Confidential: For Review Only - BMJ · 2019. 9. 16. · Confidential: For Review Only 2 Institute, 52 Fu-cheng Road, Haidian District, Beijing 100142, China. Phone: 86-10-88196937,

Confidential: For Review OnlyHelicobacter pylori treatment, vitamin and garlic

supplementation for the prevention of gastric cancer: 22.3-year follow-up of a randomized intervention trial

Journal: BMJ

Manuscript ID BMJ-2019-050223

Article Type: Research

BMJ Journal: BMJ

Date Submitted by the Author: 13-Apr-2019

Complete List of Authors: Li, Wenqing; Peking University Cancer HospitalZhang, Jing-Yu; Peking University Cancer HospitalMa, Junling; Peking University Cancer HospitalLi, Zhe-Xuan; Peking University Cancer HospitalZhang, Lian; Peking University Cancer HospitalZhang, Yang; Peking University Cancer HospitalGuo, Yang; Peking University Cancer HospitalZhou, Tong; Peking University Cancer HospitalLi, Jiyou; Peking University Cancer HospitalShen, Lin; Peking University Cancer HospitalLiu, Wei-Dong; Peking University Cancer HospitalHan, Zhong-Xiang; Peking University Cancer HospitalBlot, William; International Epidemiology InstituteGail, Mitchell; Division of Cancer Epidemiology & Genetics, National Cancer Institute, National Institutes of HealthPan, Kai-Feng; Peking University Cancer HospitalYou, Wei-cheng; Peking University Cancer Hospital

Keywords: cancer epidemiology, gastric cancer, cancer prevention, Helicobacter pylori, vitamin, garlic

https://mc.manuscriptcentral.com/bmj

BMJ

Confidential: For Review Only

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Helicobacter pylori treatment, vitamin and garlic supplementation for the prevention of gastric

cancer: 22.3-year follow-up of a randomized intervention trial

Wen-Qing Li1*, Jing-Yu Zhang1*, Jun-Ling Ma1, Zhe-Xuan Li, Lian Zhang1, Yang Zhang1,

Yang Guo1, Tong Zhou1, Ji-You Li1, Lin Shen1, Wei-Dong Liu2, Zhong-Xiang Han2, William J.

Blot3, Mitchell H. Gail4, Kai-Feng Pan1, Wei-Cheng You1

* WQL and JYZ contributed equally to this paper.

Author Affiliations: 1 Key Laboratory of Carcinogenesis and Translational Research (Ministry

of Education/Beijing), Department of Cancer Epidemiology, Peking University Cancer Hospital

& Institute, Beijing, China; 2 Linqu County Public Health Bureau, Shandong, China;

3International Epidemiology Institute, Ltd., Rockville, MD, and Vanderbilt University Medical

Center, Nashville, TN; 4Division of Cancer Epidemiology and Genetics, National Cancer

Institute, Bethesda, MD, United States.

Corresponding author:

Wei-Cheng You, Key Laboratory of Carcinogenesis and Translational Research (Ministry of

Education/Beijing), Department of Cancer Epidemiology, Peking University Cancer Hospital &

Institute, 52 Fu-cheng Road, Haidian District, Beijing 100142, China. Phone: 86-10-88196866,

Fax: 86-10-88122437, E-mail: [email protected].

Kai-Feng Pan, Key Laboratory of Carcinogenesis and Translational Research (Ministry of

Education/Beijing), Department of Cancer Epidemiology, Peking University Cancer Hospital &

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Institute, 52 Fu-cheng Road, Haidian District, Beijing 100142, China. Phone: 86-10-88196937,

Fax: 86-10-88122437, E-mail: [email protected]

Short title: Effects of H. pylori treatment, vitamin and garlic supplementation

Word count: Abstract (340); Text (3518).

Number of tables: 3 Number of figures: 4

Number of Supplementary tables: 2

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Abstract

Objective: During 14.7-years’ follow-up in the Shandong Intervention Trial, 2-week treatment

for Helicobacter pylori (H. pylori) resulted in statistically significant reduction in gastric cancer

(GC) incidence. Results for GC mortality and for the effects of garlic and vitamin

supplementation, though promising, were not statistically significant. Longer follow-up was

needed to determine the effects of H. pylori treatment, vitamin and garlic supplementation on

GC incidence and cause-specific mortality.

Design: A blinded randomized factorial placebo-controlled trial.

Setting: Linqu county, a well-defined high-risk area for GC in China.

Population: 3365 participants were included.

Interventions: H. pylori treatment, using amoxicillin and omeprazole for 2 weeks (among H.

pylori positive participants); vitamin (C, E and selenium) and garlic (extract and oil)

supplementation for 7.3 years (1995-2003).

Main Outcomes and Measures: Cumulative GC incidence was identified via scheduled

endoscopies in 1999 and 2003, and active clinical follow-up through 2017. GC mortality and

causes of death were obtained from death certificates and hospital records.

Results: During 1995-2017, we identified 151 incident GC cases and 94 GC deaths. A

protective effect of H. pylori treatment on GC incidence persisted 22 years post-intervention

(odds ratio [OR]=0.48, 95% confidence interval [CI]=0.32-0.71). Vitamin, but not garlic

supplementation, also decreased GC incidence significantly (OR=0.64, 95% CI=0.46-0.91). All

three interventions significantly reduced GC mortality, with hazard ratios (95% CIs) of 0.62

(0.39-0.99) for H. pylori treatment, 0.48 (0.31-0.75) for vitamin, and 0.66(0.43-1.00) for garlic

supplementation. Effects of H. pylori treatment on both GC incidence and mortality and of

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vitamin supplementation on GC mortality appeared early, but effects of vitamins and garlic on

GC incidence and of garlic on GC mortality only appeared later. We did not find statistically

significant associations of interventions with other types of cancer or cardiovascular disease

(secondary outcomes).

Conclusion: Short-term H. pylori treatment and 7.3-year vitamin and garlic supplementation

each significantly reduced GC mortality 22.3 years after randomization. H. pylori treatment and

vitamin supplementation also reduced GC incidence statistically significantly. The findings offer

many opportunities for GC prevention.

Trial registration: NCI PDQ database (trial No. NCI-OH-95-C-N029; available at

http://www.cancer.gov/clinicaltrials).

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Introduction

Gastric cancer (GC) remains the third leading cause of cancer deaths worldwide, with almost

half of the estimated deaths from GC occurring in China in 20181. Linqu County, a rural area in

Shandong province in northeastern China, has one of the highest GC mortality rates in the

world2. Epidemiologic studies have provided solid evidence linking Helicobacter pylori (H.

pylori) infection to the progression of precancerous gastric lesions and development of GC,

whereas diets rich in vitamin and garlic consumption may protect against GC in this high-risk

area3-5. In 1995, the Shandong Intervention Trial (SIT, clinicaltrials.gov identifier:

NCT00339768) was initiated in Linqu, to evaluate the effects of three interventions to prevent

the progression of precancerous gastric lesions and occurrence of GC6-9. The interventions

included H. pylori treatment for 2 weeks, vitamin supplementation, and garlic supplementation,

each for 7.3 years. After 14.7 years’ follow-up (1995-2010), SIT reported a statistically

significant reduction in GC incidence and non-statistically significant reduction in GC mortality

associated with H. pylori treatment, and was recognized as the first single trial to show a clear

reduction in GC incidence from H. pylori treatment8 10 11. Although both garlic and vitamin

supplementation showed favorable trends for decreased GC incidence and mortality, these

effects were not statistically significant8.

While SIT suggested a potential role of H. pylori treatment in GC prevention in the near

term, there was a need for additional follow-up to determine whether the reductions in GC

incidence from H. pylori treatment would persist and lead to a demonstrable reduction in GC

mortality. It also remained unknown whether vitamin and garlic supplementation would yield a

statistically significant reduction in GC incidence and mortality with additionally extended

follow-up. We therefore extended the follow-up of the SIT participants to 22.3 years after

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randomization to ascertain GC incidence and mortality. In addition, to clarify the entire

spectrum of effects of these interventions, we also examined their associations with other

cause-specific mortality rates as secondary outcomes.

Methods

Ethics statement

The original trial and study extension were approved by institutional review boards of Peking

University Cancer Hospital, and the US National Cancer Institute (NCI), and subjects provided

written informed consent.

Study population

Details of the SIT, including study population, trial design and randomization, and treatments

have been described previously6-8. In brief, a total of 3411 subjects aged 35-64 years in Linqu

were randomly assigned on July 23, 1995 (Figure 1). After excluding 46 subjects due to

violations of eligibility, 3365 eligible subjects remained. 2258 H. pylori-seropositive subjects, as

determined by IgG serology from enzyme-linked immunoassay in 1994, were randomly

assigned to three interventions (2-week of H. pylori treatment, and/or 7.3 years of garlic

supplementation and/or 7.3 years of vitamin supplementation) or their placebos in a 2×2×2

factorial design. A total of 1107 H. pylori-seronegative subjects were randomly assigned in a

2×2 factorial trial of vitamin and garlic supplementation, and also received placebo for

antibiotics to preserve masking. Randomized treatment assignments were generated at Westat

(Rockville, MD). Both the participants and the investigators were masked to treatment

assignment.

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From September 15 to November 29, 1995, H. pylori-seropositive subjects received the

combination of amoxicillin (1 g) and omeprazole (20 mg) (n=1130) or placebo (n=1128) twice

daily for 2 weeks for H. pylori treatment. A repeat 2-week course of active treatment was

implemented on 382 subjects for whom the initial active therapy did not eradicate H. pylori, as

determined by 13C urea breath test from January to March 1996. To preserve masking, 383

subjects in the placebo group matched on village, age and sex were offered re-treatment with

placebo. The vitamin and garlic oral supplements were taken twice daily between November 30,

1995 and March 31, 2003, a duration of 7.3 years. The vitamin supplement contained vitamin C

(250 mg), vitamin E (100 IU), and selenium (37.5μg) (n=1677) or placebo (n=1688). From

December 1995 to May 1996, the vitamin supplement also contained beta-carotene (7.5 mg).

The reason for the removal of beta-carotene has been detailed previously6. The garlic

supplement (n=1678) contained 400 mg of aged garlic extract and 2 mg of steam-distilled garlic

oil or placebo (n=1687). The trial was registered at the NCI PDQ database (trial No.

NCI-OH-95-C-N029; available at http://www.cancer.gov/clinicaltrials).

Follow-up and assessment of study endpoints

Participants were followed from the date of trial randomization (July 23, 1995). During the

period of active treatment through March 31 of 2003, participants were visited monthly to

distribute supplements. The initial trial follow-up ended on May 1, 2003. The extended

follow-up was continued through Dec 1, 2017.

The primary outcomes were GC incidence and mortality. We also assessed other

cause-specific mortality as secondary outcomes. Incidence of GC was ascertained either from

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scheduled gastroscopies in 1999 and 2003 for all subjects, with biopsies at seven standard sites;

from gastroscopies conducted from May 2, 2003 to Dec 1, 2017 for those diagnosed with

moderate or severe dysplasia (DYS) at any biopsy site or with mild DYS at two or more sites in

2003; or from cancer registry or autopsy reports, which were confirmed by reviewing medical

records. Details of gastroscopy and biopsy procedures and histopathologic criteria were

described elsewhere2 12. Causes of death were obtained from the Reporting System managed by

the Chinese Center for Disease Control and Prevention, summarizing the information from

Disease Surveillance Points. This internet-based Reporting System integrates death certificates

from hospitals, as well as police and judicial departments in Linqu. To avoid any missed record

of new GC cases or deaths due to delayed reporting, a village doctor supervised the follow-up in

each village and documented the vital status and occurrence of cancer and major chronic

diseases. In addition, staff from Peking University Cancer Hospital & Institute visited each

village every 3 months after 2003 to gather information on GC incidence and cause-specific

mortality. Related medical records with pathological reports were reviewed for confirmation.

Statistical analysis

In the primary analyses, we examined the risk of GC incidence and mortality associated with the

three interventions. Because many GC cases were diagnosed at scheduled gastroscopies in 1999

and 2003, we estimated odds ratios (ORs) of GC cumulative incidence and corresponding 95%

confidence intervals (CIs). The conditional logistic analysis was stratified on baseline

histopathology, categorized as moderate chronic atrophic gastritis (CAG) or less severe, severe

CAG or superficial intestinal metaplasia (IM), deep IM, or DYS. For analysis of GC mortality,

we used the Cox proportional hazards models on the scale of time since randomization to

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estimate hazard ratios (HRs) and 95% CIs, stratified on baseline histopathology. The

proportional hazards assumption within strata was tested by including an interaction term

between time and treatment (P>0.05 for all tests). In the multivariate-adjusted models,

conditional logistic or Cox regression analyses were further adjusted for age, gender, smoking

and alcohol intake. Sensitivity analyses were conducted by including 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 with cause-specific mortality, including deaths from any cancer, from individual cancers

with at least 10 deaths among baseline H. pylori positive participants, and from cardiovascular

disease (CVD).

Kaplan-Meier survival curves were plotted to compare time to all-cause mortality and to

GC mortality for each intervention. We further examined the temporal changes in the effects of

interventions on cumulative GC incidence and on mortality by dividing the follow-up period

into three separate time intervals: the initial trial period (participant randomization to May 1,

2003)7, extended follow-up period I (May 2, 2003 to August 1, 2010)8 9, and extended follow-up

period II (August 2, 2010 to December 1, 2017) (Figure 1).

We stratified analyses to determine whether the effects of interventions varied by

participants’ baseline histopathology or age. Heterogeneity of ORs or HRs across strata was

evaluated using Q statistics for meta-analysis. To clarify potential effect modification between

interventions, we also tested the 2-way interactions between H. pylori treatment, vitamin

supplementation and garlic supplementation on GC incidence and mortality.

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All analyses were performed using the intention-to-treat approach. All P values were

2-tailed. All 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 up of results. Study results will be

reported by publication, presentation at scientific meetings, and at public events to popularize

cancer prevention and control held by our institution. The results will also be disseminated using

social media platforms.

Results

A total of 3365 participants were included. As shown in Supplementary Table 1, blocked

random intervention assignments6 ensured balanced distribution in baseline characteristics

between active treatment and placebo groups for all three interventions. During 22.3 years’

follow-up since trial randomization (Figure 1), we identified 151 incident GC cases and 94 GC

deaths, which accounted for 12% of all deaths. Of them, 119 GC cases and 76 GC deaths

occurred among the baseline H. pylori positive participants (Table 1).

We first evaluated GC incidence associated with the three interventions (Table 2). H. pylori

treatment was inversely associated with risk of GC incidence, even after multivariate-adjustment

(OR=0.48, 95% CI=0.32-0.71). We also found statistically significant decrease in GC incidence

associated with vitamin supplementation (OR=0.64, 95% CI=0.46-0.91), and a non-significant

decrease in GC incidence associated with garlic supplementation (OR=0.81, 95% CI=0.57-1.13)

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(Table 2).

The risk of GC mortality was also examined as a primary outcome (Table 3). A statistically

significant protective effect on GC mortality was observed for all three interventions; the fully

adjusted HR (95% CI) was 0.62 (0.39-0.99) for H. pylori treatment, 0.48 (0.31-0.75) for vitamin

supplementation and 0.66 (0.43-1.00) for garlic supplementation (Table 3). Kaplan-Meier

curves showed that the cumulative protective effect on GC mortality became evident after about

8 years for H. pylori treatment and vitamin supplementation and after about 12 years for garlic

supplementation (Figure 2). For both GC incidence and mortality, sensitivity analyses that

adjusted for other interventions yielded similar findings (data not shown).

Separate analyses for the three follow-up periods did not demonstrate statistically

significant treatment effect heterogeneity in ORs for GC incidence or HRs for GC mortality

(Figure 3), perhaps because of limited power. However, the garlic supplementation effects were

negligible in the initial trial period both for GC incidence and mortality, which only became

apparent by year 14.7 and persisted through year 22.3 (Figure 3). The treatment effect for

vitamin supplementation was also negligible for GC incidence in the initial trial period, but not

for GC mortality (Figure 3).

In secondary analyses (Table 3), vitamin supplementation was marginally associated with

decreased all-cause mortality (HR=0.87, 95% CI: 0.76-1.01, P=0.07). We did not find

statistically significant associations of the interventions with all cancer mortality or with

esophageal cancer (EC)-specific mortality. H. pylori treatment was marginally associated with a

decrease in colorectal cancer mortality (P=0.07) and a non-significant increase in liver cancer

death (P=0.15). The associations with other specific causes of death were also not statistically

significant (Table 3).

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There was no statistically significant evidence of heterogeneity in the effects of H. pylori

treatment or garlic supplementation for GC incidence or mortality between participants with

baseline normal gastric mucosa, SG, or CAG versus those with IM or DYS, nor among different

age groups (Figure 4). Although tests for heterogeneity were only marginally significant for

vitamin supplementation, the data suggest greater preventive effect for those with favorable

baseline histology (normal, SG, CAG) and those under age 45 years, both for GC incidence and

mortality (Figure 4).

Tests for two-way interactions among treatment effects were not statistically significant.

Among baseline H. pylori seronegative participants, there was a non-significant indication that

those only taking vitamin supplements had a lower GC incidence than those taking both vitamin

and garlic supplements (P-interaction=0.08) (Supplementary Table 2).

Discussion

Based on a total follow-up of 22.3 years in the SIT, the preventive effect of short-term H. pylori

treatment on risk of developing GC continued 22 years post-treatment and resulted in

significantly lower GC mortality. We also found significantly decreased long-term risk of

developing GC associated with vitamin supplementation and reduced GC mortality for those

taking vitamin or garlic supplements.

Implications of findings

The effect of H. pylori treatment on GC has been examined in prior intervention trials7-9 13-18,

and recent studies19 20. Although H. pylori treatment is now recognized as a potential strategy for

GC prevention11 21, major uncertainties are yet to be clarified before the strategy can be

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implemented at the community level. The duration of effectiveness of H. pylori treatment needs

to be studied by long-term follow-up, because the development of GC involves progression

through multiple histologic stages22. Our findings confirm the statistically significant reduction

in GC incidence and the favorable, but not statistically significant reduction in GC mortality

after 14.7 years8, indicating even greater beneficial effect of H. pylori treatment on GC

incidence than we previously reported at 14.7-year (OR=0.61, 95% CI=0.38-0.96)8. The

reduction in GC incidence in SIT was also larger than in recent meta-analyses of intervention

trials23 24. With more GC deaths during longer follow-up, the reduction in GC mortality became

statistically significant 22.3 years after intervention, although the effect became visible in

Kaplan-Meier curves after roughly 8 years.

Gaps remain regarding the full range of beneficial and adverse effects from H. pylori

treatment. An inverse association of H. pylori infection with esophageal adenocarcinoma (EAC)

has been reported11 25 26. Although uncertainty remains for esophageal squamous cell carcinoma

(ESCC), a meta-analysis found decreased ESCC risk associated with H. pylori infection in

Eastern populations26. SIT provided few events and little power to detect effects of H. pylori

therapy on EC mortality and cannot distinguish ESCC from EAC; there is little indication of

adverse risk, however. Increased risk of colorectal cancer associated with H. pylori infection has

also been reported27. In our study, there was an indication of reduced colorectal cancer deaths

with H. pylori treatment, but the number of deaths was again too small to conclusively

demonstrate this effect. In addition, we found a non-significant excess of liver cancer deaths

with H. pylori treatment. It is worth noting that these comparisons were not adjusted for

multiple comparisons. Despite prolonged follow-up, SIT’s sample size for H. pylori treatment

(n=2242) limits our ability to estimate the benefits and risks for many health outcomes.

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Whether a point of no return exists in H. pylori-associated gastric carcinogenesis after

which treatment would be too late to reduce GC risk is still under debate, as H. pylori infection

causes early precancerous histopathologic changes12. The Maastricht V/Florence Consensus

Report stated that H. pylori eradication results in significant improvement of gastritis and gastric

atrophy but not of IM28. A trial also showed that H. pylori eradication did not reduce the

incidence or IM or decrease its histological severity29. However, the Consensus Report also

recognized that the progression of IM can be halted by H. pylori eradication28, as supported by

our intervention trial7.Advanced gastric lesions occur more frequently at old ages2 12, which

raises concerns about the effectiveness of prophylactic H. pylori eradication among those with

advanced gastric lesions and older individuals. Such concerns have been partly addressed by

evidence that H. pylori therapy reduces metachronous GC incidence20 30, but other reports on

new GC with precancerous lesions or metachronous GC have been contradictory15 31, and some

experts recommend using H. pylori treatment only before gastric atrophy or IM develops15. Our

long-term data confirm the earlier SIT finding9 that H. pylori treatment reduces GC incidence

and mortality also in subjects with IM and DYS at baseline and in subjects aged 55-71 years at

baseline. Thus, H. pylori infection may promote late-stage neoplastic progression. It is also

possible that H. pylori treatment has eliminated non-H.pylori bacteria crucial for progression to

GC9 32, supporting the need to explore other microbiota underlying gastric carcinogenesis. In

any case, 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 (NIT) showed a durable beneficial effect of 5.25-year’s

supplementation with “factor D”, a combination of selenium, vitamin E, and beta-carotene, on

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total and GC mortality, which lasted up to 10 years post-trial but waned later on33-35. In Linqu,

where SIT was conducted, the mean serum levels of vitamin C and selenium were well below

reference ranges3 36. Observational studies showed that GC risk was inversely associated vitamin

C intake in this nutritionally deprived population5. A high level of serum vitamin C was also

associated with a decreased risk of histologic progression to DYS and GC in Linqu3. Although

no effects of vitamin supplementation were seen on gastric histopathology or GC incidence in

SIT in the initial trial period7, follow-up for 14.7 years revealed noteworthy, but not statistically

significant, reductions in GC incidence and mortality. Thus, the statistically significant SIT

findings of reductions in GC incidence and mortality after 22.3 years are supported by earlier

clinical trial data and observational studies. There is a marginally significant indication that

vitamin supplementation is more effective in those with mild histopathology at baseline and age

under 45 years. Similarly, only participants younger than 55 years benefited from factor D in the

NIT34.

Observational data show decreased risk of GC with elevated consumption of garlic and

allium vegetables in Linqu12 and elsewhere37. Garlic and its derivatives have antioxidative,

antimicrobial, and immune modulation properties38 39. However, there are few long-term

randomized placebo-controlled intervention trials utilizing dietary or supplemental allium

vegetables for cancer prevention. One trial indicated that aged garlic extract prevented

metachronous colorectal adenomas40, while another trial revealed a statistically significant

protective effect of synthetic diallyl trisulfide (allitridum) combined with selenium on GC

incidence in men, but not in women41. After 22.3 years, garlic supplementation led to a

non-statistically significant reduction in GC incidence and a statistically significant reduction in

GC mortality, confirming favorable, but non-statistically significant trends seen at 14.7 years8.

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The time course and duration of protective effects is of interest. H. pylori treatment retarded

the progression of precancerous gastric lesions 7 and evidence began to accumulate for

protective effects on GC incidence and mortality in the initial trial period. The beneficial effects

on GC incidence and mortality persisted through year 14.78 and again through year 22.3 (Figure

3). In contrast, neither vitamin nor garlic supplementation retarded histopathologic progression

during the initial trial ending at 20037. The favorable effects for garlic supplementation came

later than for H. pylori treatment, and the favorable effects for vitamin supplementation on GC

incidence also appeared later than for H. pylori treatment (Figure 3). The effects of these

interventions on GC mortality became visible in Kaplan-Meier plots after about 8 years for H.

pylori treatment and vitamin supplementation and after about 12 years for garlic

supplementation. The mechanisms for these different time patterns in terms of treatment effects

on the carcinogenic process remain to be elucidated.

Strengths and limitations of study

Strengths of SIT included excellent treatment compliance and long-term follow-up, with

virtually complete ascertainment of GC cases and cause-specific deaths in a well-defined high-

risk population. There are several limitations. First, SIT included 3365 participants, and despite

long-term follow-up, the numbers of events were too small to be convincing for some of causes

of death in secondary analyses and also restricted more detailed subgroup analyses for GC.

Second, we cannot disentangle the effect of particular components of vitamin and garlic

supplements or characterize a dose-response relationship. Third, we did not have information

concerning participants’ H. pylori infection status or non-trial treatments for H. pylori or

nutritional or garlic supplementation after the active trial ended in 2003. Although there have

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been dramatic social and economic changes in China since 2003 and some participants may

have changed their diets or lifestyles, it is unlikely that these changes would have differed by

initial intervention assignment, because the SIT was a randomized, placebo-controlled blinded

trial. Fourth, we routinely conducted endoscopic screening during the trial period only, but any

bias in the diagnosis of endoscopically detectable GC since 2003 would be non-differential

between intervention groups. Fifth, our findings might not generalize to a well-nourished

population or a population with low GC risk.

Conclusions

In conclusion, our study found statistically significantly decreased risk of GC incidence and

mortality with short-term H. pylori treatment during 22.3 years after active treatment,

demonstrating the longest durable beneficial effect among the major randomized trials of H.

pylori treatment. Multiyear vitamin supplementation yielded statistically significant reductions

in GC incidence and mortality. Garlic supplementation also yielded a statistically significant

decrease in GC mortality and a promising, but not statistically significant, decrease in GC

incidence. These finding offer many opportunities for GC prevention. However, before major

public health campaigns for GC prevention are launched utilizing antibiotic-based H. pylori

therapy or nutritional regimens, further large-scale intervention trials are warranted to delineate

the full range of beneficial and adverse effects of H. pylori treatment, to confirm the preventive

effects of vitamin and garlic supplementation, and to identify possible risks from nutritional

regimens.

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Acknowledgment: We thank Dr. Joseph F. Fraumeni Jr (National Cancer Institute) for his

assistance with the study before and during the trial period. We are grateful to the residents,

field staff, and government of Linqu county for supporting this trial. We thank Wakunaga of

America, Ltd, 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 pro-

viding 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.

Contributors: WQ-L, KF-P and WC-Y had had full access to all of the data in the study and

takes responsibility for the integrity of the data and the accuracy of the data analysis. WQ-L,

JY-Z, Y-G, KF-P and WC-Y were responsible for the overall study design, data analysis, and

interpretation of data. WQ-L and JY-Z wrote the initial draft of the manuscript. All the authors

were involved in preparing this manuscript. WQ-L, JY-Z, MH-G, WJ-B, KF-P, and WC-Y

contributed to the critical revision of the manuscript.

Funding: This research 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 study design; in the collection, analysis, and interpretation of data; in the writing of

the report; or in the decision to submit the article for publication.

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Competing interests: All authors have completed the Unified Competing Interest form at

www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and

declare: no support from any organisation for the submitted work; no financial relationships

with any organisations 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.

An exclusive license: The corresponding author has the right to grant on behalf of all authors

and does grant on behalf of all authors, an exclusive licence (or non exclusive for government

employees) on a worldwide basis to the BMJ Publishing Group Ltd and its Licensees to permit

this article (if accepted) to be published in BMJ editions and any other BMJPGL products and

sublicences to exploit all subsidiary rights, as set out in our licence

(http://resources.bmj.com/bmj/authors/checklists-forms/licence-for-publication).

Transparency declaration: On behalf of all coauthors, the corresponding authors affirm 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; and that any discrepancies from the study

as planned (and, if relevant, registered) have been explained.

Ethical approval: The original trial and study extension were approved by institutional review

boards of Peking University Cancer Hospital, and the US National Cancer Institute (NCI), and

subjects provided written informed consent.

Data sharing: Further information on the intervention trial available upon request.

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Figure 1. The flow diagram of trial design and participant follow-up

Figure 2. The plotted Kaplan-Meier survival estimates for GC mortality (A-C) and total mortality (D-F) by Helicobacter pylori treatment, vitamin and garlic supplementation. Follow-up time begins at trial randomization.

Figure 3. The association of Helicobacter pylori treatment, vitamin and garlic supplementation with gastric cancer incidence (ORs) and mortality (HRs) in three separate time periods. The analyses were conducted adjusting for baseline histology (


24

Table 1. The number of incident gastric cancer cases and deaths by three intervention groups during the trial and extended follow-upa

No. of incident gastric cancers 　 No. of deaths due to gastric cancer

Treatment groupsNo. ofsubjects Trial

period

Extended follow-up period I

Extended follow-up period II

Total Trial

period

Extended follow-up period I

Extended follow-up period II

Total

H. pylori treatment 2258 47 39 33 119 　 18 24 34 76

Active 1130 19 15 7 41 8 10 11 29

Placebo 1128 28 24 26 78 10 14 23 47

Vitamin 3365 59 47 45 151 21 26 47 94

Active 1677 29 19 12 60 9 8 14 31

Placebo 1688 30 28 33 91 12 18 33 63

Garlic 3365 59 47 45 151 21 26 47 94

Active 1678 30 19 20 69 12 9 18 39

Placebo 1687 29 28 25 82 　 9 17 29 55

aEvents during the trial period included those from the date of random assignment (July 23, 1995), to the

initial follow-up end (May 1, 2003). The follow-up extension included two periods, the extended follow-up

period I (May 2, 2003 to August 1, 2010) and extended follow-up period II (August 2, 2010 to December 1,

2017).

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Table 2. The odds ratios (ORs) and 95% confidence intervals (CIs) for gastric cancer incidence

associated with Helicobacter pylori treatment, vitamin and garlic supplementation

Adjusted for baseline histology only 　 Fully adjusteda

InterventionsPlacebo(n/n)b

Treatment (n/n)b

OR (95% CI) P 　Placebo(n/n)b

Treatment (n/n)b

OR (95% CI) P

H. pylori treatment

78/1123 40/1119 0.48 (0.33-0.72)


26

Table 3. The hazard ratios (HRs) and 95% confidence intervals (CIs) for cause-specific death according to Helicobacter pylori treatment, vitamin and garlic

supplementation

Adjusted for baseline histology only Fully adjusteda

InterventionsPlacebo (n)

Treatment (n)

HR (95% CI) P Placebo (n)Treatment

(n)HR (95% CI) P

H. pylori treatment 1123 1119 1086 1086

Total deaths 272 264 0.98 (0.83-1.16) 0.79 254 245 1.00 (0.84-1.19) 0.96

All cancerb 141 115 0.81 (0.63-1.04) 0.10 131 105 0.81 (0.62-1.05) 0.10

Gastric cancer 47 29 0.62 (0.39-0.99) 0.045 45 29 0.62 (0.39-0.99) 0.046

Esophageal cancer 12 14 1.17 (0.54-2.53) 0.69 10 11 1.12 (0.47-2.64) 0.80

Liver cancer 11 21 1.93 (0.93-4.01) 0.08 10 18 1.78 (0.82-3.86) 0.15

Colorectal cancer 12 3 0.25 (0.07-0.89) 0.03 10 3 0.30 (0.08-1.10) 0.07

Lung cancer 40 33 0.83 (0.52-1.31) 0.42 38 31 0.82 (0.51-1.32) 0.42

Other cancer 19 15 0.79 (0.40-1.56) 0.50 18 13 0.73 (0.36-1.50) 0.40

Cardiovascular Disease 96 106 1.11 (0.84-1.47) 0.45 90 100 1.17 (0.88-1.55) 0.29

Other deaths 35 43 1.24 (0.79-1.93) 0.35 33 40 1.27 (0.80-2.01) 0.31

Vitamin 1679 1665 1627 1610

Total deaths 423 370 0.86 (0.75-0.99) 0.04 392 345 0.87 (0.76-1.01) 0.07

All cancerb 187 166 0.89 (0.72-1.09) 0.26 175 152 0.88 (0.71-1.09) 0.23

Gastric cancer 62 31 0.49 (0.32-0.76) 0.001 61 29 0.48 (0.31-0.75) 0.001


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Liver cancer 21 25 1.20 (0.67-2.15) 0.53 18 24 1.38 (0.75-2.55) 0.30


Lung cancer 49 56 1.16 (0.79-1.70) 0.46 44 53 1.23 (0.83-1.84) 0.30

Other cancer 26 29 1.13 (0.66-1.91) 0.66 26 26 1.02 (0.59-1.76) 0.94


Other deaths 68 63 0.93 (0.66-1.32) 0.70 61 61 1.02 (0.71-1.45) 0.92

Garlic 1678 1666 1631 1606

Total deaths 406 387 0.96 (0.83-1.10) 0.53 383 354 0.90 (0.78-1.04) 0.17

All cancerb 185 168 0.91 (0.74-1.12) 0.36 175 152 0.87 (0.70-1.08) 0.19

Gastric cancer 55 38 0.69 (0.46-1.04) 0.08 54 36 0.66 (0.43-1.00) 0.049


Liver cancer 22 24 1.11 (0.62-1.98) 0.73 19 23 1.26 (0.69-2.32) 0.46


Lung cancer 54 51 0.95 (0.65-1.39) 0.79 51 46 0.91 (0.61-1.36) 0.66

Other cancer 25 30 1.22 (0.72-2.07) 0.47 24 28 1.21 (0.70-2.08) 0.50


Other deaths 69 62 0.90 (0.64-1.26) 0.53 　 66 56 0.86 (0.60-1.23) 0.40aThe fully adjusted analyses were adjusted for baseline histology (


Figure 1. The flow diagram of trial design and participant follow-up

106x134mm (300 x 300 DPI)

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Figure 2. The plotted Kaplan-Meier survival estimates for GC mortality (A-C) and total mortality (D-F) by Helicobacter pylori treatment, vitamin and garlic supplementation. Follow-up time begins at trial

randomization.

1243x636mm (144 x 144 DPI)

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Figure 3. The association of Helicobacter pylori treatment, vitamin and garlic supplementation with gastric cancer incidence (ORs) and mortality (HRs) in three separate time periods. The analyses were conducted

adjusting for baseline histology (


Figure 4. The association of Helicobacter pylori treatment, vitamin and garlic supplementation with gastric cancer incidence and mortality, stratified by baseline gastric lesions and age. The analyses were conducted, adjusting for baseline histology (


Supplementary Table 1. Baseline characteristics of study subjects

H. pylori treatment Vitamin supplementation Garlic supplementationGroup Active

(n=1130) Placebo (n=1128)

Active(n=1677)

Placebo (n=1688)

Active (n=1678)

Placebo(n=1687)

Age (Mean ± SD) 46.8±9.2 46.9±9.2 47.0±9.2 47.1±9.2 47.0±9.2 47.1±9.2

Sex (%)

Female 50.4 49.7 48.8 48.6 48.8 48.6

Male 49.6 50.3 51.2 51.4 51.2 51.4

Baseline histology (%)


Supplementary Table 2. The 2-way interactions between interventions on gastric cancer

incidence and mortality

Gastric cancer incidencea 　 Gastric cancer mortalityaSubgroups

n/nb OR (95% CI) P for interactionc 　 n/nb HR (95% CI) P for interactionc

Baseline H. pylori seropositive participants

Joint effect of vitamin supplementation and H. pylori eradication

Placebo 44/549 Reference 0.72 28/549 Reference 0.56

H. pylori treatment only 25/543 0.50 (0.30-0.85) 20/543 0.69 (0.39-1.22)

Vitamin only 32/537 0.69 (0.42-1.13) 17/537 0.60 (0.33-1.11)

H. pylori treatment and vitamin 15/543 0.30 (0.16-0.55) 9/543 0.31 (0.15-0.66)

Joint effect of garlic supplementation and H. pylori eradication


H. pylori treatment only 23/546 0.54 (0.31-0.92) 16/546 0.55 (0.30-1.01)

Garlic only 36/540 0.93 (0.57-1.50) 17/540 0.59 (0.32-1.07)

H. pylori treatment and garlic 17/540 0.38 (0.21-0.69) 13/540 0.44 (0.23-0.84)

Joint effect of garlic and vitamin supplementation


Vitamin only 22/544 0.50 (0.29-0.87) 13/544 0.41 (0.22-0.79)

Garlic only 28/544 0.66 (0.39-1.10) 17/544 0.53 (0.29-0.95)

Vitamin and garlic 25/536 0.59 (0.35-1.00) 13/536 0.41 (0.21-0.78)

Baseline H. pylori seronegative participants

Joint effect of garlic and vitamin supplementation


Vitamin only 4/271 0.29 (0.09-0.90) 2/271 0.28 (0.06-1.36)

Garlic only 6/267 0.43 (0.16-1.16) 5/267 0.71 (0.22-2.28)

Vitamin and garlic 7/259 0.51 (0.20-1.32) 　 1/259 0.12 (0.02-1.00)

aThe fully adjusted analyses were adjusted for baseline histology (


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