Effects of Helicobacter pylori treatment and vitamin and garlic supplementation on gastric cancer incidence and mortality: Follow-up of a randomized intervention trial

Abstract

Objective
To assess the effects of Helicobacter pylori treatment, vitamin supplementation, and garlic supplementation in the prevention of gastric cancer.

Design
Blinded randomized placebo controlled trial.

Setting
Linqu County, Shandong province, China.

Participants
3365 residents of a high risk region for gastric cancer. 2258 participants seropositive for antibodies to H pylori were randomly assigned to H pylori treatment, vitamin supplementation, garlic supplementation, or their placebos in a 2×2×2 factorial design, and 1107 H pylori seronegative participants were randomly assigned to vitamin supplementation, garlic supplementation, or their placebos in a 2×2 factorial design.

Interventions
H pylori treatment with amoxicillin and omeprazole for two weeks; vitamin (C, E, and selenium) and garlic (extract and oil) supplementation for 7.3 years (1995-2003).

Main outcome measures
Primary outcomes were cumulative incidence of gastric cancer identified through scheduled gastroscopies and active clinical follow-up through 2017, and deaths due to gastric cancer ascertained from death certificates and hospital records. Secondary outcomes were associations with other cause specific deaths, including cancers or cardiovascular disease.

Results
151 incident cases of gastric cancer and 94 deaths from gastric cancer were identified during 1995-2017. A protective effect of H pylori treatment on gastric cancer incidence persisted 22 years post-intervention (odds ratio 0.48, 95% confidence interval 0.32 to 0.71). Incidence decreased significantly with vitamin supplementation but not with garlic supplementation (0.64, 0.46 to 0.91 and 0.81, 0.57 to 1.13, respectively). All three interventions showed significant reductions in gastric cancer mortality: fully adjusted hazard ratio for H pylori treatment was 0.62 (95% confidence interval 0.39 to 0.99), for vitamin supplementation was 0.48 (0.31 to 0.75), and for garlic supplementation was 0.66 (0.43 to 1.00). Effects of H pylori treatment on both gastric cancer incidence and mortality and of vitamin supplementation on gastric cancer mortality appeared early, but the effects of vitamin supplementation on gastric cancer incidence and of garlic supplementation only appeared later. No statistically significant associations were found between interventions and other cancers or cardiovascular disease.

Conclusions
H pylori treatment for two weeks and vitamin or garlic supplementation for seven years were associated with a statistically significant reduced risk of death due to gastric cancer for more than 22 years. H pylori treatment and vitamin supplementation were also associated with a statistically significantly reduced incidence of gastric cancer.

Trial registration
ClinicalTrials.gov NCT00339768 .

Full text

thebmj 
BMJ
2019;366:l5016 | doi: 10.1136/bmj.l5016 1
RESEARCH
Eects of
Helicobacter pylori
treatment and vitamin and garlic
supplementation on gastric cancer incidence and mortality:
follow-up of a randomized intervention trial
Wen-Qing Li,1 Jing-Yu Zhang,1 Jun-Ling Ma,1 Zhe-Xuan Li,1 Lian Zhang,1 Yang Zhang,1 Yang Guo,1
Tong Zhou,1 Ji-You Li,1 Lin Shen,1 Wei-Dong Liu,2 Zhong-Xiang Han,2 William J Blot,3,4
Mitchell H Gail,5 Kai-Feng Pan,1 Wei-Cheng You1
ABSTRACT
OBJECTIVE
To assess the eects of Helicobacter pylori treatment,
vitamin supplementation, and garlic supplementation
in the prevention of gastric cancer.
DESIGN
Blinded randomized placebo controlled trial.
SETTING
Linqu County, Shandong province, China.
PARTICIPANTS
3365 residents of a high risk region for gastric cancer.
2258 participants seropositive for antibodies to H
pylori were randomly assigned to H pylori treatment,
vitamin supplementation, garlic supplementation,
or their placebos in a 2×2×2 factorial design, and
1107 H pylori seronegative participants were
randomly assigned to vitamin supplementation, garlic
supplementation, or their placebos in a 2×2 factorial
design.
INTERVENTIONS
H pylori treatment with amoxicillin and omeprazole
for two weeks; vitamin (C, E, and selenium) and garlic
(extract and oil) supplementation for 7.3 years (1995-
2003).
MAIN OUTCOME MEASURES
Primary outcomes were cumulative incidence
of gastric cancer identied through scheduled
gastroscopies and active clinical follow-up through
2017, and deaths due to gastric cancer ascertained
from death certicates and hospital records.
Secondary outcomes were associations with
other cause specic deaths, including cancers or
cardiovascular disease.
RESULTS
151 incident cases of gastric cancer and 94 deaths
from gastric cancer were identied during 1995-
2017. A protective eect of H pylori treatment on
gastric cancer incidence persisted 22 years post-
intervention (odds ratio 0.48, 95% condence interval
0.32 to 0.71). Incidence decreased signicantly
with vitamin supplementation but not with garlic
supplementation (0.64, 0.46 to 0.91 and 0.81,
0.57 to 1.13, respectively). All three interventions
showed signicant reductions in gastric cancer
mortality: fully adjusted hazard ratio for H pylori
treatment was 0.62 (95% condence interval 0.39 to
0.99), for vitamin supplementation was 0.48 (0.31
to 0.75), and for garlic supplementation was 0.66
(0.43 to 1.00). Eects of H pylori treatment on both
gastric cancer incidence and mortality and of vitamin
supplementation on gastric cancer mortality appeared
early, but the eects of vitamin supplementation on
gastric cancer incidence and of garlic supplementation
only appeared later. No statistically signicant
associations were found between interventions and
other cancers or cardiovascular disease.
CONCLUSIONS
H pylori treatment for two weeks and vitamin or garlic
supplementation for seven years were associated
with a statistically signicant reduced risk of death
due to gastric cancer for more than 22 years. H pylori
treatment and vitamin supplementation were also
associated with a statistically signicantly reduced
incidence of gastric cancer.
TRIAL REGISTRATION
ClinicalTrials.gov NCT00339768.
Introduction
In 2018 almost half of the estimated deaths from
gastric cancer—the third leading cause of deaths from
cancer globally—occurred in China.1 Linqu County, a
rural area in Shandong province, northeastern China,
has one of the highest mortality rates from gastric
cancer worldwide (age adjusted rates per 100 000
were 55 for men and 19 for women in 1980-82).2
1Key Laboratory of
Carcinogenesis and
Translational Research
(Ministry of Education/
Beijing), Department of Cancer
Epidemiology, Peking University
Cancer Hospital and Institute,
Haidian District, Beijing
100142, China
2Linqu County Public Health
Bureau, Shandong, China
3International Epidemiology
Institute, Rockville, MD, USA
4Vanderbilt University Medical
Center, Nashville, TN, USA
5Division of Cancer
Epidemiology and Genetics,
National Cancer Institute,
Bethesda, MD, USA
Correspondence to: K-F Pan
pankaifeng2002@yahoo.com
(ORCID 0000-0002-3680-3126)
Additional material is published
online only. To view please visit
the journal online.
Cite this as: BMJ 2019;366:l5016
http://dx.doi.org/10.1136/bmj.l5016
Accepted: 15 July 2019
WHAT IS ALREADY KNOWN ON THIS TOPIC
Helicobacter pylori infection is an established risk factor for gastric cancer and H
pylori eradication could be a potential strategy for preventing gastric cancer
The duration of eectiveness of H pylori treatment on gastric cancer prevention
and the related full range of benecial and adverse eects needs to be studied
by long term follow-up
Few nutrition intervention trials have been done in populations with nutritional
deciencies, whereas nutrition supplementation eects on gastric cancer need
to be assessed with long term follow-up
WHAT THIS STUDY ADDS
Short term H pylori treatment was associated with a signicantly decreased risk
of gastric cancer incidence and mortality during 22.3 years of follow-up and was
not signicantly associated with total mortality or other major cancer specic
mortality
Both vitamin (C, E, and selenium) and garlic (extract and oil) supplementation for
7.3 years yielded statistically signicant reductions in gastric cancer mortality,
whereas a favorable eect of long term vitamin supplementation on gastric
cancer incidence was also observed
These ndings oer potential opportunities for gastric cancer prevention, but
further large scale intervention trials are required to conrm the favorable eects
of vitamin and garlic supplementation and to identify any possible risks of H
pylori treatment, and vitamin and garlic supplementation
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Solid evidence from epidemiologic studies links
infection with Helicobacter pylori to the progression
of precancerous gastric lesions and development of
gastric cancer, and shows that diets rich in vitamin
and garlic could protect against gastric cancer in
high risk people with insucient vitamin intake.3-5 In
1995, the Shandong Intervention Trial was initiated
in Linqu to evaluate the eects of three interventions
in preventing the progression of precancerous gastric
lesions to gastric cancer.6-9 The interventions included
H pylori treatment for two weeks and vitamin and garlic
supplementation for just over seven years. After almost
15 years of follow-up (1995-2010), the trial reported
a statistically significant reduction in incidence of
gastric cancer and a non-statistically significant
reduction in deaths due to gastric cancer associated
with H pylori treatment, and the trial was recognized
as the first to show a clear reduction in gastric cancer
incidence with H pylori treatment.8-11 Both garlic and
vitamin supplementation showed favorable trends for
decreased gastric cancer incidence and mortality, but
these eects were not statistically significant.8
Although the Shandong Intervention Trial suggested
a potential role of H pylori treatment in the prevention
of gastric cancer, further follow-up was needed to
determine whether the reductions would persist and
lead to a noticeable decrease in gastric cancer mortality.
It also remained unknown whether vitamin and garlic
supplementation would be associated with statistically
significant reductions in gastric cancer incidence and
mortality in the longer term. We therefore extended
the follow-up to just over 22 years after randomization
to ascertain gastric cancer incidence and mortality.
Secondary outcomes were associations with other
cause specific deaths.
Methods
Study population
In 1995 the Shandong Intervention Trial, a blinded
randomized factorial placebo controlled trial, was
initiated in Linqu, China.6-8 The year before the trial,
a census of 13 randomly selected villages within four
townships in Linqu identified 4010 residents aged
35-64 years. Of 3599 people who agreed to undergo
gastroscopy with biopsies and to provide blood for H
pylori serology, 3411 were randomly assigned to the trial
in 19956-8 (see supplementary table 1). After exclusions
for not meeting the eligibility criteria, 3365 people were
included in the trial. A total of 2258 participants who
were seropositive for antibodies to H pylori, as determined
by IgG serology from enzyme linked immunoassay in
1994, were randomly assigned to three interventions
(H pylori treatment with amoxicillin and omeprazole
for two weeks, and/or garlic supplementation for 7.3
years, and/or vitamin supplementation for 7.3 years)
or their placebos in a 2×2×2 factorial design. Overall,
1107 participants who were H pylori negative were
randomly assigned to garlic supplementation and/
or vitamin supplementation or their placebos in a 2×2
factorial design. The research service provider Westat
(Rockville, MD) generated the randomized treatment
assignments, and the participants received pill bottles
bearing assignment codes to mask both participants
and investigators to treatment.
From 15 September to 29 November 1995, H pylori
positive participants received one capsule of 1 g
amoxicillin and 20 mg omeprazole (n=1130) or a look
alike placebo capsule (n=1128) twice daily for two
weeks for H pylori treatment. To maintain masking,
H pylori negative participants received a placebo
capsule twice daily during the same period. 13C urea
breath tests from January to March 1996 detected 382
participants who were still H pylori positive after initial
treatment and they received treatment for a further
two weeks. To preserve masking, 383 participants
in the placebo group matched on village, age, and
sex received repeat placebo treatment. For vitamin
supplementation (30 November 1995 to 31 March
2003), participants received one capsule of 250 mg
vitamin C, 100 IU vitamin E, and 37.5 μg selenium
(n=1677) or a look alike placebo capsule (n=1688)
twice daily for 7.3 years. From December 1995 to May
1996, the vitamin supplement also contained 7.5 mg
β carotene.6 During this period, participants assigned
to garlic supplementation received two capsules each
containing 200 mg aged garlic extract and 1 mg steam
distilled garlic oil (n=1678), or two look alike placebo
capsules (n=1687), twice daily. Minute quantities of
garlic oil were added to the placebo bottles to mask
assignment.
Follow-up and assessment of study endpoints
We followed participants from date of randomization
(23 July 1995). Participants were visited daily for pill
countingduring H pylori treatment and participants
were visited monthly to distribute supplements and
count pills during the period of vitamin and garlic
supplementation. In addition, we measured serum
levels of vitamin E, vitamin C, and S-allylcysteine
in randomly selected participants to monitor use of
vitamin and garlic supplementation. Data from pill
counts and sampled blood assays showed excellent
treatment compliance. The initial follow-up ended on
1 May 2003 and the extended follow-up ended on 1
December 2017.
The primary outcomes were gastric cancer incidence
and mortality. We also assessed cause specific cancer
and cardiovascular disease mortality as secondary
outcomes. Incidence of gastric cancer was ascertained
from scheduled gastroscopies in 1999 and 2003 for
all participants, with biopsy samples taken from
seven standard sites; scheduled gastroscopies in 2007
for those with a diagnosis of intestinal metaplasia
or dysplasia at any biopsy site in 2003; repeat
gastroscopies every six months to one year between
2008 and 2017 for those with a diagnosis of moderate
or severe dysplasia at any biopsy site or with mild
dysplasia at two or more sites in 2003; or cancer registry
or autopsy reports, which were confirmed through
medical records. Details of gastroscopy and biopsy
procedures and histopathologic criteria are described
elsewhere.2 12 We obtained causes of death from the
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reporting system managed by the Chinese Center for
Disease Control and Prevention, which integrates
death certificates from hospitals and police and
judicial departments in Linqu. To avoid missed records
from delayed reporting, a local doctor supervised the
follow-up in each village and documented the vital
status and occurrence of cancer and major chronic
diseases. Sta from Peking University Cancer Hospital
visited the villages every three months after 2003 to
gather information on gastric cancer incidence and
cause specific mortality.
Statistical analysis
In the primary analyses, we examined the risk of
gastric cancer incidence and mortality associated
with the three interventions. Because gastric cancer
was diagnosed in many participants at scheduled
gastroscopies in 1999 and 2003, we estimated odds
ratios for cumulative incidence of gastric cancer and
corresponding 95% confidence intervals. We used
conditional logistic regression stratified on baseline
histopathology, categorized as moderate chronic
atrophic gastritis or less severe gastric lesions, severe
chronic atrophic gastritis or superficial intestinal
metaplasia, deep intestinal metaplasia, or dysplasia.
We adjusted the analyses for other potential
confounders, including age, sex, history of ever using
alcohol, and history of ever smoking. Conditional
logistic regression is helpful when there are only a few
participants per stratum, as it eliminates the nuisance
intercept, whereas unconditional logistic regression
can yield unreliable inference because of the necessity
to estimate many intercepts, one per stratum. Our study
contained only a few stratums, but as the numbers in
each stratum increase, the conditional logistic analysis
becomes asymptotically fully ecient. Conditional
logistic regression has the additional advantage of
paralleling that of stratified Cox regression.
For analysis of gastric cancer mortality, we used
the Cox proportional hazards models on the scale of
time since randomization to estimate hazard ratios
and 95% confidence intervals, stratified on baseline
histopathology. The proportional hazards assumption
within stratums was tested by including an interaction
term between time and treatment (P>0.05 for all tests).
In the multivariate adjusted models, Cox regression
analyses were further adjusted for age, sex, smoking,
and alcohol intake.
Sensitivity analyses included indicators for the
other treatments in addition to the treatment being
analyzed in the regression models. In secondary
analyses, we used the Cox model to assess associations
of interventions with all cause mortality and cause
specific mortality, including deaths from any cancer,
individual cancers with at least 10 deaths among
participants who were H pylori positive at baseline,
and cardiovascular disease.
For each intervention we plotted Kaplan-Meier
survival curves to compare time to all cause mortality
and gastric cancer mortality. We further examined the
temporal changes in the eects of interventions on
cumulative incidence of gastric cancer and on mortality
by dividing follow-up into three periods: the initial trial
period (from randomization to 1 May 2003),7 the first
extended follow-up period (2 May 2003 to 1 August
2010),8 9 and the second extended follow-up period (2
August 2010 to 1 December 2017).
We stratified analyses to determine whether the
eects of interventions varied by participants’ baseline
histopathology or age. The Q statistic for meta-analysis
was used to evaluate heterogeneity of odds ratios or
hazard ratios across stratums. To clarify potential eect
modification between interventions, we also tested
the two way interactions between H pylori treatment,
vitamin supplementation, and garlic supplementation
on gastric cancer incidence and mortality.
Analyses were performed using the intention-to-
treat approach. P values were two tailed. Statistical
calculations were performed with SAS statistical
software, version 9.4 (SAS institute, Cary, NC).
Patient and public involvement
No patients were involved in setting the research
question or the outcome measures, nor were they
involved in developing plans for recruitment, design,
or implementation of the study. No patients were
asked to advise on interpretation or writing of results.
Before the trial started, extensive information about
gastric cancer was disseminated locally to promote
the residents’ participation. Peking University Cancer
Hospital has reported and will report the results
by publication, presentation at scientific meetings,
and public events to promote cancer prevention and
control. The results will also be disseminated using
social media.
Results
A total of 3365 participants were included in
the trial (see supplementary table 2). Block
randomized intervention assignments6 ensured
balanced distribution in baseline characteristics
between treatment and placebo groups for the three
interventions. During 22.3 years of follow-up (fig 1),
151 incident cases of gastric cancer and 94 deaths from
gastric cancer were identified. Of these, 119 (79%) and
76 (81%), respectively, occurred among participants
who were baseline H pylori positive (table 1). Most of
the cancers were non-cardia types (see supplementary
table 3).
H pylori treatment was inversely associated with risk
of gastric cancer, even after multivariate adjustment
(odds ratio 0.48, 95% confidence interval 0.32 to
0.71) (table 2). Incidence decreased significantly
with vitamin supplementation but not with garlic
supplementation (0.64, 0.46 to 0.91 and 0.81, 0.57 to
1.13, respectively).
A statistically significant protective eect on
gastric cancer mortality was observed for all three
interventions: fully adjusted hazard ratio was
0.62 (95% confidence interval 0.39 to 0.99) for H
pylori treatment, 0.48 (0.31 to 0.75) for vitamin
supplementation, and 0.66 (0.43 to 1.00) for garlic
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Vitamin supplementation and garlic supplementation ends on 31 March 2003
Initial trial follow-up ends on 1 May 2003
First extended follow-up period ends on 1 August 2010
Participants aged 35-64 identified in 13 randomly selected villages
7.3 years first extended
follow-up period
7.3 years second
extended follow-up period
22.3 years aer
randomization
22 years aer H pylori
treatment ends
14.7 years aer vitamin/
garlic supplementation ends
Participants who underwent gastroscopy invited to participate in intervention trial
Refused endoscopy or were too ill
411
Eligibility exclusion
188
Pre-randomization eligiblity violations
3599
Randomly assigned on 23 July 1995
3411
Randomly assigned and eligible. Helicobacter pylori treatment for two weeks between 15 September
and 29 November 1995, vitamin and garlic supplementation implemented 30 November 1995
3365
H pylori seropositive participants entered
2x2x2 factorial trial of H pylori treatment,
vitamin supplementation, and garlic supplementation
2258
H pylori seronegative participants entered
2x2 factorial trial of vitamin supplementation
and garlic supplementation
1107
46
Lost to follow-up for vital status
2
Lost to follow-up for vital status
1
Second extended follow-up period ends on 1 December 2017
Lost to follow-up for vital status
0
4010
Fig1 | Flow diagram of trial design and participant follow-up
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supplementation (table 3). Kaplan-Meier curves
showed that the cumulative protective eect on
gastric cancer mortality became evident after about
eight years for H pylori treatment and vitamin
supplementation and after about 12 years for garlic
supplementation (fig 2). For both gastric cancer
incidence and mortality, sensitivity analyses adjusted
for other interventions yielded similar findings (data
not shown).
Separate analyses for the three follow-up periods
did not show statistically significant heterogeneity
in treatment eects in odds ratios for gastric cancer
incidence or hazard ratios for gastric cancer mortality
(fig 3), possibly owing to limited power. The eects
from garlic supplementation were, however, negligible
in the initial trial period for both gastric cancer
incidence and gastric cancer mortality, and eects only
became apparent by 14.7 years and persisted during
the 22.3 years of follow-up. The treatment eect for
vitamin supplementation in the initial trial period was
also negligible for gastric cancer incidence but not for
gastric cancer mortality.
In secondary analyses (table 3), vitamin
supplementation was marginally associated with
decreased all cause mortality (hazard ratio 0.87,
0.76 to 1.01, P=0.07). No statistically significant
associations were found for all cancer mortality
or esophageal cancer specific mortality. H pylori
treatment was marginally associated with a decrease
in risk of colorectal cancer mortality (P=0.07) and
a non-significant increase in liver cancer mortality
(P=0.15). The associations with other specific causes
of death were also non-significant (table 3).
No statistically significant evidence of heterogeneity
was found in the eects of H pylori treatment or
garlic supplementation for gastric cancer incidence
or mortality among participants with diering
baseline histopathology, or among dierent age
groups. Although tests for heterogeneity were only
marginally significant for vitamin supplementation,
the data suggest a greater preventive eect for those
with favorable baseline histology (normal, superficial
gastritis, chronic atrophic gastritis) and those younger
than 45 years, for both gastric cancer incidence and
mortality (fig 4).
We tested two way interactions for treatment eects.
Among baseline H pylori seronegative participants, a
non-significant indication suggested that participants
who only took vitamin supplements had a lower
incidence of gastric cancer than those who took
vitamin or garlic supplements (P for interaction=0.08)
(see supplementary table 4). These interaction tests
were not adjusted for multiple comparisons, however,
and were not nominally statistically significant.
Discussion
In the Shandong Intervention Trial, the preventive
eect of short term treatment (two weeks) for
Helicobacter pylori infection on risk of gastric cancer
continued 22 years post-treatment and was associated
with statistically significant fewer deaths due to gastric
cancer. We also found a significantly decreased long
Table 1 | Number of participants with incident gastric cancer and mortality by intervention groups during trial and
extended follow-up*
Intervention groups No of participants
Incident gastric cancer Gastric cancer deaths
Trial
period
Extended
follow-up
2003-10
Extended
follow-up
2010-17
Total
No
Trial
period
Extended
follow-up
2003-10
Extended
follow-up
2010-17
Total
No
Helicobacter pylori treatment:
Active 1130 19 15 741 810 11 29
Placebo 1128 28 24 26 78 10 14 23 47
Total 2258 47 39 33 119 18 24 34 76
Vitamin supplementation:
Active 1677 29 19 12 60 9 8 14 31
Placebo 1688 30 28 33 91 12 18 33 63
Total 3365 59 47 45 151 21 26 47 94
Garlic supplementation:
Active 1678 30 19 20 69 12 918 39
Placebo 1687 29 28 25 82 917 29 55
Total 3365 59 47 45 151 21 26 47 94
*Events from date of randomization to end of initial follow-up (23 July 1995 to 1 May 2003). Number of cases during trial period and rst extended
follow-up period are described in Ma et al.8
Table2 | Odds ratios (95% condence intervals) for incidence of gastric cancer by Helicobacter pylori treatment, and vitamin and garlic
supplementation
Interventions
Adjusted for baseline histology Fully adjusted*
Placebo (No with
event/No in group)
Treatment (No with
event/No in group) Odds ratio (95% CI) P value
Placebo (No with
event/No in group)
Treatment (No with
event/No in group) Odds ratio (95% CI) P value
H pylori treatment 78/1123 40/1119 0.48 (0.33 to 0.72) <0.001 76/1086 40/1086 0.48 (0.32 to 0.71) <0.001
Vitamin supplementation 90/1679 60/1665 0.66 (0.47 to 0.92) 0.02 89/1627 58/1610 0.64 (0.46 to 0.91) 0.01
Garlic supplementation 82/1678 68/1666 0.82 (0.58 to 1.14) 0.23 81/1631 66/1606 0.81 (0.57 to 1.13) 0.22
Number of participants and number of gastric cancer cases is lower than in table 1 because of missing information on baseline histology or other covariates.
*Adjusted for baseline histology (moderate chronic atrophic gastritis or less severe gastric lesions, severe chronic atrophic gastritis or supercial intestinal metaplasia, deep intestinal metaplasia,
or dysplasia), age, sex, history of ever using alcohol, and history of ever smoking.
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term risk of gastric cancer associated with vitamin
supplementation and a reduced risk of gastric cancer
mortality with vitamin or garlic supplementation.
Principal ndings and comparison with other
studies
Previous intervention trials7-9 13-18 and recent
studies19 20 have examined the eect of H pylori
treatment on gastric cancer. Although treatment is
recognized as a potential strategy for the prevention
of gastric cancer,11 21 major uncertainties require
clarification before the strategy can be implemented at
community level. As the development of gastric cancer
involves progression through multiple histologic stages,
the duration of eectiveness of H pylori treatment
needs to be studied by long term follow-up.22 Our
findings confirm the statistically significant reduction
in gastric cancer incidence and favorable although
statistically non-significant reduction in gastric cancer
mortality after 14.7 years,8 indicating an even greater
beneficial eect of H pylori treatment on incidence
of gastric cancer than we previously reported at 14.7
years (odds ratio 0.61, 95% confidence interval 0.38
to 0.96).8 The reduction in gastric cancer incidence in
the Shandong Intervention Trial was also larger than in
recent meta-analyses of intervention trials.23 24 As more
gastric cancer deaths occurred during longer follow-
up, the reduction in gastric cancer mortality became
statistically significant 22.3 years after intervention,
although the eect became visible in Kaplan-Meier
curves after roughly eight years.
Gaps remain about the full range of beneficial and
adverse eects from H pylori treatment. An inverse
association of H pylori infection with esophageal
adenocarcinoma has been reported.11 25 26 Although
uncertainty remains for esophageal squamous cell
carcinoma, a meta-analysis found a decreased risk
of this cancer associated with H pylori infection in
eastern populations.26 The Shandong Intervention
Trial provided few events and had little power to
detect eects of H pylori treatment on esophageal
cancer mortality and cannot distinguish esophageal
squamous cell carcinoma from esophageal
adenocarcinoma (rare in this region); however, there
Table3 | Hazard ratios (95% condence intervals) for cause specic death by Helicobacter pylori treatment, and vitamin and garlic supplementation
Causes of death by intervention
Adjusted for baseline histology only Fully adjusted*
No in placebo
group
No in treatment
group Hazard ratio (95% CI) P value
No in placebo
group
No in treatment
group Hazard ratio (95% CI) P value
H pylori treatment: 1123 1119   1086 1086  
Total No of deaths 272 264 0.98 (0.83 to 1.16) 0.79 254 245 1.00 (0.84 to 1.19) 0.96
Cause specic deaths:
All cancer† 141 115 0.81 (0.63 to 1.04) 0.10 131 105 0.81 (0.62 to 1.05) 0.10
Gastric cancer 47 29 0.62 (0.39 to 0.99) 0.04 45 29 0.62 (0.39 to 0.99) 0.05
Esophageal cancer 12 14 1.17 (0.54 to 2.53) 0.69 10 11 1.12 (0.47 to 2.64) 0.80
Liver cancer 11 21 1.93 (0.93 to 4.01) 0.08 10 18 1.78 (0.82 to 3.86) 0.15
Colorectal cancer 12 30.25 (0.07 to 0.89) 0.03 10 30.30 (0.08 to 1.10) 0.07
Lung cancer 40 33 0.83 (0.52 to 1.31) 0.42 38 31 0.82 (0.51 to 1.32) 0.42
Other cancer 19 15 0.79 (0.40 to 1.56) 0.50 18 13 0.73 (0.36 to 1.50) 0.40
Cardiovascular disease 96 106 1.11 (0.84 to 1.47) 0.45 90 100 1.17 (0.88 to 1.55) 0.29
Other 35 43 1.24 (0.79 to 1.93) 0.35 33 40 1.27 (0.80 to 2.01) 0.31
Vitamin supplementation 1679 1665   1627 1610  
Total No of deaths 423 370 0.86 (0.75 to 0.99) 0.04 392 345 0.87 (0.76 to 1.01) 0.07
Cause specic deaths:
All cancer† 187 166 0.89 (0.72 to 1.09) 0.26 175 152 0.88 (0.71 to 1.09) 0.23
Gastric cancer 62 31 0.49 (0.32 to 0.76) 0.001 61 29 0.48 (0.31 to 0.75) 0.001
Esophageal cancer 18 15 0.84 (0.42 to 1.67) 0.62 16 12 0.77 (0.36 to 1.63) 0.50
Liver cancer 21 25 1.20 (0.67 to 2.15) 0.53 18 24 1.38 (0.75 to 2.55) 0.30
Colorectal cancer 11 10 0.92 (0.39 to 2.17) 0.85 10 80.81 (0.32 to 2.06) 0.66
Lung cancer 49 56 1.16 (0.79 to 1.70) 0.46 44 53 1.23 (0.83 to 1.84) 0.30
Other cancer 26 29 1.13 (0.66 to 1.91) 0.66 26 26 1.02 (0.59 to 1.76) 0.94
Cardiovascular disease 168 141 0.84 (0.67 to 1.05) 0.12 156 132 0.84 (0.67 to 1.06) 0.14
Other 68 63 0.93 (0.66 to 1.32) 0.70 61 61 1.02 (0.71 to 1.45) 0.92
Garlic supplementation: 1678 1666   1631 1606  
Total No of deaths 406 387 0.96 (0.83 to 1.10) 0.53 383 354 0.90 (0.78 to 1.04) 0.17
Cause specic deaths:
All cancer† 185 168 0.91 (0.74 to 1.12) 0.36 175 152 0.87 (0.70 to 1.08) 0.19
Gastric cancer 55 38 0.69 (0.46 to 1.04) 0.08 54 36 0.66 (0.43 to 1.00) 0.05
Esophageal cancer 18 15 0.82 (0.42 to 1.64) 0.58 16 12 0.78 (0.37 to 1.65) 0.51
Liver cancer 22 24 1.11 (0.62 to 1.98) 0.73 19 23 1.26 (0.69 to 2.32) 0.46
Colorectal cancer 11 10 0.93 (0.40 to 2.19) 0.87 11 70.63 (0.24 to 1.64) 0.34
Lung cancer 54 51 0.95 (0.65 to 1.39) 0.79 51 46 0.91 (0.61 to 1.36) 0.66
Other cancer 25 30 1.22 (0.72 to 2.07) 0.47 24 28 1.21 (0.70 to 2.08) 0.50
Cardiovascular disease 152 157 1.04 (0.83 to 1.30) 0.74 142 146 1.04 (0.83 to 1.31) 0.72
Other 69 62 0.90 (0.64 to 1.26) 0.53 66 56 0.86 (0.60 to 1.23) 0.40
Number of participants and number of gastric cancer cases is lower than in table 1 because of missing information on baseline histology or other covariates.
*Adjusted for baseline histology (moderate chronic atrophic gastritis or less severe gastric lesions, severe chronic atrophic gastritis or supercial intestinal metaplasia, deep intestinal metaplasia,
or dysplasia), age, sex, history of ever using alcohol, and history of ever smoking.
†Individual cancers with at least 10 deaths among baseline H pylori positive participants.
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is little indication of adverse risk. An increased risk of
colorectal cancer associated with H pylori infection has
also been reported.27 Our study found a reduction in
deaths due to colorectal cancer with H pylori treatment,
but the number was too small to confirm this eect. In
addition, we found a non-significant excess of deaths
due to liver cancer with H pylori treatment. Despite
prolonged follow-up in our trial, the sample size
for H pylori treatment (n=2242) limited our ability
to estimate the benefits and risks for many health
outcomes.
Whether a point exists in H pylori associated gastric
carcinogenesis after which treatment would be too late
to reduce the risk of gastric cancer is still debatable,
as H pylori infection is linked to early precancerous
histopathologic changes.12 The Maastricht V/Florence
consensus report stated that H pylori eradication
results in a clear improvement of gastritis and gastric
atrophy but not of intestinal metaplasia.28 A trial also
showed that eradication of H pylori did not reduce
the incidence of intestinal metaplasia or decrease its
histological severity.29 However, the consensus report
also recognized that the progression of intestinal
metaplasia can be halted by eradicationof H pylori,28 as
supported by our intervention trial.7 Advanced gastric
lesions occur more often at old ages,2 12 which raises
concerns about the eectiveness of prophylactic H
pylori eradication among those with advanced gastric
lesions and older people. Such concerns have been
partly addressed by evidence that H pylori treatment
reduces the incidence of metachronous gastric
cancer,20 30 but other reports on new gastric cancer
with precancerous lesions or metachronous gastric
cancer have been contradictory,15 31 and some experts
H pylori treatment
Gastric cancer survival estimate All death survival estimate
Follow-up time (years)
Survival probability
95
97
98
100
99
96
0 2 4 6 8 10 12 14 16 18 20 22
Follow-up time (years)
Survival probability
75
85
90
100
95
80
0 2 4 6 8 10 12 14 16 18 20
Vitamin supplementation
Survival probability
95
97
98
100
99
96
Survival probability
75
85
90
100
95
80
Garlic supplementation
Survival probability
95
97
98
100
99
96
Survival probability
75
85
90
100
95
80
22
H pylori treatment/vitamin supplementation/garlic supplementation
Placebo
Fig2 | Kaplan-Meier survival estimates for gastric cancer mortality and total mortality by Helicobacter pylori treatment, vitamin supplementation,
and garlic supplementation. Follow-up time is from trial randomization
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recommend using H pylori treatment only before
gastric atrophy or intestinal metaplasia develops.15
Our long term data confirm the earlier finding of the
Shandong Intervention Trial9 that H pylori treatment
reduces gastric cancer incidence and mortality also in
participants with intestinal metaplasia and dysplasia
and in those aged 55-71 years at baseline. Thus H
pylori infection might promote late stage neoplastic
progression. It is also possible that H pylori treatment
eliminates non-H pylori bacteria crucial for progression
to gastric cancer,9 32 supporting the need to explore
other microbiota underlying gastric carcinogenesis.
Regardless, H pylori treatment is potentially useful
for old as well as young people and for those with
advanced as well as early precancerous gastric lesions.
Few intervention trials have been conducted
in populations with nutritional deficiencies. The
Linxian Nutrition Intervention Trial showed a durable
beneficial eect from supplementation for 5.25
years with a combination of selenium, vitamin E,
and beta-carotene (“factor D”) on total and gastric
cancer mortality, which lasted up to 10 years post-
trial but subsequently waned.33-35 In Linqu, where
the Shandong Intervention Trial was conducted, the
mean serum levels of vitamin C and selenium were
well below reference ranges.3 36 In this nutritionally
deprived population, observational studies showed
that the risk of gastric cancer was inversely associated
with vitamin C intake.5 A high level of serum vitamin C
was also associated with a decreased risk of histologic
progression to dysplasia and gastric cancer in Linqu.3
Our previous follow-up for 14.7 years revealed
noteworthy, but not statistically significant, reductions
in gastric cancer incidence and mortality. Thus, the
statistically significant reductions in gastric cancer
incidence and mortality after 22.3 years are supported
by earlier clinical trial data and observational studies.
A marginally significant indication showed that
vitamin supplementation is more eective in those
with mild histopathology at baseline and younger than
45 years. Similarly, only participants aged less than 55
years benefited from factor D in the Linxian Nutrition
Intervention Trial.34
Observational data show a decreased risk of gastric
cancer with increased consumption of garlic and
allium vegetables in Linqu12 and elsewhere.37 Garlic
and its derivatives have antioxidative, antimicrobial,
and immune modulation properties.38 39 However, few
long term randomized placebo controlled intervention
trials have utilized dietary or supplemental allium
vegetables for cancer prevention. One trial indicated
that aged garlic extract prevented metachronous
Odds ratio
0
1.0
1.5
2.0
0.5
Hazard ratio
0
1.0
1.5
2.5
2.0
0.5
P heterogeneity = 0.43 P heterogeneity = 0.17 P heterogeneity = 0.73
P heterogeneity = 0.98 P heterogeneity = 0.88 P heterogeneity = 0.63
1995-
2003
H pylori treatment Vitamin supplementation Garlic supplementation
Gastric cancer incidence
Gastric cancer mortality
2003-
10
2010-
17
1995-
2003
2003-
10
2010-
17
1995-
2003
2003-
10
2010-
17
Fig3 | Association of Helicobacter pylori treatment, vitamin supplementation, and garlic supplementation with gastric
cancer incidence and mortality during three periods (trial period 23 July 1995 to 1 May 2003, rst extended follow-
up period 2 May 2003 to 1 August 2010, and second extended follow-up period 2 August 2010 to 1 December 2017).
Analyses were adjusted for baseline histology (moderate chronic atrophic gastritis or less severe gastric lesions,
severe chronic atrophic gastritis or supercial intestinal metaplasia, deep intestinal metaplasia, dysplasia), age, sex,
history of ever using alcohol, and history of ever smoking. Whiskers represent 95% condence intervals
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colorectal adenomas,40 whereas another revealed a
statistically significant protective eect of synthetic
diallyl trisulfide (allitridum) combined with selenium
on gastric cancer incidence in men but not in
women.41 After 22.3 years, garlic supplementation
led to a non-statistically significant reduction in
gastric cancer incidence and a statistically significant
reduction in gastric cancer mortality, confirming
favorable, but non-statistically significant trends seen
at 14.7 years.8
The time course and duration of protective eects
is of interest. H pylori treatment was associated
with retardation in the progression of precancerous
gastric lesions,7 and evidence began to accumulate
for protective eects on gastric cancer incidence and
mortality in the initial trial period. The beneficial eects
on gastric cancer incidence and mortality persisted
during 14.7 years8 and again through 22.3 years
(fig 3). Neither vitamin nor garlic supplementation
significantly retarded histopathologic progression
during the initial trial, ending at 2003.7 Vitamin
supplementation showed favorable (but not
statistically significant) eects on gastric cancer
mortality during the trial period; these eects persisted
during the extended follow-up over 14.7 and 22.3 years
(fig 3). Favorable eects of vitamin supplementation
on gastric cancer incidence appeared late but were
apparent during the extended follow-up of 14.7 years
and persisted. Garlic supplementation first showed
favorable eects on gastric cancer incidence and
mortality during the extended follow-up of 14.7 years;
these eects also persisted. In Kaplan-Meier plots,
we also observed that the eects on gastric cancer
mortality became apparent after about eight years for
H pylori treatment and vitamin supplementation and
after about 12 years for garlic supplementation (fig 4).
The mechanisms for these time patterns in treatment
eects remain to be elucidated.
Although H pylori treatment represents a promising
approach to prevention of gastric cancer, it did
not eliminate gastric cancer incidence or mortality
altogether, and some H pylori strains might become
H pylori treatment
Overall
Gastric lesions
Normal/SG/CAG
IM/DYS
Age (years)
<45
45-54
55-71
Vitamin
Overall
Gastric lesions
Normal/SG/CAG
IM/DYS
Age (years)
<45
45-54
55-71
Garlic
Overall
Gastric lesions
Normal/SG/CAG
IM/DYS
Age (years)
<45
45-54
55-71
0.29
0.68
0.08
0.09
0.85
0.10
0.0 0.5 1.0 2.0 2.51.5
Odds ratio
(95% CI)
P heterogeneity
Gastric cancer incidence
0.13
0.62
0.09
0.09
0.65
0.10
0.0 1.0 2.0 4.0 5.03.0
Hazard ratio
(95% CI)
P heterogeneity
Gastric cancer mortality
Fig4 | Association of Helicobacter pylori treatment, vitamin supplementation, and garlic supplementation with gastric cancer incidence and
mortality, stratied by baseline gastric lesions and age. Analyses were adjusted for baseline histology (moderate chronic atrophic gastritis or
less severe gastric lesions, severe chronic atrophic gastritis or supercial intestinal metaplasia, deep intestinal metaplasia, dysplasia), age, sex,
history of ever using alcohol, and history of ever smoking. SG=supercial gastritis; CAG=chronic atrophic gastritis; IM=intestinal metaplasia;
DYS=dysplasia
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resistant to antibiotics. Other preventive modalities
such as vitamin and garlic supplementation are of
potential value. Because we found no evidence of
negative interactions between H pylori treatment and
the supplements, it is likely that combinations of
these interventions can further reduce gastric cancer
incidence and mortality. Even though nutritional and
garlic supplements could take years to impact on
gastric cancer incidence and mortality, they might
prove less expensive, safe, and robust interventions in
the long run.
Strengths and limitations of this study
Strengths of the Shandong Intervention Trial included
excellent treatment compliance and long term follow-
up, with virtually complete ascertainment of people
with gastric cancer and cause specific deaths in a well
defined high risk population. The study does, however,
have several limitations. Firstly, the numbers of events
were too small to be convincing for some causes of death
in secondary analyses and also restricted the power for
detailed subgroup and interaction analyses for gastric
cancer. We do not have the information on cardia or non-
cardia cancer for all people with gastric cancer, and the
limited number precluded an analysis of cardia gastric
cancer separately. Secondly, we cannot disentangle the
eect of particular components of vitamin and garlic
supplements or characterize a dose-response relation.
Thirdly, we did not have information on participants’
H pylori infection status, non-trial treatments for H
pylori, or nutritional and garlic supplementation after
the trial ended in 2003. Although social and economic
changes have occurred in China since 2003 and
some participants might have changed their diets or
lifestyles, it is unlikely that these changes would have
diered by initial intervention assignment, because of
the randomized masked trial design. Even so, studies
are warranted to explore potential eects of changes
in lifestyles and non-trial use of H pylori treatment
or nutritional supplements. Fourthly, we conducted
scheduled gastroscopies for participants during the
trial period and for those with advanced gastric lesions
during the extended follow-up. Ascertainment bias
is unlikely during the trial period. However, a group
with more advanced lesions in 2003 had a greater
chance of endoscopically ascertained gastric cancer in
extended follow-up. This could pertain to the placebo
group for H pylori treatment, as such treatment, but
not other interventions, retarded progression of gastric
lesions.7 This could result in slight overestimates of
the protective eect of H pylori treatment. Such bias
is likely to be small, however, because most incident
gastric cancer was diagnosed during the trial or
through hospital records and not by trial prescribed
endoscopy during extended follow-up. Fifthly, our
study population was from a high risk rural area
with nutritional deficiencies. Although the findings
might have implications for populations worldwide,
extrapolation to a well nourished population or a
population with low incidence of gastric cancer might
be problematic.
Conclusions and policy implications
We found statistically significantly decreased risks
of gastric cancer incidence and mortality with
short term H pylori treatment during 22.3 years of
follow-up, showing the longest durable beneficial
eect among the major randomized trials of H pylori
treatment. Multiyear vitamin supplementation yielded
statistically significant reductions in gastric cancer
incidence and mortality. Garlic supplementation also
yielded a statistically significant decrease in gastric
cancer mortality and a promising, but not statistically
significant, decrease in gastric cancer incidence. These
findings suggest many potential strategies for gastric
cancer prevention. However, before major public
health campaigns for gastric cancer prevention are
launched utilizing antibiotic based H pylori treatment
or nutritional regimens, further large scale intervention
trials are warranted to delineate the full range of
beneficial and adverse eects of H pylori treatment,
to confirm the preventive eects of vitamin and garlic
supplementation, and to identify possible risks from
nutritional regimens.
We thank Joseph F Fraumeni Jr (National Cancer Institute) for his
help before and during the trial period; the residents, eld sta, and
government of Linqu County for supporting this trial; Wakunaga of
America for performing assays of S-allyl cysteine and providing garlic
supplements; Shanghai Squibb for providing vitamin supplements;
and Astra Corporation for providing amoxicillin and omeprazole. These
study sponsors attended a planning meeting in April 2005 at which
elements of the protocol and provision of intervention materials were
discussed, but these sponsors did not write or approve the protocol,
participate in data collection (apart from providing assays for S-allyl
cysteine), interpret the data, participate in writing this article, or
influence the decision to submit this article for publication. We also
thank members of the data safety and monitoring committee for
guidance and oversight during the trial. This trial is also listed on the
National Cancer Institute’s Physician Data Query database (No NCI-
OH-95-C-N029; www.cancer.gov/clinicaltrials).
Contributors: WQL, KFP, and WCY were conceived and designed the
study. WQL, JYZ, YG, KFP, and WCY acquired, analyzed, and interpreted
the data. WQL and JYZ wrote the initial dra of the manuscript.
WQL and JYZ contributed equally to this paper. All the authors were
involved in preparing this manuscript and contributed to the critical
revision of the manuscript. WQL, KFP, and WCY are guarantors. WCY
supervised the study. The corresponding author attests that all listed
authors meet authorship criteria and that no others meeting the
criteria were omitted.
Funding: This study was supported by the Intramural Research
Program of the National Institutes of Health, National Cancer Institute,
and in part by National Cancer Institute contracts NO2-CP-71103
and NO2-CP-21169. Additional support was from the National
Basic Research Program of China (973 program: 2004CB518702
and 2010CB529303). The funding sources had no role in the study
design; collection, analysis, and interpretation of data; writing of the
report; or decision to submit the article for publication.
Competing interests: All authors have completed the ICMJE uniform
disclosure form at www.icmje.org/coi_disclosure.pdf (available on
request from the corresponding author) and declare: no support from
any organization for the submitted work; no nancial relationships
with any organizations that might have an interest in the submitted
work in the previous three years; no other relationships or activities
that could appear to have influenced the submitted work.
Ethical approval: The original trial and study extension were
approved by review boards of Peking University Cancer Hospital, and
the US National Cancer Institute, and participants provided written
informed consent.
Data sharing: Further information on the trial design and follow-up
available on request.
The lead author (WQL, KFP, and WCY) arms that the manuscript
is an honest, accurate, and transparent account of the study being
reported; that no important aspects of the study have been omitted;
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and that any discrepancies from the study as planned (and, if relevant,
registered) have been explained.
This is an Open Access article distributed in accordance with the
Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license,
which permits others to distribute, remix, adapt, build upon this work
non-commercially, and license their derivative works on dierent
terms, provided the original work is properly cited and the use is non-
commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.
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Supplementary information: additional tables 1-4
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