INTRODUCTION

As the global population continues to grow and the aging population expands, the incidence of cancer is rising annually. Cancer has become a major public health issue worldwide. Cancer is reported to be the second leading cause of death in the United States. In 2023, the US recorded 1958310 new cancer cases and 609820 cancer-related deaths¹. Bladder cancer is a common and high-incidence urological malignancy² that significantly impacts human health and places a heavy burden on healthcare systems. In 2019, the Global Burden of Disease (GBD) study reported 524300 new bladder cancer cases globally, leading to 166440 deaths³. According to the American Cancer Society, bladder cancer (BC) ranked as the fourth most common cancer and the eighth leading cause of cancer-related deaths among men in the US in 2022¹. Further primary prevention efforts are essential to alleviate the medical and economic burden of bladder cancer on populations and healthcare systems.

Contemporary overviews of BC epidemiology and current evidence on BC risk factors indicate that bladder cancer is a multifactorial disease, with both genetic and environmental factors contributing to its development. Smoking and certain occupational exposures are the most established risk factors⁴. Inhalation of tobacco smoke is the most common risk factor for bladder cancer, accounting for approximately 50% of cases⁵. Tobacco smoke contains 70 known carcinogens. Although the primary chemicals responsible for bladder cancer remain uncertain, studies suggest that aromatic amines such as 4-aminobiphenyl (4-ABP) and 2-naphthylamine (2-NA) in tobacco are linked to the disease’s development in smokers⁶. Although evaluations have been made based on the 2019 GBD data, there is a lack of studies based on the 2021 GBD data^7-9. We analyzed the latest GBD data with the goal of developing more effective policies to better address the challenges posed by smoking-related bladder cancer.

METHODS

RESULTS

Age and gender trends

Age group analysis shows that bladder cancer mortality is increasingly concentrated in individuals aged ≥80 years (Figure 1A), while DALYs due to smoking shift towards those aged ≥60 years (Figure 1C). Overall, smoking has a significant impact on bladder cancer mortality and DALYs in the elderly population. Notably, from 1990 to 2021, the age group of 75–79 years experienced the largest decline in bladder cancer mortality (1990: 12.0%; 95% UI: 10.3–13.8; 2021: 7.2%; 95% UI: 6.0–8.6) (Figure 1B). Similarly, the age group of 75–79 years showed the largest decrease in bladder cancer DALYs (Figure 1D). Over the past 30 years, the increase in bladder cancer deaths and DALYs due to smoking was much higher in men compared to women, with the growth rate approximately 2.5 times greater in men. By 2021, the absolute number of bladder cancer deaths and DALYs in men was approximately 10 times that of women. Although both age-standardized mortality and DALYs for men and women declined from 1990 to 2021, significant gender differences remain in 2021 (Tables 1 and 2). Additionally, compared to women, smoking men tend to experience bladder cancer death and disability at younger ages, whereas women are more prone to these outcomes at older ages (Supplementary file Figures 1 and 2).

Figure 1

The temporal change of the mortality rate and DALYs in bladder cancer attributable to smoking across age groups: A, C) The relative proportion of bladder cancer mortality and DALYs; B, D) The temporal changes in the mortality rate and DALYs of bladder cancer

Local drift, age, period, and cohort effects

Figure 2 provides insights into indicators derived from the age-period-cohort model, including local drift, age effects (represented by longitudinal age curves, describing the natural changes in bladder cancer mortality and DALYs), period effects (showing the relative death risk at different periods), and cohort effects for male and female cohorts (showing relative death risk in the cohort). Overall, according to the age-period-cohort model, the net drift in bladder cancer mortality due to smoking is -2.06% per year (95% CI: -2.41 – -1.98) (Table 1). However, there are differences in the net drift between men and women, with the net drift increasing as age rises in men. In contrast, women aged 55–79 years showed a decreasing trend, while those aged ≥80 years showed an increasing trend. Compared to men (-2.11%; 95% CI: -2.2 – -2.03), the decline in female bladder cancer mortality was slightly lower (-2.33%; 95% CI: -2.59 – -2.08), and a similar pattern was observed for bladder cancer DALYs (men: -2.03% (95% CI: -2.1 – -1.97), women: -2.25%; 95% CI: -2.31 – -2.19). The longitudinal age distribution of bladder cancer mortality by gender shows that mortality gradually increases with age in the smoking population. Although the DALYs results followed a similar growth pattern to male and female mortality, the growth rate in men was significantly higher than in women. Regarding period effects, the patterns of decreasing bladder cancer mortality and DALYs in smoking men and women were similar. Similarly, cohort effects show a positive decline in bladder cancer mortality and DALYs, with a slightly greater decrease in women than in men.

Figure 2

The local drifts, age effects, period effects, and cohort effects of bladder cancer mortality attributable to smoking from 1990 to 2021: A–D) mortality data; E–H) DALYs

DISCUSSION

This study, based on the latest GBD 2021 data, analyzes the impact of smoking on the burden of bladder cancer, revealing key trends and risk factors. Our results show that while the global number of bladder cancer deaths attributable to smoking has increased by 42.9% over the past 30 years (95% UI: 25.7–68.3), both the ASMR and the ASDR have declined globally, especially the significant drop in ASDR. This suggests that the burden of bladder cancer has been alleviated in some regions, partly due to a decrease in smoking rates and strengthened public health policies¹⁰. However, the total death and disability burden from smoking-related bladder cancer varies significantly across different age groups, genders, and countries with varying SDI levels. For example, while bladder cancer mortality in those aged ≥80 years continues to rise, the disability burden (DALYs) from smoking-related bladder cancer has shifted to individuals aged ≥60 years. This indicates that older adults play a crucial role in the smoking-related bladder cancer burden^2,10. Notably, between 1990 and 2021, the most significant decline in both bladder cancer mortality and disability burden occurred in the age group of 75–79 years, highlighting the positive impact of public health interventions in reducing the burden in older populations.

Compared to previous studies, this research provides a more comprehensive analysis across age, gender, and socioeconomic backgrounds. For instance, Zhang et al.¹¹ reported a global increase in bladder cancer burden and noted that despite declining smoking rates, the burden of smoking-related bladder cancer remains high in some regions. This study further emphasizes the larger impact of smoking on men, with the absolute number of bladder cancer deaths and disabilities among men being 10 times higher than in women, and the increase about 2.5 times that of women¹². This gender disparity is not only reflected in mortality rates but is also particularly prominent in the increase of DALYs¹⁰. Additionally, this study found that the burden of bladder cancer is more significant in high and middle SDI countries compared to low SDI countries. Despite improvements in health policies and public health measures in these regions, the historically high levels of smoking exposure continue to contribute to the persistent burden of bladder cancer. This finding aligns with the research by Tian et al.¹² and Huang et al.¹³, suggesting that despite tobacco control policies in high-income countries, the historical accumulation of smoking exposure continues to pose a significant bladder cancer burden.

Numerous studies have reported the link between smoking and bladder cancer risk, including a study from Japan that found an association between smoking and increased bladder cancer risk. After many years of quitting, the risk for former smokers may approach that of never smokers¹⁴. However, there are few reports on the specific mechanisms underlying this effect. These findings have important implications for public health strategies and clinical practice. First, they emphasize that smoking cessation programs should highlight bladder cancer risk reduction as a significant benefit, particularly for middle-aged smokers who might be more concerned about cancer than cardiovascular disease. Second, the gradual but incomplete risk normalization suggests that former smokers, especially those with longer smoking histories, may benefit from tailored surveillance protocols. Finally, understanding the time-dependent nature of risk reduction after cessation provides valuable information for developing personalized risk assessment tools that could guide screening recommendations based on individual smoking histories. Integrating these insights into comprehensive tobacco control programs could significantly enhance their effectiveness in reducing bladder cancer burden. The primary mechanism is through long-term exposure of bladder epithelial cells to carcinogens in tobacco smoke, causing DNA damage and genetic mutations. Aromatic amines (e.g. 4-ABP, 2-NA) and N-nitroso compounds are excreted in urine, where they come into contact with bladder epithelium and promote the development of bladder cancer¹⁵. Previous research has identified the N-acetyltransferase (NAT2) gene as being associated with bladder cancer risk. The NAT2 gene encodes an enzyme responsible for metabolizing aromatic amines, which are common carcinogens in tobacco smoke¹⁶. The largest prospective WBC DNA EWAS study on bladder cancer shows that bladder cancer risk-associated CpG sites are primarily related to smoking behavior. Smoking-related DNA methylation at CpG sites is generally associated with future bladder cancer, with most identified differential methylation regions being directly or indirectly related to smoking¹⁷.

This study further confirms the relationship between smoking and bladder cancer, finding that the impact of smoking on both mortality and disability burden increases with age, especially in older populations. Long-term smoking exposure not only increases the risk of bladder cancer mortality but also leads to higher disability burden, a trend that is especially pronounced in middle- and high-income countries¹³. Furthermore, the impact of smoking on bladder cancer is not limited to men. While the increase in mortality and disability is greater among men, women in the very old age groups (aged ≥80 years) also show higher mortality and disability rates¹⁰. This gender difference may stem from historical variations in smoking behaviors between men and women, with women typically initiating smoking habits later than men, as well as potential sex-related physiological factors that influence cancer development. These findings suggest that public health interventions should employ gender-differentiated strategies – this does not mean delaying interventions for women, but rather customizing educational messages, support systems, and health promotion activities to address the specific risk factors and concerns of different gender groups. Smoking cessation interventions for both men and women should be timely and proactive, while intervention designs should thoroughly consider the unique barriers and motivating factors that different genders may face, thereby enhancing intervention effectiveness.

Our study further examined the impact of the SDI on bladder cancer mortality and disability burden. We found a significant decline in ASMR and DALYs in high SDI countries, such as those in Western Europe and North America. This trend can be attributed to the early implementation of anti-smoking policies and the stronger public health systems in these countries. However, in middle- and high-SDI countries, despite a decrease in mortality and disability rates, the overall burden remains high, particularly among the male population. In low SDI countries, while mortality and disability rates have decreased, the overall burden remains heavy. This indicates that low-income countries still face significant challenges in smoking control, early screening, and treatment⁴. This suggests that while smoking control policies have been strengthened in various countries, disparities in economic levels and healthcare resources continue to influence the burden of bladder cancer. Particularly in low- and middle-income countries, the lack of effective smoking cessation programs and early screening methods makes it difficult to reduce the burden of bladder cancer.

CONCLUSIONS

This study reveals that smoking is a major driver of the bladder cancer burden, particularly among middle-aged and older men and in high SDI countries. Despite a global decline in smoking rates, long-term smoking exposure continues to contribute to the persistent burden of bladder cancer. To effectively reduce the incidence and mortality of bladder cancer, more proactive anti-smoking measures must be implemented, particularly among high-risk groups. Based on our findings, we recommend implementing differentiated tobacco control policies tailored to specific demographic profiles, with age-targeted cessation programs for middle-aged smokers, gender-sensitive intervention approaches, and SDI-stratified strategies that address regional development contexts. Additionally, healthcare systems should integrate bladder cancer risk assessment into routine primary care for current and former smokers while strategically allocating prevention resources toward regions showing stagnant or increasing trends in smoking-attributable bladder cancer burden.