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Asia-Pacific Consensus Guidelines on Gastric Cancer Prevention
Kwong Ming Fock; Nick Talley; Paul Moayyedi; Richard Hunt; Takeshi Azuma; Kentaro Sugano; Shiu Kum
Lam; Khean Lee Goh; Tsutomu Chiba; Naomi Uemura; Jae G Kim; Nayoung Kim; Tiing Leong Ang;
Varocha Mahachai; Hazel Mitchell; Abdul Aziz Rani; Jyh Ming Liou; Ratha-korn Vilaichone; Jose Sollano
J Gastroenterol Hepatol. 2008;23(3):351-365.
Abstract
Background and Aim: Gastric cancer is a major health burden in the Asia-Pacific region but consensus on
prevention strategies has been lacking. We aimed to critically evaluate strategies for preventing gastric cancer.
Methods: A multidisciplinary group developed consensus statements using a Delphi approach. Relevant data were
presented, and the quality of evidence, strength of recommendation, and level of consensus were graded.
Results: Helicobacter pylori infection is a necessary but not sufficient causal factor for non-cardia gastric
adenocarcinoma. A high intake of salt is strongly associated with gastric cancer. Fresh fruits and vegetables are
protective but the use of vitamins and other dietary supplements does not prevent gastric cancer. Host-bacterial
interaction in H. pylori infection results in different patterns of gastritis and differences in gastric acid secretion which
determine disease outcome. A positive family history of gastric cancer is an important risk factor. Low serum
pepsinogens reflect gastric atrophy and may be useful as a marker to identify populations at high risk for gastric
cancer. H. pylori screening and treatment is a recommended gastric cancer risk reduction strategy in high-risk
populations. H. pylori screening and treatment is most effective before atrophic gastritis has developed. It does not
exclude the existing practice of gastric cancer surveillance in high-risk populations. In populations at low risk for
gastric cancer, H. pylori screening is not recommended. First-line treatment of H. pylori infection should be in
accordance with national treatment guidelines.
Conclusion: A strategy of H. pylori screening and eradication in high-risk populations will probably reduce gastric
cancer incidence, and based on current evidence is recommended by consensus.
Introduction
Gastric cancer is a major public health burden. Globally, it is the fourth most common cancer and the second leading
cause of cancer-related death, with 700 000 deaths annually.[1] The risk of gastric cancer varies among the countries
and populations in the Asia-Pacific region. High-risk areas include East Asian countries such as China, Japan and
Korea, where the age-standardized incidence rate (ASR) is greater than 20 per 100 000. Intermediate risk countries
(ASR 11-19/100 000) include Malaysia, Singapore and Taiwan, while low-risk areas (ASR < 10/100 000) include
countries such as Australia, New Zealand, India and Thailand.[1]
Gastric cancer carcinogenesis is a multifactorial process, related to an interaction of host factors, H. pylori infection
and environmental factors such as diet. There is a precancerous cascade, in which the gastric mucosa undergoes a
series of changes resulting in gastritis, atrophy, intestinal metaplasia, and dysplasia, before developing eventually into
gastric cancer.[2] At an early stage, gastric cancer may be clinically silent and, in most countries, patients have
advanced cancer at diagnosis. When diagnosed at an early stage, 5-year survival rates for gastric cancer exceed
90%.[3,4] In addition, early gastric cancer, depending on the depth of mucosal infiltration and degree of differentiation,
may also be suitable for endoscopic mucosal resection or submucosal dissection, with lower morbidity, but similar
efficacy, when compared to surgery.[5,6] However, when diagnosed at an advanced stage, 5-year survival rates may be
only in the range of 10-20%.[7,8]
To reduce the morbidity and mortality from gastric cancer, it would be necessary to diagnose gastric cancer at an early
stage, and explore means of gastric cancer prevention by addressing modifiable environmental risk factors such as diet
and H. pylori infection. Currently, a strategy of population screening for gastric cancer is being adopted in Japan,[9]
Korea[10] and Matsu Island in Taiwan.[11] No formal programs exist in other countries, either in terms of gastric cancer
screening or screening for modifiable factors such as H. pylori infection. In order to address this major health
problem, the The Asia-Pacific Gastric Cancer Consensus Conference was convened in order to review and synthesize
the most current information, assess the evidence for current and potential intervention strategies and to decide
whether it is timely to adopt a bold proactive approach towards gastric cancer prevention by recommending H. pylori
screening and eradication.
Methods
Nature and Extent of Background Preparation
The Asia-Pacific Gastric Cancer Consensus Conference was convened specifically to address three main areas
relevant to the prevention of gastric cancer and, specifically, gastric adenocarcinoma. These areas were: (i)
epidemiology, host and bacterial factors; (ii) gastric cancer surveillance and H. pylori screening; and (iii) H. pylori
eradication to prevent gastric cancer.
The consensus conference was held from 11 to 12 November 2006 in Bangkok, Thailand. The consensus conference
was sponsored by the Asian Pacific Association of Gastroenterology. The Journal of Gastroenterology and
Hepatology Foundation provided financial support for the conference through an unrestricted educational grant.
Sixteen Asian gastroenterologists and four external experts were invited to participate in the consensus conference on
the basis of their expertise (Appendix I). None of the participants were remunerated for their participation in the
meeting.
Each of the three topics chosen for evaluation and formulation of clinical recommendations was addressed
independently. Selected papers relevant to the topics to be discussed were circulated and an overview of each topic
based on comprehensive literature searches was presented by selected participants based on their specific expertise.
This was followed by a period of discussion, in which the existing data were evaluated and critiqued. At the end of
this discussion, a recommendation with specific wording was formulated. For data related to therapeutic interventions,
the quality of the evidence and the classification of evidence relative to the recommendation were assessed. Once an
acceptable recommendation based on available evidence was established, formal voting for each statement of
recommendation was undertaken ( Table 1 ). Acceptance of a statement required that at least two-thirds of the votes
were in categories 'a (strongly agree)' or 'b (agree)'.
Preparation Process and Format of the Report
The manuscript was drafted by a working group, and this was then circulated to and reviewed by conference
participants, who approved the final draft.
Consensus Statements
Each statement below is followed by a brief summary in which the quality of supporting evidence, a classification of
the recommendation and the results of voting are summarized. (N.B. the level of evidence and the grade of
recommendation are not included with every statement for the epidemiology section, as many of the statements could
not be evaluated by randomized controlled trials.)
Consensus Statements
I: Epidemiology, Host and Bacterial Factors
Statement 1: The prevalence of H. pylori infection varies among countries in the Asia-Pacific region. This
difference is, in general, related to age, socioeconomic circumstances, but also to ethnicity
Level of agreement: a, 100%; b, 0%; c, 0%; d, 0%.
The prevalence of H. pylori infection varies markedly in different Asian countries. The prevalence rates in developing
Asian countries such as Bangladesh,[12] India,[13] Thailand[14] and Vietnam[15] have been reported to be especially high
at 92%, 81%, 74% and 75%, respectively, whereas in more industrialized and developed countries such as Japan,[16]
Korea[17] and Singapore,[18] the rates are somewhat lower at 39%, 54% and 31%, respectively. In the Anglo-Celtic
population in Australia, it is approximately 38%.[19] Within a country, the seroprevalence rate may vary between
geographic regions. In mainland China, the prevalence rate in urban areas was 52% compared to 39% in rural
areas,[20] whereas in nearby Taiwan, the prevalence rate was 54%.[21] There is also a temporal and age-related change
in the prevalence rate of H. pylori infection. In Japan,[16] the seroprevalence rates decreased from 73% in 1974 to 55%
in 1984 and finally to 39% in 1994. In Singapore,[18] the seroprevalence of H. pylori infection increased with age from
3% in children below 5 years of age to 71% in adults above 65 years. Within a country, differences in prevalence rates
between ethnic groups exist. In Singapore, the prevalence rates in Chinese, Malays and Indians were 46%, 28% and
48%, respectively.[22] In Malaysia, the prevalence rates in Chinese, Malays and Indians were 27-57.5%, 12-29% and
49-52%, respectively.[23]
Statement 2: Gastric cancer is a multifactorial disease
Level of agreement: a, 100%; b, 0%; c, 0%; d, 0%.
Gastric cancer is a multifactorial disease. Environmental factors such as H. pylori infection and diet are believed to be
major contributors to gastric carcinogenesis, but host factors have also been implicated. These factors are individually
addressed in the statements that follow.
Statement 3: For non-cardia gastric adenocarcinoma, H. pylori is a necessary but not sufficient causal factor
Level of agreement: a, 100%; b, 0%; c, 0%; d, 0%.
This statement addressed the importance of H. pylori infection as a causal factor for the development of non-cardia
gastric adenocarcinoma. It also recognized the fact that not all patients with non-cardia gastric adenocarcinoma are
positive for H. pylori, and that other factors are involved as well. As illustrated by a recent study, apart from H. pylori
infection, other risk factors such as ethnicity and diet were also independently associated with non-cardia gastric
adenocarcinoma.[24] The relationship of H. pylori with gastric cancer has been examined in a combined analysis of 12
case-control studies.[25] The prospective design of the studies[26-37] helped to circumvent the problem of classification
bias in retrospective studies, in which H. pylori infection and the circulating antibody response could be lost with
development of cancer. In these studies, blood samples for H. pylori serology were collected before diagnosis of
gastric cancer. The association with H. pylori was found to be restricted to non-cardia cancers (odds ratio [OR]: 3.0;
95% CI: 2.3-3.8) and was stronger when blood samples for H. pylori serology were collected more than 10 years
before cancer diagnosis (OR: 5.9; 95% CI: 3.4-10.3). It was concluded that 5.9 was the best estimate of the relative
risk of non-cardia cancer associated with H. pylori infection. It was further concluded that based on an average
prevalence of H. pylori of 35% in developed countries and 85% in developing countries, an OR of 5.9 would imply
that between approximately 65% and 80% of non-cardia gastric cancers were attributable to H. pylori infection and
potentially preventable. In Table 2 , the seroprevalence of H. pylori infection and the age-standardized incidence rates
(ASR) of gastric cancer in selected countries in the Asia-Pacific region are listed. It is clear that those countries with
high gastric cancer ASR have a high seroprevalence of H. pylori infection. However, there are also populations with a
high seroprevalence of H. pylori infection but a purportedly low gastric cancer ASR, such as India and Thailand.
These differences are postulated to be related to host genetic factors, bacterial virulence factors[38] and other
environmental factors.
Statement 4: A high intake of salt is strongly associated with gastric cancer in both epidemiological and animal
model studies
Level of agreement: a, 100%; b, 0%; c, 0%; d, 0%.
Salt-preserved food and dietary nitrite are potentially carcinogenic. In animal model studies, salt ingestion has been
shown to cause gastritis and enhance the effects of gastric carcinogens.[39,40] In an ecological study, the respective
importance of high salt and nitrate intake for gastric cancer mortality was assessed at the population level in 24
countries.[41] There was a significant correlation of gastric cancer mortality with sodium as well as nitrate in both men
and women. The relationship of gastric cancer mortality with sodium was stronger than with nitrate. In a recent study
from Malaysia, a high intake of salted fish and vegetables was found to be significantly associated with gastric
cancer.[24]
Statement 5: Fresh fruits and vegetables are associated with a reduced risk of gastric cancer
Level of agreement: a, 36.8%; b, 63.2%; c, 0%; d, 0%.
Level of evidence: I.
Grade of recommendation: A.
Several prospective studies have reported significant reductions in gastric cancer risk arising from consumption of
fresh fruits and vegetables. In the Cancer Prevention Study II, a high overall plant food intake was associated with
reduced risk of gastric cancer in men (relative risk [RR]: 0.79; 95% CI: 0.67-0.93) but not in women (RR: 1.18; 95%
CI: 0.93-1.50).[42] In a prospective cohort study from Japan, the relative risk associated with intake of ≥ 1 days per
week compared to < 1 day per week was 0.64 (95% CI: 0.45-0.92) for yellow vegetables, 0.48 (95% CI: 0.25-0.89)
for white vegetables and 0.70 (95% CI: 0.49-1.00) for fruits.[43] In a recent Swedish cohort study, vegetable
consumption was inversely associated with risk of gastric cancer, whereas no significant association was observed for
fruit consumption.[44] In a multicenter European study, it was observed that for intestinal type non-cardia cancer, a
negative association was possible for total vegetable intake and onion and garlic intake.[45] A case-control study from
Malaysia also showed that a high intake of fresh fruits and vegetables was protective against gastric cancer.[24] A
meta-analysis of cohort studies showed an inverse association between fruit intake and gastric cancer incidence (RR:
0.82; 95% CI: 0.73-0.93) and this was stronger for follow-up periods of ≥ 10 years (RR: 0.66; 95% CI: 0.52-0.83). [46]
For vegetables, the RR was 0.88 (95% CI: 0.69-1.13) using all incidence studies and 0.71 (95% CI: 0.53-0.94) when
considering only those with a longer follow up. However, these epidemiological associations do not establish beyond
doubt that dietary interventions will reduce gastric cancer incidence.
Statement 6: There is a protective role of ascorbic acid
Level of agreement: a, 0%; b, 52.6%; c, 47.4%; d, 0%.
Level of evidence: Ib.
Grade of recommendation: A.
This statement was rejected. There was no consensus on this statement, with about half agreeing and half disagreeing.
Epidemiological evidence suggested that a diet rich in fresh fruit and vegetables could be a protective factor against
gastric cancer. The specific nutrients that may be protective remain unclear, but may be mediated through anti-oxidant
vitamins such as ascorbic acid. Ascorbic acid is an important anti-oxidant and may inhibit tumor cell mitotic activity
without affecting normal cell growth. Decreased gastric juice dehydroascorbic acid concentrations were observed in
patients with gastric atrophy and intestinal metaplasia. Mucosal ascorbic acid concentrations were also significantly
lower in patients with H. pylori infection. These findings may have implications in H. pylori-associated
carcinogenesis.[47] However, results of specific interventional trials have largely been unconvincing. Correa et al.
conducted a randomized, controlled chemoprevention trial in subjects with histological diagnoses of multifocal
atrophy and/or intestinal metaplasia.[48] Individuals were assigned to receive H. pylori eradication triple therapy and/or
dietary supplementation with ascorbic acid, beta-carotene, or their corresponding placebos. Ascorbic acid
interventions resulted in statistically significant increases in the rates of regression (RR: 5.0; 95% CI: 1.7-14.4) in
subjects with atrophy. Corresponding relative risk of regression in subjects with intestinal metaplasia was 3.3 (95%
CI: 1.1-9.5). However, three other randomized controlled trials showed that ascorbic acid supplementation was not
helpful in preventing progression of gastric precancerous lesions.[49-51]
Statement 7: The current evidence does not support the use of vitamins and other dietary supplements to
prevent gastric cancer
Level of agreement: a, 0%; b, 100%; c, 0%; d, 0%.
Level of evidence: Ib.
Grade of recommendation: A.
Although epidemiological evidence suggested that a diet rich in fresh fruit and vegetables could be a protective factor
against gastric cancer, the precise factors involved are probably more than individual vitamins and anti-oxidants. Only
the study by Correa et al. showed that dietary supplementation with ascorbic acid and beta-carotene resulted in
statistically significant increases in the rates of regression of precancerous gastric lesions.[48] In three other
chemoprevention studies,[49-51] dietary interventions had no effect on prevention of precancerous gastric lesions.
Plummer et al. examined the effect of dietary supplementation with vitamin C, vitamin E, and beta-carotene on the
progression and regression of precancerous gastric lesions.[49] There was no statistically significant difference in the
progression rate or regression rate between vitamin and placebo groups. You et al. conducted a randomized trial to
test the effect of one-time H. pylori eradication therapy and long-term vitamin or garlic supplements in reducing the
prevalence of advanced precancerous gastric lesions.[50] No statistically significant favorable effects were seen for
garlic or vitamin supplements. Jacobs et al. examined the association between gastric cancer mortality and regular use
(≥ 15 times per month) of vitamin C supplements, vitamin E supplements, and multivitamins.[51] There was no
association between gastric cancer mortality and regular use of vitamin E or multivitamins regardless of the duration
of use. A Finnish study of over 29 000 people also failed to show that any upper aerodigestive cancers were prevented
by daily supplementation with alpha-tocopheryl acetate and/or beta-carotene in older male smokers.[52]
Statement 8: Host genetic factors are important in the response to H. pylori infection and disease outcome
Level of agreement: a, 0%; b, 100%; c, 0%; d, 0%.
H. pylori-infected patients have histological gastritis and approximately 80% are asymptomatic, 10-15% develop
peptic ulcer, 1-2% develop gastric cancer and a very small proportion develop gastric mucosa-associated lymphoid
tissue lymphoma.[53] A body of evidence supports the role of host factors in determining progression to gastric cancer
in H. pylori infection. The risk of developing gastric cancer is increased up to three-fold in individuals with an
immediate relative suffering from gastric cancer, and 10% of cases of gastric cancer show familial clustering.[54] The
observation that relatives of patients with gastric cancer had a higher prevalence of atrophy and hypochlorhydria
suggested genetic predisposition to the development of atrophy, the precursor of gastric cancer, in the presence of H.
pylori infection.[54] A strong association between pro-inflammatory polymorphisms in the interleukin (IL)-1β gene
cluster and an increased risk of developing gastric cancer has been demonstrated in Western populations[55-57] as well
as in Japan.[58] Genetic polymorphisms in tumor necrosis factor (TNF)-α and IL-10, when combined with pro-
inflammatory IL-1β gene polymorphisms, were shown to result in a high-risk genotype with a 27-fold or greater risk
of developing gastric cancer.[59] Genetic polymorphisms of the IL-8 promoter were significantly associated with an
increased risk of gastric cancer.[60,61]
Statement 9: Currently identified IL-1β polymorphisms in the Asia-Pacific region may not be associated with
gastric cancer
Level of agreement: a, 47.4%; b, 47.4%; c, 5.2%; d, 0%.
The key pathophysiological event in H. pylori infection is the initiation of an inflammatory response in which the
main mediators are cytokines. IL-1β is a potent proinflammatory cytokine and is involved in the host's response to
many antigenic challenges. El Omar et al. studied the correlation of these IL-1β genotypes with hypochlorhydria and
gastric atrophy in a Caucasian population of gastric cancer relatives. Genetic polymorphisms in the IL-1 gene cluster
significantly increased the risk of precancerous gastric lesions.[62] A positive association between these genotypes and
gastric cancer was confirmed in a follow-up study.[55]
However, the results of Asian studies are conflicting. Some studies are in agreement[63,64] whereas others did not show
any association.[65-67] However, an association with other genetic markers such as IL-8[60,61] and TNF-α[65]
polymorphisms has been proposed. A meta-analysis of the role of IL-1β and IL-1 receptor antagonist gene
polymorphisms in gastric cancer risk showed an association in Caucasians, but not in Asians.[68]
Statement 10: Currently identified cagA genotypes in the Asia-Pacific region may not be associated with gastric
cancer
Level of agreement: a, 10.5%; b, 73.7%; c, 15.8%; d, 0%.
Huang et al. conducted a meta-analysis to estimate the magnitude of the risk for gastric cancer associated with cagA
seropositivity.[69]H. pylori and cagA seropositivity significantly increased the risk for gastric cancer by 2.3- and 2.9fold, respectively. Among H. pylori-infected populations, infection with cagA-positive strains further increased the
risk for gastric cancer 1.6-fold (95% CI: 1.2-2.2) overall and 2.0-fold (95% CI: 1.2-3.3) for non-cardia gastric cancer.
Gastric cancer of the cardia was not associated with H. pylori infection or cagA-positive strains of H. pylori.
However, the prevalence of cagA in Asia is high, and currently identified cagA genotypes in the Asia-Pacific region
are not associated with gastric cancer.[69-76]
Statement 11: The host bacterial interaction in H. pylori infection results in different patterns of gastritis and
consequent differences in gastric acid secretion which determine disease outcome
Level of agreement: a, 63.2%; b, 36.8%; c, 0%; d, 0%.
H. pylori infection is associated with divergent clinical outcomes that range from simple asymptomatic gastritis to
serious conditions such as peptic ulcer disease and gastric neoplasia. The key determinants of these outcomes are the
severity and distribution of the H. pylori-induced gastritis. Patients with antral-predominant gastritis, the most
common form of H. pylori gastritis, are predisposed to duodenal ulcers, whereas patients with corpus-predominant
gastritis and multifocal atrophy are more likely to have gastric ulcers, gastric atrophy, intestinal metaplasia and,
ultimately, gastric carcinoma.[53] Compared to H. pylori-negative healthy volunteers, patients with H. pylori-related
duodenal ulcers had significantly higher basal and maximal acid output.[77] In contrast, gastritis that involved the acidsecreting corpus region resulted in hypochlorhydria, progressive gastric atrophy, and an increased risk of gastric
cancer. When compared with controls, the hypochlorhydric subjects had less dense H. pylori colonization, bodypredominant colonization and gastritis, and increased prevalence of body atrophy and intestinal metaplasia.[78]
Statement 12: Population-based screening for gastric cancer is currently undertaken at the national level in
two countries and at the local level in one country
Currently, population-based screening is being undertaken in Japan,[9] Korea[10] and Matsu island in Taiwan.[11] These
are populations with high gastric cancer risks. In Japan, screening is performed in individuals aged over 40 years
using double-contrast barium or endoscopy. In Korea, endoscopy is used, while in Taiwan, individuals are first
screened using serum pepsinogen and, if the level is low, endoscopy is performed.
Statement 13: There is a pressing need for the development of national policies to reduce the incidence of
gastric cancer which is now feasible
Level of agreement: a, 73.7%; b, 21%; c, 5.3%; d, 0%.
There is considerable morbidity and mortality associated with gastric cancer, due to frequent late presentation and,
hence, late diagnosis. In Asia, the prevalence of both gastric cancer and H. pylori infection remain high. There is a
need to further reduce the incidence of gastric cancer in high-risk populations and this should be based on
development of national policies. Appropriate approaches may include screening of high-risk populations, as well as
by addressing known risk factors, in particular, H. pylori infection.
Statement 14: A positive family history of gastric cancer is an important risk factor
Level of agreement: a, 15.8%; b, 84.2%; c, 0%; d, 0%.
H. pylori infection and a positive family history of gastric cancer are both risk factors for the disease. A familial
association may be partly related to clustering of H. pylori infection within families. For instance, El Omar et al.
examined the prevalence of atrophy and hypochlorhydria and their association with H. pylori infection in first-degree
relatives of patients with gastric cancer.[62] They found that among the relatives of cancer patients, the prevalence of
atrophy and hypochlorhydria was increased only in those with evidence of H. pylori infection. Eradication of H.
pylori infection produced resolution of the gastric inflammation in each subject, and resolution of hypochlorhydria
and atrophy in 50% of the subjects. In contrast, Brenner et al. carried out a population-based, statewide case-control
study in Saarland, Germany, to assess the individual and joint contributions of family history and H. pylori infection
to the risk of gastric carcinoma.[79] They found that although H. pylori infection and family history were positively
related, both were independently and strongly associated with a risk for gastric cancer. Compared with uninfected
subjects without a family history, subjects with both a positive family history and infection with cagA-positive H.
pylori strains had an OR of 8.2 (95% CI: 2.2-30.4) for gastric cancer overall and an OR of 16 (95% CI: 3.9-66.4) for
non-cardia gastric cancer.
Statement 15: Low serum pepsinogen I levels and low PG I/II ratio reflect gastric atrophy
Level of agreement: a, 36.8%; b, 57.9%; c, 5.3%; d, 0%.
Low serum pepsinogen (PG) has been used as a surrogate marker for atrophic gastritis.[80-84] PG, the precursor of
pepsin, exists as two main types: types I and II. Both are produced by the chief and mucus neck cells in the gastric
fundus and corpus. PG II, but not PG I, is also produced by the pyloric glands in the antrum and Brunner's glands in
the proximal duodenum. As gastritis progresses, mild inflammation leads to elevated levels of both PG I and PG II in
the circulation initially. However, as disease severity increases further, chief cells are replaced by pyloric glands and
the level of PG II remains elevated, while the level of PG I and, consequently, the PG I/II ratio, are reduced. The
differential changes in PG levels are indicative of the histological state of the gastric mucosa. Utilizing PG as
surrogate markers for gastric atrophy, the EUROGAST Study Group correlated gastric cancer rates with low serum
PG levels in men from the same population.[83]
Statement 16: Low serum pepsinogen I levels and low PG I/II ratio may be useful as a marker to identify
populations at high risk for gastric cancer
Level of agreement: a, 15.8%; b, 52.6%; c, 31.6%; d, 0%
Level of evidence: IIa.
Grade of recommendation: B.
Since the 1990s, serum PG as a marker for chronic atrophic gastritis has been incorporated into gastric cancer
screening programs, on a trial basis, to identify people who would benefit most from gastric cancer screening in
Japan.[84-90] The results have shown that PG testing is useful in detecting early-stage gastric cancer. Miki[91] performed
a meta-analysis of the sensitivity and specificity results from 42 individual studies. PG I level ≤ 70 ng/mL and PG I/II
ratio ≤ 3 had a sensitivity of 77% and false-positive rate of 27%. The positive predictive value was low and varied
between 0.77% and 1.25%, but the negative predictive value varied between 99.08% and 99.90%. In a case-control
study from Thailand, the PG I/II ratio was significantly lower in the gastric cancer group than in the normal and
chronic gastritis groups (OR: 2.3; 95% CI: 1.10-4.80).[92]
There are, however, exceptions with respect to the utility of serum pepsinogen levels. A study from Singapore
examined whether racial differences in the prevalence of H. pylori and serum PG could account for a racial difference
in gastric cancer incidence.[22] The H. pylori seroprevalence was similar between Chinese and Indian subjects, but
significantly lower among Malay subjects. The gastric cancer incidence rates correlated with H. pylori seropositivity
for the Chinese and Malay subjects, but not for the Indian subjects. The prevalence of low PG was highest in Indian
subjects even when adjusted for gender and the presence of H. pylori. This highlighted the limited usefulness of serum
PG in the Indian population for gastric cancer screening.
Statement 17: Neither cagA serology nor the presence of the cagA gene has been shown to be a useful marker
for gastric cancer risk in an individual
Level of agreement: a, 78.9%; b, 21.1%; c, 0%; d, 0%.
Level of evidence: IIa.
The prevalence of cagA in Asia is high, and currently identified cagA genotypes in the Asia-Pacific region have not
been associated with gastric cancer.[70-76] As such, there is no role for it as a marker for gastric cancer risk in an
individual.
II. Screening program for H. pylori infection and gastric cancer
Statement 18: Population H. pylori screening and treatment will reduce peptic ulcer disease and its
complications
Level of agreement: a, 90%; b, 10%; c, 0%; d, 0%.
Level of evidence: I.
Grade of recommendation: A.
Peptic ulcers are independently related to both H. pylori infection as well as non-steroidal anti-inflammatory drug(s)
(NSAIDs) use. Eradication of H. pylori infection has been shown to facilitate peptic ulcer healing, reduce recurrence
of peptic ulcers and reduce incidence of bleeding peptic ulcers in clinical trials. This provides evidence that
population H. pylori screening and treatment will reduce peptic ulcer disease and its complications.
A recent systemic review of 21 studies involving 10 146 patients showed that ulcers were more common in H. pyloripositive than in H. pylori-negative patients (OR: 4.03), irrespective of NSAID use, and more common in NSAID users
than in non-users (OR: 3.10), irrespective of H. pylori status. The risk of ulcer was 17.54-fold higher in H. pyloripositive NSAID users than in H. pylori-negative non-users and the presence of both H. pylori and NSAIDs increased
the risk of bleeding 20.83-fold.[93]
In a Cochrane review, eradication therapy was compared to placebo or pharmacological therapies in H. pylori-positive
peptic ulcers.[94] In duodenal ulcer healing, eradication therapy was superior to acid suppressants (RR of ulcer
persisting: 0.66; 95% CI: 0.58-0.76) and no treatment (RR: 0.37; 95% CI: 0.26-0.53). In gastric ulcer healing, the
efficacy was similar between eradication therapy and acid suppressants (RR: 1.25; 95% CI: 0.88-1.76). In preventing
duodenal ulcer recurrence, no significant differences were detected between eradication therapy and maintenance
therapy with acid suppressants (RR of ulcer recurring: 0.73; 95% CI: 0.42-1.25), but eradication therapy was superior
to no treatment (RR: 0.20; 95% CI: 0.15-0.26). In preventing gastric ulcer recurrence, eradication therapy was
superior to no treatment (RR: 0.29; 95% CI: 0.20-0.42). The efficacy of H. pylori eradication therapy versus
antisecretory therapy for the prevention of recurrent bleeding from peptic ulcer was assessed in another Cochrane
review.[95] It was shown that treatment of H. pylori infection was more effective than antisecretory therapy (with or
without long-term maintenance therapy) in preventing recurrent bleeding from peptic ulcer. Comparing H. pylori
eradication therapy against antisecretory therapy without long-term maintenance therapy, the rebleeding rate was
2.9% versus 20% (OR: 0.17; 95% CI: 0.10-0.32; number needed to treat [NNT]: 7; 95% CI: 5-11). Comparing H.
pylori eradication against antisecretory therapy with long-term maintenance therapy, the rebleeding rate was 1.6%
versus 5.6% (OR: 0.25; 95% CI: 0.08-0.76; NNT: 20; 95% CI: 12-100).
Statement 19: Population H. pylori screening and treatment will result in a modest reduction of dyspepsia
symptoms and costs
Level of agreement: a, 10%; b, 70%; c, 20%; d, 0%.
Level of evidence: I.
Grade of recommendation: A.
The role of H. pylori eradication in the management of dyspepsia symptoms in patients with functional dyspepsia was
assessed in a meta-analysis.[96] There was a 10% relative risk reduction in the H. pylori eradication group (95% CI: 614%) compared to placebo. The number needed to treat to cure one case of dyspepsia was 14 (95% CI: 10-25). An
economic model suggested that this modest benefit may be cost-effective. A recent study investigated the effect of
screening for H. pylori on dyspepsia and dyspepsia-related resource use over 10 years.[97] In that study, 2324 H pyloripositive individuals, aged 40-49 years, enrolled in a community screening program in the UK were randomized to
eradication therapy or placebo and followed up after 10 years. There was a significant 10-year mean saving in total
dyspepsia-related costs of US$117 per person (95% CI: 11-220). The savings were greater than the initial cost of H.
pylori screening and treatment.
Statement 20: Population H. pylori screening and treatment will increase antibiotic resistance in the community
Level of agreement: a, 95%; b, 5%; c, 0%; d, 0%.
Level of evidence: III.
Grade of recommendation: C.
There was concern about the problem of increased antibiotic resistance in the community with population H. pylori
screening and eradication. The widespread use of antimicrobials constitutes a risk for antimicrobial resistance.[98] This
will be especially so in the context of non-compliance to treatment. This may potentially impact on the efficacy of H.
pylori eradication regimens as well as the efficacy of antibiotics against other infections. An association has been
found between the consumption level of antibiotics and the rate of bacterial resistance to antimicrobials.[99-102] In
Europe, a trend toward a higher resistance of H. pylori to macrolides was noted in countries with the highest
consumption of these drugs.[103,104] Ensuring compliance to treatment would be important in preventing the selection
of resistant strains, and public health measures to monitor the patterns of drug resistance would be needed.
Statement 21: Population H. pylori screening will increase cancer anxiety in the population
Level of agreement: a, 0%; b, 75%; c, 25%; d, 0%.
Level of evidence: IV.
Grade of recommendation: C.
There are no published data on the association of cancer anxiety in the population with H. pylori screening. However,
there was a strong concern by the participants of the meeting that H. pylori screening could possibly increase cancer
anxiety, especially to a level disproportionate to the actual risk of disease. A recent paper on public awareness of
breast cancer and screening showed that increased awareness led to increased referrals and screening for breast
cancer, without an actual increase in detection rates, leading the authors to conclude that while it was encouraging that
media campaigns raised awareness, there may be a detrimental effect with increased radiation exposure, anxiety and
cancer phobia.[105]
Statement 22: H. pylori eradication does not increase reflux symptoms in the community
Level of agreement: a, 45%; b, 55%; c, 0%; d, 0%.
Level of evidence: I.
Grade of recommendation: A.
Labenz et al. initially suggested that an increase in the prevalence of gastroesophageal reflux disease (GERD)
occurred after H. pylori eradication.[106] However, subsequently, a post hoc meta-analysis of eight double-blind
studies of H. pylori eradication[107] and a large post hoc analysis of the peptic ulcer trials, GU MACH and DU
MACH[108,109] showed that H. pylori eradication for ulcer disease did not lead to development of erosive esophagitis
or new symptomatic GERD or worsening of symptoms in patients with pre-existing GERD. The results were similar
for studies conducted in patients with pre-existing GERD[110-112] and in the general population.[113,114] These data
support the statement that H pylori eradication does not increase reflux symptoms in the community.
Statement 23: Current data suggest that population-based H. pylori screening and treatment does not increase
the risk for esophageal adenocarcinoma
Level of agreement: a, 0%; b, 100%; c, 0%; d, 0%.
Level of evidence: III.
Grade of recommendation: C.
Some data suggested an inverse association between H. pylori infection and GERD or Barrett's esophagus.[115-117]
There are epidemiological studies that showed H. pylori CagA seropositivity was inversely and strongly associated
with a risk of esophageal adenocarcinoma,[118,119] although this has not been a universal observation.[120] There was
consensus that since there was no association between GERD and H. pylori, the association with Barrett's esophagus
may be spurious and the benefits of H. pylori eradication would almost certainly outweigh any theoretical impact on
Barrett's cancer.
III. H. pylori eradication and gastric cancer
Statement 24: H. pylori eradication reduces the risk of developing gastric cancer
Level of agreement: a, 90%; b, 10%; c, 0%; d, 0%.
Level of evidence: I.
Grade of recommendation: A.
The potential benefit of H. pylori eradication in reducing the risk of gastric cancer can be considered indirectly from
studies that assessed its effect on precancerous lesions and directly from its effect on cancer development.
Correa et al. assessed the effect of H. pylori eradication therapy on intestinal metaplasia, multifocal atrophy and
dysplasia in a high gastric cancer risk region of Colombia.[121] Results of the 6-year follow-up evaluation showed that
H. pylori eradication produced a significant increase in the rates of regression for intestinal metaplasia and gastric
atrophy. These findings were subsequently confirmed at the end of the 12-year follow-up period.[122] Those who were
H. pylori negative had, on average, 15% more regression and 14% less progression of precancerous gastric lesions
than subjects who were H. pylori positive. Another prospective, placebo-controlled, randomized study was performed
by Leung et al.[123] At 5 years follow up, subjects with persistent H. pylori infection had a significantly higher risk of
progression to intestinal metaplasia than those with successful eradication, with an OR of 2.13 (95% CI: 1.41-3.24).
Two other prospective, randomized, double-blind, placebo-controlled studies conducted in China reached similar
conclusions.[50,124]
Uemura et al. first provided evidence that H. pylori eradication had a direct impact on gastric cancer occurrence.[125]
They conducted a non-randomized H. pylori eradication trial in patients with early gastric cancer treated by
endoscopic resection. After a 3-year follow-up period, metachronous gastric cancer developed in 9% of those not
treated, compared with 0% in patients with H. pylori eradicated. In a prospective observational study, the same group
also showed that gastric cancer developed in persons infected with H. pylori, but not in uninfected persons.[126] A
recent non-randomized, interventional trial evaluated gastric cancer development after 3 years in H. pylori-positive
subjects and in those in whom H. pylori was eradicated.[127] At the end of the follow-up period, significantly more
patients (4% vs 1.5%) in the H. pylori-positive group developed gastric cancer. To date, five randomized placebocontrolled H. pylori eradication trials have been conducted in Asia to address this issue.[50,128-131] There were four
studies[50,128-130] evaluating H. pylori screening and treatment in the general population and all showed a nonsignificant trend towards risk reduction for gastric cancer with H. pylori eradication. One Japanese study in patients
having endoscopic mucosal resection for gastric adenocarcinoma did show a significant effect of H. pylori eradication
in the prevention of subsequent gastric neoplasia.[131] A meta-analysis was performed (Moayyedi P, unpubl. data,
2007) using the raw data from these five studies. With H. pylori eradication, the pooled relative risk of developing
gastric cancer was 0.56 (95% CI: 0.40, 0.8). Even though this meta-analysis relies on the results of two studies[128,131]
that have yet to be published in peer-reviewed journals, the consensus meeting concluded that the evidence is very
suggestive.
Statement 25: Eradication of H. pylori has been shown to reduce the incidence of gastric cancer development
even at a late age
Level of agreement: a, 10%; b, 85%; c, 0%; d, 5%.
Level of evidence: I.
Grade of recommendation: A.
As elaborated in the discussion following statement 24,[121-130] the results of both randomized and non-randomized
studies suggested that in a subpopulation of treated subjects, H. pylori eradication prevented the progression of
precancerous gastric lesions. However, H. pylori eradication seemed to reduce the incidence of gastric cancer in
patients without baseline precancerous gastric lesions.[129] Hence, the issue of the optimal population age cut-off for
treatment of infection to prevent cancer remains unknown. The choice of an arbitrary age cut-off for population
screening and eradication for H. pylori infection would depend on local resources and ethical considerations. The sole
rejection in the voting was made on the basis that the actual age of cut-off remained unknown.
Statement 26: Gastric cancer can still occur despite eradication of the infection
Level of agreement: a, 80%; b, 20%; c, 0%; d, 0%.
Level of evidence: I.
Grade of recommendation: A.
Even though H. pylori eradication may represent a primary chemopreventive strategy, gastric cancer may still develop
despite successful eradication therapy. This is clear from studies that used occurrence of precancerous gastric lesions
as a surrogate outcome measure for gastric cancer development, as well as those that directly assessed the incidence of
gastric cancer.
The effect of H. pylori eradication therapy on precancerous gastric lesions such as intestinal metaplasia, multifocal
atrophy and dysplasia was assessed by several studies. In a study from Colombia, at the end of the 12-year follow-up
period, although those who were H. pylori negative had more regression and less progression of precancerous gastric
lesions than subjects who remained H. pylori positive, approximately one-third of the patients successfully treated still
experienced progression of precancerous gastric lesions.[122] In a study by Leung et al., progression of intestinal
metaplasia was found in approximately one-third of patients in whom H. pylori was successfully eradicated.[123] In
another prospective randomized trial, after a follow-up period of 7 years, You et al. noted that progression of
precancerous lesions occurred in 45% in the active treatment group versus 49% in the placebo group.[50] Similar
findings were noted by Zhou et al.[124] Collectively, these data suggest that although H. pylori eradication was able to
induce regression of precancerous gastric lesions, particularly in those with early and non-severe lesions, up to 45% of
treated subjects would still show disease progression. The occurrence of gastric cancer after successful H. pylori
eradication has also been assessed. Ogura et al. reported that at the 3-year follow up, 4% in the H. pylori-positive
group and 1.5% in the H. pylori-negative group developed gastric cancer.[127] In the study by Wong et al. during the
period of follow-up of 7.5 years, 0.9% of treated subjects and 1.3% of placebo developed gastric cancer.[129]
Statement 27: H. pylori screen and treat is a gastric cancer risk reduction strategy in high-risk populations
Level of agreement: a, 55%; b, 45%; c, 0%; d, 0%.
Level of evidence: I.
Grade of recommendation: A.
Based on the results of the published data on H. pylori eradication and its impact on the progression of precancerous
gastric lesions and occurrence of gastric cancer discussed earlier,[121-130] it was felt that screening for H. pylori
infection and eradicating it in high-risk populations would have an impact on reduction of gastric cancer incidence.
All these studies were conducted in high-risk populations. By targeting high-risk populations, there would be a better
return for the economic resources that need to be committed for such a strategy. Indeed, economic modeling using
efficacy data from the meta-analysis presented in statement 24 and randomized controlled trial data[97] with Asian
costs applied suggested this strategy would be cost-effective in developed countries where gastric cancer rates were
high.
Statement 28: In high gastric cancer-risk populations in the Asia-Pacific region, population screening and
treatment of H. pylori infection is the strategy of choice
Level of agreement: a, 10%; b, 90%; c, 0%; d, 0%.
Level of evidence: I.
Grade of recommendation: A.
To date, all randomized controlled trials on H. pylori eradication to prevent precancerous gastric lesions and gastric
cancer have been conducted in high-risk populations. In the long term, if H. pylori infection were to be eradicated, it
may even mean that endoscopic surveillance for gastric cancer may no longer be necessary, if this eradication
occurred before the development of advanced precancerous gastric lesions. For developing countries in the AsiaPacific region, affordability would be a major concern and, on a national level, individual strategies need to be
developed.
Statement 29: H. pylori screening and treatment does not exclude the existing practice of gastric cancer
surveillance in high-risk populations such as in Japan and Korea
Level of agreement: a, 75%; b, 25%; c, 0%; d, 0%.
Level of evidence: IV.
Grade of recommendation: C.
Current evidence suggests that H. pylori eradication might represent a primary chemopreventive strategy in a subset
of subjects without advanced precancerous gastric lesions. However, H. pylori eradication in those patients who have
already developed advanced precancerous gastric lesions does not prevent gastric cancer development and, as such, in
high-risk populations such as Japan and Korea, endoscopic surveillance may continue to be performed.
Statement 30: In populations at low risk for gastric cancer, screening for H. pylori is not recommended
Level of agreement: a, 0%; b, 100%; c, 0%; d, 0%.
Level of evidence: IV.
Grade of recommendation: C.
To date, the limited published data on H. pylori eradication and gastric cancer prevention have been from high-risk
populations. Even within these high-risk populations, the benefit is not universal because advanced precancerous
changes may continue to progress. Hence, it is not recommended at this time to adopt a strategy of H. pylori screening
and eradication with the aim of decreasing the already low incidence of gastric cancer in low-risk populations.
However, quite apart from gastric cancer prevention, there are data that suggest that screening for H pylori and
eradicating it would reduce total dyspepsia-related health-care costs.[97]
Statement 31: Opportunistic testing and treating of H. pylori infection offers the possibility to reduce the risk of
peptic ulcer disease and gastric cancer
Level of agreement: a, 20%; b, 80%; c, 0%; d, 0%.
Level of evidence: I.
Grade of recommendation: A.
In light of the data concerning the relationship between H. pylori and gastric cancer,[25] and peptic ulcer disease,[94]
and the data that showed reduced occurrence of gastric cancer[125,126] and peptic ulcer disease[94] after H. pylori
eradication, it was felt that opportunistic testing and treating of H. pylori infection offered a possibility to reduce the
risk of peptic ulcer disease and gastric cancer. However, the issue of costs and affordability of this strategy of
screening and subsequent treatment for H. pylori eradication have not been addressed in the region.
Statement 32: In a high-risk population, screening for H. pylori infection is most effective before atrophic
gastritis has developed
Level of agreement: a, 5%; b, 95%; c, 0%; d, 0%.
Level of evidence: IIa.
Grade of recommendation: B.
The participants based their decision on the indirect evidence from the randomized controlled study by Wong et
al.[129] During the period of follow up, the incidence of gastric cancer development at the population level was similar
between those who received H. pylori eradication and controls. However, in the subgroup of patients with no
precancerous lesions (gastric atrophy, intestinal metaplasia, or gastric dysplasia) at presentation, no patient developed
gastric cancer after H. pylori eradication compared to 6% in controls (P = 0.02). The occurrence of precancerous
lesions may represent a stage of irreversibility in the pathogenesis of gastric cancer.
Statement 33: In high-risk populations, screening for H. pylori infection is recommended 10-20 years before the
take-off age for gastric cancer
Level of agreement: a, 0%; b, 100%; c, 0%; d, 0%.
Level of evidence: IV.
Grade of recommendation: C.
The unanimous consensus was based on knowledge that the occurrence of gastric cancer goes through a cascade, and
that it takes time for precancerous lesions to occur. It was felt that screening for H. pylori infection 10-20 years before
the take-off age for gastric cancer in the population would allow H. pylori eradication before the onset of irreversible
precancerous changes. This strategy assumes reinfection would be low in adults successfully treated.[132,133]
Statement 34: A serological test for H. pylori that has been locally validated is recommended for population
screening
Level of agreement: a, 25%; b, 65%; c, 10%; d, 0%.
Level of evidence: IIb.
Grade of recommendation: B.
Serological tests for diagnosis of H. pylori infection rely on the detection of immunoglobulin (Ig)G antibodies to H.
pylori antigens. They are widely available and inexpensive, and were used in population screening for H. pylori
infection in epidemiological studies.[83] Overall, the diagnostic accuracy is low at approximately 80-84%. However
some kits have a high accuracy rate (> 90%) and may be used when locally validated. Local validation is optimal
because H. pylori strains differ across geographic locations.[134]
Statement 35: Childhood screening of H. pylori infection to prevent gastric cancer is not recommended
Level of agreement: a, 75%; b, 20%; c, 5%; d, 0%.
Level of evidence: IV.
Grade of recommendation: C.
Childhood screening of H. pylori infection to prevent gastric cancer is not recommended. H. pylori infection is usually
acquired in childhood, and as children would not have not harbored the organism for long enough to have developed
precancerous lesions, childhood is theoretically an attractive time for H. pylori eradication and, thus, could help
prevent gastric cancer later in life. However, as H. pylori prevalence and the incidence of gastric cancer are low in
childhood, widespread population screening programs would be enormously expensive and not justifiable at a national
level.[135,136] There is also an increased risk of reinfection after successful eradication therapy in childhood when
compared to adulthood.[137] The interval between screening and preventing gastric cancer would be lengthened and
therefore payers for the program would have to wait a longer time before seeing any return on their investment. The
program would therefore also be less financially attractive from a third-party payer perspective.
Statement 36: Repeated testing for H. pylori infection as part of the screening strategy is not necessary
Level of agreement: a, 20%; b, 80%; c, 0%; d, 0%.
Level of evidence: III.
Grade of recommendation: B.
The targeted group for H. pylori screening are the adults in high-risk populations. Infections are generally acquired
during childhood.[53] Serological tests, in particular antibodies against the specific antigen CagA, are immunogenic
and long-lasting, for which reason they are useful for epidemiological studies.[138,139] As such, the risk of falsenegative results are minimal and do not justify the costs of repeated testing for H. pylori infection.
Statement 37: First-line treatment of H. pylori infection should be in accordance with national treatment
guidelines
Level of agreement: a, 100%; b, 0%; c, 0%; d, 0%.
Level of evidence: I.
Grade of recommendation: A.
It was unanimously agreed that first-line treatment of H. pylori infection should be in accordance with national
treatment guidelines. Standard first-line H. pylori eradication regimens are based on triple therapy comprising twice
daily proton pump inhibitors, clarithromycin and amoxicillin or metronidazole for at least 7 days. These first-choice
H. pylori treatments are recommended worldwide. However, it is recognized that the exact choice of antimicrobials
may differ based on local patterns of antibiotic resistance, and that the decision to treat for 1 or 2 weeks would also
depend on the results of locally validated data.[134]
Statement 38: Confirmation of H. pylori eradication is not practical or cost-effective to consider on a
population basis
Level of agreement: a, 35%; b, 60%; c, 5%; d, 0%.
Level of evidence: IV.
Grade of recommendation: C.
For the individual patient, there should be confirmation of the success of H. pylori eradication by using nonserological tests, which should be performed at least 4 weeks after treatment has been completed.[134] In clinical
practice, approximately 20% of patients will fail to eradicate H. pylori infection with the recommended treatment
regimens. Major causes of treatment failure are poor patient compliance and antibiotic resistance.[140] However, at the
population level, because of the costs involved and the resources required, confirmation of H. pylori eradication is not
practical or cost-effective to consider. One may however, consider retesting and follow-up therapy on a case by case
basis, such as in patients with dyspepsia symptoms and those who request confirmation of successful H. pylori
eradication.
Conclusion
After carefully reviewing the literature and weighing the evidence and uncertainties, this consensus conference has
concluded that there is a definite causal link between H. pylori infection and gastric cancer, and it has come time to try
and intervene to prevent this cancer at the population level. Current evidence suggests that H. pylori eradication can
prevent the progression of precancerous gastric lesions and, in those without advanced precancerous lesions, H. pylori
eradication probably reduces the incidence of gastric cancer. A strategy of H. pylori screening and eradication in highrisk populations (Fig. 1) should reduce gastric cancer incidence and is recommended by this consensus conference.
This approach may be considered in intermediate-risk populations, although it is acknowledged that supporting data
are lacking and such a strategy is not recommended at this time. Finally, screening in low-risk populations is not
currently recommended. At the same time, the current gastric surveillance programs in populations at high risk for
gastric cancer such as in Japan and Korea should be continued.
Figure 1.
Strategy of H. pylori Screening and Eradication in Populations at High or Intermediate Risk for Gastric Cancer.
Table 1. Level of Evidence, Classification of Recommendations and Voting Scheme
Quality of evidence
Ia. Evidence obtained from meta-analysis of randomized trials.
Ib. Evidence obtained from at least one randomized controlled trial.
IIa. Evidence obtained from at least one well-designed controlled study, without randomization.
IIb. Evidence obtained from at least one other type of well-designed quasi-experimental study.
III. Evidence obtained from well-designed non-experimental descriptive studies, correlation studies and case studies.
IV. Evidence obtained from expert committee reports or opinions and/or clinical experience of respected authorities.
Classification of recommendations
A. Requires at least one randomized controlled trial as part of a body of literature of overall good quality and
consistency addressing the specific recommendation.
B. Requires the availability of well-conducted clinical studies, but no randomized clinical trials on the topic of the
recommendation.
C. Requires evidence obtained from expert committee reports or opinions and/or clinical experience of respected
authorities. Indicates an absence of directly applicable clinical studies of good quality.
Voting on the recommendations†
a. Strongly agree
b. Agree
c. Disagree
d. Reject
Table 2. Prevalence of H. pylori and Gastric Cancer in the Asia-Pacific Region
Country
Australia[19]
Seroprevalence of H. pylori (%) Age-standardized incidence rate (per 100 000)
Male
Female
38%
13.8
6.5
86%
81.3
31.7
19.3
9.6
8.9
6
62.1
26.1
58
25
China[20]
Changle
Hong Kong 58.4%
India[13]
< 5 years: 22-57%
> 20 years: 80-90%
Japan[16]
1974: 72.7%
1984: 54.6%
1994: 39.3%
Korea[17]
Overall: 46.6%
Age > 40 years: 78.5%
Malaysia[23]
Chinese
26.7-57.5%
11.9
8.7
Malay
11.9-29.2%
2.6
1.3
Indian
49.4-52.3%
12.9
7.9
Chinese
46.3%
21.4
10.8
Malay
27.9%
6.6
3.8
Indian
48.1%
7.8
6.1
Taiwan[21]
54.7%
18.6
10.5
Thailand[14]
5-9 years: 17.5%
5.8
2.9
23.7
10.8
Singapore[22]
20-29 years: 55%
30-49 years: 75%
Vietnam[15]
74.6%
References
1. Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics 2005. CA Cancer J. Clin. 2005; 55: 74-108.
2. Correa P, Piazuelo MB, Camargo MC. The future of gastric cancer prevention. Gastric Cancer. 2004; 7: 916.
3. Kikuchi S, Katada N, Sakuramoto S et al. Survival after surgical treatment of early gastric cancer: surgical
techniques and long-term survival. Langenbecks Arch. Surg. 2004; 389: 69-74.
4. Onodera H, Tokunaga A, Yoshiyuki T et al. Surgical outcome of 483 patients with gastric cancer: prognosis,
postoperative morbidity and mortality, and gastric remnant cancer. Hepatogastroenterology 2004; 51: 82-5.
5. Ishikawa S, Togashi A, Inoue M et al. Indications for EMR/ESD in cases of early gastric cancer: relationship
between histological type, depth of wall invasion, and lymph node metastasis. Gastric Cancer 2007; 10: 35-8.
6. Gotoda T. Endoscopic resection of early gastric cancer. Gastric Cancer 2007; 10: 1-11.
7. Ries LAG, Kosary CL, Hankey BF et al. SEER Cancer Statistics Review 1973-1994, National Cancer
Institute, NIH Publication No. 97-2789. Bethesda: Department of Health and Human Services, 1997.
8. Berrino F, Capocaccia R, Esteve J. Survival of Cancer Patients in Europe: The EUROCARE-2 Study. IARC.
Scientific Publications No. 151. Lyon: IARC, 1999.
9. Hisamichi S. Screening for gastric cancer. World J. Surg. 1989; 13: 31-7.
10. Kim YS, Park HA, Kim BS, Yook JH, Lee MS. Efficacy of screening for gastric cancer in a Korean adult
population: a case-control study. J. Korean Med. Sci. 2000; 15: 510-15.
11. Liu CY, Wu CY, Lin JT, Lee YC, Yen AM, Chen TH. Multistate and multifactorial progression of gastric
cancer: results from community-based mass screening for gastric cancer. J. Med. Screen. 2006; 13 (Suppl. 1):
S2-5.
12. Ahmad MM, Rahman M, Rumi AK et al. Prevalence of Helicobacter pylori in asymptomatic population - a
pilot serological study in Bangladesh. J. Epidemiol. 1997; 7:251-4.
13. Ramakrishna BS. Helicobacter pylori infection in India: the case against eradication. Indian J. Gastroenterol.
2006; 25: 25-8.
14. Perez-Perez GI, Taylor DN, Bodhidatta L et al. Seroprevalence of Helicobacter pylori infections in Thailand.
J. Infect. Dis. 1990; 161: 1237-41.
15. Hoang TT, Bengtsson C, Phung DC et al. Seroprevalence of Helicobacter pylori infection in urban and rural
Vietnam. Clin. Diagn. Lab. Immunol. 2005; 12: 81-5.
16. Fujisawa T, Kumagai T, Akamatsu T et al. Changes in seroepidemiological pattern of Helicobacter pylori and
hepatitis A virus over the last 20 years in Japan. Am. J. Gastroenterol. 1999; 94: 2094-9.
17. Malaty HM, Kim JG, Kim SD et al. Prevalence of Helicobacter pylori infection in Korean children: inverse
relation to socioeconomic status despite a uniformly high prevalence in adults. J. Epidemiol. 1996; 143: 25762.
18. Fock KM. Helicobacter pylori infection - current status in Singapore. Ann. Acad. Med. Singap. 1997; 26: 63741.
19. Lin SK, Lambert JR, Nicholson L et al. Prevalence of Helicobacter pylori in a representative Anglo-Celtic
population of urban Melbourne. J. Gastroenterol. Hepatol. 1998; 13: 505-10.
20. Mitchell HM, Li YY, Hu PJ et al. Epidemiology of Helicobacter pylori in southern China: identification of
early childhood as the critical period for acquisition. J. Infect. Dis. 1992; 166: 149-52.
21. Lin JT, Wang LY, Wang JT et al. Ecological study of association between Helicobacter pylori infection and
gastric cancer in Taiwan. Dig. Dis. Sci. 1995; 40: 385-8.
22. Ang TL, Fock KM, Dhamodaran S et al. Racial differences in Helicobacter pylori, serum pepsinogen and
gastric cancer incidence in an urban Asian population. J. Gastroenterol. Hepatol. 2005; 20: 1603-9.
23. Goh KL, Parasakthi N. The racial cohort phenomenon. Seroepidemiology of Helicobacter pylori infection in
a multiracial South-East Asian Country. Eur. J. Gastroenterol. Hepatol. 2001; 13: 177-83.
24. Goh KL, Cheah PL, Md N et al. Ethnicity and H. pylori as risk factors for gastric cancer in Malaysia: a
prospective case control study. Am. J. Gastroenterol. 2007; 102: 40-5.
25. Helicobacter and Cancer Collaborative Group. Gastric cancer and Helicobacter pylori: a combined analysis of
12 case control studies nested within prospective cohorts. Gut 2001; 49: 347-53.
26. Parsonnet J, Friedman GD, Vandersteen DP et al. Helicobacter pylori infection and the risk of gastric
carcinoma. N. Engl. J. Med. 1991; 325: 1127-31.
27. Nomura A, Stemmermann GN, Chyou PH et al. Helicobacter pylori infection and gastric carcinoma among
Japanese-Americans in Hawaii. N. Engl. J. Med. 1991; 325: 1132-6.
28. Simán JH, Forsgren A, Berglund G et al. Association between Helicobacter pylori infection and gastric
carcinoma in the city of Malmo, Sweden. A prospective study. Scand. J. Gastroenterol. 1997; 32: 1215-21.
29. Forman D, Newell DG, Fullerton F et al. Association between infection with Helicobacter pylori and risk of
gastric cancer: evidence from a prospective investigation. Br. Med. J. 1991; 302: 1302-5.
30. Lin JT, Wang LY, Wang JT et al. A nested case-control study on the association between Helicobacter pylori
infection and gastric cancer risk in a cohort of 9775 men in Taiwan. Anticancer Res. 1995; 15: 603-6.
31. Aromaa A, Kosunen TU, Knekt P et al. Circulating anti-Helicobacter pylori immunoglobulin A antibodies
and low serum pepsinogen I level are associated with increased risk of gastric cancer. Am. J. Epidemiol.
1996; 144: 142-9.
32. Webb P, Yu M, Forman D et al. An apparent lack of association between Helicobacter pylori infection and
risk of gastric cancer in China. Int. J. Cancer 1996; 67: 603-7.
33. Wong BC, Lam SK, Ching CK et al. Differential Helicobacter pylori infection rates in two contrasting gastric
cancer risk regions of South China. China Gastric Cancer Study Group.J. Gastroenterol. Hepatol. 1999; 14:
120-5.
34. Watanabe Y, Kurata J, Mizuno S et al. Helicobacter pylori infection and gastric cancer. A nested case-control
study in a rural area of Japan. Dig. Dis. Sci. 1997; 42: 1383-7.
35. Hansen S, Melby K, Aase S et al. Helicobacter pylori infection and risk of cardia and non-cardia gastric
cancer: a nested case-control study. Scand. J. Gastroenterol. 1999; 34: 353-60.
36. Wald N, Law M, Morris J et al. Helicobacter pylori infection and mortality from ischaemic heart disease:
negative result from a large prospective study. BMJ 1997; 315: 1199-201.
37. Limburg PJ, Qiao YL, Mark SD et al. Helicobacter pylori seropositivity and subsite-specific gastric cancer
risks in Linxian, China. J. Natl Cancer Inst. 2001; 93: 226-33.
38. Azuma T, Yamazaki S, Yamakawa A et al. Association between diversity in the Src homology 2 domaincontaining tyrosine phosphatase binding site of Helicobacter pylori CagA protein and gastric atrophy and
cancer. J. Infect. Dis. 2004; 189: 820-7.
39. Tatematsu M, Takahashi M, Fukushima S et al. Effects in rats of sodium chloride on experimental gastric
cancers induced by N-methyl-N-nitro-N-nitrosoguanidine or 4-nitroquinoline-1-oxide. J. Natl Cancer Inst.
1975; 55: 101-6.
40. Takahashi M, Hasegawa R. Enhancing effects of dietary salt on both initiation and promotion stages of rat
gastric carcinogenesis. In: Hayashi Y, Nagao M, Sugimura T et al., eds. Diet, Nutrition and Cancer. Utrecht:
Japan Scientific Society Press, 1986;169-82.
41. Joossens JV, Hill MJ, Elliott P et al. Dietary salt, nitrate and stomach cancer mortality in 24 countries.
European Cancer Prevention (ECP) and the INTERSALT Cooperative Research Group. Int. J. Epidemiol.
1996; 25: 494-504.
42. McCullough ML, Robertson AS, Jacobs EJ et al. A prospective study of diet and stomach cancer mortality in
United States men and women. Cancer Epidemiol. Biomarkers Prev. 2001; 10: 1201-5.
43. Kobayashi M, Tsubono Y, Sasazuki S et al. Vegetables, fruit and risk of gastric cancer in Japan: a 10-year
follow-up of the JPHC Study Cohort I. Int. J. Cancer 2002; 102: 39-44.
44. Larsson SC, Bergkvist L, Wolk A. Fruit and vegetable consumption and incidence of gastric cancer: a
prospective study. Cancer Epidemiol. Biomarkers Prev. 2006; 15: 1998-2001.
45. Gonzalez CA, Pera G, Agudo A et al. Fruit and vegetable intake and the risk of stomach and oesophagus
adenocarcinoma in the European Prospective Investigation into Cancer and Nutrition (EPIC-EURGAST). Int.
J. Cancer 2006; 118: 2559-66.
46. Lunet N, Lacerda-Vieira A, Barros H. Fruit and vegetables consumption and gastric cancer: a systematic
review and meta-analysis of cohort studies. Nutr. Cancer 2005; 53: 1-10.
47. Zhang ZW, Abdullahi M, Farthing MJ. Effect of physiological concentrations of vitamin C on gastric cancer
cells and Helicobacter pylori. Gut 2002; 50: 165-9.
48. Correa P, Fontham ET, Bravo JC et al. Chemoprevention of gastric dysplasia: randomized trial of antioxidant
supplements and anti-helicobacter pylori therapy. J. Natl Cancer Inst. 2000; 92: 1881-8.
49. Plummer M, Vivas J, Lopez G, Bravo JC et al. Chemoprevention of precancerous gastric lesions with
antioxidant vitamin supplementation: a randomized trial in a high-risk population.J. Natl Cancer Inst. 2007;
99: 137-46.
50. You WC, Brown LM, Zhang L et al. Randomized double-blind factorial trial of three treatments to reduce the
prevalence of precancerous gastric lesions. J. Natl Cancer Inst. 2006; 98: 974-83.
51. Jacobs EJ, Connell CJ, McCullough ML et al. Vitamin C, vitamin E, and multivitamin supplement use and
stomach cancer mortality in the Cancer Prevention Study II cohort. Cancer Epidemiol. Biomarkers Prev.
2002; 11: 35-41.
52. Wright ME, Virtamo J, Hartman AM et al. Effects of alpha-tocopherol and beta-carotene supplementation on
upper aerodigestive tract cancers in a large, randomized controlled trial. Cancer 2007; 109: 891-8.
53. Suerbaum S, Michetti P. Helicobacter pylori infection. N. Engl. J. Med. 2002; 347: 1175-86.
54. Fox JG, Wang TC. Inflammation, atrophy, and gastric cancer.J. Clin. Invest. 2007; 117: 60-9.
55. El-Omar EM, Carrington M, Chow WH et al. Interleukin-1 polymorphisms associated with increased risk of
gastric cancer. Nature 2000; 404: 398-402.
56. Machado JC, Pharoah P, Sousa S et al. Interleukin 1B and interleukin 1RN polymorphisms are associated
with increased risk of gastric carcinoma. Gastroenterology 2001; 21: 823-9.
57. Palli D, Saieva C, Luzzi I et al. Interleukin-1 gene polymorphisms and gastric cancer risk in a high-risk
Italian population. Am. J. Gastroenterol. 2005; 100: 1941-8.
58. Furuta T, Shirai N, Sugimoto M. Controversy in polymorphisms of interleukin-1beta in gastric cancer risks.
J. Gastroenterol. 2004; 39: 501-3.
59. El-Omar EM, Rabkin CS, Gammon MD et al. Increased risk of noncardia gastric cancer associated with
proinflammatory cytokine gene polymorphisms. Gastroenterology 2003; 124: 1193-201.
60. Lee WP, Tai DI, Lan KH et al. The -251T allele of the interleukin 8 promoter is associated with increased
risk of gastric carcinoma featuring diffuse-type histopathology in Chinese population. Clin. Cancer Res.
2005; 11: 6431-41.
61. Taguchi A, Ohmiya N, Shirai K et al. Interleukin-8 promoter polymorphism increases the risk of atrophic
gastritis and gastric cancer in Japan. Cancer Epidemiol. Biomarkers Prev. 2005; 14: 2487-93.
62. El-Omar EM, Oien K, Murray LS et al. Increased prevalence of precancerous changes in relatives of gastric
cancer patients: critical role of H. pylori. Gastroenterology 2000; 118: 22-30.
63. Yang J, Hu Z, Xu Y et al. Interleukin-1B gene promoter variants are associated with an increased risk of
gastric cancer in a Chinese population. Cancer Lett. 2004; 215: 191-8.
64. Furuta T, El-Omar EM, Xiao F et al. Interleukin 1beta polymorphisms increase risk of hypochlorhydria and
atrophic gastritis and reduce risk of duodenal ulcer recurrence in Japan. Gastroenterology 2002; 123: 92-105.
65. Sugimoto M, Furuta T, Shirai N et al. Different effects of polymorphisms of tumor necrosis factor-alpha and
interleukin-1 beta on development of peptic ulcer and gastric cancer. J. Gastroenterol. Hepatol. 2007; 22: 519.
66. Kato S, Onda M, Yamada S et al. Association of the interleukin-1 beta genetic polymorphism and gastric
cancer risk in Japanese.J. Gastroenterol. 2001; 36: 696-9.
67. Zeng ZR, Hu PJ, Hu S et al. Association of interleukin 1B gene polymorphism and gastric cancers in high
and low prevalence regions in China. Gut 2003; 52: 1684-9.
68. Camargo MC, Mera R, Correa P et al. Interleukin-1beta and interleukin-1 receptor antagonist gene
polymorphisms and gastric cancer: a meta-analysis. Cancer Epidemiol. Biomarkers Prev. 2006; 15: 1674-87.
69. Huang JQ, Zheng GF, Sumanac K et al. Meta-analysis of the relationship between caga seropositivity and
gastric cancer. Gastroenterology 2003; 125: 1636-44.
70. Mahachai V, Tangkijvanich P, Wannachai N et al. CagA and VacA: virulence factors of Helicobacter pylori
in Thai patients with gastroduodenal diseases. Helicobacter 1999; 4: 143-7.
71. Zheng PY, Hua J, Yeoh KG et al. Association of peptic ulcer with increased expression of Lewis antigens but
not cagA, iceA, and vacA in Helicobacter pylori isolates in an Asian population. Gut 2000; 47: 18-22.
72. Kumar S, Dhar A, Srinivasan S et al. Antibodies to Cag A protein are not predictive of serious
gastroduodenal disease in Indian patients. Indian J. Gastroenterol. 1998; 17: 126-8.
73. Tan HJ, Rizal AM, Rosmadi MY et al. Distribution of Helicobacter pylori cagA, cagE and vacA in different
ethnic groups in Kuala Lumpur, Malaysia. J. Gastroenterol. Hepatol. 2005; 20: 589-94.
74. Perng CL, Lin HJ, Sun IC et al. Helicobacter pylori cagA, iceA and vacA status in Taiwanese patients with
peptic ulcer and gastritis.J. Gastroenterol. Hepatol. 2003; 18: 1244-19.
75. Wong BC, Lam SK, Ching CK et al. Seroprevalence of cytotoxin-associated gene A positive Helicobacter
pylori strains in Changle, an area with very high prevalence of gastric cancer in south China. Aliment
Pharmacol. Ther. 1999; 13: 1295-302.
76. Yamaoka Y, Kodama T, Gutierrez O et al. Relationship between Helicobacter pylori iceA, cagA, and vacA
status and clinical outcome: studies in four different countries. J. Clin. Microbiol. 1999; 37: 2274-9.
77. El-Omar EM, Penman ID, Ardill JE et al. Helicobacter pylori infection and abnormalities of acid secretion in
patients with duodenal ulcer disease. Gastroenterology 1995; 109: 681-91.
78. El-Omar EM, Oien K, El Nujumi A et al. Helicobacter pylori infection and chronic gastric acid
hyposecretion. Gastroenterology 1997; 113: 15-24.
79. Brenner H, Arndt V, Sturmer T et al. Individual and joint contribution of family history and Helicobacter
pylori infection to the risk of gastric carcinoma. Cancer 2000; 88: 274-9.
80. Samloff IM, Varis K, Ihamaki T et al. Relationships among serum pepsinogen I, serum pepsinogen II, and
gastric mucosal histology: a study in relatives of patients with pernicious anemia. Gastroenterology 1982; 83:
204-9.
81. Miki K, Ichinose M, Shimizu A et al. Serum pepsinogens as a screening test of extensive chronic gastritis.
Gastroenterol. Jpn. 1987; 22: 133-41.
82. Bodger K, Wyatt JI, Heatley RV. Variation in serum pepsinogens with severity and topography of
Helicobacter associated chronic gastritis in dyspeptic patients referred for endoscopy. Helicobacter 2001; 6:
216-24.
83. Webb P, Hengels KJ, Moller H et al. The epidemiology of low serum pepsinogen A levels and an
international association with gastric cancer rates. Gastroenterology 1994; 107: 1335-44.
84. Mukoubayashi C, Yanaoka K, Ohata H et al. Serum pepsinogen and gastric cancer screening. Intern. Med.
2007; 46: 261-6.
85. Miki K, Ichinose M, Ishikawa K et al. The clinical application of the serum pepsinogen I and II levels as a
mass screening method to detect stomach cancer. Jpn. J. Cancer Res. 1993; 84: 1086-90.
86. Kodoi A, Yoshihara M, Sumii K et al. Serum pepsinogen in screening for gastric cancer. J. Gastroenterol.
1995; 30:452-60.
87. Hattori Y, Tashiro H, Kawamoto T et al. Sensitivity and specificity of mass screening for gastric cancer using
the measurement of serum pepsinogens. Jpn. J. Cancer Res. 1995; 86: 1210-15.
88. Kitahara F, Kobayashi K, Sato T et al. Accuracy of screening for gastric cancer using serum pepsinogen
concentrations. Gut 1999; 44: 693-7.
89. Yoshihara M, Sumi K, Haruma K et al. The usefulness of gastric mass screening using serum pepsinogen
levels compared with photofluorography. Hiroshima J. Med. Sci. 1997; 46: 81-6.
90. Miki K, Morita M, Sasajima M et al. Usefulness of gastric cancer screening using the serum pepsinogen test
method. Am. J. Gastroenterol. 2003; 98: 735-9.
91. Miki K. Gastric cancer screening using the serum pepsinogen test method. Gastric Cancer 2006; 9: 245-53.
92. Yamada S, Matsuhisa T, Makonkawkeyoon L et al. Helicobacter pylori infection in combination with the
serum pepsinogen I/II ratio and interleukin-1beta-511 polymorphisms are independent risk factors for gastric
cancer in Thais. J. Gastroenterol. 2006; 41: 1169-77.
93. Papatheodoridis GV, Sougioultzis S, Archimandritis AJ. Effects of Helicobacter pylori and nonsteroidal antiinflammatory drugs on peptic ulcer disease: a systematic review. Clin. Gastroenterol. Hepatol. 2006; 4: 13042.
94. Ford AC, Delaney BC, Forman D, Moayyedi P. Eradication therapy for peptic ulcer disease in Helicobacter
pylori positive patients. Cochrane Database Syst. Rev. 2006; (2): CD003840.
95. Gisbert JP, Khorrami S, Carballo F et al. H. pylori eradication therapy vs. antisecretory non-eradication
therapy (with or without long-term maintenance antisecretory therapy) for the prevention of recurrent
bleeding from peptic ulcer. Cochrane Database Syst. Rev. 2004; (2): CD004062.
96. Moayyedi P, Soo S, Deeks J et al. Eradication of Helicobacter pylori for non-ulcer dyspepsia. Cochrane
Database Syst. Rev. 2006; (2): CD002096.
97. Ford AC, Forman D, Bailey AG et al. A community screening program for Helicobacter pylori saves money:
10-year follow-up of a randomized controlled trial. Gastroenterology 2005.; 129: 1910-17.
98. Gerrits MM, van Vliet AH, Kuipers EJ, Kusters JG. Helicobacter pylori and antimicrobial resistance:
molecular mechanisms and clinical implications. Lancet Infect. Dis. 2006; 6: 699-709.
99. Lepper PM, Grusa E, Reichl H et al. Consumption of imipenem correlates with beta-lactam resistance in
Pseudomonas aeruginosa. Antimicrob. Agents Chemother. 2002; 46: 2920-5.
100.
Harthug S, Jureen R, Mohn SC et al. Norwegian Enterococcal Study Group. The prevalence of faecal
carriage of ampicillin-resistant and high-level gentamicin-resistant enterococci among inpatients at 10 major
Norwegian hospitals. J. Hosp. Infect. 2002; 50: 145-54.
101.
Bruinsma N, Filius PM, De Smet PA et al. Antibiotic usage and resistance in different regions of the
Dutch community. Microb. Drug Resist. 2002; 8: 209-14.
102.
Garcia-Rey C, Aguilar L, Baquero F et al. Pharmacoepidemiological analysis of provincial differences
between consumption of macrolides and rates of erythromycin resistance among Streptococcus pyogenes
isolates in Spain. J. Clin. Microbiol. 2002; 40: 2959-63.
103.
Glupczynski Y, M'egraud F, Lopez-Brea M et al. European multicentre survey of in vitro
antimicrobial resistance in Helicobacter pylori. Eur. J. Clin. Microbiol. Infect. Dis. 2001; 20: 820-3.
104.
Perez Aldana L, Kato M, Nakagawa S et al. The relationship between consumption of antimicrobial
agents and the prevalence of primary Helicobacter pylori resistance. Helicobacter 2002; 7: 306-9.
105.
Twine C, Barthelmes L, Gateley CA. Kylie Minogue's breast cancer: effects on referrals to a rapid
access breast clinic in the UK. Breast 2006; 15: 667-9.
106.
Labenz J, Blum AL, Bayerdorffer E et al. Curing Helicobacter pylori infection in patients with
duodenal ulcer may provoke reflux esophagitis. Gastroenterology 1997; 112: 1442-7.
107.
Laine L, Hopkins RJ, Girrardi L. Has the impact of Helicobacter pylori therapy on ulcer recurrence in
the United States been overstated? A meta-analysis of rigorously designed trials. Am. J. Gastroenterol. 1998;
93: 1409-15.
108.
Malfertheiner P, Dent J, Zeijlon L et al. Impact of Helicobacter pylori eradication on heartburn in
patients with gastric or duodenal ulcer disease—Results from a randomized trial programme. Aliment.
Pharmacol. Ther. 2002; 16: 1431-42.
109.
Veldhuyzen van Zanten SJO, Bradette M, Farley A et al. The DU-MACH study: eradication of
Helicobacter pylori and ulcer healing in patients with acute duodenal ulcer using omeprazole based triple
therapy. Aliment. Pharmacol. Ther. 1999; 13: 289-95.
110.
Moayyedi P, Bardhan C, Young L et al. Helicobacter pylori eradication does not exacerbate reflux
symptoms in gastroesophageal reflux disease. Gastroenterology 2001; 121: 1120-6.
111.
Schwizer W, Thumshirn M, Dent J et al. Helicobacter pylori and symptomatic relapse of gastrooesophageal reflux disease: a randomised controlled trial. Lancet 2001; 357: 1738-42.
112.
Wu JC, Chan FK, Wong SK et al. Effect of Helicobacter pylori eradication on oesophageal acid
exposure in patients with reflux oesophagitis. Aliment. Pharmacol. Ther. 2002; 16: 545-52.
113.
Vaira D, Vakil N, Rugge M et al. Effect of Helicobacter pylori eradication on development of
dyspeptic and reflux disease in healthy asymptomatic subjects. Gut 2003; 52: 1543-7.
114.
Moayyedi P, Feltbower R, Brown J et al. Effect of population screening and treatment for
Helicobacter pylori on dyspepsia and quality of life in the community: a randomized controlled trial. Leeds
HELP Study Group. Lancet 2000; 355: 1665-9.
115.
Warburton-Timms VJ, Charlett A, Valori RM et al. The significance of CagA Helicobacter pylori in
reflux oesophagitis. Gut 2001; 49: 341-6.
116.
Vicari JJ, Peek RM, Falk GW et al. The seroprevalence of CagA-positive Helicobacter pylori strains
in the spectrum of gastroesophageal reflux disease. Gastroenterology 1998; 115: 50-7.
117.
Weston AP, Badar AS, Topalovski M et al. Prospective evaluation of the prevalence of gastric
Helicobacter pylori infection in patients with GERD, Barrett's esophagus, Barrett's dysplasia, and Barrett's
adenocarcinoma. Am. J. Gastroenterol. 2000; 95: 387-94.
118.
Chow WH, Blaser MJ, Blot WJ et al. An inverse relation between CagA+ strains of Helicobacter
pylori infection and risk of esophageal gastric cardia adenocarcinoma. Cancer Res. 1998; 58: 588-90.
119.
Ye W, Held M, Lagergren J et al. Helicobacter pylori infection and gastric atrophy: risk of
adenocarcinoma and squamous cell carcinoma of the esophagus and adenocarcinoma of the gastric cardia. J.
Natl Cancer Inst. 2004; 96: 396-402.
120.
Wu AH, Crabtree JE, Bernstein L et al. Role of Helicobacter pylori Cag A+ strains and risk of
adenocarcinoma of the stomach and esophagus. Int. J. Cancer. 2003; 103: 815-21.
121.
Correa P, Fontham ET, Bravo JC et al. Chemoprevention of gastric dysplasia: randomized trial of
antioxidant supplements and anti-Helicobacter pylori therapy. J. Natl Cancer Inst. 2000; 92: 1881-8.
122.
Mera R, Fontham ET, Bravo LE et al. Long term follow up of patients treated for Helicobacter pylori
infection. Gut 2005; 54: 1536-40.
123.
Leung WK, Lin SR, Ching JY et al. Factors predicting progression of gastric intestinal metaplasia:
results of a randomized trial on Helicobacter pylori eradication. Gut 2004; 53: 1244-9.
124.
Zhou LY, Sung JJ, Lin S et al. A five year follow-up study on the pathological changes of gastric
mucosa after H. pylori eradication. Chin. Med. J. (Engl.). 2003; 116: 11-14.
125.
Uemura N, Mukai T, Okamoto S et al. Effect of Helicobacter pylori eradication on subsequent
development of cancer after endoscopic resection of early gastric cancer. Cancer Epidemiol. Biomarkers
Prev. 1997; 6: 639-42.
126.
Uemura N, Okamoto S, Yamamoto S et al. Helicobacter pylori infection and the development of
gastric cancer. N. Engl. J. Med. 2001; 345: 784-9.
127.
Ogura K, Hirata Y, Yanai A et al. The effect of Helicobacter pylori eradication on incidence of gastric
cancer. Gastroenterology 2006; 130 (Suppl. 2): A183.
128.
Zhou LY, Lin SR, Ding SG et al. The changing trends of the incidence of gastric cancer after
Helicobacter pylori eradication in Shandong area. Chin J. Dig. Dis. 2005; 6: 114-15.
129.
Wong BC, Lam SK, Wong WM et al. Helicobacter pylori eradication to prevent gastric cancer in a
high-risk region of China: a randomized controlled trial. JAMA 2004; 291: 187-94.
130.
Saito D, Boku N, Fujioka T et al. Impact of H. pylori eradication on gastric cancer prevention:
endoscopic results of the Japanese Intervention Trial (JITHP-Study). A Randomized Multi-Center Trial.
Gastroenterology 2005; 128 (Suppl. 2): A4.
131.
Kato M, Asaka M. Eradication of Helicobacter pylori for the incidence of metachronous gastric cancer
after endoscopic resection. J. Gastroenterol. Hepatol. 2007; 22: A64.
132.
Rollan A, Giancaspero R, Fuster F et al. The long-term reinfection rate and the course of duodenal
ulcer disease after eradication of Helicobacter pylori in a developing country. Am. J. Gastroenterol. 2000; 95:
50-6.
133.
Hildebrand P, Bardhan P, Rossi L et al. Recrudescence and reinfection with Helicobacter pylori after
eradication therapy in Bangladeshi adults. Gastroenterology 2001; 121: 792-8.
134.
Malfertheiner P, Megraud F, O'morain C et al. Current concepts in the management of Helicobacter
pylori infection—The Maastricht III Consensus Report. Gut 2007; 56: 772-81.
135.
Sonnenberg A, Inadomi JM. Review article: medical decision models of Helicobacter pylori therapy to
prevent gastric cancer. Aliment. Pharmacol. Ther. 1998; 12 (Suppl. 1): 111-21.
136.
Bourke B. Will treatment of Helicobacter pylori infection in childhood alter the risk of developing
gastric cancer? Can J. Gastroenterol. 2005; 19: 409-11.
137.
Rowland M, Kumar D, Daly K, O'Connor P, Vaughan D, Drumm B. Low rates of Helicobacter pylori
reinfection in children. Gastroenterology 1999; 117: 336-41.
138.
Ekstrom AM, Held M, Hansson LE et al. Helicobacter pylori in gastric cancer established by CagA
immunoblot as a marker of past infection. Gastroenterology 2001; 121: 784-91.
139.
Enroth H, Kraaz W, Rohan T et al. Does the method of Helicobacter pylori detection influence the
association with gastric cancer risk? Scand. J. Gastroenterol. 2002; 37: 884-90.
140.
Wolle K, Malfertheiner P. Treatment of Helicobacter pylori. Best Pract. Res. Clin. Gastroenterol.
2007; 21: 315-24