Gastroenterology 2023;165:600–612

Incidence, Risk Factors, and Temporal Trends of Small Intestinal

Cancer: A Global Analysis of Cancer Registries
Junjie Huang,1,2 Sze Chai Chan,1 Yat Ching Fung,1 Fung Yu Mak,1 Veeleah Lok,3 Lin Zhang,4,5
Xu Lin,6 Don Eliseo Lucero-Prisno III,7 Wanghong Xu,8 Zhi-Jie Zheng,9 Edmar Elcarte,10
Mellissa Withers,11 Martin C. S. Wong,1,2,5,9 and the NCD Global Health Research Group,
GI CANCER

Association of Pacific Rim Universities

1
The Jockey Club School of Public Health and Primary Care, Faculty of Medicine, Chinese University of Hong Kong, Hong
Kong SAR, China; 2Center for Health Education and Health Promotion, Faculty of Medicine, The Chinese University of Hong
Kong, Hong Kong SAR, China; 3Department of Global Public Health, Karolinska Institute, Karolinska University Hospital,
Stockholm, Sweden; 4The School of Public Health and Preventive Medicine, Monash University, Victoria, Australia; 5School of
Public Health, The Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; 6Department of
Thoracic Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China;
7
Department of Global Health and Development, London School of Hygiene and Tropical Medicine, London, United Kingdom;
8
School of Public Health, Fudan University, Shanghai, China; 9Department of Global Health, School of Public Health, Peking
University, Beijing, China; 10University of the Philippines, Manila, the Philippines; and 11Department of Population and Health
Sciences, Institute for Global Health, University of Southern California, Los Angeles, California

Incidence, Risk Factors, and Temporal Trends of Small Intestinal Cancer:

a global analysis of cancer registries
Gender Risk Factors Trend
Total cases: 64,477
(ASR: 0.60) HDI (β=0.119)
Overall: 17 countries
GDP (β=0.088)
Subregions Smoking (β=0.032) Subgroups
ASR: 0.73 > 0.49
Alcohol (β=0.032) 15 1
Northern America Age IBD (β=0.198)
ASR: 1.4 Physical inactivity(β=0.030) 14 0
15 0
Oceania (50-74 years) (15-49 years) 9 3
ASR: 0.96 ASR: 2.3 > 0.20

BACKGROUND & AIMS: Small intestinal cancer is a rare disease burden found in North America (1.4). Higher small
cancer, with limited studies exploring its epidemiology. To intestinal cancer incidence was associated with higher human
our knowledge, this study is the first effort to comprehen- development index; gross domestic product; and prevalence
sively analyze the incidence, risk factors, and trends for small of smoking, alcohol drinking, physical inactivity, obesity,
intestinal cancer by sex, age, and country. METHODS: Global diabetes, lipid disorder, and IBD (b ¼ 0.008–0.198; odds ra-
Cancer Observatory, Cancer Incidence in Five Continents Plus, tios, 1.07–10.01). There was an overall increasing trend of
and Global Burden of Disease were accessed to estimate the small intestinal cancer incidence (average annual percent
age-standardized rates of small intestinal cancer incidence change, 2.20–21.67), and the increasing trend was compara-
(International Classification of Diseases, 10th Revision, Clin- ble among the 2 sexes but more evident in the older popu-
ical Modification: C17) and prevalence of lifestyle risk factors, lation aged 50–74 years than in the younger population aged
metabolic risk factors, and inflammatory bowel disease (IBD). 15–49 years. CONCLUSION: There was a substantial
Risk factor associations were assessed by linear and logistic geographic disparity in the burden of small intestinal cancer,
regressions. Average annual percent change was calculated with higher incidence observed in countries with higher hu-
using joinpoint regression. RESULTS: A total of 64,477 small man development index; gross domestic product; and prev-
intestinal cancer cases (age-standardized rate, 0.60 per alence of unhealthy lifestyle habits, metabolic disorders, and
100,000) were estimated globally in 2020, with a higher IBD. There was an overall increasing trend in small intestinal
September 2023 Global Small Intestinal Cancer 601

cancer incidence, calling for the development of preventive

WHAT YOU NEED TO KNOW
strategies.
BACKGROUND AND CONTEXT
Small intestinal cancer is a rare malignancy with a
Keywords: Small Bowel; Malignancy; Epidemiology.
relatively poor prognosis. There was a lack of studies on
the investigation of its global distribution, risk factors,
and temporal trends.

S mall intestinal cancer is a rare cancer although the

small intestine makes up the majority of the digestive
system.1 It has been reported that small intestinal cancer
NEW FINDINGS
A greater disease burden of small intestinal cancer was
was diagnosed in only 0.3% of all autopsies.2 Small intes- found in more developed regions with a higher
prevalence of lifestyle and metabolic risk factors. There

GI CANCER
tinal cancer is complex because of its diversity of cell types,
was an overall increasing trend of small intestinal cancer
with 4 distinct subtypes: adenocarcinomas, carcinoid tu-
incidence for the past decade.
mors, lymphomas, and sarcomas. Some common diagnostic
modalities include laparotomy, upper gastrointestinal LIMITATIONS
barium study, upper gastrointestinal endoscopy, and There might be a possible overestimation of 2020
computerized tomography scan.3 The median age at diag- incidence rates due to the drop in cancer diagnoses
nosis for small intestinal cancer was comparable among caused by the COVID-19 pandemic–related lockdown
countries at around 66 years.4 Common clinical symptoms because estimates were based on incidence trends from
past years.
include abdominal pain, anorexia, gastrointestinal bleeding,
weight loss, perforation, small bowel obstruction, and CLINICAL RESEARCH RELEVANCE
obstructive jaundice. Malignant small intestinal tumors are The increasing number of small intestinal cancers was
often diagnosed after they have metastasized, resulting in a probably due to the surge in the prevalence of risk factors
relatively poor prognosis.5 The 5-year relative survival rate and the improvement in diagnostic capabilities. Intensive
of small intestinal cancer was 68.5% in 2018.6 lifestyle modification and medical resource reallocation
Some diseases have been identified to be associated with are warranted to cope with the expected rise in incidence.
a higher risk of small intestinal cancer, including celiac BASIC RESEARCH RELEVANCE
disease, inflammatory bowel disease (IBD), and hereditary The higher prevalence of risky lifestyle habits, metabolic
cancer syndromes.7–9 Common lifestyle risk factors for factors, and IBD might also be a driving factor behind
small intestinal cancer are similar to those for colon cancer, the difference in disease burden because these factors
such as overconsumption of red meat and high intake of were associated with higher small intestinal cancer
fat.10–12 Other preventable lifestyle and metabolic risk fac- incidence. Future basic research may confirm the causal
tors might include smoking,13 alcohol consumption,13 relationship between these risk factors and the risk of
small intestinal cancer.
obesity,14 and diabetes mellitus.15 Nevertheless, further
research is needed to explore the associations between these
risk factors and small intestinal cancer. Because of the rarity based on data from international or national cancer registries
of small intestinal cancer, research on its global epidemiology included in GLOBOCAN.19
has been lacking. Some studies evaluated the incidence of To determine the trend of small intestinal cancer incidence,
small intestinal cancer, but they were limited to certain the Cancer Incidence in Five Continents Plus (CI5 Plus) data-
countries or regions,16,17 or they reported relatively old base was used, which provides 10-year cancer incidence in 108
countries.20 The CI5 Plus database consists of data from
data.10,18 This study aims to comprehensively estimate the
different countries in the world, and it compiles cancer inci-
global disease burden, risk factors, and temporal trends of
dence data from population-based cancer registries on all
small intestinal cancer by sex, age, and country. To the best of
continents. It follows established standards and is continuously
our best knowledge, this is the first effort of its kind to use evaluated for quality control, ensuring that the data collected
international and national cancer registries of good quality to and analyzed are reliable and accurate. However, it is important
provide insight into the prevention of small intestinal cancer. to note that not all countries or regions have established
population-based cancer registries, especially in developing
Methods countries. Therefore, it is necessary to interpret the data with
Data Sources
The incidence of small intestinal cancer, as defined by the Abbreviations used in this paper: AAPC, average annual percent change;
ASR, age-standardized rate; CD, Crohn’s disease; CI, confidence interval;
International Classification of Diseases, 10th Revision, Clinical CI5 Plus, Cancer Incidence in Five Continents Plus; GBD, global burden of
Modification (C17), in 2020 among 185 countries was derived disease; GDP, gross domestic product; GLOBOCAN, Global Cancer Ob-
indirectly from the Global Cancer Observatory (GLOBOCAN) servatory; HDI, human development index; IBD, inflammatory bowel dis-
ease; OR, odds ratio; SIR, standardized incidence ratio.
database.1 GLOBOCAN is an online database that provides
statistics on the incidence and mortality rate of 26 different Most current article
types of cancer on a global scale, including respiratory, © 2023 The Author(s). Published by Elsevier Inc. on behalf of the AGA
alimentary, and hematologic cancers. The incidence-to- Institute. This is an open access article under the CC BY license (http://
creativecommons.org/licenses/by/4.0/).
mortality ratio of the cancer-related statistics, trend analysis 0016-5085
prediction, and approximation from surrounding countries was https://doi.org/10.1053/j.gastro.2023.05.043
 602 Huang et al Gastroenterology Vol. 165, Iss. 3

caution and consider any limitations or biases that may exist. transformed, and corresponding standard errors were deter-
We used proportional estimates (small intestinal cancer inci- mined. Subsequently, the AAPC and the 95% CI were deter-
dence out of all cancers in the alimentary tract) from the CI5 mined for different demographic groups. The temporal trends
database to estimate the incidence of small intestinal cancer of the incidence of small intestinal cancer were illustrated by
from GLOBOCAN. Additionally, we conducted a sensitivity the AAPC; a positive AAPC indicated an upward trend, and vice
analysis using small intestinal cancer incidence out of all versa. The accuracy of trend estimations was evaluated using
digestive cancers as an additional proportional estimate. the 95% CI. An interval that overlaps with 0 indicates a stable
To analyze risk factors, we obtained country-specific data trend without a significant increase or decrease. Additionally,
from the Global Burden of Disease (GBD) database.21 The risk changes in small intestinal cancer incidence were examined by
variables included the prevalence of smoking, alcohol, un- sex (male and female), age (all population, 0–85þ years; young
healthy diet, physical inactivity, obesity, hypertension, diabetes, population, 15–49 years; and old population, 50–74 years), and
GI CANCER

lipid disorder, and IBD for each country. The GBD database geographic region (Asia, Oceania, North America, South Amer-
aims to assess health loss caused by specific illnesses, accidents, ica, Europe, and Africa). The age group 0–14 years was
and risk factors to improve health care systems and advance excluded from the subgroup analysis because small intestinal
health equity. Data on early death and disability resulting from cancer is rare in children and may not be comparable with that
more than 350 diseases and injuries have been collected and in adults. Contrarily, we excluded the age group >75 years
evaluated by 7000 researchers in 156 countries and regions. because this population may have an extremely higher inci-
The GBD database handles countries with missing data for dence of cancer and other comorbidities, which may reduce its
lifestyle risk factors by using (1) data from neighboring or comparability with other populations.
similar countries, assuming that the patterns of risk factors are
similar; (2) statistical models to interpolate or extrapolate Ethical Statement
missing values based on available data; and (3) expert opinion
This study was approved by the Survey and Behavioural
and stakeholder consultations to gather information on un-
Research Ethics Committee, The Chinese University of Hong
known risk factor prevalence in certain regions.22 Moreover,
Kong (No. SBRE-20-332).
the human development index (HDI) and gross domestic
product (GDP) per capita for each country were acquired from
the United Nations23 and the World Bank,24 respectively. Results
Small Intestinal Cancer Incidence in 2020
Statistical Analysis In 2020, there were an estimated total of 64,477 new
Small intestinal cancer incidence was standardized using cases of small intestinal cancer, with an ASR of 0.60 per
direct standardization to the Segi-Doll world population to 100,000 people (Table 1). The highest ASR was found in
obtain the age-standardized rates (ASRs) for different coun- North America (1.4), and the lowest ASR was observed in
tries. The ASR is the weighted arithmetic mean of age-specific Sab-Saharan Africa (0.12). Among countries, higher ASRs
rates per 100,000 people, where the weights correspond to were observed in French Guiana (1.5) and Norway (1.5). A
the ratio of people in the respective age groups of the standard
higher ASR was observed among the male population (0.73;
population. To investigate the relationships between the inci-
35,949 cases) (Figure 1 and Supplementary Table 1A) than
dence of small intestinal cancer and risk variables such as HDI,
the female population (0.49; 28,528 cases) and among the
GDP per capita, lifestyle habits, metabolic factors, and IBD, for
each nation by sex and age, univariable linear regression ana-
older population (2.3; 40,644 cases) (Figure 2 and
lyses were conducted. Multivariable linear regression analysis Supplementary Table 1B) than the younger population (0.2;
was also conducted to explore the associations between life- 8,631 cases).
style risk factors and small intestinal cancer incidence. Beta Stratifying by HDI, similar regional differences were
coefficients (b) and the corresponding 95% confidence in- observed. Among countries with very high HDI, the highest
tervals (CIs) were generated from the linear regression. b es- ASR was found in North America (range of ASR, 1.1–1.4,
timates represent the ratio of the change in the outcome median, 1.25), whereas Central and Eastern Europe (range,
variable (ASR of incidence) to the change in the predictor 0.21–0.93; median, 0.43) had the lowest ASR. In terms of
variable, expressed as a unit increase in the risk factor. Statis- GDP level, among countries with high GDP, North America
tical significance was defined as a P value of less than .05. had the highest ASR (range, 1.1–1.4; median, 1.25), whereas
Additionally, logistic regression was conducted to obtain the the lowest ASR was observed in Central and Eastern Europe
odds ratios (ORs) by dividing all countries into 2 groups. (range, 0.21–0.93; median, 0.49). Detailed results are listed
Countries with an incidence equal to or higher than the median in Supplementary Table 1C and D. Sensitivity analysis
were categorized as having a high incidence, whereas those showed similar results (Supplementary Figures 1 and 2 and
with an incidence lower than the median were categorized as Supplementary Table 2).
the lower-incidence group.
The joinpoint regression analysis program, developed by
the Surveillance, Epidemiology, and End Results Program of the Associations of Risk Factors With Small Intestinal
National Cancer Institute of the United States, was used to Cancer Incidence
conduct the trend analysis. The temporal trend of small intes- On a population level, the small intestinal cancer inci-
tinal cancer incidence was determined by measuring the dence was significantly associated with higher HDI (b ¼
average annual percent change (AAPC) using the most recent 0.119) (Supplementary Table 3A); GDP per capita (b ¼
10-year data.25 The incidence data were logarithmically 0.088); and higher prevalence of smoking (b ¼ 0.032),
September 2023 Global Small Intestinal Cancer 603

alcohol drinking (b ¼ 0.032), physical inactivity (b ¼ 0.030), male population. Among the female population, 14 countries
obesity (b ¼ 0.011), hypertension (b ¼ 0.008), diabetes presented rising trends, and the most significant rise was
(b ¼ 0.025), lipid disorder (b ¼ 0.018), and IBD (b ¼ 0.198). found in Poland (AAPC, 30.26). The remaining 27 countries
Logistic regression has found significant associations be- did not show significant rising or declining trends during
tween higher small intestinal cancer incidence and HDI (OR, the specific period.
2.14) (Supplementary Table 3B); GDP per capita (OR, 2.11); The rising trend of small intestinal cancer was more
and higher prevalence of smoking (OR, 1.23), alcohol evident in the older population than in the younger popu-
drinking (OR, 1.21), physical inactivity (OR, 1.20), obesity lation (Figure 6). Among the older population, 15 countries
(OR, 1.07), diabetes (OR, 1.19), lipid disorder (OR, 1.12), and showed rising trends, with the most significant increase
IBD (OR, 10.01). Multivariate linear regression results reported in Poland (AAPC, 21.37). The remaining 26 coun-
showed that higher small intestinal cancer incidence was tries did not present any significant trends during the spe-

GI CANCER
associated with smoking, alcohol drinking, and physical cific period. Among the younger population, 9 countries
inactivity (b ¼ 0.018–0.025) (Supplementary Table 3C). showed significant increasing trends, and 3 countries pre-
sented significant declining trends. Poland reported the
highest rise (AAPC, 22.13), whereas Malta (AAPC, –25.95)
Associations of Risk Factors With Small Intestinal
reported the most significant declining trend. The other 28
Cancer Incidence by Subgroup countries did not report any significant increasing or
Among male individuals, small intestinal cancer inci- declining trends during the period.
dence was significantly associated with higher HDI; GDP per
capita; and higher prevalence of smoking, alcohol, unhealthy
diet, physical inactivity, obesity, hypertension, diabetes, Discussion
lipid disorder, and IBD (b ¼ 0.007–0.243) (Figure 3).
Similarly, among female individuals, small intestinal cancer Summary of Major Findings
incidence was significantly associated with higher HDI; GDP This is a multifaceted investigation of the global disease
per capita; and higher prevalence of smoking, alcohol burden, risk factors, and temporal incidence trends of small
drinking, physical inactivity, obesity, diabetes, lipid disorder, intestinal cancer. There are some major findings: (1) A greater
and IBD (b ¼ 0.008–0.155) (Figure 4). Among the younger disease burden of small intestinal cancer was found in regions
population, small intestinal cancer incidence was associated with higher HDI and GDP, such as North America, Oceania,
with higher HDI; GDP per capita; and higher prevalence of and Northern Europe. (2) A substantial difference in the dis-
smoking, alcohol drinking, unhealthy diet, physical inac- ease burden was found between sexes and age groups, with
tivity, obesity, diabetes, lipid disorder, and IBD (b ¼ 0.002– the male population and the older population having signifi-
0.063). Similarly, among the older population, small intes- cantly higher incidence. (3) Several unhealthy lifestyle habits
tinal cancer incidence was associated with higher HDI; GDP and diseases, including smoking, alcohol drinking, diabetes,
per capita; and higher prevalence of smoking, alcohol and IBD, were associated with a higher incidence at the
drinking, physical inactivity, obesity, diabetes, lipid disorder, population level. (4) An overall increasing trend was observed
and IBD (b ¼ 0.021–0.625). The results were also supported worldwide; such trends were comparable between the 2
by an additional sensitivity analysis on the risk factor as- sexes but were more pronounced among the older population.
sociations (Supplementary Table 4).
Variation in Disease Burden
Trend Analysis of Small Intestinal Cancer A considerable geographic difference in the disease
Incidence burden was observed in 2020, as highly developed and
There was an overall rising trend of small intestinal predominantly White regions had a remarkably greater
cancer, with 17 countries showing increasing trends but no disease burden. Meanwhile, a lower incidence was observed
country showing a decreasing trend (Supplementary in the African region. Such findings are in line with a pre-
Figures 3 and 4 and Supplementary Table 5). The most vious review in terms of the regional difference.26 The
significant increase was observed in Poland (AAPC, 21.67). regional difference is unlikely a result of racial difference
The remaining 24 countries did not show significant because the incidence of small intestinal cancer was almost
increasing or decreasing trends during the period. 2 times higher among Black than White individuals in a US
study,27 but is possibly a consequence of detection bias due
to a systematic difference in the capacity of gastrointestinal
Age- and Sex-Specific Trends Analysis by endoscopy,28,29 highlighting the inequities in access to di-
Subgroup agnostics. Previous literature has indicated insufficient
A similar increasing trend of small intestinal cancer population awareness of the existence of cancer in Africa,
observed was observed in both male and female populations which is compounded by the scarcity of reliable national
(Figure 5). Among the male population, 15 countries pre- statistical data on cancer, delaying plans for the financing of
sented rising trends, and 1 country presented a declining cancer control plans and access to care for the general
trend. The most significant increasing trend was found in population.30 The difference might also be attributable to
India (AAPC, 17.37); Chile (AAPC, –11.84) was the only the variation in lifestyle due to social class differences
country showing a significant decreasing trend among the because the previous study found that small intestinal
 604 Huang et al Gastroenterology Vol. 165, Iss. 3

cancer was most common in higher social classes.31 Similar lifetimes,13 and a higher risk of small intestine adenocarci-
to previous studies from the United Kingdom and United nomas (adjusted OR, 4.6; 95% CI, 1.0–20.7) and carcinoids
States,32,33 a higher incidence was found among the male (adjusted OR, 4.2; 95% CI, 0.8–22.4) was found for cigarette
population and the older population. The drivers behind the smoking.37 Nevertheless, the effect of smoking on small in-
sexual disparity remain unexplored,26,33 but the interna- testinal cancer may not be conclusive.38–40 Similarly, pre-
tional correlation between the rates of small intestine and vious findings on the effects of alcohol drinking on small
colon cancer might be an indication that the 2 cancers share intestinal cancer have been mixed. Heavy drinkers had a 3-
some common risk factors, such as consumption of animal fold increased risk of small intestinal cancer compared to
protein and fat, that have been more commonly found moderate and nondrinkers,13 whereas a higher intake of
among the male population.34 beer or spirits was associated with a 3.5-times (95% CI, 1.5–
8.0) and 3.4-times (95% CI, 1.3–9.2) higher risk of small
GI CANCER

Associated Risk Factors intestine adenocarcinoma, respectively.38 However, no as-

Association analyses in our study revealed that several sociation was found with wine intake, with speculations that
risk factors were associated with small intestinal cancer on a the protective components of wine counterbalanced the
population level, including higher prevalence of smoking, carcinogenic effect of alcohol on the small intestine.38
alcohol drinking, physical inactivity, obesity, hypertension, Furthermore, our findings on the association between un-
diabetes, lipid disorder, and IBD. These findings are generally healthy diets and the risk of small intestinal cancer among
in line with those of previous studies using data on an indi- the male population were akin to those in the previous
vidual level. Crohn’s disease (CD) and ulcerative colitis are literature. Diets with a high content of animal fat and protein
the 2 main types of IBD. A previous cohort study has iden- were associated with a higher risk of small intestinal can-
tified a higher risk of small intestinal adenocarcinoma among cer,11 whereas high red and salt-cured/smoked meat intake
patients with CD (standardized incidence ratio [SIR], 8.3; doubled the risk of cancer.34 On the contrary, the consump-
95% CI, 5.9–11.3) or ulcerative colitis (SIR, 2.0; 95% CI, 1.2– tion of fibers has been found to reduce the risk of cancer,
3.1).35 Similarly, in our study, IBD was found to be associated probably because of the lowered carcinogen exposure due to
with a higher incidence of small intestinal cancer among faster transmit times.41 A protective effect of physical activity
populations of both sexes and age groups, especially among has also been found, with a higher level of leisure time
the older population, which was in line with previous find- physical activity being associated with a lower risk of small
ings identifying the long duration of CD as a risk factor.36 intestinal cancer (hazard ratio, 0.78; 95% CI, 0.60–1.00).
For lifestyle habits, a 3-fold increased risk was found in Metabolic syndrome played a significant role in the
men who smoked more than 100 cigarettes during their development of small intestinal cancer. Obesity significantly

Table 1.Estimated Global Incidence of Small Intestinal Cancer by Continent by Sex and Age

Location Overall Male Female Young Old

World 64,477; 0.60 35,949; 0.73 28,528; 0.49 8631; 0.20 40,644; 2.3
Eastern Asia 26,850; 0.75 15,354; 0.92 11,496; 0.59 2897; 0.21 18,181; 2.9
Southeastern Asia 2416; 0.33 1501; 0.46 915; 0.23 544; 0.14 1422; 1.2
South-Central Asia 5319; 0.28 3063; 0.32 2256; 0.24 1250; 0.12 3224; 1.0
Western Asia 1254; 0.51 735; 0.63 519; 0.41 319; 0.21 722; 1.9
Oceania 655; 0.96 368; 1.14 287; 0.79 97; 0.44 380; 3.7
North America 9243; 1.4 5017; 1.55 4226; 1.2 1153; 0.62 6008; 5.4
Central America and Caribbean 1046; 0.49 565; 0.57 481; 0.41 196; 0.18 644; 1.9
South America 3930; 0.66 1954; 0.77 1976; 0.57 506; 0.22 2,281; 2.5
Northern Europe 2242; 0.94 1229; 1.11 1013; 0.79 187; 0.34 1307; 3.9
Western Europe 4424; 0.89 2418; 1.07 2006; 0.72 383; 0.40 2477; 3.6
Southern Europe 3060; 0.74 1740; 0.95 1320; 0.56 295; 0.30 1681; 3.0
Central and Eastern Europe 2408; 0.43 1240; 0.57 1168; 0.34 262; 0.16 1635; 1.8
Northern Africa 927; 0.43 470; 0.46 457; 0.41 255; 0.21 396; 1.1
Sub-Saharan Africa 703; 0.12 295; 0.11 408; 0.13 287; 0.07 286; 0.29

NOTE. Values are presented as number of cases; age-standardized incidence. Young refers to individuals aged 15–49 years
old. Old refers to individuals aged 50–74 years old.
September 2023 Global Small Intestinal Cancer 605

Male

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(.985,1.83]
(.77,.985]
(.605,.77]
(.46,.605]
(.28,.46]
(.1,.28]
[.05,.1]
No data

Female

(.635,1.98]
(.5,.635]
(.415,.5]
(.33,.415]
(.22,.33]
(.12,.22]
[.06,.12]
No data

Figure 1. Global age-standardized incidence of small intestinal cancer by sex, all ages, in 2020.

elevated the risk for small intestinal cancer in men (SIR, 4.0; alcohol cessation, have been shown to reduce small intes-
95% CI, 2.2–9.3),14 and midlife diabetes remarkably tinal cancer by varying degrees.4
increased the risk of small intestinal cancer (OR, 5.78; 95%
CI, 1.72–19.40), especially in women (OR, 8.57; 95% CI,
1.50–48.92).15 As far as lipid disorder is concerned, there Increasing Small Intestinal Cancer Trends
was a strong association between triglycerides and the risk We found an overall increasing trend in the incidence of
of small intestinal cancer in women (hazard ratio per small intestinal cancer, and the trend was consistent among
standard deviation, 1.23; 95% CI, 1.04–1.46).42 Despite the the 2 sexes. Because hereditary or predisposing conditions
mixed findings in some risk factors, lifestyle modifications, were the causes of only 20% of small intestinal cancers, the
including physical activity, weight loss, and smoking and trend was likely attributable to the surge in the prevalence
 606 Huang et al Gastroenterology Vol. 165, Iss. 3

Young (15-49 years)

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(.29,.63]
(.23,.29]
(.19,.23]
(.145,.19]
(.105,.145]
(.07,.105]
[.02,.07]
No data

Old (50-74 years)

(3.21,6.56]
(2.29,3.21]
(1.855,2.29]
(1.335,1.855]
(.79,1.335]
(.26,.79]
[.13,.26]
No data

Figure 2. Global age-standardized incidence of small intestinal cancer by age, both sexes, in 2020.

of associated lifestyle habits, metabolic factors, IBD, and from 6.4%.46,47 IBD has also recently become a global dis-
improved diagnosis.4 For instance, there have been sub- ease, with accelerating incidence in newly industrialized
stantial increases in the prevalence of alcohol consumption countries whose societies have become more westernized.48
of 1% and in binge drinking of 3% per year, especially Conversely, significant declining trends have been found in
among middle aged and older adults,43 which might be one several countries; possible explanations include unexpect-
of the drivers behind the more pronounced increasing edly high ASRs in the first few years and sudden change in
trends among the older population. Moreover, the increased diagnostic capability caused by a shortage of gastroenter-
prevalence of physical inactivity, particularly in wealthier ologists; whereas stable trends may be a result of slower
countries, might have contributed to the rise in small in- adoption of risk behaviors due to delayed westernization.49
testinal cancer incidence.44,45 The age-standardized preva- Nevertheless, the drivers behind individual country-specific
lence of obesity had more than tripled in men, to 10.8% in trends are often multifaceted, and further investigations
2014 from 3.2% in 1975, and doubled in women, to 14.9% using national temporal data measuring the prevalence of
September 2023 Global Small Intestinal Cancer 607

Incidence (ASR) of Small Intestine Cancer

2.5

Incidence (ASR) of Small Intestine Cancer

2.5
2

2
1.5

1.5
1

1
.5

.5
0

0
4 6 8 10 0 5 10 15
HDI (1/10) GDP per capita (10000 USD)

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Incidence (ASR) of Small Intestine Cancer
2.5

Incidence (ASR) of Small Intestine Cancer

2.5
2

2
1.5

1.5
1

1
.5

.5
0

0
0 10 20 30 40 0 10 20 30
Prevalence of current smoking (%) Total amount of alcohol consumption (L)
Incidence (ASR) of Small Intestine Cancer

Incidence (ASR) of Small Intestine Cancer

2.5

2.5
2

2
1.5

1.5
1

1
.5

.5
0

20 40 60 80 0 5 10 15 20
Prevalence of unhealthy diet (%) Prevalence of physical inactivity (%)
Incidence (ASR) of Small Intestine Cancer

Incidence (ASR) of Small Intestine Cancer

2.5

2.5
2

2
1.5

1.5
1

1
.5

.5
0

0 20 40 60 10 20 30 40 50 60
Prevalence of obesity (%) Prevalence of hypertention (%)
Incidence (ASR) of Small Intestine Cancer
2.5

Incidence (ASR) of Small Intestine Cancer

2
2

1.5
1.5

1
1

.5
.5

0
0

5 10 15 20 25 30 10 20 30 40 50 60
Prevalence of diabetes (%) Prevalence of elevated cholesterol (%)

Men: Individual country 95% CI Fitted values Women: Individual country 95% CI Fitted values

Figure 3. Associations between risk factors and small intestinal cancer by sex.
 608 Huang et al Gastroenterology Vol. 165, Iss. 3

Incidence (ASR) of Small Intestine Cancer

8

Incidence (ASR) of Small Intestine Cancer

8
6

6
4

4
2

2
0

0
4 6 8 10
0 5 10 15
HDI (1/10)
GDP per capita (10000 USD)
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Incidence (ASR) of Small Intestine Cancer

Incidence (ASR) of Small Intestine Cancer

8

8
6

6
4

4
2

2
0

0
0 10 20 30 0 5 10 15 20
Prevalence of current smoking (%) Total amount of alcohol consumption (L)

Incidence (ASR) of Small Intestine Cancer

Incidence (ASR) of Small Intestine Cancer

8
8

6
6

4
4

2
2

0
0

0 20 40 60 80 0 5 10 15 20
Prevalence of unhealthy diet (%) Prevalence of physical inactivity (%)
Incidence (ASR) of Small Intestine Cancer

Incidence (ASR) of Small Intestine Cancer

8

8
6

6
4

4
2

2
0

0 20 40 60 80 0 20 40 60 80
Prevalence of obesity (%) Prevalence of hypertention (%)
Incidence (ASR) of Small Intestine Cancer

Incidence (ASR) of Small Intestine Cancer

8

6 8
6

4
4

2
2

0
0

0 20 40 60 0 20 40 60 80
Prevalence of diabetes (%) Prevalence of elevated cholesterol (%)

Young Fitted values Old Fitted values

Figure 4. Associations between risk factors and small intestinal cancer by age (15–49 years vs 50–74 years).
September 2023 Global Small Intestinal Cancer 609

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Figure 5. AAPC of small intestinal cancer incidence by sex, all ages.

risk factors and improvement in health care facilities are made when interpreting the associations, especially when
required. these associations are hypothesis generating have yet to be
confirmed by other observational studies. Third, because
cancer registries were subject to changes in some countries,
Limitations comparing the data directly over time might not be appro-
With high-quality cancer data from international regis- priate. However, the comparison of the data of countries,
tries, disease burden, risk factors, and temporal trends of regions, and sexes from the same period should be robust.
small intestinal cancer were comprehensively estimated in Fourth, because of the rarity of cancer, there were limited
this study. Nevertheless, there were several limitations. data on the disease burden and incidence trend of the
First, because of suboptimal diagnostic capabilities in subtype of small intestinal cancer. Future studies might
developing countries, there is a possibility that small in- explore the epidemiology of small intestinal cancer by
testinal cancer may be underdiagnosed or misclassified. subtype. Finally, within-country variation in the ASRs of
Completeness of reporting may also be lower in these small intestinal cancer may exist in addition to the between-
countries, artificially decreasing cancer incidence. We also country variation. Future studies could investigate the
need to be cautious in the interpretation of associations subnational differences in small intestine cancer incidence.
between lifestyle factors and disease because lower inci-
dence due to underdiagnosis and underreporting will also
affect the estimation. On the other hand, there might be a Conclusion
possible overestimation of 2020 incidence rates due to the A substantial geographic disparity was found in the
drop in cancer diagnoses caused by the COVID-19 disease burden of small intestinal cancer, possibly due to
pandemic–related lockdown, because estimates were the different diagnostic capacities between countries of
based on incidence trends from past years. Second, a different income levels. The higher prevalence of risky life-
cautious interpretation of the risk factor association results style habits, metabolic factors, and IBD might also be a
should be performed, and the possibility of nonlinear as- driving factor behind the difference in disease burden,
sociation should not be neglected. Also, because of the because these factors were associated with higher small
design of the study, in which country-level data were used, intestinal cancer incidence. This highlights the importance
there is a potential ecologic fallacy bias. Cautions should be of lifestyle modification and chronic disease management
 610 Huang et al Gastroenterology Vol. 165, Iss. 3
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Figure 6. AAPC of small intestinal cancer incidence by age, both sexes.

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human development index in 76 countries. Prev Med Acknowledgments

The NCD Global Health Research Group, Association of Pacific Rim
2011;53:24–28. Universities includes Mellissa Withers,1 Martin C. S. Wong,2 Junjie Huang,2
46. NCD Risk Factor Collaboration. Trends in adult body-mass Edmar Elcarte,3 Sze Chai Chan,2 Yat Ching Fung,2 Fung Yu Mak,2 Veeleah
index in 200 countries from 1975 to 2014: a pooled anal- Lok,4 Lin Zhang,5 Xu Lin,6 Don Eliseo Lucero-Prisno III,7 Wanghong Xu,8 and
Zhi-Jie Zheng9; from the 1University of Southern California, Los Angeles,
ysis of 1698 population-based measurement studies with California; 2Chinese University of Hong Kong, Hong Kong SAR, China;
3
19$2 million participants. Lancet 2016;387:1377–1396. University of the Philippines, Manila, the Philippines; 4Karolinska Institute,
Stockholm, Sweden; 5The University of Melbourne, Victoria, Australia;
47. Pineda E, Sanchez-Romero LM, Brown M, et al. Fore- 6
Zhejiang University, Hangzhou, Zhejiang, China; 7London School of Hygiene
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48. Ng SC, Shi HY, Hamidi N, et al. Worldwide incidence and CRediT Authorship Contributions
prevalence of inflammatory bowel disease in the 21st Junjie Huang, MD, PhD (Conceptualization: Lead; Supervision: Lead; Writing –
review & editing: Lead).
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century: a systematic review of population-based Sze Chai Chan, MSc (Data curation: Lead; Formal analysis: Lead; Writing –
studies. Lancet 2017;390:2769–2778. original draft: Equal).
Yat Ching Fung, BSocSc (Writing – original draft: Equal).
49. Huang J, Lucero-Prisno DE 3rd, Zhang L, et al. Updated Fung Yu Mak, BSocSc (Writing – original draft: Equal).
epidemiology of gastrointestinal cancers in East Asia. Veeleah Lok, MPH (Writing – review & editing: Equal).
Nat Rev Gastroenterol Hepatol 2023;20:271–287. Lin Zhang, PhD (Writing – review & editing: Equal).
Xu Lin, MD (Writing – review & editing: Equal).
Don Eliseo Lucero-Prisno III, PhD (Writing – review & editing: Equal).
Wanghong Xu, PhD (Writing – review & editing: Equal).
Author names in bold designate shared co-first authorship. Zhi-Jie Zheng, PhD (Writing – review & editing: Equal).
Edmar Elcarte, MA (Writing – review & editing: Equal).
Received December 29, 2022. Accepted May 5, 2023. Mellissa Withers, PhD (Writing – review & editing: Equal).
Martin C. S. Wong, MD (Conceptualization: Lead; Supervision: Lead; Writing –
Correspondence review & editing: Equal).
Address correspondence to: Martin C. S. Wong, MD, MPH, Postgraduate
Education Center, Prince of Wales Hospital, Room 407, 4/F, 30-32 Ngan Conflicts of interest
Shing Street, Shatin, N.T., Hong Kong. e-mail: [email protected]. The authors disclose no conflicts.