Global burden of Tracheal, bronchus, and lung cancer based on age and sex: a systematic trend analysis of the global burden of disease study 2021

Global burden of Tracheal, bronchus, and lung cancer based on age and sex: a systematic trend analysis of the global burden of disease study 2021 | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Global burden of Tracheal, bronchus, and lung cancer based on age and sex: a systematic trend analysis of the global burden of disease study 2021 Bo Yang, Mengmeng Teng, ying Chen, Tao Zhang This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6607233/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 13 You are reading this latest preprint version Abstract Background Tracheal, bronchus, and lung (TBL) cancer is a serious respiratory disease. Epidemiological patterns of TBL cancer across 204 countries and territories from 1990 to 2021 was analyzed in this study. Methods Data was extracted from the Global Burden of Disease (GBD) 2021 study. Population was divided into young-set (25 ~ 49), middle-set (50 ~ 69) and old-set (≥ 70) based on age. Age-stratified and sex-stratified TBL cancer patterns were analyzed at global, region and nation levels. Average annual percent change (AAPC) was calculated to exhibit the TBL cancer trend based on age standardized incidence rate (ASIR) and age standardized mortality rate (ASMR). ASMR trends caused by causes were also investigated to uncover the risk shifts of TBL cancer deaths. Besides, the Bayesian age-period-cohort model incorporating integrated nested Laplace approximations was applied to forecast future TBL cancer burden. Results Globally, ASIR and ASMR per 100,000 population decreased from 28.54 and 27.58 in 1990 to 26.43 and 25.85 in 2021, respectively. However, female ASIR and ASMR are increasing lightly. The ASIR and ASMR of young-set TBL cancer decreased significantly with AAPC of -1.38[95% confidence interval (CI): -1.54~-1.22; P < 0.05] and − 1.62[95%CI: -1.76 ~ -1.49; P < 0.05]. The ASIR and ASMR also decreased with AAPC of -0.82 [95%CI: -0.90 ~ -0.73; P < 0.05] and − 1.14[95%CI: -1.23~-1.06; P < 0.05] among middle-set. Conversely, the old-set ASIR and ASMR increased with AAPC of 0.47 [95%CI: 0.41 ~ 0.53; P < 0.05] and 0.16 [95%CI: 0.02 ~ 0.30; P < 0.05]. Behavioral/occupational risks were the main reasons for TBL cancer deaths. In the future, old-set population would still possess the highest TBL cancer burden, and female burden would furtherly increase. Conclusion Although the global TBL cancer burden is experiencing decreasing, sex-specific and age-specific disparities still persisted. Tobacco is still main reason for TBL cancer deaths. Female deserves more attention due to predicted heavy female TBL cancer trend. GBD 2021 database age standardized rates age-sex-specific rate risk shifts Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 1 Introduction With the change in the age structure of social population and the deterioration of environment, the incidence rates of chronic non-communicable diseases are rising dramatically[ 1 ]. Tracheal, bronchus, and lung (TBL) cancer is a kind of deadly respiratory disease, which was not only a serious public health problem but also the core of disease prevention policy making [ 2 , 3 ]. Among all kinds of TBL cancer, lung cancer is the most common cancer worldwide and the leading cause of cancer mortality[ 4 , 5 ]. According to the latest global cancer research, there are approximately 2480301 new lung cancer patients and 1817172 patients died from lung cancer in 2022[ 6 ]. It is widely believed that the application of early detection methods are beneficial to reduce lung cancer related mortality[ 7 ]. However, lacking the awareness of regular physical examinations in patients and no obvious symptoms at the early stage of lung cancer contribute to the high mortality rate[ 5 ]. Although the global burden of lung cancer is heavy, lung cancer-related screening program has not been fully conducted in many countries. There are still many potential lung cancer patients at the early or advanced stage has not been diagnosed. There is a fact that men have higher probability of being diagnosed with cancers in their lifetime. And the higher probability can be well explained by greater exposure to carcinogenic environmental and lifestyle factors, such as smoking[ 8 ]. The incidence rate and mortality rate has been decreasing for years due to decline smoking rate in man. However, the incidence rate of lung cancer among women has been increasing dramatically for smoking or environmental exposure in many countries, which forewarning of a relatively higher overall TBL cancer burden among women in future decades[ 6 ]. Despite these reports, there is still a lack of understanding about the sex differences in the prevalence and burden of TBL cancer by age, countries, and regions. A comprehensive comparison of the epidemiology and burden of TBL cancer and their trends in the past three decades between men and women at the global, regional and national level will provide valuable information for healthcare practice. In this study, data was extracted from the Global Burden of Disease (GBD) 2021 study to present global pattern of TBL cancer. Various subgroup analyses were conducted to show the temporal trends of TBL cancer incidence and mortality among population with different age and gender at nation and region level from 1990 to 2021. The pattern of TBL cancer from 2022 to 2040 was furtherly investigated to offer suggestions for future management. 2 Methods 2.1 Data source This observational cross-sectional study was designed to analyze age/sex-stratified TBL cancer incidence and mortality at global, region and nation levels. All related cross-sectional data used in this study was extracted from the Global Health Data Exchange Online Query Tool (GHDx) ( https://vizhub.healthdata.org/gbd-results/ ) of the GBD 2021 database. The GBD study evaluated approximately 370 diseases and injuries and 87 risk factors in 204 countries, 21 regions, and 7 super-regions, offering statistical data on epidemical index (e.g., incidence, mortality) to describe disease trends over years[ 9 ]. Patients were furtherly stratified into three age groups similar to the previous published study[ 10 ]. Young-set was defined for TBL cancer patients aged at the range of 25–49, middle-set and old-set for TBL cancer patients aged at the range of 50–69 and over 70 years old, respectively. Age-specific TBL cancer burden was furtherly analyzed across genders among 21 GBD regions, 6 world health organization (WHO) regions, 4 world bank regions and 5 regions with different socio-demographic index levels. The socio-demographic index (SDI), ranging from 0 to 1, was calculated based on per capital income, average education levels and total fertility rates[ 11 ]. Therefore, the location-specific SDI is considered to be an indicator reflecting the development level of the location and may impact human health outcome. Locations were furtherly divided into low SDI (0.00 ~ 0.466), low-middle SDI (0.466 ~ 0.619), middle (0.619 ~ 0.712), high-middle (0.712 ~ 0.810) and high (0.810 ~ 1.00) regions[ 12 ]. There are 87 risk factors recorded and divided into four hierarchies in GBD 2021. Environmental/occupational factor, behavioral factor and metabolic factor were listed in level 1 risk factors. And 19 main risk factors were integrated into the level 2 risk factors, among which air pollution, other environmental risks, tobacco, high fasting plasma glucose, dietary risks, occupational risks were considered to be closely associated TBL cancer deaths. The trends of TBL cancer death caused by various risk factors were furtherly explored among subgroups in this study. The sample workflow of our study is presented in Fig. 1 . 2.2 Statistical analysis Extensive analyses have been performed to evaluate the national or regional burden of TBL cancer. Furthermore, the study compared the sex-specific trends of TBL cancer across different age cohorts. Age-standardized rate (ASR) and average annual percent change (AAPC) were used to quantify the temporal pattern of TBL cancer. The following formula was utilized to calculate the ASRs per 100,000 individuals to exhibit the TBL cancer burden in different age groups. $$\:\varvec{A}\varvec{S}\varvec{R}=\frac{{\sum\:}_{\varvec{i}=1}^{\varvec{A}}{{\varvec{a}}_{\varvec{i}}\varvec{W}}_{\varvec{i}}}{\sum\:_{\varvec{i}=1}^{\varvec{A}}{\varvec{W}}_{\varvec{i}}}\times\:\text{100,000}$$ (ASR: age-standardized rate; A: the number of age groups; a i : the crude rate in i th age group; W i : standard population composition ratio in i th age group) Jointpoint regression analysis was utilized to describe the TBL cancer trends over time. The core of Jointpoint regression is to cut the time period into different intervals through connect points and establish segmented regression according to the temporal characteristics on disease distribution, perform trend fitting and optimization for each interval, and so as to evaluate the disease change characteristics specific to different times intervals within the global time range[ 13 ]. Annual percent change (APC) describing disease trend in fixed time intervals and AAPC making it possible to use a single number to describe the average APCs over a period of multiple years are the main results of Jointpoint regression analysis. The AAPC is calculated using a weighted average of the slope coefficients of every segmented regression with the weights equal to the length of each segment over the interval according to the following formula: $$\:\varvec{A}\varvec{A}\varvec{P}\varvec{C}=\left\{\mathbf{exp}\left(\frac{\sum\:_{\varvec{i}=1}^{\varvec{n}}{\varvec{W}}_{\varvec{i}}{\varvec{b}}_{\varvec{i}}}{\sum\:_{\varvec{i}=1}^{\varvec{n}}{\varvec{W}}_{\varvec{i}}}\right)\right\}$$ (AAPC: average annual percent change; n: the number of segment intervals in the range of years; W i : the length of each segment in the range of years; b i : the slope coefficient for the i th segment). The relative risk or the odds ratio is usually used to assess the association between risk exposure and the occurrence of a particular outcome in epidemic research. However, the impact of the risk factor on the population level was not well described because of ignoring the prevalence of the risk factor. The population attributable fraction (PAF) is an index, taking into account not only the association between risk factors and outcome, but also prevalence of risk factors in the population[ 14 ]. PAF was calculated as the following formula to assess the proportion of a specific outcome in a population that is attributable to exposure to risk factors. $$\:\varvec{P}\varvec{A}\varvec{F}=\frac{\sum\:_{\varvec{i}=1}^{\varvec{n}}{\varvec{R}\varvec{R}}_{\varvec{i}}{\varvec{P}}_{\varvec{i}}-1}{\sum\:_{\varvec{i}=1}^{\varvec{n}}{\varvec{R}\varvec{R}}_{\varvec{i}}{\varvec{P}}_{\varvec{i}}}$$ (PAF: population attributable fraction; RR i : the relative risk corresponding to i th exposure; P i : the proportion of persons at i th exposure in the relevant population) The future TBL cancer burden from 2022 to 2040 was also projected with statistical model. Age–period–cohort model was generally accepted to project based on the age groups of the individual, the date of the event that is considered (period) and the birth cohort of the individual. The wrong conclusion also generated in process of projection due to the impossibility to identify the full set of age, period, and cohort effects in the analysis of mortality or other vital rates[ 15 ]. Bayesian age–period–cohort (BAPC) models is a better method to achieved higher performance in prediction due to no parametric assumptions involved. However, BAPC models have been criticized for producing too wide credible bands and complex convergence concerns introduced by Markov chain Monte Carlo (MCMC) in process of BAPC fitting[ 16 , 17 ]. The two main defects limited the BAPC using in routine practice of epidemiologists. BAPC model incorporating integrated nested Laplace approximations was proposed to address the problems mentioned before[ 16 ]. It was utilized to predict future TBL cancer trend from 2022 to 2040. Statistics of all data in this study were performed using R software (version 4.3.2) and P < 0.05 was considered statistically significant. 3 Result 3.1 Global trends of TBL cancer As the global age-standardized incidence rate (ASIR) and age-standardized mortality rate (ASMR) presented from 1990 to 2021, the global TBL cancer burden has decreased lightly (Fig. 2 A). The global ASIR and ASMR of TBL cancer per 100,000 population declined from 28.54 and 27.58 in 1990 to 26.43 and 23.50 in 2021, respectively. As oppose to continuous downward TBL cancer burden in male, upward trend in female ASIR and ASMR slowed down the global decline in TBL cancer burden. Besides, the gender composition of TBL cancer was furtherly investigated based on age groups (Fig. 2 B). The male/female ratios presented downward trend over past three decades, no matter which measure (incidence or mortality) was used to discuss TBL cancer trends. Especially, the steepest decrease of male/female ratio could be observed in middle-set. These results mean that the patterns of TBL cancer burden differ among different age and sex groups. 3.2 Age- and gender-specific global TBL cancer trend The ASIR and ASMR of TBL cancer in different age and sex groups were furtherly analyzed to uncover their contributions to decreasing global TBL burden. Table 1 presented the global TBL cancer burden based on age and sex in detail. In young-set population, the overall ASIR of TBL cancer per 100,000 population decreased from 6.67 in 1990 to 4.33 in 2021, with AAPC of -1.38 [95%confidence interval (CI): -1.54~-1.22, P < 0.05]. Significant decreasing was observed in male ASIR from 9.29 to 5.41 (AAPC: -1.79 [95%CI: -2.01~-1.57, P < 0.05]), while smaller decreasing in female from 3.95 to 3.24 (AAPC: -0.63[95%CI: -0.73~-0.54, P < 0.05]). The overall global ASMR per 100,000 population decreased from 5.78 in 1990 to 3.46 in 2021 (AAPC: -1.62 [95%CI: -1.76~-1.49, P < 0.05]). Male ASMR per 100,000 population declined from 8.13 to 4.47 with AAPC of -1.95 [95%CI: -2.11~ -1.78, P < 0.05], female ASMR declined from 3.34 to 2.45 with AAPC of -1.00 [95%CI: -1.09~ -0.92, P < 0.05]. For middle-set population, the overall global ASIR per 100,000 decreased from 92.79 to 72.41 with AAPC of -0.82 [95%CI: -0.90 ~ -0.73, P < 0.05] over the past 30 years. However, ASIRs showed inconsistent patterns across genders, which may explain the steepest decrease in middle-set male/female ratio (Fig. 2 B). While the male ASIR declined from 146.10 to 101.37 (AAPC: -1.19 [95%CI: -1.37~-1.07, P < 0.05]), female ASIR increased from 42.40 to 45.08 (AAPC:0.18 [95%CI: 0.13 ~ 0.22, P < 0.05]). The decrease in female ASMR and male ASMR resulted in significant decline in overall ASMR from 85.00 to 59.83 (AAPC: -1.14 [95%CI: -1.23~-1.06, P < 0.05]). For the old-set population, the ASIR trends of TBL cancer shared the same pattern regardless of gender. Totally, overall ASIR increased form195.08 to 227.84 with AAPC of 0.47 [95%CI: 0.41 ~ 0.53, P < 0.05]. Male ASIR increased negligibly from 335.05 to 337.25 (AAPC: 0.01[95%CI: -0.07 ~ 0.09, P = 0.87]), while female ASIR increased significantly from 100.96 to 144.60 (AAPC: 1.16[95%CI: 1.07 ~ 1.24, P < 0.05]). ASMRs showed opposite pattern across gender and female ASMR finally determined overall ASMR trend. Female ASMR increased from 104.65 to 135.93(AAPC: 0.84[95%CI: 0.73 ~ 0.95, P < 0.05]), with overall ASMR increasing from 204.87 to 217.16 (AAPC: 0.16 [95%CI: 0.02 ~ 0.30, P < 0.05]). In contrast, the male ASMR reduced from 356.01 to 325.56 (AAPC: -0.32 [95%CI: -0.45~-0.19, P < 0.05]). All in all, the global ASIR and ASMR of TBL cancer declined, the TBL cancer burden in old-set population remains high and continues to increase. The Joinpoint regression analysis was furtherly used to identify the years when notable changes happened to the TBL cancer trend. Although a negligible increase with APC in ASIR of young-set TBL cancer was observed from 1990 to 1996 (APC = 0.06, P > 0.05), the young-set ASIR kept decreasing since 1996 (Fig. 3 A). And ASMR also continued to decrease after keeping at a relative stable level for 5 years since 1990 (Fig. 3 D). Significant decreasing could be observed in ASIR and ASMR in middle-set TBL cancer over the past 30 years (Fig. 3 B, 3 E). Different from the patterns in other two groups, long-term significant increasing trend could be observed in old-set TBL cancer burden. A rapid increase in old-set ASIR can be observed until 2010, when a slow decline occurred (Fig. 3 C). As for the old-set ASMR, it had increased for 14 years and declined for 3 years with similar pace since 1990. There was a slight rebound until 2010 when it began to decline (Fig. 3 F). Besides, according to age-sex-specific ASIR and ASMR trends presented in supplementary Fig. 1, old-det female population would face heavier TBL cancer burden in the future. 3.3 Regional and national trend The global pattern of TBL cancer burden from 1990 to 2021 are shown in Fig. 4 . Male and female trends of TBL cancer burden are also presented in supplementary Fig. 2 and supplementary Fig. 3, respectively. The TBL cancer burden was furtherly analyzed in different regions. Based on the WHO region classification, the distribution pattern of TBL cancer has changed a lot over the past 30 years. The highest ASIR and ASMR, as well as continuous upward trends observed in Western Pacific region in most age groups indicated the highest TBL cancer burden in this region in 2021(Table 2 and Table 3 ). The region of Americas, the only region with decreasing ASIR in old-set population, depicts the steepest decrease of ASIR (young-set AAPC: -3.01 [95%CI: -3.24 ~ 2.79, P < 0.05]; Middle-set AAPC: -2.21 [95%CI:-2.36~-2.06, P < 0.05]; old-set AAPC: -0.76 [95%CI: -0.87~-0.64, P < 0.05]) and ASMR(young-set AAPC: -3.11 [-3.32~-2.91, P < 0.05]; Middle-set AAPC: -2.40 [95%CI: -2.60~-2.21, P < 0.05]; old-set AAPC: -0.93 [95%CI: -1.04~-0.82, P < 0.05]; Table 2 and Table 3 ). The TBL cancer burden was also analyzed base on levels of health system and world bank income. Unexpectedly, people living in regions with higher levels of health system and world bank income faced heavier TBL cancer burden. But in regions with high level of world bank income, TBL cancer ASIR (young-set AAPC: -2.53 [95%CI: -2.63~-2.43, P < 0.05]; middle-set AAPC: -1.35 [95%CI: -1.45~-1.25, P < 0.05]; old-set AAPC: -0.01 [95%CI: -0.11 ~ 0.10, P = 0.93]; Table 2 ) and ASMR (young-set AAPC: -3.12 [95%CI: -3.25~-2.98, P < 0.05]; middle-set AAPC: -1.81 [95%CI: -1.91~-1.71, P < 0.05]; old-set AAPC: -0.38 [95%CI: -0.46~-0.30, P = 0.93]; Table 3 ) exhibited the steepest decrease. Besides, regions with advanced health system presented decreasing TBL cancer ASMRs (young-set AAPC: -2.98[95%CI: -3.08~-2.88, P < 0.05]; middle-set AAPC: -1.75[95%CI: -1.86~-1.64, P < 0.05]; old-set AAPC: -0.32[95%CI: -0.40~-0.25, P < 0.05]; Table 3 ). The TBL cancer incidence in the region with basic health system increased dramatically in population over 50, which may predict the highest TBL cancer burden in the future (middle-set AAPC: 0.11 [95%CI: -0.01 ~ 0.23, P < 0.05]; old-set AAPC: 1.49 [95%CI: 1.28 ~ 1.70, P < 0.05]; Table 2 ). Table 2 and Table 3 also presented TBL cancer burden in 21 GBD regions. Population living in Western Sub-Saharan Africa faced the lowest TBL cancer burden over the past 30 years. Central Europe and high-income North America exhibited the highest TBL cancer burden among population aging from 25 to 69 and over 70, respectively. The ASIR and ASMR among population aging from 25 to 69 showed a downward trend in most regions. Conversely, old-set female TBL cancer burden exhibited a upward trend in most regions, while old-set male downward trend observed in half of the regions according to sex-specific ASIRs and ASMRs presented in supplementary Table S1 -S4. 3.4 Burden of TBL cancer based on SDI The majority of incident cases and deaths were predominantly observed in regions with higher SDI levels (Table 2 ). The variation trends of ASIR and ASMR based on SDI in different regions and countries were furtherly investigated. The good news is that, as shown in Fig. 5 , female old-set ASIR and ASMR were positively correlated with SDI regardless of SDI changes, while for other groups, a positive correlation with SDI was only observed when SDI was low. Besides, female TBL cancer burden based national level shared completely positive pattern in all age groups (Fig. 6 D-F, J-L). These results forewarning higher female TBL cancer burden in the future, especially in counties with high SDI level. 3.5 Burden of TBL based on cause Considering heavy TBL cancer burden worldwide, the cause-specific mortality rates were of paramount importance to be explored. As shown in Fig. 7 A-C, behavioral risk is the main cause to TBL cancer deaths in most subgroups. Notably, environmental/occupational risk has been the most dangerous factor lead female TBL cancer deaths among young-set population since 2010 (Fig. 7 A). The trends of TBL cancer ASMRs caused by level 2 risk factors were furtherly investigated. Among six level 2 risks, the tobacco using was the leading cause of TBL cancer deaths (Fig. 7 D-F). Given the differences in the rates of decline, air pollution might be the most dangerous risk factor for female TBL cancer deaths in young-set (Fig. 7 D). Different from the patterns in other sex and age groups, the old-set male group had more TBL cancer deaths caused by occupational risks than by air pollution (Fig. 7 F). 3.6 Global disease burden prediction for TBL cancer to 2040 The BAPC model incorporating integrated nested Laplace approximations was employed to forecast the future TBL cancer burden from 2022 to 2040. Although downward trend of TBL cancer burden observed in men, the burden would still keep at a high level in men and population over 70 (Fig. 8 ). In the next 20 years, as TBL cancer trends in men were relatively stable, women will play a major role in determining TBL cancer trends in the old-set (Fig. 8 A). 4 Discussion Based on the GBD 2021 database, our study utilized descriptive statistical analysis to examine globally the temporal, spatial, and demographic distribution of TBL cancer from 1990 to 2021. Despite upward trend in the total number of incident cases and deaths over the past three decades, the overall ASIR and ASMR of TBL cancer exhibited continuous downward trend. Notably, the large decrease in ASIR and ASMR in men explained the observed overall decline, whereas the slight increase in ASIR and ASMR in women slower the rate of decline. As previous research described that advancing age is the most determinative risk factor for cancer overall and for many individual cancer types, the heaviest TBL cancer burden was found in population over 70 years old[ 18 ]. Age is not only a marker capturing the duration of exposures and the accumulation of cancer risks, but also senescence explained by telomere dysfunction and cell cycle arrest due to shortening of telomeres[ 19 , 20 ]. The heaviest TBL cancer burden among elderly people largely attributes to long-term accumulation of carcinogenic exposures (e.g., smoking, air pollution) and somatic mutations, as well as changes happened to the immune system with aging[ 21 – 24 ]. Surprisingly, oncogene-induced senescence and telomere-based crisis exert powerful anticancer effects[ 19 ]. Therefore, the manners of reducing accumulation of carcinogenic exposures are efficient to control TBL cancer burden. As to carcinogenic exposures, behavioral/occupational risk and environmental risk are main reasons to high TBL cancer death rate. More specifically, tobacco, air pollution as well as occupational risks are main causes associated with TBL cancer burden. The WHO Framework Convention on Tobacco Control (FCTC) was negotiated in 2003 and ratified in 2005 to implement effective tobacco control measures[ 25 ]. Especially, pictorial health warnings and tobacco advertisement, promotion, as well as sponsorship ban were most implemented among all smokeless tobacco policies worldwide[ 26 ]. Currently, this treaty has been admitted and signed by 183 countries. It is obtrusively that ASMR among old-set population showed a clear upward trend before the time point when FCTC was ratified. It is worth noting that air pollution-related ASMR has shown a slight increase in young-set women in recent years, which may make air pollution-related ASMR surpass tobacco-related ASMR. And air pollution has the second highest ASMR among all level 2 risk factors. Especially, indoor air pollution is considered to be a major risk factor for TBL cancer in never-smoking women living in several regions of Asia[ 27 ]. Promotion of growth of lung epithelial cells harbouring EGFR mutations might be related to air pollution, which explained the higher frequency of EGFR mutation observed in Asian lung cancer patients[ 28 ]. High ASMR caused by air pollution could be explained by the role of women aged 25 to 49 as mothers in their families. Women has higher possibility to expose to coal burning in poorly ventilated houses, burning of wood and other solid fuels, as well as fumes from high-temperature cooking using unrefined vegetable oils such as rapeseed oil[ 29 , 30 ]. Old-set men had the second highest ASMR related to occupational exposure, which can largely attribute exposure to carcinogens (e.g., metals and mixed occupation exposures, diesel exhaust, polycyclic aromatic hydrocarbons) during the process of industrialization and urbanization[ 27 ]. Therefore, continuous promotion of smoking cessation and improve air quality, as well as less exposure to occupational carcinogens still are effective ways to control TBL cancer burden. However, ASIR and ASMR showed different pattern in old-set population. In regions with higher socioeconomic development or advanced heath system, old-set ASIR showed upward trend, while old-set ASMR showed downward trend. The observed disparities in TBL cancer incidence can be attributed to several factors. Tobacco was considered a symbol of higher social status in some high SDI regions[ 31 ]. Compared lower SDI regions, higher ASIR and upward trends are closely associated with long-term tobacco exposure in higher SDI regions. In addition, TBL cancer ASIR difference also can be explain by medical disparities. On the one hand, TBL cancer was more likely to be diagnosed due to the application of more advanced technologies and the gradual implementation of screening programs in higher SDI regions[ 32 ]. On the other hand, some areas with lower SDI lack a complete disease registration system, resulting in systematic underreporting. As for decreasing ASMR trend in high SDI region can be explained by following reasons. Early diagnosis and treatment assisted by low-dose computed tomography (LDCT) can effectively reduce TBL cancer mortality[ 33 ]. Besides, it can also attribute to the quality and availability of cancer treatment in each SDI regions. More effective and safer anti-cancer drugs (e.g., targeted therapy, immunotherapy, antibody-drug conjugates) are applied in clinical practice in higher SDI regions, while clinical drugs not only have limited efficacy but also result in huge economic burden to patients in regions with lower SDI[ 30 , 34 ]. All in all, although the global TBL cancer burden is experiencing decreasing, regional, sex-specific and age-specific disparities still persisted. Measures should be taken from the aspects of onset, diagnosis, treatment, and prognosis to reduce the TBL cancer burden. Corresponding education should be opened to citizens to deepen their recognition of TBL cancer. Policies should be formulated to reduce exposure to carcinogens, especially air pollution and tobacco. And large-scale screening programs and more advanced technology for diagnosis should be open to people worldwide. Last but not list, the quality and availability should be enhanced globally in cancer treatment to control the TBL cancer burden in lower SDI regions. 5 Conclusion Overall, our study highlights the decreasing burden of TBL cancer and significant trends disparities between age and gender. Citizens over 70 years was identified as the main victim of TBL cancer, and female TBL cancer burden have shown a progressive increase over the past three decades. Besides, regional disparities were also observed in territories of different socio-economic development. Although higher SDI levels regions possessed heavier TBL cancer burden, these regions did better in the prevention and treatment of TBL cancer due to the local advanced medical systems. Excitingly, as FCTC is recognized worldwide, great progression in control of TBL cancer deaths caused by tobacco has been made worldwide as the result of series of effective tobacco control measures implemented in many countries. Last but not least, female TBL cancer burden, which may determine the global TBL cancer trend in the future, deserves more attention and more effective policies for prevention and treatment. Declarations Acknowledgment We are thankful for the contribution of the GBD2021 database supplying cancer research information. Author contributions BY: Writing – original draft, Formal analysis, Data curation. MMT: Writing – review & editing, Formal analysis, Data curation. SYC: Writing – review & editing, Methodology, Data curation. TZ: Writing – review & editing, Methodology, Formal analysis. Funding This work is supported by the National Science Fund for Distinguished Young Scholars (82404762). Data Availability statement The data presented in this study can be found in the GBD 2021 database (https://vizhub.healthdata.org/gbd-results/). Ethical approval and consent to participate All data from the GBD2021 database was free, and this study was approved by the Institutional Research Committee of the College of Stomatology, Xi’an Jiaotong University. Consent for publication Not applicable. Competing interests The authors declare no competing interests. References Deng Y, Peng L, Li N, Zhai Z, Xiang D, Ye X, et al. Tracheal, bronchus, and lung cancer burden and related risk factors in the United States and China. Am J Transl Res. 2021;13:1928–51. Huang B, Hua J, Liu S, Wang X, Sun Z, Bai R, et al. 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CA: A Cancer Journal for Clinicians. 2024;74:229–63. Wolf AMD, Oeffinger KC, Shih TY-C, Walter LC, Church TR, Fontham ETH, et al. Screening for lung cancer: 2023 guideline update from the American Cancer Society. https://doi.org/10.3322/caac.21811. Siegel RL, Giaquinto AN, Jemal A. Cancer statistics, 2024. CA: A Cancer Journal for Clinicians. 2024;74:12–49. Safiri S, Sohrabi M-R, Carson-Chahhoud K, Bettampadi D, Taghizadieh A, Almasi-Hashiani A, et al. Burden of Tracheal, Bronchus, and Lung Cancer and Its Attributable Risk Factors in 204 Countries and Territories, 1990 to 2019. J Thorac Oncol. 2021;16:945–59. Walker B, Jani CT, Liu W, Punjwani S, Kareff S, Ceglowski P, et al. Does a “Western Lifestyle” Confer a Higher Burden of Colorectal Cancer? A Comparison of EU15+ Countries versus Global Trends between 1990 and 2019. Cancers. 2024;16:2277. Zhang Y, Mi M, Zhu N, Yuan Z, Ding Y, Zhao Y, et al. Global burden of tracheal, bronchus, and lung cancer attributable to occupational carcinogens in 204 countries and territories, from 1990 to 2019: results from the global burden of disease study 2019. Ann Med. 2023;55:2206672. Global Burden of Disease Collaborative Network. Global Burden of Disease Study 2021 (GBD 2021) Socio-Demographic Index (SDI) 1950–2021 | GHDx. 2024. https://ghdx.healthdata.org/record/global-burden-disease-study-2021-gbd-2021-socio-demographic-index-sdi-1950%E2%80%932021. Accessed 8 Sep 2024. Kim HJ, Fay MP, Feuer EJ, Midthune DN. Permutation tests for joinpoint regression with applications to cancer rates. Stat Med. 2000;19:335–51. Laaksonen MA, Knekt P, Härkänen T, Virtala E, Oja H. Estimation of the Population Attributable Fraction for Mortality in a Cohort Study Using a Piecewise Constant Hazards Model. American Journal of Epidemiology. 2010;171:837–47. Held L, Riebler A. Comment on “Assessing Validity and Application Scope of the Intrinsic Estimator Approach to the Age-Period-Cohort (APC) Problem.” Demography. 2013;50:1977–9. Riebler A, Held L. Projecting the future burden of cancer: Bayesian age-period-cohort analysis with integrated nested Laplace approximations. Biom J. 2017;59:531–49. Clements MS, Armstrong BK, Moolgavkar SH. Lung cancer rate predictions using generalized additive models. Biostatistics. 2005;6:576–89. Siegel RL, Giaquinto AN, Jemal A. Cancer statistics, 2024. CA: A Cancer Journal for Clinicians. 2024;74:12–49. Hornsby PJ. Senescence as an anticancer mechanism. J Clin Oncol. 2007;25:1852–7. D B, P I, L H, R C, L M, S E, et al. The multitude and diversity of environmental carcinogens. Environmental research. 2007;105. Palmer S, Albergante L, Blackburn CC, Newman TJ. Thymic involution and rising disease incidence with age. Proceedings of the National Academy of Sciences of the United States of America. 2018;115:1883. C F, M B, G F, E G. Biology of cancer and aging: a complex association with cellular senescence. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2014;32. Mc W, Dm H, Je B, La P, M G, Sj H. Age and cancer risk: a potentially modifiable relationship. American journal of preventive medicine. 2014;46 3 Suppl 1. Ce D, Kd M, W D, Sg M, Hj C, Cr L, et al. Cancer statistics for adults aged 85 years and older, 2019. CA: a cancer journal for clinicians. 2019;69. Arora M, Chugh A, Jain N, Mishu M, Boeckmann M, Dahanayake S, et al. Protocol: Global impact of tobacco control policies on smokeless tobacco use: a systematic review protocol. BMJ Open. 2020;10. The global impact of tobacco control policies on smokeless tobacco use: a systematic review. The Lancet Global Health. 2023;11:e953–68. Malhotra J, Malvezzi M, Negri E, Vecchia CL, Boffetta P. Risk factors for lung cancer worldwide. European Respiratory Journal. 2016;48:889–902. Hendriks LEL, Remon J, Faivre-Finn C, Garassino MC, Heymach JV, Kerr KM, et al. Non-small-cell lung cancer. Nat Rev Dis Primers. 2024;10:1–22. Malhotra J, Malvezzi M, Negri E, Vecchia CL, Boffetta P. Risk factors for lung cancer worldwide. European Respiratory Journal. 2016;48:889–902. Kuang Z, Wang J, Liu K, Wu J, Ge Y, Zhu G, et al. Global, regional, and national burden of tracheal, bronchus, and lung cancer and its risk factors from 1990 to 2021: findings from the global burden of disease study 2021. eClinicalMedicine. 2024;75:102804. Wong ML, Clarke CA, Yang J, Hwang J, Hiatt RA, Wang S. Incidence of Non–Small-Cell Lung Cancer among California Hispanics According to Neighborhood Socioeconomic Status. Journal of Thoracic Oncology. 2013;8:287–94. Sha R, Kong X, Li X, Wang Y. Global burden of breast cancer and attributable risk factors in 204 countries and territories, from 1990 to 2021: results from the Global Burden of Disease Study 2021. Biomark Res. 2024;12:87. Aberle DR, Black WC, Chiles C, Church TR, Gareen IF, Gierada DS, et al. Lung Cancer Incidence and Mortality with Extended Follow-up in the National Lung Screening Trial National Lung Screening Trial Writing Team. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer. 2019;14:1732. A F, M S, D L, W H, M J, B G, et al. Access to cancer medicines deemed essential by oncologists in 82 countries: an international, cross-sectional survey. The Lancet Oncology. 2021;22. Tables Tables are available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files Supplementmaterial.docx Tables.docx Cite Share Download PDF Status: Under Review Version 1 posted Reviews received at journal 15 May, 2026 Reviews received at journal 09 Feb, 2026 Reviewers agreed at journal 20 Jan, 2026 Reviewers agreed at journal 03 Nov, 2025 Reviewers agreed at journal 31 Jul, 2025 Reviews received at journal 26 Jul, 2025 Reviewers agreed at journal 26 Jul, 2025 Reviewers agreed at journal 14 Jul, 2025 Reviewers invited by journal 02 Jul, 2025 Editor invited by journal 01 Jul, 2025 Editor assigned by journal 28 May, 2025 Submission checks completed at journal 28 May, 2025 First submitted to journal 06 May, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6607233","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":453065747,"identity":"e7a1f99e-1157-41c6-8e8c-fd6da9d46d14","order_by":0,"name":"Bo Yang","email":"","orcid":"","institution":"The First Affiliated Hospital of Xi’an Jiaotong University","correspondingAuthor":false,"prefix":"","firstName":"Bo","middleName":"","lastName":"Yang","suffix":""},{"id":453065759,"identity":"3dd49933-ab5b-404f-9938-0f90e386047e","order_by":1,"name":"Mengmeng Teng","email":"","orcid":"","institution":"The First Affiliated Hospital of Xi’an Jiaotong University","correspondingAuthor":false,"prefix":"","firstName":"Mengmeng","middleName":"","lastName":"Teng","suffix":""},{"id":453065760,"identity":"acec484c-2815-4ed9-92de-93405e28d699","order_by":2,"name":"ying Chen","email":"","orcid":"","institution":"The First Affiliated Hospital of Xi’an Jiaotong University","correspondingAuthor":false,"prefix":"","firstName":"ying","middleName":"","lastName":"Chen","suffix":""},{"id":453065761,"identity":"8a6dcec7-10c9-40bb-bd57-9c64d43cfbbf","order_by":3,"name":"Tao Zhang","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA6klEQVRIiWNgGAWjYDACCSjNz8CQAKIZG4jTAlQs2cCQ2ECaFoMDENWEtcjPbn728OsPOznjGwnPH/Mw2MhuOMD87AE+LYxzjpkbyyQkG5udOZDYzMOQZrzhAJu5AT4tzBIJZtISCcyJ2443gLQcTtxwgIdNAp8WNon0b0At9YmbmxlAWv4T1sIjkWMm+SEBaDg72JYDhLVISOSUSTOkHTeWAPpl5hyDZOOZh9nM8GqRn5G+TfKHTbUc/4ychA9vKuxk+443P8OrBQSYeSBuTADGDohLSD0QMP4AU+wHiFA7CkbBKBgFIxEAANmFRwAP4ly7AAAAAElFTkSuQmCC","orcid":"","institution":"College of Stomatology, Xi’an Jiaotong University","correspondingAuthor":true,"prefix":"","firstName":"Tao","middleName":"","lastName":"Zhang","suffix":""}],"badges":[],"createdAt":"2025-05-07 02:23:24","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6607233/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6607233/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":82688838,"identity":"a5d53abe-af06-4624-af76-b1455678c4e2","added_by":"auto","created_at":"2025-05-14 07:24:15","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":107818,"visible":true,"origin":"","legend":"\u003cp\u003eFlowchart illustrating the systematic procedure for data analysis within the context of the study. ASIR: age-standardized incidence rate; ASMR: age-standardized mortality rate; AAPC: average annual percent change; WHO: world health organization; WB: world bank income; SDI: socio-demographic index; BAPC: Bayesian age–period–cohort\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-6607233/v1/3b7efb7ffeb41d59b22c95b2.png"},{"id":82688842,"identity":"eb990bbe-9654-4a96-905c-4418e5474202","added_by":"auto","created_at":"2025-05-14 07:24:15","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":154333,"visible":true,"origin":"","legend":"\u003cp\u003eGlobal TBL cancer burden. (A) Global age-standardized incidence rate and age-standardized mortality rate for genders. (B) Global age-standardized incidence rate and age-standardized mortality rate among pre-defined age groups. TBL: Tracheal, bronchus, and lung.\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-6607233/v1/26914f3894cda85101fa6811.png"},{"id":82688839,"identity":"f8508f55-e059-4386-ace1-35f2d0bb00a8","added_by":"auto","created_at":"2025-05-14 07:24:15","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":234892,"visible":true,"origin":"","legend":"\u003cp\u003eThe overall age-specific ASIR and ASMR trends of TBL cancer from 1990 to 2021. (A) AAPC for global young-set TBL cancer incidence rate. (B) AAPC of global young-set TBL cancer mortality rate. (C) AAPC for global middle-set TBL cancer incidence rate. (D) AAPC for global middle-set TBL cancer mortality rate. (E) AAPC for global old-set TBL cancer incidence rate. (F) AAPC for global old-set TBL cancer mortality rate. *: \u003cem\u003eP\u003c/em\u003e\u0026lt;0.05. TBL: Tracheal, bronchus, and lung.\u003c/p\u003e","description":"","filename":"floatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-6607233/v1/4fffde5c47130e865eff9556.png"},{"id":82688846,"identity":"fbd10872-d4f3-438e-ab03-35fc10138697","added_by":"auto","created_at":"2025-05-14 07:24:16","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":3813704,"visible":true,"origin":"","legend":"\u003cp\u003eWorld map for TBL cancer pattern in 2021 and TBL cancer burdens from 1990 to 2021 in pre-defined age groups. (A) ASIR for young-set TBL cancer. (B) ASIR for middle-set TBL cancer. (C) ASIR for old-set TBL cancer. (D) ASMR for young-set TBL cancer. (E) ASMR for middle-set TBL cancer. (F) ASMR for old-set TBL cancer. (G) ASIR trend for young-set TBL cancer. (H) ASIR trend for middle-set TBL cancer. (I) ASIR trend for old-set TBL cancer. (J) ASMR trend for young-set TBL cancer. (K) ASMR trend for middle-set TBL cancer. (L) ASMR trend for old-set TBL cancer. TBL: Tracheal, bronchus, and lung; ASIR: age-standardized incidence rate; ASMR: age-standardized mortality rate.\u003c/p\u003e","description":"","filename":"floatimage4.png","url":"https://assets-eu.researchsquare.com/files/rs-6607233/v1/573e65d72236bcc3b5598a5b.png"},{"id":82688845,"identity":"6160b4e9-6729-4c28-b913-6357da1066b3","added_by":"auto","created_at":"2025-05-14 07:24:15","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":1205472,"visible":true,"origin":"","legend":"\u003cp\u003eGender-age-specific ASIR and ASMR trends for TBL cancer in 21 regions stratified by socio-demographic index (SDI) from 1990 to 2021. (A) ASIR trend for young-set male TBL cancer. (B) ASIR trend for middle-set male TBL cancer. (C) ASIR trend for old-set male TBL cancer. (D) ASIR trend for young-set female TBL cancer. (E) ASIR trend for middle-set female TBL cancer. (F) ASIR trend for old-set female TBL cancer. (G) ASMR trend for young-set male TBL cancer. (H) ASMR trend for middle-set male TBL cancer. (I) ASMR trend for old-set male TBL cancer. (J) ASMR trend for young-set female TBL cancer. (K) ASMR trend for middle-set female TBL cancer. (L) ASMR trend for old-set female TBL cancer. TBL: Tracheal, bronchus, and lung; ASIR: age-standardized incidence rate; ASMR: age-standardized mortality rate.\u003c/p\u003e","description":"","filename":"floatimage5.png","url":"https://assets-eu.researchsquare.com/files/rs-6607233/v1/118af2a8d75c3581a1630295.png"},{"id":82690058,"identity":"a36c82cd-c4da-4098-a3cf-12e8bb73bcb7","added_by":"auto","created_at":"2025-05-14 07:40:16","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":3839232,"visible":true,"origin":"","legend":"\u003cp\u003eGender-age-specific ASIR and ASMR trends for TBL cancer in 204 countries or territories stratified by socio-demographic index (SDI) from 1990 to 2021. (A) ASIR trend for young-set male TBL cancer. (B) ASIR trend for middle-set male TBL cancer. (C) ASIR trend for old-set male TBL cancer. (D) ASIR trend for young-set female TBL cancer. (E) ASIR trend for middle-set female TBL cancer. (F) ASIR trend for old-set female TBL cancer. (G) ASMR trend for young-set male TBL cancer. (H) ASMR trend for middle-set male TBL cancer. (I) ASMR trend for old-set male TBL cancer. TBL: Tracheal, bronchus, and lung; ASIR: age-standardized incidence rate; ASMR: age-standardized mortality rate. (J) ASMR trend for young-set female TBL cancer. (K) ASMR trend for middle-set female TBL cancer. (L) ASMR trend for old-set female TBL cancer. TBL: Tracheal, bronchus, and lung; ASIR: age-standardized incidence rate; ASMR: age-standardized mortality rate.\u003c/p\u003e","description":"","filename":"floatimage6.png","url":"https://assets-eu.researchsquare.com/files/rs-6607233/v1/4e91d10234acc394a6ec41e2.png"},{"id":82690056,"identity":"e61bfd5d-af51-419e-b895-e535c58c085f","added_by":"auto","created_at":"2025-05-14 07:40:16","extension":"png","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":989126,"visible":true,"origin":"","legend":"\u003cp\u003eCause-specific ASMR of TBL cancer. (A) Level 1 cause-specific ASMR for young-set TBL cancer. (B) Level 1 cause-specific ASMR for middle-set TBL cancer. (C) Level 1 cause-specific ASMR for old-set TBL cancer. (D) Level 2 cause-specific ASMR for young-set TBL cancer. (E) Level 2 cause-specific ASMR for middle-set TBL cancer. (F) Level 2 cause-specific ASMR for old-set TBL cancer. TBL: Tracheal, bronchus, and lung; ASMR: age-standardized mortality rate.\u003c/p\u003e","description":"","filename":"floatimage7.png","url":"https://assets-eu.researchsquare.com/files/rs-6607233/v1/647266cb011f8be68439090a.png"},{"id":82688852,"identity":"7134b08b-5df7-4f68-a671-1b9d07a24995","added_by":"auto","created_at":"2025-05-14 07:24:16","extension":"png","order_by":8,"title":"Figure 8","display":"","copyAsset":false,"role":"figure","size":280734,"visible":true,"origin":"","legend":"\u003cp\u003eProjections of TBL cancer burden from 2022 to 2040. (A) Age-standardized incidence rate. (B) Age-standardized mortality rate. TBL: Tracheal, bronchus, and lung.\u003c/p\u003e","description":"","filename":"floatimage8.png","url":"https://assets-eu.researchsquare.com/files/rs-6607233/v1/c04c1d4c931a90e9b0063c80.png"},{"id":82691411,"identity":"aa27997f-4feb-4153-9fb4-94c8eb8b1564","added_by":"auto","created_at":"2025-05-14 07:56:27","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":9365762,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6607233/v1/23bd2ecb-63ba-4ba2-98f8-2542a83bc8fe.pdf"},{"id":82688844,"identity":"fd345384-e78f-4998-ad3c-39dd4f59922a","added_by":"auto","created_at":"2025-05-14 07:24:15","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":882909,"visible":true,"origin":"","legend":"","description":"","filename":"Supplementmaterial.docx","url":"https://assets-eu.researchsquare.com/files/rs-6607233/v1/2eecc785fd7344848f5d9733.docx"},{"id":82689298,"identity":"4439a8cb-b363-4020-90d5-85de8de14ea2","added_by":"auto","created_at":"2025-05-14 07:32:15","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":82210,"visible":true,"origin":"","legend":"","description":"","filename":"Tables.docx","url":"https://assets-eu.researchsquare.com/files/rs-6607233/v1/97a6265b6c53617fd9c1e20f.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Global burden of Tracheal, bronchus, and lung cancer based on age and sex: a systematic trend analysis of the global burden of disease study 2021","fulltext":[{"header":"1 Introduction","content":"\u003cp\u003eWith the change in the age structure of social population and the deterioration of environment, the incidence rates of chronic non-communicable diseases are rising dramatically[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Tracheal, bronchus, and lung (TBL) cancer is a kind of deadly respiratory disease, which was not only a serious public health problem but also the core of disease prevention policy making [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Among all kinds of TBL cancer, lung cancer is the most common cancer worldwide and the leading cause of cancer mortality[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. According to the latest global cancer research, there are approximately 2480301 new lung cancer patients and 1817172 patients died from lung cancer in 2022[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. It is widely believed that the application of early detection methods are beneficial to reduce lung cancer related mortality[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. However, lacking the awareness of regular physical examinations in patients and no obvious symptoms at the early stage of lung cancer contribute to the high mortality rate[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Although the global burden of lung cancer is heavy, lung cancer-related screening program has not been fully conducted in many countries. There are still many potential lung cancer patients at the early or advanced stage has not been diagnosed.\u003c/p\u003e \u003cp\u003eThere is a fact that men have higher probability of being diagnosed with cancers in their lifetime. And the higher probability can be well explained by greater exposure to carcinogenic environmental and lifestyle factors, such as smoking[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. The incidence rate and mortality rate has been decreasing for years due to decline smoking rate in man. However, the incidence rate of lung cancer among women has been increasing dramatically for smoking or environmental exposure in many countries, which forewarning of a relatively higher overall TBL cancer burden among women in future decades[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Despite these reports, there is still a lack of understanding about the sex differences in the prevalence and burden of TBL cancer by age, countries, and regions. A comprehensive comparison of the epidemiology and burden of TBL cancer and their trends in the past three decades between men and women at the global, regional and national level will provide valuable information for healthcare practice.\u003c/p\u003e \u003cp\u003eIn this study, data was extracted from the Global Burden of Disease (GBD) 2021 study to present global pattern of TBL cancer. Various subgroup analyses were conducted to show the temporal trends of TBL cancer incidence and mortality among population with different age and gender at nation and region level from 1990 to 2021. The pattern of TBL cancer from 2022 to 2040 was furtherly investigated to offer suggestions for future management.\u003c/p\u003e"},{"header":"2 Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2.1 Data source\u003c/h2\u003e \u003cp\u003eThis observational cross-sectional study was designed to analyze age/sex-stratified TBL cancer incidence and mortality at global, region and nation levels. All related cross-sectional data used in this study was extracted from the Global Health Data Exchange Online Query Tool (GHDx) (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://vizhub.healthdata.org/gbd-results/\u003c/span\u003e\u003cspan address=\"https://vizhub.healthdata.org/gbd-results/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e) of the GBD 2021 database. The GBD study evaluated approximately 370 diseases and injuries and 87 risk factors in 204 countries, 21 regions, and 7 super-regions, offering statistical data on epidemical index (e.g., incidence, mortality) to describe disease trends over years[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e].\u003c/p\u003e \u003cp\u003ePatients were furtherly stratified into three age groups similar to the previous published study[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Young-set was defined for TBL cancer patients aged at the range of 25\u0026ndash;49, middle-set and old-set for TBL cancer patients aged at the range of 50\u0026ndash;69 and over 70 years old, respectively. Age-specific TBL cancer burden was furtherly analyzed across genders among 21 GBD regions, 6 world health organization (WHO) regions, 4 world bank regions and 5 regions with different socio-demographic index levels. The socio-demographic index (SDI), ranging from 0 to 1, was calculated based on per capital income, average education levels and total fertility rates[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Therefore, the location-specific SDI is considered to be an indicator reflecting the development level of the location and may impact human health outcome. Locations were furtherly divided into low SDI (0.00\u0026thinsp;~\u0026thinsp;0.466), low-middle SDI (0.466\u0026thinsp;~\u0026thinsp;0.619), middle (0.619\u0026thinsp;~\u0026thinsp;0.712), high-middle (0.712\u0026thinsp;~\u0026thinsp;0.810) and high (0.810\u0026thinsp;~\u0026thinsp;1.00) regions[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThere are 87 risk factors recorded and divided into four hierarchies in GBD 2021. Environmental/occupational factor, behavioral factor and metabolic factor were listed in level 1 risk factors. And 19 main risk factors were integrated into the level 2 risk factors, among which air pollution, other environmental risks, tobacco, high fasting plasma glucose, dietary risks, occupational risks were considered to be closely associated TBL cancer deaths. The trends of TBL cancer death caused by various risk factors were furtherly explored among subgroups in this study. The sample workflow of our study is presented in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e2.2 Statistical analysis\u003c/h2\u003e \u003cp\u003eExtensive analyses have been performed to evaluate the national or regional burden of TBL cancer. Furthermore, the study compared the sex-specific trends of TBL cancer across different age cohorts. Age-standardized rate (ASR) and average annual percent change (AAPC) were used to quantify the temporal pattern of TBL cancer. The following formula was utilized to calculate the ASRs per 100,000 individuals to exhibit the TBL cancer burden in different age groups.\u003cdiv id=\"Equa\" class=\"Equation\"\u003e\u003cdiv format=\"TEX\" class=\"mathdisplay\" id=\"FileID_Equa\" name=\"EquationSource\"\u003e\n$$\\:\\varvec{A}\\varvec{S}\\varvec{R}=\\frac{{\\sum\\:}_{\\varvec{i}=1}^{\\varvec{A}}{{\\varvec{a}}_{\\varvec{i}}\\varvec{W}}_{\\varvec{i}}}{\\sum\\:_{\\varvec{i}=1}^{\\varvec{A}}{\\varvec{W}}_{\\varvec{i}}}\\times\\:\\text{100,000}$$\u003c/div\u003e\u003c/div\u003e\u003c/p\u003e \u003cp\u003e(ASR: age-standardized rate; A: the number of age groups; a\u003csub\u003ei\u003c/sub\u003e: the crude rate in i\u003csup\u003eth\u003c/sup\u003e age group; W\u003csub\u003ei\u003c/sub\u003e: standard population composition ratio in i\u003csup\u003eth\u003c/sup\u003e age group)\u003c/p\u003e \u003cp\u003eJointpoint regression analysis was utilized to describe the TBL cancer trends over time. The core of Jointpoint regression is to cut the time period into different intervals through connect points and establish segmented regression according to the temporal characteristics on disease distribution, perform trend fitting and optimization for each interval, and so as to evaluate the disease change characteristics specific to different times intervals within the global time range[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Annual percent change (APC) describing disease trend in fixed time intervals and AAPC making it possible to use a single number to describe the average APCs over a period of multiple years are the main results of Jointpoint regression analysis. The AAPC is calculated using a weighted average of the slope coefficients of every segmented regression with the weights equal to the length of each segment over the interval according to the following formula:\u003cdiv id=\"Equb\" class=\"Equation\"\u003e\u003cdiv format=\"TEX\" class=\"mathdisplay\" id=\"FileID_Equb\" name=\"EquationSource\"\u003e\n$$\\:\\varvec{A}\\varvec{A}\\varvec{P}\\varvec{C}=\\left\\{\\mathbf{exp}\\left(\\frac{\\sum\\:_{\\varvec{i}=1}^{\\varvec{n}}{\\varvec{W}}_{\\varvec{i}}{\\varvec{b}}_{\\varvec{i}}}{\\sum\\:_{\\varvec{i}=1}^{\\varvec{n}}{\\varvec{W}}_{\\varvec{i}}}\\right)\\right\\}$$\u003c/div\u003e\u003c/div\u003e\u003c/p\u003e \u003cp\u003e(AAPC: average annual percent change; n: the number of segment intervals in the range of years; W\u003csub\u003ei\u003c/sub\u003e: the length of each segment in the range of years; b\u003csub\u003ei\u003c/sub\u003e: the slope coefficient for the i\u003csup\u003eth\u003c/sup\u003e segment).\u003c/p\u003e \u003cp\u003eThe relative risk or the odds ratio is usually used to assess the association between risk exposure and the occurrence of a particular outcome in epidemic research. However, the impact of the risk factor on the population level was not well described because of ignoring the prevalence of the risk factor. The population attributable fraction (PAF) is an index, taking into account not only the association between risk factors and outcome, but also prevalence of risk factors in the population[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. PAF was calculated as the following formula to assess the proportion of a specific outcome in a population that is attributable to exposure to risk factors.\u003cdiv id=\"Equc\" class=\"Equation\"\u003e\u003cdiv format=\"TEX\" class=\"mathdisplay\" id=\"FileID_Equc\" name=\"EquationSource\"\u003e\n$$\\:\\varvec{P}\\varvec{A}\\varvec{F}=\\frac{\\sum\\:_{\\varvec{i}=1}^{\\varvec{n}}{\\varvec{R}\\varvec{R}}_{\\varvec{i}}{\\varvec{P}}_{\\varvec{i}}-1}{\\sum\\:_{\\varvec{i}=1}^{\\varvec{n}}{\\varvec{R}\\varvec{R}}_{\\varvec{i}}{\\varvec{P}}_{\\varvec{i}}}$$\u003c/div\u003e\u003c/div\u003e\u003c/p\u003e \u003cp\u003e(PAF: population attributable fraction; RR\u003csub\u003ei\u003c/sub\u003e: the relative risk corresponding to i\u003csup\u003eth\u003c/sup\u003e exposure; P\u003csub\u003ei\u003c/sub\u003e: the proportion of persons at i\u003csup\u003eth\u003c/sup\u003e exposure in the relevant population)\u003c/p\u003e \u003cp\u003eThe future TBL cancer burden from 2022 to 2040 was also projected with statistical model. Age\u0026ndash;period\u0026ndash;cohort model was generally accepted to project based on the age groups of the individual, the date of the event that is considered (period) and the birth cohort of the individual. The wrong conclusion also generated in process of projection due to the impossibility to identify the full set of age, period, and cohort effects in the analysis of mortality or other vital rates[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Bayesian age\u0026ndash;period\u0026ndash;cohort (BAPC) models is a better method to achieved higher performance in prediction due to no parametric assumptions involved. However, BAPC models have been criticized for producing too wide credible bands and complex convergence concerns introduced by Markov chain Monte Carlo (MCMC) in process of BAPC fitting[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. The two main defects limited the BAPC using in routine practice of epidemiologists. BAPC model incorporating integrated nested Laplace approximations was proposed to address the problems mentioned before[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. It was utilized to predict future TBL cancer trend from 2022 to 2040. Statistics of all data in this study were performed using R software (version 4.3.2) and \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered statistically significant.\u003c/p\u003e \u003c/div\u003e"},{"header":"3 Result","content":"\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e\n \u003ch2\u003e3.1 Global trends of TBL cancer\u003c/h2\u003e\n \u003cp\u003eAs the global age-standardized incidence rate (ASIR) and age-standardized mortality rate (ASMR) presented from 1990 to 2021, the global TBL cancer burden has decreased lightly (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003eA). The global ASIR and ASMR of TBL cancer per 100,000 population declined from 28.54 and 27.58 in 1990 to 26.43 and 23.50 in 2021, respectively. As oppose to continuous downward TBL cancer burden in male, upward trend in female ASIR and ASMR slowed down the global decline in TBL cancer burden. Besides, the gender composition of TBL cancer was furtherly investigated based on age groups (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003eB). The male/female ratios presented downward trend over past three decades, no matter which measure (incidence or mortality) was used to discuss TBL cancer trends. Especially, the steepest decrease of male/female ratio could be observed in middle-set. These results mean that the patterns of TBL cancer burden differ among different age and sex groups.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e\n \u003ch2\u003e3.2 Age- and gender-specific global TBL cancer trend\u003c/h2\u003e\n \u003cp\u003eThe ASIR and ASMR of TBL cancer in different age and sex groups were furtherly analyzed to uncover their contributions to decreasing global TBL burden. Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e presented the global TBL cancer burden based on age and sex in detail. In young-set population, the overall ASIR of TBL cancer per 100,000 population decreased from 6.67 in 1990 to 4.33 in 2021, with AAPC of -1.38 [95%confidence interval (CI): -1.54~-1.22, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05]. Significant decreasing was observed in male ASIR from 9.29 to 5.41 (AAPC: -1.79 [95%CI: -2.01~-1.57, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05]), while smaller decreasing in female from 3.95 to 3.24 (AAPC: -0.63[95%CI: -0.73~-0.54, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05]). The overall global ASMR per 100,000 population decreased from 5.78 in 1990 to 3.46 in 2021 (AAPC: -1.62 [95%CI: -1.76~-1.49, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05]). Male ASMR per 100,000 population declined from 8.13 to 4.47 with AAPC of -1.95 [95%CI: -2.11~ -1.78, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05], female ASMR declined from 3.34 to 2.45 with AAPC of -1.00 [95%CI: -1.09~ -0.92, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05].\u003c/p\u003e\n \u003cdiv\u003eFor middle-set population, the overall global ASIR per 100,000 decreased from 92.79 to 72.41 with AAPC of -0.82 [95%CI: -0.90 ~ -0.73, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05] over the past 30 years. However, ASIRs showed inconsistent patterns across genders, which may explain the steepest decrease in middle-set male/female ratio (Fig. \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003eB). While the male ASIR declined from 146.10 to 101.37 (AAPC: -1.19 [95%CI: -1.37~-1.07, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05]), female ASIR increased from 42.40 to 45.08 (AAPC:0.18 [95%CI: 0.13\u0026thinsp;~\u0026thinsp;0.22, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05]). The decrease in female ASMR and male ASMR resulted in significant decline in overall ASMR from 85.00 to 59.83 (AAPC: -1.14 [95%CI: -1.23~-1.06, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05]).\u003c/div\u003e\n \u003cp\u003eFor the old-set population, the ASIR trends of TBL cancer shared the same pattern regardless of gender. Totally, overall ASIR increased form195.08 to 227.84 with AAPC of 0.47 [95%CI: 0.41\u0026thinsp;~\u0026thinsp;0.53, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05]. Male ASIR increased negligibly from 335.05 to 337.25 (AAPC: 0.01[95%CI: -0.07\u0026thinsp;~\u0026thinsp;0.09, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.87]), while female ASIR increased significantly from 100.96 to 144.60 (AAPC: 1.16[95%CI: 1.07\u0026thinsp;~\u0026thinsp;1.24, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05]). ASMRs showed opposite pattern across gender and female ASMR finally determined overall ASMR trend. Female ASMR increased from 104.65 to 135.93(AAPC: 0.84[95%CI: 0.73\u0026thinsp;~\u0026thinsp;0.95, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05]), with overall ASMR increasing from 204.87 to 217.16 (AAPC: 0.16 [95%CI: 0.02\u0026thinsp;~\u0026thinsp;0.30, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05]). In contrast, the male ASMR reduced from 356.01 to 325.56 (AAPC: -0.32 [95%CI: -0.45~-0.19, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05]). All in all, the global ASIR and ASMR of TBL cancer declined, the TBL cancer burden in old-set population remains high and continues to increase.\u003c/p\u003e\n \u003cp\u003eThe Joinpoint regression analysis was furtherly used to identify the years when notable changes happened to the TBL cancer trend. Although a negligible increase with APC in ASIR of young-set TBL cancer was observed from 1990 to 1996 (APC\u0026thinsp;=\u0026thinsp;0.06, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026gt;\u0026thinsp;0.05), the young-set ASIR kept decreasing since 1996 (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003eA). And ASMR also continued to decrease after keeping at a relative stable level for 5 years since 1990 (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003eD). Significant decreasing could be observed in ASIR and ASMR in middle-set TBL cancer over the past 30 years (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003eB, \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003eE). Different from the patterns in other two groups, long-term significant increasing trend could be observed in old-set TBL cancer burden. A rapid increase in old-set ASIR can be observed until 2010, when a slow decline occurred (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003eC). As for the old-set ASMR, it had increased for 14 years and declined for 3 years with similar pace since 1990. There was a slight rebound until 2010 when it began to decline (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003eF). Besides, according to age-sex-specific ASIR and ASMR trends presented in supplementary Fig.\u0026nbsp;1, old-det female population would face heavier TBL cancer burden in the future.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\n \u003ch2\u003e3.3 Regional and national trend\u003c/h2\u003e\n \u003cp\u003eThe global pattern of TBL cancer burden from 1990 to 2021 are shown in Fig. \u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e. Male and female trends of TBL cancer burden are also presented in supplementary Fig. 2 and supplementary Fig. 3, respectively. The TBL cancer burden was furtherly analyzed in different regions. Based on the WHO region classification, the distribution pattern of TBL cancer has changed a lot over the past 30 years. The highest ASIR and ASMR, as well as continuous upward trends observed in Western Pacific region in most age groups indicated the highest TBL cancer burden in this region in 2021(Table \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e and Table \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e). The region of Americas, the only region with decreasing ASIR in old-set population, depicts the steepest decrease of ASIR (young-set AAPC: -3.01 [95%CI: -3.24\u0026thinsp;~\u0026thinsp;2.79, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05]; Middle-set AAPC: -2.21 [95%CI:-2.36~-2.06, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05]; old-set AAPC: -0.76 [95%CI: -0.87~-0.64, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05]) and ASMR(young-set AAPC: -3.11 [-3.32~-2.91, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05]; Middle-set AAPC: -2.40 [95%CI: -2.60~-2.21, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05]; old-set AAPC: -0.93 [95%CI: -1.04~-0.82, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05]; Table \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e and Table \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e\n \u003cdiv\u003eThe TBL cancer burden was also analyzed base on levels of health system and world bank income. Unexpectedly, people living in regions with higher levels of health system and world bank income faced heavier TBL cancer burden. But in regions with high level of world bank income, TBL cancer ASIR (young-set AAPC: -2.53 [95%CI: -2.63~-2.43, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05]; middle-set AAPC: -1.35 [95%CI: -1.45~-1.25, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05]; old-set AAPC: -0.01 [95%CI: -0.11\u0026thinsp;~\u0026thinsp;0.10, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.93]; Table \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e) and ASMR (young-set AAPC: -3.12 [95%CI: -3.25~-2.98, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05]; middle-set AAPC: -1.81 [95%CI: -1.91~-1.71, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05]; old-set AAPC: -0.38 [95%CI: -0.46~-0.30, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.93]; Table \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e) exhibited the steepest decrease. Besides, regions with advanced health system presented decreasing TBL cancer ASMRs (young-set AAPC: -2.98[95%CI: -3.08~-2.88, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05]; middle-set AAPC: -1.75[95%CI: -1.86~-1.64, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05]; old-set AAPC: -0.32[95%CI: -0.40~-0.25, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05]; Table \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e). The TBL cancer incidence in the region with basic health system increased dramatically in population over 50, which may predict the highest TBL cancer burden in the future (middle-set AAPC: 0.11 [95%CI: -0.01\u0026thinsp;~\u0026thinsp;0.23, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05]; old-set AAPC: 1.49 [95%CI: 1.28\u0026thinsp;~\u0026thinsp;1.70, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05]; Table \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/div\u003e\n \u003cp\u003eTable \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e and Table \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e also presented TBL cancer burden in 21 GBD regions. Population living in Western Sub-Saharan Africa faced the lowest TBL cancer burden over the past 30 years. Central Europe and high-income North America exhibited the highest TBL cancer burden among population aging from 25 to 69 and over 70, respectively. The ASIR and ASMR among population aging from 25 to 69 showed a downward trend in most regions. Conversely, old-set female TBL cancer burden exhibited a upward trend in most regions, while old-set male downward trend observed in half of the regions according to sex-specific ASIRs and ASMRs presented in supplementary Table \u003cspan class=\"InternalRef\"\u003eS1\u003c/span\u003e-S4.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e\n \u003ch2\u003e3.4 Burden of TBL cancer based on SDI\u003c/h2\u003e\n \u003cp\u003eThe majority of incident cases and deaths were predominantly observed in regions with higher SDI levels (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e). The variation trends of ASIR and ASMR based on SDI in different regions and countries were furtherly investigated. The good news is that, as shown in Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e5\u003c/span\u003e, female old-set ASIR and ASMR were positively correlated with SDI regardless of SDI changes, while for other groups, a positive correlation with SDI was only observed when SDI was low. Besides, female TBL cancer burden based national level shared completely positive pattern in all age groups (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e6\u003c/span\u003eD-F, J-L). These results forewarning higher female TBL cancer burden in the future, especially in counties with high SDI level.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e\n \u003ch2\u003e3.5 Burden of TBL based on cause\u003c/h2\u003e\n \u003cp\u003eConsidering heavy TBL cancer burden worldwide, the cause-specific mortality rates were of paramount importance to be explored. As shown in Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e7\u003c/span\u003eA-C, behavioral risk is the main cause to TBL cancer deaths in most subgroups. Notably, environmental/occupational risk has been the most dangerous factor lead female TBL cancer deaths among young-set population since 2010 (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e7\u003c/span\u003eA). The trends of TBL cancer ASMRs caused by level 2 risk factors were furtherly investigated. Among six level 2 risks, the tobacco using was the leading cause of TBL cancer deaths (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e7\u003c/span\u003eD-F). Given the differences in the rates of decline, air pollution might be the most dangerous risk factor for female TBL cancer deaths in young-set (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e7\u003c/span\u003eD). Different from the patterns in other sex and age groups, the old-set male group had more TBL cancer deaths caused by occupational risks than by air pollution (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e7\u003c/span\u003eF).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\n \u003ch2\u003e3.6 Global disease burden prediction for TBL cancer to 2040\u003c/h2\u003e\n \u003cp\u003eThe BAPC model incorporating integrated nested Laplace approximations was employed to forecast the future TBL cancer burden from 2022 to 2040. Although downward trend of TBL cancer burden observed in men, the burden would still keep at a high level in men and population over 70 (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e8\u003c/span\u003e). In the next 20 years, as TBL cancer trends in men were relatively stable, women will play a major role in determining TBL cancer trends in the old-set (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e8\u003c/span\u003eA).\u003c/p\u003e\n\u003c/div\u003e"},{"header":"4 Discussion","content":"\u003cp\u003eBased on the GBD 2021 database, our study utilized descriptive statistical analysis to examine globally the temporal, spatial, and demographic distribution of TBL cancer from 1990 to 2021. Despite upward trend in the total number of incident cases and deaths over the past three decades, the overall ASIR and ASMR of TBL cancer exhibited continuous downward trend. Notably, the large decrease in ASIR and ASMR in men explained the observed overall decline, whereas the slight increase in ASIR and ASMR in women slower the rate of decline. As previous research described that advancing age is the most determinative risk factor for cancer overall and for many individual cancer types, the heaviest TBL cancer burden was found in population over 70 years old[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Age is not only a marker capturing the duration of exposures and the accumulation of cancer risks, but also senescence explained by telomere dysfunction and cell cycle arrest due to shortening of telomeres[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. The heaviest TBL cancer burden among elderly people largely attributes to long-term accumulation of carcinogenic exposures (e.g., smoking, air pollution) and somatic mutations, as well as changes happened to the immune system with aging[\u003cspan additionalcitationids=\"CR22 CR23\" citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. Surprisingly, oncogene-induced senescence and telomere-based crisis exert powerful anticancer effects[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Therefore, the manners of reducing accumulation of carcinogenic exposures are efficient to control TBL cancer burden.\u003c/p\u003e \u003cp\u003eAs to carcinogenic exposures, behavioral/occupational risk and environmental risk are main reasons to high TBL cancer death rate. More specifically, tobacco, air pollution as well as occupational risks are main causes associated with TBL cancer burden. The WHO Framework Convention on Tobacco Control (FCTC) was negotiated in 2003 and ratified in 2005 to implement effective tobacco control measures[\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. Especially, pictorial health warnings and tobacco advertisement, promotion, as well as sponsorship ban were most implemented among all smokeless tobacco policies worldwide[\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. Currently, this treaty has been admitted and signed by 183 countries. It is obtrusively that ASMR among old-set population showed a clear upward trend before the time point when FCTC was ratified. It is worth noting that air pollution-related ASMR has shown a slight increase in young-set women in recent years, which may make air pollution-related ASMR surpass tobacco-related ASMR. And air pollution has the second highest ASMR among all level 2 risk factors. Especially, indoor air pollution is considered to be a major risk factor for TBL cancer in never-smoking women living in several regions of Asia[\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. Promotion of growth of lung epithelial cells harbouring EGFR mutations might be related to air pollution, which explained the higher frequency of EGFR mutation observed in Asian lung cancer patients[\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. High ASMR caused by air pollution could be explained by the role of women aged 25 to 49 as mothers in their families. Women has higher possibility to expose to coal burning in poorly ventilated houses, burning of wood and other solid fuels, as well as fumes from high-temperature cooking using unrefined vegetable oils such as rapeseed oil[\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. Old-set men had the second highest ASMR related to occupational exposure, which can largely attribute exposure to carcinogens (e.g., metals and mixed occupation exposures, diesel exhaust, polycyclic aromatic hydrocarbons) during the process of industrialization and urbanization[\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. Therefore, continuous promotion of smoking cessation and improve air quality, as well as less exposure to occupational carcinogens still are effective ways to control TBL cancer burden.\u003c/p\u003e \u003cp\u003eHowever, ASIR and ASMR showed different pattern in old-set population. In regions with higher socioeconomic development or advanced heath system, old-set ASIR showed upward trend, while old-set ASMR showed downward trend. The observed disparities in TBL cancer incidence can be attributed to several factors. Tobacco was considered a symbol of higher social status in some high SDI regions[\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. Compared lower SDI regions, higher ASIR and upward trends are closely associated with long-term tobacco exposure in higher SDI regions. In addition, TBL cancer ASIR difference also can be explain by medical disparities. On the one hand, TBL cancer was more likely to be diagnosed due to the application of more advanced technologies and the gradual implementation of screening programs in higher SDI regions[\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. On the other hand, some areas with lower SDI lack a complete disease registration system, resulting in systematic underreporting. As for decreasing ASMR trend in high SDI region can be explained by following reasons. Early diagnosis and treatment assisted by low-dose computed tomography (LDCT) can effectively reduce TBL cancer mortality[\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. Besides, it can also attribute to the quality and availability of cancer treatment in each SDI regions. More effective and safer anti-cancer drugs (e.g., targeted therapy, immunotherapy, antibody-drug conjugates) are applied in clinical practice in higher SDI regions, while clinical drugs not only have limited efficacy but also result in huge economic burden to patients in regions with lower SDI[\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAll in all, although the global TBL cancer burden is experiencing decreasing, regional, sex-specific and age-specific disparities still persisted. Measures should be taken from the aspects of onset, diagnosis, treatment, and prognosis to reduce the TBL cancer burden. Corresponding education should be opened to citizens to deepen their recognition of TBL cancer. Policies should be formulated to reduce exposure to carcinogens, especially air pollution and tobacco. And large-scale screening programs and more advanced technology for diagnosis should be open to people worldwide. Last but not list, the quality and availability should be enhanced globally in cancer treatment to control the TBL cancer burden in lower SDI regions.\u003c/p\u003e"},{"header":"5 Conclusion","content":"\u003cp\u003eOverall, our study highlights the decreasing burden of TBL cancer and significant trends disparities between age and gender. Citizens over 70 years was identified as the main victim of TBL cancer, and female TBL cancer burden have shown a progressive increase over the past three decades. Besides, regional disparities were also observed in territories of different socio-economic development. Although higher SDI levels regions possessed heavier TBL cancer burden, these regions did better in the prevention and treatment of TBL cancer due to the local advanced medical systems. Excitingly, as FCTC is recognized worldwide, great progression in control of TBL cancer deaths caused by tobacco has been made worldwide as the result of series of effective tobacco control measures implemented in many countries. Last but not least, female TBL cancer burden, which may determine the global TBL cancer trend in the future, deserves more attention and more effective policies for prevention and treatment.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgment\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe are thankful for the contribution of the GBD2021 database supplying cancer research information.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBY: Writing \u0026ndash; original draft, Formal analysis, Data curation. MMT: Writing \u0026ndash; review \u0026amp; editing, Formal analysis, Data curation. SYC: Writing \u0026ndash; review \u0026amp; editing, Methodology, Data curation. TZ: Writing \u0026ndash; review \u0026amp; editing, Methodology, Formal analysis.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work is supported by the National Science Fund for Distinguished Young Scholars (82404762).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data presented in this study can be found in the GBD 2021 database (https://vizhub.healthdata.org/gbd-results/).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthical approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll data from the GBD2021 database was free, and this study was approved by the Institutional Research Committee of the College of Stomatology, Xi\u0026rsquo;an Jiaotong University.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eDeng Y, Peng L, Li N, Zhai Z, Xiang D, Ye X, et al. 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Global Burden of Disease Study 2021 (GBD 2021) Socio-Demographic Index (SDI) 1950\u0026ndash;2021 | GHDx. 2024. https://ghdx.healthdata.org/record/global-burden-disease-study-2021-gbd-2021-socio-demographic-index-sdi-1950%E2%80%932021. Accessed 8 Sep 2024.\u003c/li\u003e\n\u003cli\u003eKim HJ, Fay MP, Feuer EJ, Midthune DN. Permutation tests for joinpoint regression with applications to cancer rates. Stat Med. 2000;19:335\u0026ndash;51.\u003c/li\u003e\n\u003cli\u003eLaaksonen MA, Knekt P, H\u0026auml;rk\u0026auml;nen T, Virtala E, Oja H. Estimation of the Population Attributable Fraction for Mortality in a Cohort Study Using a Piecewise Constant Hazards Model. American Journal of Epidemiology. 2010;171:837\u0026ndash;47.\u003c/li\u003e\n\u003cli\u003eHeld L, Riebler A. 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Protocol: Global impact of tobacco control policies on smokeless tobacco use: a systematic review protocol. BMJ Open. 2020;10.\u003c/li\u003e\n\u003cli\u003eThe global impact of tobacco control policies on smokeless tobacco use: a systematic review. The Lancet Global Health. 2023;11:e953\u0026ndash;68.\u003c/li\u003e\n\u003cli\u003eMalhotra J, Malvezzi M, Negri E, Vecchia CL, Boffetta P. Risk factors for lung cancer worldwide. European Respiratory Journal. 2016;48:889\u0026ndash;902.\u003c/li\u003e\n\u003cli\u003eHendriks LEL, Remon J, Faivre-Finn C, Garassino MC, Heymach JV, Kerr KM, et al. Non-small-cell lung cancer. Nat Rev Dis Primers. 2024;10:1\u0026ndash;22.\u003c/li\u003e\n\u003cli\u003eMalhotra J, Malvezzi M, Negri E, Vecchia CL, Boffetta P. Risk factors for lung cancer worldwide. European Respiratory Journal. 2016;48:889\u0026ndash;902.\u003c/li\u003e\n\u003cli\u003eKuang Z, Wang J, Liu K, Wu J, Ge Y, Zhu G, et al. Global, regional, and national burden of tracheal, bronchus, and lung cancer and its risk factors from 1990 to 2021: findings from the global burden of disease study 2021. eClinicalMedicine. 2024;75:102804.\u003c/li\u003e\n\u003cli\u003eWong ML, Clarke CA, Yang J, Hwang J, Hiatt RA, Wang S. Incidence of Non\u0026ndash;Small-Cell Lung Cancer among California Hispanics According to Neighborhood Socioeconomic Status. Journal of Thoracic Oncology. 2013;8:287\u0026ndash;94.\u003c/li\u003e\n\u003cli\u003eSha R, Kong X, Li X, Wang Y. Global burden of breast cancer and attributable risk factors in 204 countries and territories, from 1990 to 2021: results from the Global Burden of Disease Study 2021. Biomark Res. 2024;12:87.\u003c/li\u003e\n\u003cli\u003eAberle DR, Black WC, Chiles C, Church TR, Gareen IF, Gierada DS, et al. Lung Cancer Incidence and Mortality with Extended Follow-up in the National Lung Screening Trial National Lung Screening Trial Writing Team. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer. 2019;14:1732.\u003c/li\u003e\n\u003cli\u003eA F, M S, D L, W H, M J, B G, et al. Access to cancer medicines deemed essential by oncologists in 82 countries: an international, cross-sectional survey. The Lancet Oncology. 2021;22.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables are available in the Supplementary Files section.\u003c/p\u003e\n"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-pulmonary-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"pulm","sideBox":"Learn more about [BMC Pulmonary Medicine](http://bmcpulmmed.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/pulm/default.aspx","title":"BMC Pulmonary Medicine","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"GBD 2021 database, age standardized rates, age-sex-specific rate, risk shifts","lastPublishedDoi":"10.21203/rs.3.rs-6607233/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6607233/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eTracheal, bronchus, and lung (TBL) cancer is a serious respiratory disease. Epidemiological patterns of TBL cancer across 204 countries and territories from 1990 to 2021 was analyzed in this study.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eData was extracted from the Global Burden of Disease (GBD) 2021 study. Population was divided into young-set (25\u0026thinsp;~\u0026thinsp;49), middle-set (50\u0026thinsp;~\u0026thinsp;69) and old-set (\u0026ge;\u0026thinsp;70) based on age. Age-stratified and sex-stratified TBL cancer patterns were analyzed at global, region and nation levels. Average annual percent change (AAPC) was calculated to exhibit the TBL cancer trend based on age standardized incidence rate (ASIR) and age standardized mortality rate (ASMR). ASMR trends caused by causes were also investigated to uncover the risk shifts of TBL cancer deaths. Besides, the Bayesian age-period-cohort model incorporating integrated nested Laplace approximations was applied to forecast future TBL cancer burden.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eGlobally, ASIR and ASMR per 100,000 population decreased from 28.54 and 27.58 in 1990 to 26.43 and 25.85 in 2021, respectively. However, female ASIR and ASMR are increasing lightly. The ASIR and ASMR of young-set TBL cancer decreased significantly with AAPC of -1.38[95% confidence interval (CI): -1.54~-1.22; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05] and \u0026minus;\u0026thinsp;1.62[95%CI: -1.76 ~ -1.49; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05]. The ASIR and ASMR also decreased with AAPC of -0.82 [95%CI: -0.90 ~ -0.73; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05] and \u0026minus;\u0026thinsp;1.14[95%CI: -1.23~-1.06; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05] among middle-set. Conversely, the old-set ASIR and ASMR increased with AAPC of 0.47 [95%CI: 0.41\u0026thinsp;~\u0026thinsp;0.53; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05] and 0.16 [95%CI: 0.02\u0026thinsp;~\u0026thinsp;0.30; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05]. Behavioral/occupational risks were the main reasons for TBL cancer deaths. In the future, old-set population would still possess the highest TBL cancer burden, and female burden would furtherly increase.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eAlthough the global TBL cancer burden is experiencing decreasing, sex-specific and age-specific disparities still persisted. Tobacco is still main reason for TBL cancer deaths. Female deserves more attention due to predicted heavy female TBL cancer trend.\u003c/p\u003e","manuscriptTitle":"Global burden of Tracheal, bronchus, and lung cancer based on age and sex: a systematic trend analysis of the global burden of disease study 2021","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-05-14 07:24:11","doi":"10.21203/rs.3.rs-6607233/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"editorInvitedReview","content":"","date":"2026-05-15T18:55:18+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-02-09T10:24:06+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"291682641096611978887338148770209533274","date":"2026-01-20T09:33:18+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"334386118142961116352281281029194566476","date":"2025-11-03T16:43:51+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"185222676777828869769615938596257494853","date":"2025-07-31T16:27:53+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-07-26T05:06:30+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"101244632154676472120037844194140344029","date":"2025-07-26T04:02:43+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"142898462950712731982045181661355930882","date":"2025-07-14T06:51:04+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-07-02T19:37:13+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-07-01T09:02:05+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-05-28T10:59:51+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-05-28T10:54:53+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Pulmonary Medicine","date":"2025-05-07T02:21:14+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-pulmonary-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"pulm","sideBox":"Learn more about [BMC Pulmonary Medicine](http://bmcpulmmed.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/pulm/default.aspx","title":"BMC Pulmonary Medicine","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"3e328791-4255-4e42-977e-b55299af61cc","owner":[],"postedDate":"May 14th, 2025","published":true,"recentEditorialEvents":[{"type":"editorInvitedReview","content":"","date":"2026-05-15T18:55:18+00:00","index":172,"fulltext":""}],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2025-07-02T19:53:08+00:00","versionOfRecord":[],"versionCreatedAt":"2025-05-14 07:24:11","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6607233","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6607233","identity":"rs-6607233","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}