Global Epidemiology of Early‐Onset Digestive System Malignancy: A Systematic Analysis for the Global Burden of Disease Study 2021

Jiayi Wang; Deming Li; Fangzhou Ye; Jian Li; Zhe Qing; Xiaohong Zhang; Huanqing Li; Li Feng

doi:10.1111/jgh.17012

. 2025 May 22;40(6):1525–1535. doi: 10.1111/jgh.17012

Global Epidemiology of Early‐Onset Digestive System Malignancy: A Systematic Analysis for the Global Burden of Disease Study 2021

Jiayi Wang ¹, Deming Li ¹, Fangzhou Ye ¹, Jian Li ¹, Zhe Qing ¹, Xiaohong Zhang ^1,^✉, Huanqing Li ^1,^✉, Li Feng ^1,^✉

PMCID: PMC12136802 PMID: 40401498

ABSTRACT

Background and Aim

The researches on the global burden of digestive system malignancy in young populations were limited. This study aimed to comprehensively investigate the burden of early‐onset digestive system malignancy (often defined as cancers diagnosed below the age of 50) based on the Global Burden of Disease 2021.

Methods

Data of incidence, prevalence, deaths, disability‐adjusted life years (DALYs), and risk factors for the five major early‐onset digestive system malignancies, including early‐onset esophageal cancer (EOEC), early‐onset gastric cancer (EOGC), early‐onset liver cancer (EOLC), early‐onset pancreatic cancer (EOPC), and early‐onset colorectal cancer (EOCRC), were extracted from GBD 2021. The average annual percent change (AAPC) was calculated using joinpoint regression analysis. The Bayesian age–period–cohort (BAPC) model was utilized to predict the burden up to 2030.

Results

From 1990 to 2021, the age‐standardized incidence rate (ASIR) of early‐onset digestive system malignancies, except for EOCRC (AAPC, 0.37), showed a decreasing pattern. Meanwhile, the age‐standardized mortality rate (ASMR) and age‐standardized DALYs rate (ASDR) of early‐onset digestive system malignancy presented a downward trend. Notably, high‐middle sociodemographic index (SDI) countries experienced higher disease burdens. Dietary risk factors, tobacco, alcohol consumption, and metabolic factors were the main risk factors. The ASIR of EOEC and EOCRC was projected to increase in 2030, whereas the trend for EOGC, EOLC, and EOPC was projected to decrease.

Conclusions

Early‐onset digestive system malignancy presented notable heterogeneity across gender, geography, and cancer types. This emphasizes the urgency of addressing the public health challenge of early‐onset digestive system malignancy.

Keywords: early‐onset digestive system malignancy, epidemiology, risk factor, trend in global burden

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1. Introduction

The principal malignant cancers of digestive system include esophageal cancer (EC), gastric cancer (GC), liver cancer (LC), pancreatic cancer (PC), and colorectal cancer (CRC) [1]. The digestive system malignancies in 2018 made up more than 26% of all cancer incidence and accounted for more than 35% of cancer‐related mortality worldwide [1]. The most common digestive system malignancy is CRC, with 38.8% of digestive system malignancies incidence and 26.0% of digestive system malignancies related mortality, followed by GC (21.7% / 23.2%), LC (17.9% / 23.2%), EC (12.2% / 15.0%), and PC (12.2% / 15.0%) [1]. The incidence and mortality rates for digestive system malignancies are still increasing and are predicted to increase by 58% and 73% by 2040, respectively [2].

Although most cancers predominantly occur in individuals over 50 years, there is an increasing trend in early‐onset cancers (< 50 years), which was also termed the “early‐onset cancer epidemic” [3]. The early‐onset cancer epidemic is likely attributable to changes in diet, lifestyle, and environmental factors in early life, such as Westernized diets, smoking, physical activity, obesity, microbiota, and environmental pollution [3, 4, 5, 6, 7, 8, 9]. Due to early‐onset cancers' aggressive biology, advanced stage, and a range of sequelae of survivors, which could considerably increase the disease burden [3, 10]. In the United States, digestive system malignancies had the highest fastest‐growing incidence rates among all early‐onset cancers from 2010 to 2019 [4]. Meanwhile, different types of early‐onset digestive system malignancies displayed various incidence rates and patterns [4]. Therefore, a comprehensive assessment of the global burden and epidemiologic trends of early‐onset digestive system malignancies is crucial.

The majority of previous studies focused on a single digestive system malignancy or a single area in the incidence and death of all‐age digestive system malignancies, and only a small number of researches investigated the disease burden of early‐onset digestive system malignancies and worldwide epidemiology [11]. A comprehensive and systematic assessment of the global burden and epidemiologic trends of early‐onset digestive system malignancies is crucial, which can assist in disease prevention, early detection, diagnosis, and treatment. Hence, we conducted this study to describe the global burden of five major early‐onset digestive system malignancies based on the Global Burden of Disease (GBD) 2021 study, which included early‐onset esophageal cancer (EOEC), early‐onset gastric cancer (EOGC), early‐onset liver cancer (EOLC), early‐onset pancreatic cancer (EOPC), and early‐onset colorectal cancer (EOCRC), aims to provide insight into the prevention and control of early‐onset digestive system malignancies.

2. Material and Methods

2.1. Study Population and Data Source

Data for this study is sourced from the GBD 2021 database (https://ghdx.healthdata.org/gbd‐2021). Five major digestive system malignancies were obtained based on administrative data according to the International Classification of Disease 10th revision (ICD‐10) codes. The ICD codes of the five major digestive system malignancy are shown in Table S1. Early‐onset digestive system malignancies were defined as the occurrence of digestive system malignancies in individuals younger than 50 years [3]. In total, we extracted the incidence, prevalence, deaths, disability‐adjusted life years (DALYs), and risk factor proportion along with their 95% uncertainty intervals (UI) for five major early‐onset digestive system malignancies from 1990 to 2021 based on GBD 2021. In addition, 204 countries were divided into five categories according to the sociodemographic Index (SDI), to further investigate the association between the early‐onset digestive system malignancies trends and the level of development.

2.2. Statistical Analysis

To ensure comparability across different populations worldwide, the age‐standardized rates (ASRs) were calculated by applying the direct standardization method using the same standard population in the GBD study [12, 13]. All ASRs were reported per 100 000 population. To evaluate the trends in age‐standardized incidence rate (ASIR), age‐standardized prevalence rate (ASPR), age‐standardized mortality rate (ASMR), and age‐standardized DALYs rate (ASDR), we used the joinpoint regression model to estimate the average annual percent change (AAPC), annual percentage change (APC), and their respective 95% confidence interval (CI). Frontier analysis was applied to evaluate the relationship between the burden of early‐onset digestive system malignancies and sociodemographic development, which can identify the potential areas of improvement and gap between countries [14]. Absolute and relative gradient inequality were measured using the slope index and concentration index, which can be used for quantifying the distributive inequality of the burden of early‐onset digestive system malignancies across countries [15]. Specific methods of calculating the two indices can be found in previous study [16]. Additionally, to better provide evidence for public health policy establishment and allocate healthcare resources, the Bayesian age–period–cohort (BAPC) model integrating nested Laplace approximation was utilized to predict the early‐onset digestive system malignancies burden in the next decades [17, 18]. All analyses were performed using R (Version 4.3.3), and a two‐tailed p < 0.05 was considered statistically significant.

3. Results

3.1. Global Trends of Early‐Onset Digestive System Malignancies From 1990 to 2021

In 2021, the incidence number of early‐onset digestive system malignancies was 490 558 (31.20% increase since 1990). Among them, the EOCRC had the highest incidence, prevalence, deaths, and DALYs (Table 1). The incidence of EOCRC showed the fastest increasing trend (AAPC, 0.37), whereas the other early‐onset cancers showed a declining trend (Figure 1A). Globally, the number of early‐onset digestive system malignancies deaths in 2021 was 279 906, but in 1990 was 273 434. The deaths and DALYs rates of five early‐onset digestive malignancies decreased from 1990 to 2021, and the EOGC had the fastest decreasing trends (Figure 1C,D).

TABLE 1.

Global numbers and ASRs per 100 000 cases of incidence, prevalence, deaths, and DALYs of early‐onset digestive system malignancy in 1990 and 2021 for both sexes, with AAPC in ASRs per 100 000 cases from 1990 to 2021.

Type	Number in 1990 (95% UI)	Age‐standardized rate in 1990 (95% UI)	Number in 2021 (95% UI)	Age‐standardized rate in 2021 (95% UI)	AAPC (age‐standardized rate, 95% CI)	p
Incidence
EOEC	41 836 (47 066–37 074)	1.18 (1.32–1.04)	42 698 (48 266–37 737)	0.65 (0.74–0.58)	−1.9 (−2.07 to −1.73)	< 0.001
EOGC	146 368 (160 638–126 373)	3.98 (4.37–3.43)	125 121 (144 715–107 269)	1.93 (2.23–1.65)	−2.34 (−2.49 to −2.18)	< 0.001
EOLC	59 029 (68 078–51 011)	1.55 (1.78–1.34)	79 318 (94 130–67 886)	1.24 (1.47–1.06)	−0.71 (−0.79 to −0.63)	< 0.001
EOPC	19 366 (20 734–18 093)	0.54 (0.57–0.5)	31 531 (34 624–28 678)	0.48 (0.53–0.44)	−0.34 (−0.45 to −0.23)	< 0.001
EOCRC	107 310 (114 716–99 381)	2.9 (3.1–2.69)	211 890 (233 097–192 406)	3.26 (3.59–2.96)	0.37 (0.27–0.47)	< 0.001
Prevalence
EOEC	92 118 (103 017–81 443)	2.56 (2.86–2.26)	109 329 (123 231–96 733)	1.67 (1.88–1.48)	−1.36 (−1.61 to −1.12)	< 0.001
EOGC	335 662 (366 087–293 661)	9.01 (9.83–7.89)	336 311 (390 682–285 667)	5.19 (6.02–4.41)	−1.76 (−1.92 to −1.61)	< 0.001
EOLC	136 883 (168 395–90 991)	3.3 (4.02–2.29)	161 178 (195 011–127 708)	2.62 (3.18–2.04)	−0.74 (−0.82 to −0.66)	< 0.001
EOPC	24 480 (26 100–22 957)	0.66 (0.7–0.62)	42 254 (45 940–38 708)	0.65 (0.71–0.6)	−0.06 (−0.27–0.14)	0.538
EOCRC	585 832 (621 698–547 028)	15.83 (16.77–14.81)	1 342 468 (1 480 974–1 220 443)	20.66 (22.79–18.78)	0.85 (0.71–1)	< 0.001
Deaths
EOEC	36 654 (41 302–32 498)	1.03 (1.16–0.91)	32 922 (37 215–29 239)	0.5 (0.57–0.45)	−2.32 (−2.53 to −2.12)	< 0.001
EOGC	108 838 (120 127–93 404)	2.97 (3.28–2.55)	78 871 (90 532–68 334)	1.21 (1.39–1.05)	−2.87 (−3.03 to −2.71)	< 0.001
EOLC	51 517 (59 425–44 496)	1.36 (1.56–1.18)	61 613 (72 811–52 893)	0.96 (1.13–0.82)	−1.12 (−1.29 to −0.95)	< 0.001
EOPC	17 193 (18 465–16 038)	0.48 (0.51–0.45)	26 996 (29 699–24 481)	0.41 (0.45–0.37)	−0.47 (−0.58 to −0.36)	< 0.001
EOCRC	59 232 (64 263–53 962)	1.6 (1.73–1.46)	79 504 (86 916–72 382)	1.22 (1.34–1.11)	−0.86 (−1 to −0.72)	< 0.001
DALYs
EOEC	1 745 986 (1 966 110–1 546 641)	48.56 (54.68–43.06)	1 551 915 (1 752 980–1 378 422)	23.75 (26.82–21.1)	−2.31 (−2.51 to −2.11)	< 0.001
EOGC	5 396 666 (5 950 432–4 631 978)	145.12 (160.13–124.52)	3 859 036 (4 415 836–3 341 401)	59.52 (68.06–51.54)	−2.8 (−3.06 to −2.69)	< 0.001
EOLC	2 783 973 (3 219 406–2 394 131)	71.31 (82.31–61.46)	3 131 849 (3 707 282–2 686 150)	49.26 (58.36–42.2)	−1.17 (−1.45 to −0.88)	< 0.001
EOPC	832 544 (894 826–775 301)	22.79 (24.48–21.25)	1 285 174 (1 414 369–1 164 789)	19.72 (21.7–17.87)	−0.47 (−0.58 to −0.37)	< 0.001
EOCRC	3 026 077 (3 287 109–2 746 951)	80.17 (86.96–72.98)	4 002 756 (4 378 198–3 638 488)	61.83 (67.63–56.2)	−0.84 (−1 to −0.69)	< 0.001

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Abbreviations: AAPC, average annual percentage change; ASR, age‐standardized rate; CI, confidence interval; DALYs, disability‐adjusted life years; EOCRC, early‐onset colorectal cancer; EOEC, early‐onset esophagus cancer; EOGC, early‐onset gastric cancer; EOLC, early‐onset liver cancer; EOPC, early‐onset pancreatic cancer; UI, uncertain intervals.

The APC and AAPC of ASR for incidence (A), prevalence (B), deaths (C), and DALYs (D) in early‐onset digestive system malignancy at the global level based on the joinpoint regression analysis model.

Over the past 30 years, the new cases of early‐onset digestive system malignancies increased by 25.08% in females and 34.59% in males. In 2021, among females, the highest ASIR, ASPR, ASMR, and ASDR were found in EOCRC (Table S2). However, among males, EOGC had the highest ASMR and ASDR, and the highest ASIR and ASPR were found in EOCRC (Table S3). Between 1990 and 2021, ASIR, ASMR, and ASDR decreased in early‐onset digestive system malignancies in both females and males, except for EOCRC in males with an increase in ASIR. In particular, EOGC displayed the largest decrease of ASIR, ASMR, and ASDR in both male and females (Figure S1 and Figure S2).

3.2. Early‐Onset Cancer Burden in Different World Regions

In 2021, the highest ASIR of EOEC, EOGC, EOLC, EOPC, and EOCRC were in Southern Sub‐Saharan Africa (1.44 per 100 000), East Asia (4.42 per 100 000), East Asia (3.00 per 100 000), Eastern Europe (1.02 per 100 000), and high‐income North America (6.53 per 100 000), respectively. The regions with the highest ASDR were Southern Sub‐Saharan Africa (60.85 per 100 000), Oceania (119.10 per 100 000), Western Sub‐Saharan Africa (87.15 per 100 000), Eastern Europe (42.91 per 100 000), and East Asia (98.93 per 100 000) for EOEC, EOGC, EOLC, EOPC, and EOCRC, respectively (Tables S3–S8). Notably, high‐middle SDI countries experienced higher disease burdens (Tables S3–S8). In addition, the global maps of countries with ASIR, ASPR, ASMR, and ASDR of early‐onset digestive system malignancies are presented in Figures S3–S6.

3.3. Correlations of ASR With SDI

In the analysis between SDI and ASR, we compared the ASRs of early‐onset digestive system malignancies in 21 territories and 204 countries with different SDIs. The actual regional and national ASR in terms of SDI and the expected level are shown in Figure S7 (ASIR) and Figure S8 (ASDR). In 2021, nations with higher SDI seemed to have higher rates of EOCRC incidence (Figure S7J). For EOEC and EOLC, there was a negative correlation between SDI and ASIR, as well as ASDR (Figures S7B,F and S8B,F). Interestingly, it was demonstrated that the ASDR of EOGC, EOPC, and EOCRC initially increased with rising SDI, reaching the highest point, and then the rates tend to decrease with a further increase of SDI (Figure S8D,H,J). With the improvement of the economy, the overall disease burden is on the down (Figure S8).

3.4. Frontier Analysis of ASDR

Frontier analyses assessed the potential for reducing early‐onset digestive system malignancies burdens relative to national development levels (Figure 2). The solid black line represented the frontier line, which delineated the countries and territories with optimal performers of DALYs given their SDI. The gap between this frontier line and actual DALYs, termed the effective difference, showed the disparity between observed and achievable DALYs. For EOEC, EOGC, and EOLC, this gap decreased with higher SDI (Figure 2A,C,E), whereas EOPC and EOCRC presented the opposite trend (Figure 2G,I). The top 15 countries with the largest gaps were highlighted in black. Examples of frontier countries with low effective difference and low SDI (< 0.5) were labeled in blue, and high effective difference and high SDI (> 0.85) were labeled in red. Blue dots indicated a decrease in ASDR, and red dots demonstrated an increase from 1990 to 2021 (Figure 2B,D,F,H,J).

Frontier analysis based on the age‐standardized rates of DALYs for early‐onset esophagus cancer (A,B), early‐onset gastric cancer (C,D), early‐onset liver cancer (E,F), pancreatic cancer (G,H), and early‐onset colon and rectum cancer (I,J) and SDI over the decades (1990–2021) and specifically in 2021.

3.5. Cross‐Country Inequality of Early‐OnsetDigestive System Malignancies

The absolute and relative inequalities in early‐onset digestive system malignancies burden associated with SDI were revealed through cross‐country inequality analysis. For EOLC, EOPC, and EOCRC, the inequality slope index presented a narrowing in the ASDR disparity between the highest and lowest SDI countries, whereas the opposite changes were seen in EOEC and EOGC from 1990 to 2021 (Figure S9A,C,I,E,G). The concentration index shifted slightly: EOEC (0 in 1990 vs. −0.05 in 2021), EOGC (0.08 in 1990 vs. 0.06 in 2021), EOLC (−0.02 in 1990 vs. 0.01 in 2021), EOPC (0.28 in 1990 vs. 0.28 in 2021), and EOCRC (0.14 in 1990 vs. 0.16 in 2021) (Figure S9B,D,F,H,J).

3.6. Risk Factors for Early‐Onset Digestive System Malignancies

We investigated the metabolic and behavioral risk factors for DALYs and deaths of early‐onset digestive system malignancies in 2021 (Figure 3). Globally, tobacco was the top risk factor for EOEC DALYs, followed by alcohol use (27.8%) and dietary risks (20.6%) (Figure 3A). For EOGC DALYs, dietary risks (11.6%) and tobacco (10.7%) were leading factors (Figure 3B). EOLC risk factors included alcohol use (17.4%), tobacco (15.2%), high body mass index (BMI) (12.2%), and high fasting plasma glucose (1.2%) (Figure 3C). For EOPC DALYs, tobacco (25.4%), high fasting plasma glucose (18.1%), and high BMI (2.5%) were the main risk factors. EOCRC DALYs were mainly influenced by dietary risks (57.2%), high BMI (13.6%), alcohol use (10%), tobacco (6.9%), high fasting plasma glucose (5.4%), and low physical activity (3%). We ranked the changes in DALYs risk factors for early‐onset digestive system malignancies from 1990 to 2021 for both genders. In females, the ranking of risk factors for EOEC and EOGC remained unchanged. For EOLC, alcohol use and high BMI swapped places, whereas in EOPC, tobacco and high fasting plasma glucose interchanged. In EOCRC, alcohol use dropped in rank, and high fasting plasma glucose rose. In males, the rankings for EOEC, EOGC, EOLC, and EOPC stayed the same, but for EOCRC, high BMI rose in rank, and tobacco fell (Figure S10).

The risk factors of early‐onset esophagus cancer (A), early‐onset gastric cancer (B), early‐onset liver cancer (C), pancreatic cancer (D), and early‐onset colon and rectum cancer (E) worldwide in 21 GBD and 5 SDI regions, 2019.

3.7. Prediction of the Incidence and Death of Early‐OnsetDigestive System Malignancies

From 2022 to 2030, the global ASIR of EOCRC was expected to rise (Figure 4A), particularly among males (Figure S11A,D). Meanwhile, the ASIR of EOEC presented a slight increase (Figure 4A), especially in males (Figure S11D). Conversely, the ASIR for EOGC, EOLC, and EOPC is projected to decline (Figure 4A). Overall, the ASMR and ASDR of early‐onset digestive system malignancies showed a decreasing trend globally from 2022 to 2030 (Figure 4B,C).

Projected burden of global early‐onset digestive system malignancy, 2022–2030.

4. Discussion

This study comprehensively assessed the global burden, trends, and risk factors of the five major early‐onset digestive system malignancies over three decades using the most updated database from GBD 2021. The statistics of incidence, prevalence, deaths, DALYs, and risk factors by sex and geography suggested that the spectrum of early‐onset GI cancers varied significantly across the world.

We found the global burden of EOEC presented a downward trend from 1990 to 2021, consistent with findings from previous study [11]. This study highlighted dietary, tobacco, and alcohol use as primary risk factors for EOEC. Importantly, the ASIR, ASMR, and ASDR for EOEC were higher in males than in females, likely due to higher rates of alcohol and tobacco use among males [19]. It has been reported that compared to average‐onset esophagogastric cancer, early‐onset esophagogastric cancer is characterized by a genomically stable molecular subtype, a longer time from symptom onset to diagnosis, and higher frequency of presenting symptoms [20]. Future research should prioritize the development of innovative strategies for the diagnosis and management of esophagogastric cancer.

In 2021, the ASIR and ASPR of EOGC were highest in East Asia, whereas Oceania exhibited the highest ASMR and ASDR. Globally, the ASIR, ASPR, ASMR, and ASDR of EOGC presented a downward trend from 1990 to 2021, indicating substantial progress in the prevention and treatment of EOGC. This reduction may be attributed to the management of potential risk factors, early screening, and effective therapy. For instance, Helicobacter pylori infection, a dominant risk factor for GC, has shown a decreasing prevalence due to early screening and effective treatment strategies [21]. Various guidelines underscore the importance of monitoring precancerous lesions, such as intestinal metaplasia and chronic atrophic gastritis, which may enhance public awareness and prevent the development of EOGC [22, 23, 24]. Furthermore, this study identified dietary and tobacco as major risk factors for EOGC, suggesting that the burden of EOGC could be mitigated through healthy dietary practices and smoking cessation.

Compared with late‐onset LC, EOLC patients had a lower prevalence of cirrhosis [25], suggesting differences in disease etiology. Metabolic risks like nonalcoholic steatohepatitis, diabetes, and obesity are rising global risk factors for EOLC [26]. Our study also identified tobacco, alcohol, high BMI, and high fasting plasma glucose as EOLC risk factors. We observed the burden of EOLC generally experienced a decreasing trend from 1990 to 2021, partly due to the success of the HBV vaccine program and antiviral treatment [27]. However, East Asia still faces a high EOLC burden, likely due to increased metabolic risks. To address the rise in metabolic risk–related EOLC, combined behavioral and dietary interventions are necessary.

PC is the seventh most common cause of cancer‐related mortality globally, with the average age at diagnosis being 65 years in the United States [28]. Recent data reported that diagnoses of PC are increasing in younger adults, with a more pronounced rise observed in females [29, 30]. This study revealed that males had higher ASIR, ASMR, and ASDR of EOPC compared to females. The increased prevalence of diabetes, alcohol use, smoking, and obesity was claimed to be responsible for the increasing EOPC [31]. Our finding identified tobacco, high BMI, and high fasting plasma glucose as the primary risk factors contributing to the DALYs of EOPC. Regionally, the aforementioned ASRs were distinctively high in Eastern Europe. It has been reported western diet may increase the risk of EOPC, whereas the consumption of green tea, nuts, vitamin D, and anti‐inflammatory diets in appropriate amounts may offer protective benefits [32]. Previous studies suggested younger patients diagnosed with PC were more likely to present with poorly differentiated tumors and perineural invasion phenotypes [10, 33]. However, compared to average‐onset PC patients, those with EOPC tend to have better outcomes when the tumor metastasizes and possess more targetable genetic alterations [34]. Therefore, genetic screening would be an indispensable tool for early‐onset cancer prevention and treatment.

Among the five major early‐onset digestive system malignancies, EOCRC exhibited the highest ASIR, ASPR, ASMR, and ASDR in 2021. Furthermore, the incidence of EOCRC demonstrated the most rapid increase, particularly among males. Compared to the late‐onset CRC, EOCRC is more frequently diagnosed at an advanced stage [35]. Thus, promoting early diagnosis and identifying potential risk factors are crucial for the prevention and management of EOCRC. The majority of EOCRC cases were diagnosed following the onset symptoms rather than through screening or incident detection, likely due to most guidelines recommend initiating screening colonoscopy for CRC at the age of 50 years [36]. In 2018, the American Cancer Society proposed commencing screening at 45 years of age [37], which may provide an effective balance of life‐years gained and colonoscopy burden. This study identified several key risk factors for EOCRC, including dietary, high BMI, alcohol use, tobacco, high fasting plasma glucose, and low physical activity. The findings align with previous researches that emphasized lifestyle changes, such as unhealthy diets, insufficient physical activity, antibiotic use, and obesity as significant contributors to EOCRC development [38, 39, 40]. Additionally, alterations in gut microbiome may play a vital role in this context [41]. Our analysis also revealed a higher incidence and mortality rate of EOCRC among males compared to females, consistent with earlier studies [40, 42]. A substantial portion of the global burden in males can be attributed to higher rates of smoking and drinking among this demographic [43]. Some studies have suggested oral contraceptives and endogenous estrogens may reduce the risk of CRC in females [44, 45]. Furthermore, our findings indicated a greater impact of tobacco and alcohol consumption on DALYs in males than females. Consequently, lowering the screening age for EOCRC, particularly for individuals at high risk, could potentially mitigate the disease burden.

To our knowledge, this was the first study comprehensively assessed the global burden and future burden of five major early‐onset digestive system malignancies and how the corresponding risk factors changed, along with heterogeneous burden across sex and country. However, there were several limitations in this study. Firstly, there were some deviations in the accuracy and completeness of the GBD data. The under‐diagnosis and under‐reporting of early‐onset cancers in developing countries may lead to underestimation of the deaths and incidence. Secondly, the GBD framework did not include the subsite and histological data, so we are unable to specifically explore the different subtypes of digestive system malignancies.

5. Conclusions

This study provided up‐to‐date epidemiological insights into early‐onset digestive system malignancies. From 1990 to 2021, there was a global decline in the burden of these malignancies, with the exception of EOCRC. In 2021, dietary risk factors, alcohol use, tobacco consumption, and metabolic risk factors were the main risk factors for early‐onset digestive system malignancies. Promoting healthy lifestyles may help mitigate this burden. Furthermore, developing personalized screening approaches and re‐evaluating screening guidelines for early‐onset cancers should be put on the agenda. Future research is necessary to investigate the etiology and carcinogenesis, thereby contributing to precision prevention.

Ethics Statement

The data used in this study were obtained from the publicly available Global Burden of Disease database and did not necessitate any institutional review board approval, ethics clearance, or consent from study subjects.

Conflicts of Interest

The authors declare no conflicts of interest.

Supporting information

Table S1. International Classification of Disease 10th revision codes for five major digestive system malignancy.

Table S2. Global numbers and ASRs per 100 000 cases of incidence, prevalence, deaths, and DALYs of early onset digestive system malignancy in 1990 and 2021 for female, along with AAPC in ASRs per 100 000 cases from 1990 to 2021.

Table S3. Global numbers and ASRs per 100 000 cases of incidence, prevalence, deaths, and DALYs of early onset digestive system malignancy in 1990 and 2021 for male, along with AAPC in ASRs per 100 000 cases from 1990 to 2021.

Table S4. ASRs per 100 000 cases of incidence, prevalence, deaths, and DALYs of early‐onset esophageal cancer in 1990 and 2021 by region and sociodemographic index level.

Table S5. ASRs per 100 000 cases of incidence, prevalence, deaths, and DALYs of early‐onset gastric cancer in 1990 and 2021 by region and sociodemographic index level.

Table S6. ASRs per 100 000 cases of incidence, prevalence, deaths, and DALYs of early‐onset liver cancer in 1990 and 2021 by region and sociodemographic index level.

Table S7. ASRs per 100 000 cases of incidence, prevalence, deaths, and DALYs of early‐onset pancreatic cancer in 1990 and 2021 by region and sociodemographic index level.

Table S8. ASRs per 100 000 cases of incidence, prevalence, deaths, and DALYs of early‐onset colorectal cancer in 1990 and 2021 by region and sociodemographic index level.

Figure S1. The APC and AAPC of ASR for incidence (A), prevalence (B), deaths (C), and DALYs (D) in early‐onset digestive system malignancy among female at the global level based on the joinpoint regression analysis model.

Figure S2. The APC and AAPC of ASR for incidence (A), prevalence (B), deaths (C), and DALYs (D) in early‐onset digestive system malignancy among male at the global level based on the joinpoint regression analysis model.

Figure S3. Global maps of age‐standardized incidence rate for early‐onset esophagus cancer (A), early‐onset gastric cancer (B), early‐onset liver cancer (C), pancreatic cancer (D), and early‐onset colon and rectum cancer (E) for both sex combined in 2021.

Figure S4. Global maps of age‐standardized prevalence rate for early‐onset esophagus cancer (A), early‐onset gastric cancer (B), early‐onset liver cancer (C), pancreatic cancer (D), and early‐onset colon and rectum cancer (E) for both sex combined in 2021.

Figure S5. Global maps of age‐standardized mortality rate for early‐onset esophagus cancer (A), early‐onset gastric cancer (B), early‐onset liver cancer (C), pancreatic cancer (D), and early‐onset colon and rectum cancer (E) for both sex combined in 2021.

Figure S6. Global maps of age‐standardized DALY rate for early‐onset esophagus cancer (A), early‐onset gastric cancer (B), early‐onset liver cancer (C), pancreatic cancer (D), and early‐onset colon and rectum cancer (E) for both sexes combined in 2021.

Figure S7. Age‐standardized incidence rates for 21 GBD regions and 204 countries and territories for early‐onset esophagus cancer (A,B), early‐onset gastric cancer (C,D), early‐onset liver cancer (E,F), pancreatic cancer (G,H), and early‐onset colon and rectum cancer (I,J) by socio‐demographic index, 1990–2021.

Figure S8. Age‐standardized DALYs rates for 21 GBD regions and 204 countries and territories for early‐onset esophagus cancer (A,B), early‐onset gastric cancer (C,D), early‐onset liver cancer (E,F), pancreatic cancer (G,H), and early‐onset colon and rectum cancer (I,J) by sociodemographic index, 1990–2021.

Figure S9. The inequality slope index and concentration index for DALYs of early‐onset esophagus cancer (A,B), early‐onset gastric cancer (C,D), early‐onset liver cancer (E,F), pancreatic cancer (G,H), and early‐onset colon and rectum cancer (I,J) worldwide in 1990 and 2021.

Figure S10. The ranking change of DALYs risk factors for early‐onset digestive system malignancy from 1990 to 2021 among female and male.

Figure S11. Projected burden of global early‐onset digestive system malignancy by sex, female (A–C), male (D–F), 2022–2030.

JGH-40-1525-s001.pdf^{(10.7MB, pdf)}

Acknowledgments

We appreciate the high‐quality data provided by the Global Burden of Disease study 2021 collaborators. The graphical abstract was partially designed by Figdraw.

Funding: This work was supported by Natural Science Research Project of Minhang District in Shanghai (Grant Number 2021MHZ040), School‐level Project of Minhang Central Hospital (Grant Number 2020MHJC02), National Natural Science Foundation of China (Grant Number 8217100675), and Minhang District Medical Teaching and Research Collaborative Health Service System under the high‐level specialist backbone physician training project (Grant number: 2024MZYS16).

Contributor Information

Xiaohong Zhang, Email: zxh_njzx@163.com.

Huanqing Li, Email: 176545456@qq.com.

Li Feng, Email: feng_li@fudan.edu.cn.

Data Availability Statement

Information from the 2021 Global Burden of Disease study is available through the Global Health Data Exchange (GHDx) query tool, maintained by the Institute for Health Metrics and Evaluation at https://vizhub.healthdata.org/gbd‐results/.

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