Contribution of H. pylori and Smoking Trends to US
Incidence of Intestinal-Type Noncardia Gastric
Adenocarcinoma: A Microsimulation Model
Jennifer M. Yeh1*, Chin Hur2, Deb Schrag3, Karen M. Kuntz4, Majid Ezzati5, Natasha Stout6,
Zachary Ward1, Sue J. Goldie1
1Center for Health Decision Science, Harvard School of Public Health, Boston, Massachusetts, United States of America, 2Massachusetts General Hospital Institute for
Technology Assessment, Boston, Massachusetts, United States of America, 3Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, United States
of America, 4University of Minnesota School of Public Health, Minneapolis, Minnesota, United States of America, 5Imperial College of London, London, England,
United Kingdom, 6Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute, Boston, Massachusetts, United States of
Background: Although gastric cancer has declined dramatically in the US, the disease remains the second leading cause of
cancer mortality worldwide. A better understanding of reasons for the decline can provide important insights into effective
preventive strategies. We sought to estimate the contribution of risk factor trends on past and future intestinal-type
noncardia gastric adenocarcinoma (NCGA) incidence.
Methods and Findings: We developed a population-based microsimulation model of intestinal-type NCGA and calibrated it
to US epidemiologic data on precancerous lesions and cancer. The model explicitly incorporated the impact of Helicobacter
pylori and smoking on disease natural history, for which birth cohort-specific trends were derived from the National Health
and Nutrition Examination Survey (NHANES) and National Health Interview Survey (NHIS). Between 1978 and 2008, the
model estimated that intestinal-type NCGA incidence declined 60% from 11.0 to 4.4 per 100,000 men, ,3% discrepancy
from national statistics. H. pylori and smoking trends combined accounted for 47% (range=30%–58%) of the observed
decline. With no tobacco control, incidence would have declined only 56%, suggesting that lower smoking initiation and
higher cessation rates observed after the 1960s accelerated the relative decline in cancer incidence by 7% (range=0%–
21%). With continued risk factor trends, incidence is projected to decline an additional 47% between 2008 and 2040, the
majority of which will be attributable to H. pylori and smoking (81%; range=61%–100%). Limitations include assuming all
other risk factors influenced gastric carcinogenesis as one factor and restricting the analysis to men.
Conclusions: Trends in modifiable risk factors explain a significant proportion of the decline of intestinal-type NCGA
incidence in the US, and are projected to continue. Although past tobacco control efforts have hastened the decline, full
benefits will take decades to be realized, and further discouragement of smoking and reduction of H. pylori should be
priorities for gastric cancer control efforts.
Please see later in the article for the Editors’ Summary.
Citation: Yeh JM, Hur C, Schrag D, Kuntz KM, Ezzati M, et al. (2013) Contribution of H. pylori and Smoking Trends to US Incidence of Intestinal-Type Noncardia
Gastric Adenocarcinoma: A Microsimulation Model. PLoS Med 10(5): e1001451. doi:10.1371/journal.pmed.1001451
Academic Editor: Jonathan M. Samet, University of Southern California, United States of America
Received November 16, 2012; Accepted April 5, 2013; Published May 21, 2013
Copyright: ? 2013 Yeh et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted
use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: JMY was funded by the National Institutes of Health’s National Cancer Institute (K07-CA143044). The funder had no role in study design, data collection
and analysis, decision to publish, or preparation of the manuscript.
Competing Interests: The authors have declared that no competing interests exist.
Abbreviations: GC, gastric cancer; NCGA, noncardia gastric adenocarcinoma; NHANES, National Health and Nutrition Examination Survey; NHIS, National Health
Interview Survey; SEER, Surveillance, Epidemiology and End Results.
* E-mail: firstname.lastname@example.org
PLOS Medicine | www.plosmedicine.org1 May 2013 | Volume 10 | Issue 5 | e1001451
Gastric cancer (GC) is the second most common cause of
cancer-related deaths worldwide, responsible for an estimated
700,000 deaths each year (10.4% of all cancer deaths) . Based
on current age-specific rates of GC and projected demographic
changes, the annual number of expected deaths worldwide will
increase to 1.4 million in 2030. Once diagnosed, the prognosis and
treatment options are poor, with less than 27% surviving more
than 5 y . Reducing GC incidence through modification of risk
factors may therefore be the most effective way to reduce GC
In the US, GC was the leading cause of cancer-related deaths
among men in the early 1900s. While it has fallen dramatically
since then, the precise reasons for the ‘‘unplanned triumph’’ are
not well-established , though broadly attributed to improve-
ments in living conditions and availability of refrigeration. The
decline has been more pronounced for noncardia cancers, in
particular intestinal-type tumors for which H. pylori infection is the
leading risk factor . Recent evidence suggests that cardia
cancers may be increasing in frequency [5,6]. Although histologic
subtypes are sometimes difficult to distinguish, these trends in
cancer incidence may suggest possible differences in tumor
Intestinal-type noncardia gastric adenocarcinoma (NCGA),
which accounts for over 50% of all GC cases in the US ,
develops through a series of relatively well-defined histological
steps over several decades , and the influence of H. pylori and
smoking influence on the carcinogenesis process have been well-
described by epidemiologic studies [9–14]. By initiating the
precancerous process, H. pylori infection increases intestinal-type
NCGA risk by as much as 6-fold , while smoking elevates
cancer risk by 2-fold by increasing progression risk of existing
lesions to more advanced lesions . As intestinal-type NCGA
incidence has fallen over the past century, prevalence of both
risk factors has also drastically changed. Only 33% of adults are
currently infected with H. pylori , and after peaking to more
than 50% in the 1955, smoking rates have declined to 20% since
the 1964 publication of the first US Surgeon General’s Report
on Smoking and Health [17–19]. Other risk factors, including
genetic factors and diet (e.g., low intake of fresh fruits and
vegetables and/or high salt intake), are also important, although
their effects on the gastric carcinogenesis are less well-
Understanding the combined effects of underlying risk factor
trends on population-level intestinal-type NCGA outcomes can
help to predict future cancer trends and burden in the US and
globally. While data on H. pylori prevalence and smoking rates in
the US are available from the National Health and Nutrition
Examination Survey (NHANES)  and National Health
Interview Survey (NHIS) , these databases do not contain
information on GC. Similarly, the Surveillance, Epidemiology and
End Results (SEER) Program provides estimates of population-
based cancer incidence, but lacks data on risk factors.
We employ a mathematical modeling framework capable of inte-
grating available epidemiologic, clinical, and demographic data to
understand the effect of risk factor trends on past and future
population-level intestinal-type NCGA incidence rates among US
men. Specifically, we aim to estimate the contribution of H. pylori and
smoking trends on the decline in cancer incidence and explore the
magnitude by which anti-smoking campaigns following the US
Surgeon General’s 1964 Report on Smoking and Health accelerated
We developed a population-based microsimulation model of
intestinal-type NCGA to estimate the impact of observed risk factor
trends on past and future cancer incidence for US men (Figure 1).
We focused on this subset of GCs, defined by criteria proposed and
used by Lauren , Henson et al., , and Wu et al. , as the
precancerous process and role of risk factors for this histologically
distinct subgroup of distally located tumors has been well-
established. The model explicitly incorporated the impact of H.
pylori and smoking on disease natural history. To accomplish this,
birth cohort trends were derived from NHANES and NHIS data,
and the model was calibrated to US data on precancerous lesions
and cancer to ensure model predictions were consistent with
epidemiologic data. Using the model, we projected population-
based intestinal-type NCGA outcomes between 1978 and 2040 in
which all risk factortrends wereallowedto vary over time (base-case
scenario). We then used the model to evaluate alternative risk factor
scenarios to provide insights on the potential benefit of past and
future GC control efforts.
Intestinal-Type NCGA Natural History Microsimulation
To allow for greater flexibility in capturing multiple dimensions
of heterogeneity, we refined a previously described intestinal-type
NCGA natural history model  to function as a microsimula-
tion model that simulates individuals within multiple 5-y birth
cohorts (born between 1881 and 2025) to generate population-
based cancer outcomes for men between 1978 and 2040. In the
model, intestinal-type NCGA develops through a series of
precancerous lesions, which may progress to dysplasia and
eventually invasive cancer (Figure 2). At the start of the simulation,
20-y-old individuals are assigned a birth cohort-specific risk factor
profile and enter the model. Each month, using rates derived via
previously described model calibration methods (see Table 1 and
Text S1) , individuals face a risk of progression among the
health states. On the basis of epidemiologic studies, we assumed
that in addition to causing gastritis, H. pylori increases the risk of
atrophy , while smoking increases the risk of progression to
intestinal metaplasia and dysplasia [11,12].
For each individual, we assigned H. pylori status at age 20 based
on NHANES data (Figure 3). As H. pylori infection is acquired in
childhood and persists unless treated with antibiotics [24,25], we
assumed that an individual’s status remained unchanged through-
out their lifetime. Smoking profiles for each individual, including
initiation and cessation age, were derived from the NHIS-based
Smoking History Generator (SHG) developed by the National
Cancer Institute (NCI) Cancer Intervention and Surveillance
Modeling Network (CISNET) (Figure 3) [26,27]. As the impact of
smoking on disease progression varies by intensity [11,12], we
categorized smokers into four subgroups: low (,10 cigarettes per
day [CPD]), moderate (10–19 CPD), heavy ($20 CPD), and
former smokers. The effect of smoking cessation on disease
progression was also assumed to be immediate upon quitting, with
progression rates declining and remaining at former smoker levels.
Given the multifactorial etiology of intestinal-type NCGA,
factors other than H. pylori and smoking have contributed to the
observed decline in cancer incidence. As such, we allowed birth
cohort-specific disease risk to vary over time, an approach
commonly used in population-based microsimulation models
. Specifically, as multi-stage models of gastric carcinogenesis
suggest exposures early on are likely responsible for incidence
declines among successive birth cohorts [3,8,29], we operationa-
Risk Factors and the US Decline of NCGA
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Risk Factors and the US Decline of NCGA
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Background. Cancer of the stomach (gastric cancer) is
responsible for a tenth of all cancer deaths world-wide, with
an estimated 700,000 people dying from this malignancy
every year, making it the second most common cause of
global cancer-related deaths after lung cancer. Unfortunate-
ly, the projected global burden of this disease estimate that
deaths from gastric cancer will double by 2030. Gastric
cancer has a poor prognosis with only a quarter of people
with this type of cancer surviving more than five years. In
order to reduce deaths, it is therefore of utmost importance
to identify and reduce the modifiable risk factors associated
with gastric cancer. Smoking and chronic gastric infection
with the bacteria Helicobacter pylori (H. pylori), are known to
be two common modifiable risk factors for gastric cancer,
particularly for a type of gastric cancer called intestinal-type
noncardia gastric adenocarcinoma (NCGA), which occurs at
the distal end of the stomach and accounts for more than
half of all cases of gastric cancer in US men.
Why Was This Study Done? H. pylori initiates a
precancerous process, and so infection with this bacteria
can increase intestinal-type NCGA risk by as much as 6-fold
while smoking doubles cancer risk by advancing increasing
progression of existing lesions. Changes in these two risk
factors over the past century (especially following the US
Surgeon General’s Report on Smoking and Health in 1964)
have led to a dramatic decline in the rates of gastric cancer in
US men. Understanding the combined effects of underlying
risk factor trends on health outcomes for intestinal-type
NCGA at the population level can help to predict future
cancer trends and burden in the US. So in this study, the
researchers used a mathematical model to estimate the
contribution of H. pylori and smoking trends on the decline
in intestinal-type NCGA incidence in US men.
What Did the Researchers Do and Find? The researchers
used birth cohorts derived from data in two national
databases, the National Health and Nutrition Examination
Survey (NHANES) and National Health Interview Survey
(NHIS) to develop a population-based model of intestinal-
type NCGA. To ensure model predictions were consistent
with epidemiologic data, the researchers calibrated the
model to data on cancer and precancerous lesions and using
the model, projected population outcomes between 1978
and 2040 for a base-case scenario (in which all risk factor
trends were allowed to vary over time). The researchers then
evaluated alternative risk factors scenarios to provide
insights on the potential benefit of past and future efforts
to control gastric cancer.
Using these methods, the researchers estimated that the
incidence of intestinal-type NCGA (standardized by age) fell
from 11.0 to 4.4 per 100,000 men between 1978 and 2008, a
drop of 60%. When the researchers incorporated only H.
pylori prevalence and smoking trends into the model (both
of which fell dramatically over the time period) they found
that intestinal-type NCGA incidence fell by only 28% (from
12.7 to 9.2 per 100,000 men), suggesting that H. pylori and
smoking trends are responsible for 47% of the observed
decline. The researchers found that H. pylori trends alone
were responsible for 43% of the decrease in cancer but
smoking trends were responsible for only a 3% drop. The
researchers also found evidence that after the 1960s,
observed trends in lower smoking initiation and higher
cessation accelerated the decline in intestinal-type NCGA
incidence by 7%. Finally, the researchers found that
intestinal-type NCGA incidence is projected to decline an
additional 47% between 2008 and 2040 (4.4 to 2.3 per
100,000 men) with H. pylori and smoking trends accounting
for more than 80% of the observed fall.
What Do These Findings Mean? These findings suggest
that, combined with a fall in smoking rates, almost half of the
observed fall in rates of intestinal-type NCGA cancer in US
men between 1978 and 2008 was attributable to the decline
in infection rates of H. pylori. Rates for this cancer are
projected to continue to fall by 2040, with trends for both H.
pylori infection and smoking accounting for more than 80%
of the observed fall, highlighting the importance of the
relationship between risk factors changes over time and
achieving long-term reduction in cancer rates. This study is
limited by the assumptions made in the model and in that it
only examined one type of gastric cancer and excluded
women. Nevertheless, this modeling study highlights that
continued efforts to reduce rates of smoking and H. pylori
infection will help to reduce rates of gastric cancer.
Additional Information. Please access these Web sites via
the online version of this summary at http://dx.doi.org/10.
N The National Cancer Institute gives detailed information
about gastric cancer
N The Gastric Cancer Foundation has information on gastric
cancer for patients and professionals
N Cancer Research UK explains types of gastric cancer
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