014)

In the majority of Arab world countries data on bladder cancer is scarce. A study by Sharif-Askari (Sharif-Askari et al., 2018) on the incidence of UBC in Libya from (1983-2009) found age specific incidence for both genders to be higher than the age specific incidence globally. This study speculated that the incidence of Bladder cancer is expected to grow due to the rise in smoking populations, life expectancy, a shift to sedentary lifestyle, diabetes, and obesity. Our data illustrates that the age specific incidence and ASIR in Libya are indeed higher than the global values as seen in Table 2 . Despite this finding, there was no significant difference in the ASIR between the Arab World and the Global ASIR (p=0.1) ( Figure 4 A ).

A study by Parkin et al showed that mortality rates are, for the most part, decreasing in developed countries and increasing in developing countries (albeit trends are more variable in developing countries). Noteworthy, the highest estimated mortality was in Egypt. (Parkin, 2008) This is supported by our results, where Egypt also had the highest number of deaths and MIR is higher in low SDI Arab countries, as shown in the data in Tables 4 , 5 .

Previous literature reveals that incidence rates in males are about fourfold that in females, this coincides with our results as seen in Table 3 (Ploeg et al., 2009). Recent data shows that mortality due to UBC caused by smoking increased in women, as opposed to men where the mortality has decreased in developed countries (Dy et al., 2017). Further evidence as shown by Mun et al reveals that women present with more advanced UBC and have stage-for-stage worse outcome compared with men. (Mun et al., 2019) This coincides with our results where a higher MIR is seen in women compared to men in all Arab countries ( Table 5 ).

Risk Factors

UBC incidence increases with age, particularly in men, which increases its burden in older individuals. Environmental risk factors for UBC in Western countries are smoking and occupational exposures, whereas in developing countries (namely countries in Africa and the Middle East) chronic infection with Schistosoma haematobium accounts for up to 50% of the total burden of the disease (Jemal et al., 2011). Nonetheless, cigarette smoking remains the most important risk factor worldwide while various occupational and environmental exposures to chemicals are also held responsible (Nesi et al., 2019). This is illustrated in our study by positive correlation between UBC-ASIR and smoking prevalence in males and females ( Figure 7 ).

There is a well-established link between bladder cancer and schistosomiasis, which is highly prevalent in Egypt, Sudan and Yemen. A case-control study conducted in Egypt by Bedwani et al looked for an association between the duration of exposure to urinary schistosomiasis and its risk of causing bladder cancer. The risk of developing UBC in subjects exposed to urinary schistosomiasis under the age of 15 years was higher with an Odds Ratio (OR) of 3.3, suggesting a duration-risk relationship. The (OR) was also 15.8 for male ever-smokers with a history of urinary schistosomiasis. All in all, this study concludes that tobacco smoking is a far greater risk factor for bladder cancer in Egypt, and a clinical history of urinary schistosomiasis accounts for only about 16% of bladder cancer cases of the Egyptian population (Bedwani et al., 1998).

Other risk factors for UBC have been defined in the literature. For instance, a meta-analysis involving 14 prospective studies on 12,642 cases was conclusive of a strong direct non-linear relationship between bladder cancer risk and Body Mass Index (SRR = 1.03, 95% CI: 1.01-1.06, P-nonlinearity =0.031). Further conclusions from the study suggested that a dose-response relationship to the disease existed and amounted to be a 3.1% increase in UBC risk for each increment of 5kg/m2 (SRR: 1.10, 95% CI: 1.03-1.17) (Zhao et al., 2017). Another meta-analysis implicated that processed meat could be associated with an increased risk for bladder cancer. A positive association was noted only in case-control studies, while no association was observed in prospective studies (Crippa et al., 2018). A study by Lippi et al shows that increased processed meat consumption was also associated with other malignancies such as colorectal, esophageal, and gastric cancers (Lippi et al., 2016). Ben Fradj et al., (2018) evaluated fatty acid plasma levels as a risk for developing UBC which revealed that palmitic acid was associated with increased risk and oleic acid with decreased risk of developing the disease. This highlights a possible protective effect of dietary modification.

According to evidence presented by Castelao et al., (2000) with the exception of pyrazolon derivatives, intake of NSAIDs showed an inverse dose-dependent association with risk of developing bladder cancer. This is believed to be due to the suppression of COX-1 activity which deprives the tumor of growth signals mediated by prostaglandins.

Statistically significant occupations with high risk of developing UBC were noted by Al-Zalabani et al., (2016) and included Relative Risk (RR) for tobacco workers (1.72), dye workers (1.58), and chimney sweeps (1.53). The combined probability of causation was 81.8 %. A study by Jemal et al., (2011) has shown a 14 fold variation in incidence internationally which implies that environmental factors may play a significant role in the development of bladder cancer.

Screening

An area of controversy in recent literature is application of screening programs for UBC. A study by Britton et al., (1992) investigated the effectiveness of urine dipsticks as an initial test to detect early bladder cancer in men aged 60 years or more; 2,356 men were tested with a dipstick for hematuria and 474 had dipstick hematuria and 319 agreed to undergo further urological evaluation. An asymptomatic bladder tumor was found in only 17 men. Although urine dipstick as an initial test for hematuria is an inexpensive and simple screening test for bladder cancer, applying this to the general population as a screening method would produce a very large number of individuals requiring further investigations due to low specificity. Further research for effective screening programs for bladder cancer in the general population is required (Britton et al., 1992). Furthermore, comparison between patients who underwent screening using dipstick showed no difference in detection of bladder cancer compared to those who were unscreened (Messing et al., 1995).

Ramakumar et al., (1999) suggested that urinary telomerase had a high combination of sensitivity and specificity (70 and 99%, respectively) for the screening of bladder cancer. Telomerase was found to be superior to cytology, dipstick and other cellular markers including BTA stat, NMP22, and FDP, for the prediction of UBC.

MIR

Due to lack of adequate data documentation of cancer patients in proper cancer registries in most Arab countries, MIR values were used in this study as a crude estimate of cancer survival in the Arab world. Although incidence and mortality rates for bladder cancer vary widely throughout the world, the MIR is higher in less developed countries (Greiman et al., 2017). This is supported by our data where the highest MIR for both males and females was recorded in Somalia (0.83 and 0.86 respectively), followed by Comoros (0.81 and 0.82 respectively), and Mauritania (0.73 and 0.76 respectively) which are all countries with a low SDI (SDI<0.5) ( Table 5 ).

Treatment

Optimizing therapy of UBC requires the use of multimodal therapy, including chemotherapy, radiotherapy, surgery, and immunotherapy (Nadal and Bellmunt, 2019). Many Arab countries face difficulties in establishing multidisciplinary care and rely on scattered care to treat cancer. This haphazard approach in treatment (and screening) results in poor patient care, which is reflected by the significant difference in the ASDR and ASDALYs between the Arab World and the Global values (p=0.02 and p=0.03 respectively). Therefore, careful interventions to improve cancer care infrastructure in Arab countries must be implemented as soon as possible.

In conclusion, we showed that the incidence of UBC is high in multiple Arab Countries with predominance in males. High mortality and disability make this cancer a high priority for Arab countries. According to the GBD, UBC is the 4 th most common cancer in the Arab World. It is the 8 th most common cause of neoplastic death and the 10 th most common cause of years of life lost due to disease. We aspire that this research will influence future researches into evaluating different screening methods for UBC in Arab countries, tackling different risk factors to decrease incidence, improving data collection and cancer registration and optimizing management schemes in order to decrease the burden of this disease.

Author Contribution Statement

Author 1 - Ibrahim Al Saidi

• Conceived and designed the analysis

• Wrote the paper: wrote the original draft of the paper

Author 2 – Ali Mohamedabugroon

• Performed the analysis

• Other contribution: reviewing and validating the draft

Author 3 – Amer Sawalha

• Collected the data: through Global Burden of Disease Results Tool

• Contributed data and analysis tools

• Other contribution: reviewing and validating the draft

Author 4 – Iyad Sultan

• Other contributions: supervision and final approval of the version to be published

All data in this research was obtained from the Global Burden of Disease data available on their website.

Acknowledgements

The authors received no financial support for the research, authorship, and/or publication of this article.

Statement of Conflict of Interest

Ibrahim Al Saidi, Ali Mohamedabugroon, Amer Sawalha and Iyad Sultan declare that they have no conflict of interest.

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