Alimentary Pharmacology and Therapeutics

Review article: the epidemiology and prevention of gastric cancer

K. M. Fock

Changi General Hospital, Singapore.

Correspondence to:
Dr K. M. Fock, Changi General
Hospital, 2 Simei Street 3, 529889,
Singapore.
Email: Kwong_ming_fock@cgh.com.sg

Publication data
Submitted 16 October 2013
First decision 1 November 2013
Resubmitted 11 March 2014
Resubmitted 22 April 2014
Resubmitted 4 May 2014
Resubmitted 12 May 2014
Accepted 12 May 2014
EV Pub Online 10 June 2014
This commissioned review article was
subject to full peer-review.

SUMMARY
Background
Gastric cancer can be divided into cardia and noncardia gastric adenocarcinoma (NCGA). Non cardia gastric cancer is a disease that has declined in global incidence but has remained as an extremely lethal cancer.
Aim
To review recent advances in epidemiology and strategies in prevention of non
cardia gastric cancer.
Methods
A rapid literature search strategy was developed for all English language literature
published before March 2013. The search was conducted using the electronic databases PubMed and EMBASE. The search strategy included the keywords stomach neoplasms, gastric cancer, epidemiology, risk factor, early detection of
cancer, mass screening, cancer burden, prevention and cost-effectiveness.
The search strategy was adjusted according to different requirements for each
database. The specic search was also performed in cancer-related websites for
country-specic information. The search was limited to past 10 years.
Results
Gastric cancer is the fth most common cancer but the third leading cause of
cancer death. The case fatality rate is 75%. Screening by radiological or endoscopic methods has limited success in prevention of gastric cancer. Helicobacter
pylori has been identied as a carcinogen, accounting for 6070% of gastric cancer globally and eradication is a potential preventive measure. A meta-analysis in
2009 demonstrated that individuals treated with H. pylori eradication therapy can
reduce gastric cancer risk. The extended Shandong Intervention trial that lasted
14.3 years showed that H. pylori eradication therapy signicantly reduced gastric
cancer incidence by 39%. Consensus groups from Asia, Europe and Japan have
recommended H. pylori eradication as primary prevention in high-risk areas. Following eradication therapy, endoscopic surveillance of pre-malignant lesions
using enhanced imaging appears to be another promising preventive strategy.
Conclusions
Gastric cancer remains a major diagnostic and therapeutic challenge. There is
emerging evidence that H. pylori eradication in high gastric cancer regions can
lead to a decline in the incidence of this highly lethal disease.
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doi:10.1111/apt.12814

Review: gastric cancer epidemiology and prevention

EPIDEMIOLOGY
Incidence of gastric cancer
Till 2008, stomach cancer was still the fourth most common cancer in the world.1 According to Globocan 2012,2
there were about 952 000 new cases of stomach cancer
in the world accounting for 6.8% of all cancer making it
the fth most common malignancy globally after lung,
breast, colorectum and prostate. This represents a substantial change since 1975 when stomach cancer was the
most common malignancy. More than 70% of gastric
cancer occurs in developing countries. Currently, three
East Asia countries: China, Japan and Korea account for
60% of total cases. Age-standardised incidence rates of
gastric cancer are about twice as high in men as in
women, at 35.4 per 100 000 in Eastern Asia males and
13.8 in Eastern Asia females. United States of America,
Africa and Eastern Mediterranean region have the lowest
incidence rates.
Regional variations in incidence of gastric cancer in
part reect differences in dietary patterns, salt intake,
prevalence of Helicobacter pylori infection, host factors
as well as H. pylori virulence factors. Helicobacter pylori
has been estimated to account for 60% of gastric cancer
cases worldwide.3 As shown in the Eurogast study, H.
pylori prevalence and gastric cancer incidence have a
close correlation. There are exceptions leading to the
term Indian Enigma and African enigma for countries
where there is a high prevalence of H. pylori infection
and yet a disproportionately low gastric cancer incidence
or mortality (Table 1).2, 410
Mortality rate. Although gastric cancer is the fth most
common malignancy in the world, it is the third leading
cause of death in both sexes (723 000 deaths) accounting
for 8.8% of the total deaths from cancer. The highest
mortality rates are in East Asia being 24 per 100 000 in
men, 9.8 per 100 000 in women and the lowest in North
America1 (2.8 and 1.5 respectively for males and
females). High mortality rates are also present in both
sexes in Central, Eastern Europe and South America.
Case fatality rate. The case fatality rate is the mortality
rate divided by the incidence rate for a specic period of
time. The overall case fatality rate of stomach cancer is
74.5% compared with 50.4% for colorectal cancer, 95.2%
for liver cancer and 96.8% for pancreatic cancer.11 There
is no gender difference in the case fatality rate of stomach cancer (74.0 males vs. 74.5 females). However, a difference of about 23% is seen in the case fatality rate for
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Table 1 | Prevalence of Helicobacter pylori infection and

incidence of gastric cancer

Country
High risk
Bulgaria
China
Estonia
Italy
Japan
Korea
Portugal
Vietnam
Intermediate risk
Chile
Czech Republic
Germany
Hong Kong
Malaysia
Overall
Chinese
Malay
Indian
Singapore
Overall
Chinese
Malay
Indian
Taiwan
Low risk
Australia
Bangladesh
Brazil
Canada
India
The Netherlands
Nigeria
The Thailand
Sweden
UK
USA

Helicobacter
pylori
prevalence (%)

Age-standardised
incidence rate of
gastric
cancer
(per 100 000)
Male

Female

61.75
58.074
69.05
58.06
39.34
59.64
84.27
74.64

23.42
41.44
30.72
22.12
62.14
69.74
27.92
21.84

11.22
19.24
15.32
11.42
26.14
26.84
13.22
10.04

36.05
42.15
48.85
58.43

28.42
16.52
15.82
19.34

9.22
8.02
8.42
9.64

35.94
26.757.84
11.929.34
49.452.34

11.94
2.64
12.94

8.74
1.34
7.94

31.04
48.34
27.94
48.14
54.54

21.44
6.64
7.84
18.64

10.84
3.84
6.14
10.54

15.14
92.04
82.05
23.15
79.04
48.09
91.05
574
11.05
27.68
30.710

9.84
1.64
9.62
5.32
5.74
7.62
2.02
4.32
7.22
6.44
5.32

4.14
1.04
5.02
3.82
2.84
3.92
2.02
2.72
4.32
3.14
2.72

low-income countries compared with high-income countries (81.6% vs. 58.3%). This suggests that with appropriate resource allocation, it is possible to improve the
outcome. Resources spent on early detection and treatment, i.e., secondary prevention could reduce mortality.
In Japan, the 5-year survival for gastric cancer has been
4060% compared with 27% in USA and 22% in Europe.
The comparatively better overall survival in Japan is
attributed to the larger proportion of early stage gastric
cancer being diagnosed, and differences in tumour
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K. M. Fock
biology and location.12 Between 1995 and 2000, 53% of
gastric cancer in Japan were localised (early gastric cancer) at time of diagnosis which is higher than 1420%
reported by US SEER programme.13 The 5-year survival
rate for localised tumour is 86% compared with 32% for
advanced gastric cancer. It has been shown that the
improvement in survival rates in Japan has been in tandem with the increase in the proportion of gastroscopic
examinees, but not with the incidence in cases detected
by photourographic screening.14

Time trends of gastric cancer

The incidence of noncardia gastric adenocarcinoma
(NCGA) declined steadily worldwide, although there are
variations in the magnitude of decline among countries.
In the USA, incidence rates have decreased by more than
80% since 1950, whereas in countries such as Japan,
China and Korea, the decline has been much less.15
Between 1977 and 2006, the incidence of NCGA in the
USA declined among all race and age groups except for
whites aged 2939 years for whom there was a signicant increase from 0.27 to 0.45 per 100 000 population.16
The reasons for this global decrease in incidence and
mortality rates are not fully understood but currently are
thought to be due to:
(i) increased refrigeration leading to increased availability of fresh fruits and vegetables;
(ii) decreased reliance on salted and preserved foods;
(iii) reduction in chronic H. pylori infection due to
improvement in public health measures;
(iv) increased screening activities in certain high-risk
countries;
(v) reduction in smoking may have contributed to a
decrease in stomach cancer rates in Western countries notably UK and USA. Smoking is thought to
contribute to 10% of all gastric cancer worldwide;
(vi) In developed countries with frequent use of antibiotics, serendipitous eradication of H. pylori is
thought to partly account for decline in gastric
cancer.
Although non cardia gastric cancer incidence rates
have declined, incidence of gastric cardia cancer in the
USA and several European countries have increased and
is thought to be linked to a rise in gastro-oesophageal
reux disease associated with the increase in obesity that
is reaching epidemic proportions in these countries.
Another contributing factor for the increase in gastric
cardia cancer is the improved differentiation between
adenocarcinoma of oesophagus and gastric cardia cancer
252

through standardised international classication of the

site of cancer.

Prevention
The preceding sections of this article have focused on
epidemiology of gastric cancer. Ultimately, the goal of
epidemiology is to provide information in designing policies targeted at preventing the development of cancer.
Prevention of gastric cancer can be achieved at three
levels:
(i) Primary prevention which involves reducing exposure to risk factors or by increasing the resistance
to risk factors.
(ii) Secondary prevention which is targeted at early
detection and treatment of disease. Screening is an
important part of secondary prevention of individuals who are still in the pre-clinical or asymptomatic phase.
(iii) Tertiary prevention refers to treatment, rehabilitation, and palliation to improve the outcome of illness in affected individuals.
There are four potential areas for prevention of gastric
cancer:
(i) Helicobacter pylori eradication
(ii) Life style modication, eliminating contributing factors smoking cessation and managing obesity
(iii) Early detection through screening activities
(iv) Surveillance of pre-malignant lesions

Helicobacter pylori eradication

In February 2009, an expert group reviewed the list of
infectious agents that were classied by International
Agency for Research on Cancer (IARC) as carcinogenic
to humans to determine the global burden of cancers
attributable to infectious agents.17 This is an extension of
the work done previously in 2002. The group dened
population attributable fraction (PAF) as the proportion
of new cancer cases (i.e. incidence) in a specic population that would have been prevented by a hypothetical
intervention on a specic exposure to infection. World
Health Organization (WHO) has dened PAF as the
reduction in incidence that would be observed if the
population was entirely unexposed compared with its
current (actual) exposure pattern.18 It is a measure of
the burden of disease attributed to a specied risk exposure.17 The PAF for gastric cancer for H. pylori infection
was estimated to be 75%. The total number of cases
attributable to H. pylori infection was 650 000 based on

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a relative risk (RR) estimate of H. pylori infection in
noncardia gastric cancer to be 5.9 (based on nested studies) and H. pylori sero-prevalence in gastric cancer estimated to be 90%.17 The potential for reducing the
incidence of gastric cancer through H. pylori eradication
is enormous.
Earlier in 2008, the Asian Pacic Consensus on gastric cancer prevention recommended population screening and antibiotic treatment of H. pylori in high-risk
population. Their recommendation was based on a
meta-analysis of pooled data of ve randomised studies
of screening and eradicating H. pylori in East Asia.19
The meta-analysis performed for the consensus meeting
and subsequently revised based on all of the available
data concluded that the pooled RR of developing gastric
cancer after H. pylori eradication therapy was 0.56 (95%
CI: 0.40.8). The data were considered highly suggestive
of a cancer protective role for H. pylori eradication. This
was further corroborated by another meta-analysis a
year later that included seven randomised control studies
of which all but one were performed in Asia.20 One
study (Fukase) included patients who already had early
gastric cancer, but after endoscopic resection were
randomised to receive H. pylori eradication or placebo.21
Excluding Fukase study, 37 of 3388 (1.1%) treated
patients developed gastric cancer compared with 56 of
3307 (1.7%) untreated participants. The RR for gastric
cancer based on these 6685 participants was 0.65 (95%
CI: 0.430.98).20 Adding Fukase study to the pooled
analysis (i.e. including gastric cancer recurrence) yielded
a RR of 0.57 (95% CI: 0.400.81). Subgroup analysis of
the two studies that looked at gastric cancer incidence as
primary outcome yielded a RR of 0.46 (CI: 0.260.82).
Subgroup analysis of the ve studies that examined the
effects of therapy on progression of pre-neoplastic
lesions yielded a RR of 0.66 (CI: 0.411.04). Although
the studies were performed in areas with high gastric
cancer incidence regimens, individually they were underpowered and failed to show reduction of gastric cancer
incidence. To achieve adequate statistical power to demonstrate a 50% reduction in gastric cancer incidence
would require 17 625 subjects and a follow-up of
10 years or more.22
The Shandong Intervention trial was one of the studies
included in the meta-analysis by Fuccio. After the initial
report was published, the authors further extended the
period of follow-up by 7.3 years.23 In brief, the interventions used in the study to prevent gastric cancer were: (i)
2 weeks of amoxicillin and omeprazole given to H. pylori
seropositive subjects or (ii) 7 years of supplementation
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with garlic extract or (iii) supplementation with vitamins

C, E and selenium. In the rst phase of the study, H.
pylori eradication signicantly reduced the prevalence of
pre-cancerous gastric lesions whereas use of garlic and
vitamins did not. With the extended follow-up to
14.3 years, the incidence of gastric cancer was signicantly reduced in H. pylori-eradicated group compared
with the garlic- or vitamins-supplemented groups (3% vs.
4.6%) with odds ratio 0.6 (95% CI: 0.380.96, P = 0.032)
corresponding to an absolute risk reduction of 1.6% (CI:
0.03.2%) or 39% of gastric cancers. Deaths from gastric
cancer were 1.5% in the subjects treated with antibiotics
compared with 2.1% in those assigned to vitamins or placebo, with a hazard risk of 2.67 (95% CI: 0.361.28). This
is the rst single trial that demonstrated that H. pylori
eradication therapy signicantly reduced gastric cancer
incidence. It is noteworthy that the study needed almost
15 years of follow-up to demonstrate efcacy.

Cost effectiveness of screening and treatment of H.

pylori as a preventive measure
The data supporting H. pylori eradication as a strategy
for gastric cancer prevention in regions with high gastric cancer incidence are increasing. Once this strategy
is recognised as a feasible public health preventive measure, implementation issues need to be resolved. The
Asia Pacic Consensus on Gastric Cancer Prevention
suggested that the age for screening and treatment
should begin 1020 years before the incidence of gastric
cancer starts to increase or take-off in that country, i.e.
before pre-malignant changes occur. The rationale for
such an approach is based on Correas hypothesis of
gastric carcinogenesis that begins with chronic active
gastritis progressing to chronic atrophic gastritis, intestinal metaplasia (IM), dysplasia and nally gastric cancer.24 In 2008, Yeh et al. used an empirically calibrated
model of gastric cancer to project reduction of gastric
cancer risks, life expectancy and cost effectiveness based
on three scenarios:25
(i) One time screening and treatment at age 20, 30 or 40
(ii) One time screening followed by rescreening subjects with negative results
(iii) Universal treatment for H. pylori at age 20, 30 or 40
The projection used data from the literature for
pre-cancerous lesions, H. pylori prevalence, sensitivity
and specicity of diagnostic tests and effectiveness of
treatment. The projection showed that screening and
treatment for H. pylori at age 20 was most cost effective
and reduced the mean lifetime cancer risk by 14.5% in
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K. M. Fock
men and 26.6% in women and could result in prevention
of one in every four to six cases of gastric cancer in
China. The cost per year of life saved (YLS) would be
less than $1500 compared to no screening. Universal
treatment could prevent an additional 1.52.3% of gastric
cancer, but incremental cost effectiveness ratio (ICER)
would exceed $2500 YLS. The authors argued that on
cost effectiveness criteria, screening and treatment should
commence at age 20 years.
In countries with a low incidence of stomach cancer
such as the UK, at least two reviews have been published. Hillier et al.26 in 2009 reviewed the literature on
stomach cancer screening concluded that the potential
harm outweighs the potential benets of a national
stomach cancer screening programme in the UK. The
initial test for H. pylori was either invasive or has risks
associated with radioactivity. Furthermore, the programme was unlikely to be cost effective. By using NHS
costs based on year 2000 prices, a health technology
assessment in 200327 estimated the cost effectiveness of
H. pylori screening on mortality and morbidity from gastric cancer and peptic ulcer disease by using a
patient-oriented simulation model. The study found that
the cost effectiveness of H. pylori screening improved
with age and was under 10 000 per life year (LYS) for
all age groups, which compared favourably with other
screening programmes. However, the efcacy of H. pylori
eradication on pre-malignant lesions were uncertain at
that time and more evidence would be required before it
could be recommended as a national policy. Nevertheless, a pilot H. pylori screening programme screening of
all 4049 years old and then all individuals as they
reached the age of 40 was suggested.

Combined primary and secondary preventive

strategies for gastric cancer in Matsu Island
The Asia Pacic consensus on Gastric Cancer screening
further stated that primary prevention of gastric cancer
by H. pylori eradication should not replace the existing
practice of screening/surveillance. In fact from a systems
perspective by combining the primary and secondary
prevention strategies, the outcome is expected to be better than if either strategy is employed alone. A study
took place in Matsu island, located between China and
Taiwan where the residents have a high prevalence of H.
pylori infection and the annual death rate for gastric cancer was 39 that of Taiwan.28 Between 1995 and 1998, a
secondary prevention programme based on an initial
biomarker test (serum pepsinogen and anti-H. pylori
antibody), with those who were identied as high risk
254

for gastric cancer were referred for endoscopy was

implemented. From 1999 to 2003, there was no further
screening programme for gastric cancer although screening for chronic disease (diabetes, hypertension and hyperlipidaemia) was carried out. This was considered to
be a washout period prior to instituting a primary prevention programme in 20042008. During the second
period, participants positive for urea breath test (UBT)
underwent endoscopic screening, histological assessment,
H. pylori eradication therapy and post treatment UBT.
Repeat treatment, consisting of a levooxacin-based triple therapy was given to treatment failures followed by
another UBT. In 2008, another course of chemoprevention and endoscopic assessment was carried out. The
Matsu study was actually a combined chemoprevention
and endoscopic surveillance study although the report of
the study focused on the efcacy of mass chemoprevention. The main ndings of the study showed that H.
pylori eradication signicantly reduced the incidence of
gastric atrophy and peptic ulcer disease and the reinfection/recrudescence rate was 1% per person year. Helicobacter pylori eradication did not reduce the incidence of
IM or decrease its histological severity, supporting the
concept that IM is the point of no-return. The study did
show increased incidence of oesophagitis which was also
associated with increased waist circumference in male
gender. There was a decline in the 5-year average incidence of gastric cancer from 40.3 to 30.4 per 100 000
person years, but the rate ratio and intervention effectiveness were statistically not signicant. With the information from the Shandong intervention trial, this is not
surprising, and extrapolating from Shandong study, a
statistically signicant reduction in incidence gastric cancer in Matsu could emerge about 15 years from 2004,
i.e. 2019 onwards.
The same group that carried out the Matsu study performed a cost effectiveness analysis earlier in 2007 comparing primary and secondary prevention, based on the
data obtained from the Matsu study up to 2005. The
ICER for once only chemoprevention at age 30 years vs.
no screening was US$17 044 per YLS. Annual screening
at age 50 years vs. no screening gave an ICER of US
$29 741 YLS. Chemoprevention was more cost effective
than surveillance, but could be dominated by high-risk
surveillance when the screening age was older than
44 years.29
Further evidence supporting the efcacy of H. pylori
eradication in prevention of gastric cancer emerged from
Finland, a country with low gastric cancer risk.30 Helicobacter pylori antibody data from 26 700 patients from
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Review: gastric cancer epidemiology and prevention

1986 to 1998 were available in the diagnostic service laboratory of the University of Helsinki. They were divided
into three groups according to the H. pylori antibody
status at baseline and subsequent changes in antibody
levels. There were 3650 patients who were seropositive at
baseline and whose antibody titres fell rapidly, categorised as Hp+ cured. A second group of 11 628 initially
seropositive and subsequent serological information
regarding cure was lacking (Hp + No Info) and a third
group of 11 422 who were H. pylori ve. The mean follow-up was 10 years and the number of gastric cancers
from this cohort derived from Finnish Cancer Registry
was 72. For the Hp+ cured, the standardised incidence
ratio was 1.62, but decreased from the 6th year to 0.14
(CI: 0.000.75) showing that curing H. pylori infection
led to a signicantly reduced incidence of gastric cancer
even in low gastric cancer risk regions.

Strategised approach for gastric cancer prevention in

Japan
In Japan, the Japanese Society of Gastroenterology, the
Japan Gastroenterological Endoscopy and The Japanese
Society for Helicobacter Research working with the Japanese Minister of Health, Labour and Welfare have developed a new approach for elimination of gastric cancer in
Japan. The plan which was implemented in 2013 consists
of two tiers:31
(i) For younger generation dened as 20 years and
below
(ii) For people 50 years and above
A test-and-treat strategy to H. pylori infection is recommended in younger people below 20 years. For people
aged 50 years or older, primary prevention, i.e. H. pylori
eradication combined with secondary prevention by
endoscopic examination is the intervention recommended. This new approach is aimed at reducing the
incidence and mortality of gastric cancer at a reduced
cost to the current cost of 300 billion yen (US 3 billion
dollars) per year spent on gastric cancer treatment in
Japan. The rationale for the two tier strategy is based on
the observation that chemoprevention in younger people
is more effective than in older people, particularly those
without pre-cancerous lesions.

Japanese and European Consensus Guidelines on H.

pylori infection
One of the advocates for the proposed two tier preventive strategy, the Japanese Society for Helicobacter
Research had revised their guidelines for management of
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H. pylori infection in Japan in 2010 to include the gastric

cancer indications for H. pylori eradication as follows:32
(i) Patients after endoscopic treatment of early gastric
cancer (Level II Evidence) to prevent metachronous
gastric cancer
(ii) Atrophic gastritis (Level I evidence) leading to
improvement of gastric mucosal atrophy but no
improvement of IM.
The European Helicobacter study group (EHSG) in
Maastricht IV report has33 also supported the views of
their Asian counterparts with the following key statements:
(i) Helicobacter pylori infection is the most consistent
risk factor for gastric cancer. Its elimination is
therefore the most promising strategy to reduce the
incidence of gastric cancer (Evidence level: 1a)
(ii) The risk of gastric cancer can be reduced more
effectively by employing eradication treatment
before the development of pre-neoplastic condition
(Evidence level: 1a)
(iii) Helicobacter pylori eradication to prevent gastric
cancer should be undertaken in populations at high
risk (Evidence level: 1c)
(iv) The inuence of environmental factor is subordinate to the level of H. pylori infection (Evidence
level: 1c)
The Second Asia Pacic Consensus Guidelines for H.
pylori infection34 published in 2009 also endorsed the
Asia Pacic Consensus on gastric cancer prevention, reiterating that screen and treat for H. pylori infection in
population with high incidence of gastric cancer is an
effective strategy for gastric cancer prevention. The consensus group further emphasised that eliminating
H. pylori infection through improvements in public health
and education will have the greatest impact in reducing
the burden of gastric cancer. A global consensus in H.
pylori gastritis held in Kyoto from January to February
2014 has also endorsed the need for primary prevention
through H. pylori eradication (K. Sugano, personal
communication) and the report will be published shortly.

Surveillance of pre-malignant conditions

As endoscopic surveillance of pre-malignant conditions
are mostly performed with standard white light endoscopy (WLE), enhanced endoscopic imaging by high
magnication, narrow band imaging (NBI) or confocal
endoscopy were innovations introduced to improve the
diagnostic yield. Our group has performed a comparison

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K. M. Fock
of NBI with standard WLE using Olympus GIF FQ260Z,
a magnifying endoscope with NBI as well as conventional WLE. Over a 30-month period, 458 patients were
endoscoped. WLE detected focal lesions in 200 patients
and made a denitive diagnosis in 148. NBI-ME correctly claried the nature of the remaining 52 lesions.
NBI detected an additional 69 lesions missed by WLE.
Using NBI-ME, 67 lesions were diagnosed as IM, one
lesion diagnosed as early gastric cancer and one lesion
was benign. The incremental yield of NBI over WLE for
detection of IM was 3.7-fold (Figures 14).35 Several
other researchers have found that NBI have good sensitivity and specicity for diagnosis of gastric lesions.3639
In an attempt to reach consensus, a working group
from the European study of Gastrointestinal Endoscopy,
EHSG, European Study of Pathology, European Society
of Pathology and the Sociedade Portuguesa de Endoscopia Digestiva jointly noted in their guidelines that conventional WLE cannot diagnose pre-neoplastic gastric
conditions/lesions. Magnication chromo-endoscopy or
NBI endoscopy with or without magnication may be
offered in those cases as it improves diagnosis of gastric
pre-neoplastic lesions. The group further advised at least
four biopsies of the proximal and distal stomach and use
systems of histopathological scoring OLGA (operative
link for gastritis assessment) and OLGIM (operative link
for gastritis IM) to improve endoscopic surveillance.40
Patients with extensive atrophy and/or extensive IM
should be offered endoscopic surveillance every 3 years.
Further studies are needed to estimate cost effectiveness
of this strategy. Detection of early gastric cancers may
not lead to better clinical outcome as extensive surgery
may not be feasible in elderly patients. Emerging endo-

NBI

Figure 2 | Intestinal metaplasia demonstrated by NBI.

Figure 3 | White light endoscopy. Early gastric cancer.

scopic therapeutic technologies such as endoscopic

mucosal resection and endoscopic submucosal dissection
can allow removal of dysplastic and early cancerous
lesions in elderly patients without need for surgery. Japanese studies have shown that the 5-year survival rates
are greater than 85% in patients less than 80 years old
using these endoscopic techniques.41

Figure 1 | White light endoscopy. Appearance only

suggestive of gastritis.
256

Other environmental risk factors

Salt and salt-preserved foods. There is evidence from
casecontrol, ecological and cohort studies that link high
dietary salt intake and salt-preserved foods such as salted
sh, vegetables and canned meat with gastric cancer.
Studies have found an increased risk of about twofold
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Review: gastric cancer epidemiology and prevention

COLL: 40 NBI

Figure 4 | NBI with 100-fold magnication. Presence of

distorted microsurface and microvessel patterns.

for frequent consumption of salt and salted-preserved

foods.42 The increased risk is associated with H. pylori
infection and atrophic gastritis. In 2007, salt and
salted/fatty foods were classied as probable risk factors for gastric cancer.43 The decline in the incidence
of gastric cancer worldwide over the last 50 years have
been attributed, at least in part, to the use of refrigeration which would in turn reduce the need for salt-based preservation of food.44 High-salt diet has been
shown to exacerbate gastritis by increasing H. pylori
colonisation in C57B4G mice and may potentiate H.
pylori-associated carcinogenesis.45 It has also been
shown in Mongolian Gerbils that high-salt diet has a
synergistic promoting effect on H. pylori infection and
gastric carcinogenesis.46

Foods, vegetables, bre, alcohol and nitrosamine. Intake

of fruits and vegetables has been shown to be protective
against gastric cancer in case studies. The risk reduction
has been estimated to be 30% for vegetables and 40% for
fruits.47 On the other hand, a meta-analysis estimated
the RR of gastric cancer associated with consumption of
30 g48 of preserved meat was 1.15 (95% CI: 1.041.27)
presumably from N-nitroso compound. There is a lack
of association between moderate alcohol ingestion and
gastric cancer risk49 as shown in a recent meta-analysis.
Smoking. Smoking is associated with an increased risk of
stomach cancer. The RR in current smoker is 1.6 and former smoker is 1.2.50 A prospective study performed in Europe by the European Prospective Investigation into cancer
and Nutrition (EPIC) found that the risk declined after
10 years of cessation of smoking.51 According to IARC,
smoking is responsible for about 10% of all cases of gastric
cancer.52 Smoking increases the risk of both cardia and
non cardia stomach cancer, although less in the latter.53
Genetic polymorphisms and gastric cancer
In addition to environmental factors, genetic factors also
play an important role in gastric carcinogenesis, as evidenced by the fact that only 1% of individuals infected
with H. pylori develop gastric cancer. Molecular epidemiological studies have identied a number of genetic polymorphisms, mostly single nucleotide polymorphisms
(SNP) as risk factors for gastric cancer. These SNPs are
involved in inammatory response, DNA repair, tumour
suppression and metabolism of chemical carcinogens.
There are considerable inconsistencies of the reports thus
far and a summary of the ndings from meta-analyses is
provided.

Table 2 | Interventions for primary prevention of gastric cancer

Interventions for primary prevention of gastric cancer
I. Helicobacter pylori infection eradication
Meta-analysis of seven randomised studies in high gastric cancer risk areas suggest that eradication of H. pylori infection may
reduce gastric cancer risk (1.7% vs. 1.1%; RR = 0.65; CI: 0.430.98)
In Shandong, China extension of an intervention study to 14.3 years, saw a reduction in incidence of gastric cancer by 39%
Mortality from gastric cancer in that study was 1.5% vs. 2.1% and hazard risk 2.67 (CI: 0.361.28)
II. Cessation of smoking
Relative risk of gastric cancer in former smokers 1.2 and in current smokers 1.6
Risk of cancer decreased with smoking cessation
III. Diet
Diet with excessive salt increases risk of gastric cancer by twofold
Animal studies showed that high-salt diet has a synergistic on promoting effect on H. pylori infection and gastric cancer
Increased intake of vegetables and salt has been estimated to reduce gastric cancer risk by 30% and 40% respectively
No conclusive data if dietary changes alone can reduce gastric cancer incidence
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K. M. Fock
IL-1B and IL-1RN. IL-1B is a potent pro-inammatory
cytokine that regulates pro-inammatory reaction and
immune response. Early investigation by El-Omar et al.54
showed an association of gastric cancer risk with genotypes carrying IL-1B-511T, IL-IB-3IT and IL-1RN *2/*2
with odds ratio of 2.5 (95% CI: 1.63.8), 2.6 (95% CI:
1.73.9) and 3.7 (CI: 2.15.7) for the homozygotes
respectively. However, studies performed on Koreans55
and Taiwanese Chinese56 did not nd any association
between IL-1B and IL-1RN polymorphisms and gastric
cancer risk. Three meta-analyses have been performed to
assess the association of IL-1 polymorphisms with gastric
cancer and two57, 58 have found an association with
IL-1B-511T and IL IRN*2 and increased gastric cancer
risk in Caucasian but not in Asian population.
TNF-a. Tumour necrosis factor alpha (TNF-a) is
another potent pro-inammatory cytokine and acid
inhibitor with increased expression in H. pylori infection.
There are multiple polymorphisms in the TNFA gene.
Early reports suggest that pro-inammatory genotypes
were associated with increased gastric cancer risks.59
Two meta-analyses support an association of
TNFA-308A and TNFA-857T alleles with increased risk
of gastric cancer particularly in Caucasian population.60
Methylenetetrahydrofolate reductase. Methylenetetrahydrofolate reductase has up to 281 polymorphisms.
MTHR 677C>T had been reported to be associated with
gastric cancer risk in East Asians but not in Caucasians
whereas 1298H>C was associated with gastric cancer
only in East Asians.61
Cyp2e1. CYP2E1 is one of the major cytochrome P450
isoenzymes that catalyses the activation of various nitrosamines and other low-molecular weight carcinogens. CYP2E1*2 (C2) allele has been shown in a
meta-analysis by Boccia to be associated with gastric
cancer risk in Asians but not in Caucasian population,
perhaps due to a lower prevalence of CYP2E1 C2
allele in Caucasian.62

The genetic susceptibility described above could inuence the population attributable risk by modulating the
effects of environmental risk factors including H. pylori
in a given population and could explain the African
enigma and Indian enigma. Despite the advances in
the eld of cancer epidemiology, a re-evaluation of gastric cancer susceptibility and potential functional polymorphisms in genes is needed as there are signicant
inconsistencies in the results so far.

CONCLUSION
Despite the declining incidence, gastric cancer remains a
disease with high mortality rate with nearly three quarter
of a million people dying annually. Helicobacter pylori is
the single most important factor estimated to account for
6070% of all cases. In the last 5 years, data have emerged
demonstrating that eradicating H. pylori can reduce the
progression of pre-neoplastic lesions except chronic atrophic gastritis, IM and dysplasia. A clinical trial in China
has shown that gastric cancer incidence was reduced by
39% over a period of 15 years after H. pylori eradication
(Table 2). Combining H. pylori eradication with endoscopic screening has shown promise in reducing gastric
cancer incidence in communities with high gastric cancer
incidence. The Asia Pacic Gastric Cancer Prevention
group is now joined by the European and Japanese counterparts in advocating a primary and secondary gastric
cancer programme in high gastric cancer incidence
region. This risk stratied approach to gastric cancer prevention is being adopted in Japan and could pave the way
for eradicating this highly lethal cancer.
AUTHORSHIP
Guarantor of the article: Kwong Ming Fock.
Author contributions: K. M. Fock approved the nal version of the manuscript.
ACKNOWLEDGEMENTS
Declaration of personal and funding interests: Prof Fock
Kwong Ming has been invited as a speaker by Eisai,
Takeda and Reckitt Benckiser.

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