Trends in the global, regional, and national burden of bladder cancer from 1990 to 2021: an observational study from the global burden of disease study 2021

This study employed GBD 2021 data to analyze the most recent data on bladder cancer incidence, mortality, and DALYs at the global, regional, and national levels from 1990 to 2021. It further conducted a comprehensive assessment covering time trends, decomposition analysis, health inequalities, and future predictions. From 1990 to 2021, the global burden of BC in terms of incidence, mortality, and DALYs generally exhibited an upward trend, yet there were disparities among different regions, countries, sexes, and SDI levels. Simultaneously, the ASRs of these three indicators showed a downward trend globally. Decomposition analysis revealed that population growth and aging are the main drivers of changes in the burden of BC, while epidemiological change factors contribute to reducing the disease burden. Health inequality analysis indicated that the disease burden of BC is disproportionately concentrated in countries with a higher SDI level. Although the relative inequality related to SDI has decreased over time, this difference remains highly evident. According to predictions by the BAPC model, from 2022 to 2036, the ASRs of incidence, mortality, and DALYs will decline slightly each year. However, considering population aging and the growth of the world population, the disease burden of BC will continue to increase. This demonstrates that in the coming decades, the prevention and management of BC will still face enormous challenges.

In 2021, the global incidence of BC amounted to 0.26 million cases, with the number of deaths standing at 0.12 million, and the number of DALYs cases reaching 2.73 million. Among these, the burden of BC in males is significantly higher than that in females. The numerical ratio is approximately 3:1, while the ratio in terms of ASRs is close to 4:1. The ASRs of the global BC burden that are showing a downward trend are inconsistent with previous studies, which may be related to the update of GBD 2021 data^8,12. Regarding the ASR of bladder cancer burden, high-income North America has the highest ASIR, whereas Central Europe has the highest ASMR and ASDR. Regions with the most significant increase over the past decades, such as Central Europe which has had the largest increase in the ASR of incidence and Oceania which has witnessed the largest increase in the ASRs of deaths and DALYs, are of concern and demand extra attention. At the level of 204 countries or territories, the differences and changing trends of the complex burden of BC make it necessary to formulate personalized public health policies to strengthen the control of the burden of BC. In 2021, Lebanon had the highest ASR of bladder cancer incidence, Mali had the highest ASR of mortality, and Malawi had the highest ASR of DALYs. However, in 2021, China had the highest number of BC incidence, deaths, and DALYs in the world, as well as the highest increase in the number of disease burden from 1990 to 2021. The United States was the second country in terms of the number of BC burden in 2021, and its increase in disease burden is also among the top. Although China does not possess the highest ASR of bladder cancer burden, it undeniably shoulders the greatest BC burden, a situation likely attributed to its massive population size. Likewise, the United States, boasting a significant population and a relatively high ASIR, also endures a remarkably heavy BC burden. From 1990 to 2021, in China, the ASIR of bladder cancer showed a slight upward trend, while ASMR and ASDR exhibited a relatively obvious downward trend. In the United States, the ASIR and ASMR of bladder cancer remained stable, and the ASDR showed a slight downward trend. A previous study predicted that from 2017 to 2030, the incidence of BC in countries with middle SDI would increase significantly while the mortality rate would decline, and China’s situation is in line with this³⁸. The reasons for the increase in ASIR of bladder cancer in China may be related to factors such as increased life expectancy, the implementation of early disease screening, increased smoking, and changes in lifestyle¹¹. The substantial burden of BC in China, along with the uneven distribution of medical resources, may jointly present a formidable challenge to the management of BC²⁵. The ASIR, ASMR, and ASDR of bladder cancer in Cape Verde, the Northern Mariana Islands, and American Samoa showed the most significant growth, suggesting that they should take more measures in the control of BC. Similar to previous studies, our research observed an increase in the number of incidence, deaths, and DALYs of bladder cancer, indicating that the burden of BC has increased globally over time⁹. Given that BC is prone to recurrence and metastasis by nature, it incurs direct economic losses (such as cystoscopy and imaging reexaminations, drug treatment, radiotherapy, and surgical treatment), indirect economic losses (including absenteeism and premature death), as well as intangible personal costs (such as emotional distress, fatigue, and activity limitations)⁴. Bladder cancer is the tumor with the highest lifetime treatment cost for patients among all cancers³⁹. It is estimated that the total related cost in the United States was as high as 3.98 billion US dollars in 2010. It is expected to cause economic losses of nearly 4.9 billion euros in Europe in 2012^40,41. Nowadays, the economic burden caused by BC is incalculable globally. Therefore, developing prevention strategies for bladder cancer, enhancing management measures, and discovering effective treatments are particularly crucial.

When dividing bladder cancer ASIR, ASMR, and ASDR trends into sub-periods, we find that from 1990 to 1996, ASIR showed an upward trend. From 1990 to 1994, there was no significant change in ASMR and ASDR. Later, these three global BC indicators continued to decline. This trend of increased disease burden number but decreased age-standardized rate is similar to previous studies^4,9,12. The early increase in the ASIR of BC that has been observed might not necessarily signify a genuine elevation in the risk of BC occurrence. Instead, it could potentially reflect the growing prevalence and enhancement of physical examination screening, early detection, and diagnostic techniques such as urine cytology, cystoscopy, and CT scan^13,42. Of course, there are also reasons such as the increased prevalence of risk factors for BC (including smoking, obesity, alcohol consumption, and consumption of red meat) due to the previously rapidly developing world economy, as well as higher exposure to occupational and environmental carcinogens, or the lag in tobacco control⁴². This requires more detailed epidemiological studies for elaboration, even down to the level of individual countries or risk factors.

The observed downward change in the ASR of the bladder cancer burden globally seems to reflect the geographical distribution differences and changes of risk factors prevalence. Studies have found that economic development level has a significant impact on the BC. The results show that 55% of BC cases and 43% of BC deaths occur in countries with a high human development index (HDI), while only 5% of the BC occurs in countries with a low HDI, which is disproportionate to the population². Simultaneously, this research also observed a reduction in the incidence and mortality rates of BC in regions such as Western Europe, North America, and Oceania in recent years². Our study additionally detected a continuous decline in ASIR and ASMR in areas with high SDI and high-middle SDI as well as in the aforementioned regions. This might drive down the ASR of the global BC burden. Smoking is the most important risk factor for BC, accounting for about 50% of cases³. Thus, the trends in the incidence and mortality rates of BC are partly influenced by the manifestations of tobacco prevalence. Marie Ng and her collaborators found that from 1980 to 2012, at the global level, the estimated prevalence of daily smoking among men and women has significantly decreased⁴³. However, the decades-long lag of tobacco control on the risk of BC incidence must be considered⁴⁴. Particularly in the past few decades, the significant decline in the male smoking rate in regions with high HDI levels such as North America and many European countries may explain the reasons for the observed decline in the incidence and mortality rates of BC in these areas^2,39. The attributable risk analysis of BC deaths also verifies that the proportion of bladder cancer deaths and DALYs caused by smoking in 2021 was significantly lower than that in 1990¹³. In addition, in the past few decades, exposure to occupational carcinogens in the European Union still exists but has been controlled and significantly improved. Due to the long latency period of BC, occupation-related BC may continue to decrease in the coming decades. At the same time, there is still much room for improvement in occupational health in low- and middle-income countries to reduce the burden of bladder cancer⁴. The improvement of environmental factors may also be one of the reasons for the reduction of the burden of BC. Although the relationship between arsenic and chlorine in drinking water and the risk of BC occurrence has been clearly defined at present, unfortunately, there is currently no evidence to show how reducing environmental exposure affects the risk of BC occurrence³. Schistosomiasis is an endemic disease affecting hundreds of millions of people in sub-Saharan Africa and parts of the Middle East. Schistosomiasis plus the chronic inflammatory infection it causes significantly increases the risk of squamous cell BC. Taking Egypt as an example, through the extensive use of the effective anthelmintic drug praziquantel for treatment and the improvement of water supply and sanitation conditions, the incidence of BC caused by schistosomiasis in Egypt has significantly decreased⁴⁵. However, the prevention and management of bladder cancer are not as optimistic as imagined. A study has revealed that tobacco consumption in developing countries is increasing and has surpassed that in developed countries where the prevalence of tobacco consumption has commenced to decline⁴³. For instance, in some countries in Central America, South America, Central and Eastern Europe, the smoking rate has only recently begun to decline or is even still on the rise². The growth in smoking prevalence, environmental pollution, and aging, along with the ascent of the HDI, may result in an upsurge in the incidence of BC in these regions with low SDI levels in the coming decades⁴. This is in accordance with the upward trend of ASIR in regions with middle SDI, low- middle SDI, and low SDI that we have detected in the past ten years. This inevitably leads us to worry that the burden of bladder cancer is gradually being transferred to regions with lower SDI levels.

Age-period-cohort analysis observed that the relative risks of BC incidence and mortality showed an increasing trend with age. The relative risks increased significantly after the ages of 50 and 65 respectively. In fact, aging is undoubtedly the most important factor in the burden of BC. This may be attributed to the cumulative exposure to a large number of risk factors throughout life and the decline in physical function^4,46. For the period effect, it is detected that the relative incidence and mortality risk decrease as the period progresses. This may be related to the gradual reduction of risk factors for bladder cancer. In particular, smoking prevalence has gradually decreased as global smoking cessation control is implemented⁴³. Regarding the birth cohort effect, the relative risks of incidence and mortality show a trend of first rising and then falling with the increase in birth cohorts, which means that individuals born earlier exhibit a higher risk of BC than those born later. For one thing, for individuals born at an earlier time, the longer the period they have gone through industrialization and social development, the greater the cumulative total of risk factors to which they have been exposed. For another, the decline in smoking, occupational exposure and other risk factors, as well as the improvement of screening and treatment measures, are the results of efforts in recent decades. This has a lagging effect on the effect of BC burden⁴.

Our decomposition analysis results show that population aging and growth are important factors contributing to the increased global burden of BC. This is consistent with previous studies that have emphasized the role of population size and structural changes in driving BC burden^8,39. Interestingly, we also discovered disparities in the impacts of population aging and population growth in regions with varying SDI levels. This underscores the significance of the need for customized prevention and early detection strategies in different countries. The role of epidemiological changes is in line with previous results and generally exhibits a reducing effect on the growth of the burden of BC. However, it is worth noting that the epidemiological changes in male in regions with lower SDI have a positive contribution to the incidence of BC, indicating that these regions should increase investment in preventive measures for male BC.

It is observed that a disproportionate burden of BC is concentrated in countries with higher SDI, which is similar to previous studies^8,47. The countries with high SDI levels always inevitably have an aging population, better detection rates and the prevalence of risk factors such as smoking and occupational exposure, thus promoting the occurrence of BC. With the further increase of SDI level, the adequacy of medical resources in developed countries enhances the treatment level of BC, thereby reducing the mortality rate and DALYs of BC in countries with the highest SDI level. This may be the reason why the ASMR and ASDR reach their peaks when the SDI is 0.78, unlike the ASIR which continues to rise. Countries with a lower SDI are faced with the challenges of population growth, insufficient medical resources and changes in the prevalence of risk factors. This indicates that with the improvement of the social and demographic development level, the prevention, management and treatment of BC should be strengthened, especially for modifiable risk factors such as smoking, schistosomiasis and occupational exposure. Regarding the control of schistosomiasis, the new WHO guidelines in 2022 recommend expanding the preventive chemotherapy regimen from only school-aged children to the entire community. Meanwhile, it is suggested to adjust the frequency of the preventive chemotherapy regimen according to the community prevalence and to prioritize additional interventions for it, including improving water, sanitation and personal hygiene⁴⁸. This recommendation indicates that low- and middle-income countries, mainly those in sub-Saharan Africa, need to make their prevention and control measures for schistosomiasis more refined and comprehensive. Controlling smoking is of crucial significance in mitigating the impact of smoking on bladder cancer, with Australia and Singapore serving as exemplary cases. In Australia, a series of measures including the imposition of progressive tobacco taxes, the launch of public health campaigns and the implementation of plain packaging laws have been adopted; similarly, Singapore has stipulated smoke-free zones in public places and on transportation, prohibited tobacco advertising, promotion and sponsorship, and elevated the minimum legal age for consuming traditional cigarettes^12,49. These combined efforts in both countries are worthy of being learned and referenced by those regions and countries that are struggling with slow progress in reducing the smoking-related burden of bladder cancer. The exposure to certain dyes, aromatic amines, rubber products, as well as paint and leather work, associated with industrialization, is linked to an increased risk of bladder cancer⁵⁰. This suggests that developing countries should strengthen environmental protection and occupational exposure safeguards during their economic development to avoid the significant harm to human health that occurred during industrialization in many developed countries.

Although predicted declines in bladder cancer ASRs of incidence, prevalence, and DALYs until 2036, decomposition analysis shows that the increase in global BC burden over the past three decades is mainly due to population growth and aging. Thus, BC control and management are not promising, still facing heavy burdens and challenges. The global population aging problem is severe, and it is expected that by 2050, the world’s population over 60 years old will reach 2.1 billion, accounting for 22% of the total population, with the number of people aged 80 or above being as high as 426 million⁵¹. In developing countries, population growth and the prevalence of disease risk factors brought about by social and economic development will also increase the burden of BC⁴. Therefore, countries around the world should improve their medical policies according to the characteristics of their own population changes and be fully prepared for the increase in disease burden brought about by this demographic transition.

The findings of this study hold significant implications for bladder cancer public health and clinical practice. Firstly, this study investigates the spatiotemporal changing trends of incidence, mortality, and DALYs of bladder cancer on a global scale over the past three decades. Secondly, from 1990 to 2021, driven by population growth and aging, the burden quantity of bladder cancer has increased markedly. In contrast, the ASRs have gradually decreased, and this trend is expected to continue in the future. Thirdly, in countries with a high SDI, the burden of bladder cancer is highly concentrated. Nevertheless, the ASIR in regions with a lower SDI has been on a continuous rise in the past ten years, indicating signs of a transfer of burden. However, several limitations should be noted. Firstly, in some countries with insufficient medical resources, potential misdiagnosis, missed diagnosis, and literature loss reduce the quality and availability of data. Although the application of data processing and statistical modeling methods by GBD collaborators can effectively help address this issue, it introduces uncertainty to the data analysis results. Secondly, it should be noted that there is a delay in GBD data update. The burden of BC is calculated using data from 1990 to 2021 and cannot fully reflect the current situation. Thirdly, our research mainly analyzes the epidemiology of BC and lacks an analysis of disease risk factors, which limits the conclusion of causal inference. Finally, since GBD data focuses on the overall situation of diseases and lacks more detailed information on diseases, we cannot further discuss the situation of specific subtypes of diseases.