T h e n e w e ng l a nd j o u r na l o f m e dic i n e
n engl j med 382;5 nejm.org January 30, 2020 427
From the Center for Gastric Cancer
(I.J.C., C.G.K., J.Y.L., Y.-I.K., M.-C.K.), the
Division of Cancer Epidemiology and
Management, Research Institute (I.J.C.,
Y.-I.K., B.P., J.J.), and the Biostatistics
Collaboration Team, Research Core Center, Research Institute (B.P.) — all at the
National Cancer Center, Goyang, South
Korea. Address reprint requests to Dr.
Choi at the Center for Gastric Cancer, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang, Gyeonggi, 10408, South
Korea, or at [email protected].
N Engl J Med 2020;382:427-36.
DOI: 10.1056/NEJMoa1909666
Copyright © 2020 Massachusetts Medical Society.
BACKGROUND
Helicobacter pylori infection and a family history of gastric cancer are the main risk
factors for gastric cancer. Whether treatment to eradicate H. pylori can reduce the
risk of gastric cancer in persons with a family history of gastric cancer in firstdegree relatives is unknown.
METHODS
In this single-center, double-blind, placebo-controlled trial, we screened 3100 firstdegree relatives of patients with gastric cancer. We randomly assigned 1838 participants with H. pylori infection to receive either eradication therapy (lansoprazole
[30 mg], amoxicillin [1000 mg], and clarithromycin [500 mg], each taken twice
daily for 7 days) or placebo. The primary outcome was development of gastric
cancer. A prespecified secondary outcome was development of gastric cancer according to H. pylori eradication status, assessed during the follow-up period.
RESULTS
A total of 1676 participants were included in the modified intention-to-treat population for the analysis of the primary outcome (832 in the treatment group and
844 in the placebo group). During a median follow-up of 9.2 years, gastric cancer
developed in 10 participants (1.2%) in the treatment group and in 23 (2.7%) in the
placebo group (hazard ratio, 0.45; 95% confidence interval [CI], 0.21 to 0.94;
P=0.03 by log-rank test). Among the 10 participants in the treatment group in
whom gastric cancer developed, 5 (50.0%) had persistent H. pylori infection. Gastric cancer developed in 0.8% of participants (5 of 608) in whom H. pylori infection
was eradicated and in 2.9% of participants (28 of 979) who had persistent infection
(hazard ratio, 0.27; 95% CI, 0.10 to 0.70). Adverse events were mild and were more
common in the treatment group than in the placebo group (53.0% vs. 19.1%;
P<0.001).
CONCLUSIONS
Among persons with H. pylori infection who had a family history of gastric cancer
in first-degree relatives, H. pylori eradication treatment reduced the risk of gastric
cancer. (Funded by the National Cancer Center, South Korea; ClinicalTrials.gov
number, NCT01678027.)
A BS TR AC T
Family History of Gastric Cancer
and Helicobacter pylori Treatment
Il Ju Choi, M.D., Ph.D., Chan Gyoo Kim, M.D., Ph.D., Jong Yeul Lee, M.D.,
Young-Il Kim, M.D., Myeong-Cherl Kook, M.D., Ph.D., Boram Park, Ph.D.,
and Jungnam Joo, Ph.D.
Original Article
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428 n engl j med 382;5 nejm.org January 30, 2020
T h e n e w e ng l a nd j o u r na l o f m e dic i n e
Helicobacter pylori mon bacterial infection of the human stomach that affects more than half the infection is a comworld population.1 Two nested case–control studies conducted in the United States showed an
association between H. pylori infection and gastric cancer.2,3 A long-term observational study
from Japan subsequently showed that gastric
cancer developed only in patients with H. pylori
infection who had various gastric diseases.4 Our
recent randomized trial involving patients with
early gastric cancer (a population that usually
has severe atrophic changes in the gastric mucosa) showed that treatment of H. pylori infection reduced the risk of metachronous gastric
cancer by 50%.5 Treatment of H. pylori infection
in the general population to prevent gastric cancer is supported by moderate-quality evidence
from a meta-analysis of six randomized trials
that showed a relative risk of cancer of 0.66.6 The
working group report from the International
Agency for Research on Cancer suggested that
population-based screening and treatment for
H. pylori infection should be tailored to local
conditions, and further studies are required to
investigate the feasibility, efficacy, and adverse
consequences of this strategy.7
A family history of gastric cancer in a firstdegree relative is associated with double to triple
the risk of gastric cancer.8 Patients with gastric
cancer and their relatives share risk factors, including exposure to H. pylori in the environment
and genetic features that may affect immune
responses to H. pylori infection.8-10 Family members of patients with gastric cancer have higher
rates of H. pylori infection than persons in the
general population, and the precancerous histologic changes in the gastric mucosa are more
severe in these persons.11-15 However, whether
treatment of H. pylori infection can reduce the
risk of gastric cancer is still unclear because of
a lack of evidence from trials in primary prevention. Despite the uncertainty, regional and
global consensus reports recommend treatment
of H. pylori infection in the relatives of patients
with gastric cancer.16-18 In contrast, the American
College of Gastroenterology clinical guideline
published in 2017 made no recommendation
regarding routine testing for and treatment of
H. pylori infection in this high-risk group because of insufficient evidence.19 We conducted a
randomized trial to evaluate whether treatment
of H. pylori infection reduces the risk of gastric
cancer in first-degree relatives of patients with
gastric cancer.
Me thods
Trial Design and Oversight
This single-center, double-blind, placebo-controlled, randomized trial was conducted at the
National Cancer Center in South Korea. The institutional review board at the National Cancer
Center approved the trial protocol (available with
the full text of this article at NEJM.org), and all
participants provided written informed consent
before enrollment. The authors vouch for the accuracy and completeness of the data and analyses and for the fidelity of the trial to the protocol. An independent data and safety monitoring
board oversaw the progress and safety of the
trial. The trial was not registered until all participants had been enrolled because at the time
the trial was initiated, registration was not mandatory. The registration of the trial was delayed
further because of an administrative error. The
authors verify that no change was made to the
trial design, the sample size, or the definition of
the primary outcome from the initiation of the
protocol to the time the trial was registered.
Further details are available in the Supplementary Appendix, available at NEJM.org.
Participants
Participants were eligible if they were 40 to 65
years of age and if they had confirmed H. pylori
infection and at least one first-degree relative
with gastric cancer whose diagnosis had been
histologically confirmed at the National Cancer
Center or one of the other referral hospitals in
South Korea. Key exclusion criteria were a history
of gastric cancer, peptic ulcer, or other organ
cancer; previous H. pylori eradication therapy;
and a history of serious side effects associated
with antibiotic therapy. Patients were also excluded if they had severe nonmalignant disease,
were pregnant, or had a gastric disease (such as
peptic ulcer disease, gastric dysplasia, or cancer) diagnosed on the endoscopy performed at
screening.
Randomization, Treatment, and Follow-up
After consent was obtained, endoscopy was performed to confirm the absence of coexisting
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n engl j med 382;5 nejm.org January 30, 2020 429
Gastric Cancer and H. pylori Treatment
disease and to confirm that participants had
H. pylori infection. Eligible participants were randomly assigned in a 1:1 ratio, stratified according to sex, to receive either H. pylori treatment or
placebo. When the trial was designed and executed, treatment of asymptomatic H. pylori infection was not standard practice. The computergenerated randomization sequence was kept at the
trial pharmacy and was not accessible to the investigators who enrolled participants. Throughout the trial, participants and investigators, including the endoscopist, pathologist, physician,
research nurse, and statistician, were unaware of
trial-group assignments.
The treatment group received amoxicillin
(1000 mg), clarithromycin (500 mg), and the
proton-pump inhibitor lansoprazole (30 mg) twice
daily for 7 days. The placebo group received the
same number of pills, identical in appearance
and taste, as the treatment group. Data on adherence to the trial regimen and adverse events
were collected by means of telephone contact.
Surveillance endoscopies were performed every
2 years. A closeout endoscopy, with H. pylori
evaluation, was performed at the end of the trial
period (during the period from January 2016
through December 2018). For ethical reasons,
participants who still had H. pylori infection received bismuth-based quadruple therapy (a protonpump inhibitor, bismuth, metronidazole, and
tetracycline) for 10 days.
Assessments
At each surveillance endoscopy, biopsy specimens
were obtained from suspicious lesions to test for
gastric cancer. The World Health Organization
classification system was used for histologic classification of gastric cancer (Table S1 in the Supplementary Appendix).20 Gastric epithelial lesions
were classified as adenoma or carcinoma according to the criteria of the Vienna classification of
gastrointestinal epithelial neoplasia (Table S2).21
At the endoscopy performed at screening,
biopsy specimens were obtained from the gastric antrum lesser, corpus lesser, and corpus
greater curvatures and were evaluated with the
use of the updated Sydney System for the classification and grading of gastritis (Fig. S1).22 H. pylori
infection status was determined with the use of
a rapid urease test on a biopsy specimen obtained
from the corpus greater curvature and with
Wright–Giemsa staining of biopsy specimens
from the three prespecified sites. Positive results
on at least two of the four tests were considered
to confirm the presence of H. pylori infection, as
required for eligibility in the trial.
At the first follow-up endoscopy, H. pylori infection status was evaluated with the use of a
rapid urease test on two biopsy specimens obtained from the corpus and antrum. Status with
respect to H. pylori infection was concealed from
all participants and investigators throughout the
trial. At the closeout endoscopy, H. pylori infection status was reevaluated with the use of a
rapid urease test to determine whether the participant should receive salvage treatment.
Outcomes
The primary outcome was development of gastric cancer. Data for participants were censored
at the date of the last endoscopy, death, or withdrawal from the trial. In January 2019, we obtained access to the Korea National Cancer Incidence Database to confirm the cases of gastric
cancer that had been diagnosed in our trial by
means of surveillance. The database included
data on cancer diagnoses for almost the entire
South Korean population through December 31,
2016 (e.g., data on the incidence of cancer in
2015 were 98.2% complete).23
Prespecified secondary outcomes were the development of gastric cancer according to H. pylori
eradication status during the follow-up period
(after receipt of H. pylori treatment or placebo),
overall survival, and the development of adenoma.
Overall survival was defined as the time from
randomization to the date of death from any
cause. The Statistics Korea database was accessed to obtain the date and cause of death for
participants who had died by December 31,
2017. Survival data were censored at the date of
the closeout endoscopy performed in 2018 or on
December 31, 2017 (for participants who did not
undergo endoscopy in 2018 and were still alive
on that date, as confirmed in the database).
Statistical Analysis
On the basis of age-specific incidence data in
South Korea, we estimated that the annual incidence of gastric cancer in the H. pylori–infected
average-risk population would be about 165
cases per 100,000 persons 40 to 65 years of age
(250 cases per 100,000 men and 80 cases per
100,000 women, with a male-to-female ratio of
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430 n engl j med 382;5 nejm.org January 30, 2020
T h e n e w e ng l a nd j o u r na l o f m e dic i n e
1:1). The cumulative incidence of gastric cancer
would be about 1% (1000 cases per 100,000 persons) at 6 years. Persons with a family history of
gastric cancer might have triple the risk of gastric cancer, which would result in a cumulative
incidence of 3% at 6 years. We assumed that
treatment of H. pylori infection would reduce the
risk of gastric cancer to one third of that 3%
incidence, which would result in a cumulative
incidence of 1% at 6 years. Assuming a 15% loss
to follow-up, we calculated that 1810 participants (905 in each group) would be required to
give the trial 80% power to detect a difference
between the treated group and the placebo
group, at a two-sided significance level of 0.05.
An interim analysis was not planned.
The primary outcome of development of gastric cancer was assessed in the modified intention-to-treat population, which included all participants who underwent randomization, with the
exception of those who did not start H. pylori
treatment or placebo, those who did not have
any follow-up data, and those who met major
exclusion criteria. Overall survival was assessed
in all participants who underwent randomization. The safety analysis included all participants
who underwent randomization and received at
least one dose of H. pylori treatment or placebo.
To assess the robustness of the primary analysis,
sensitivity analyses that included all participants
who underwent randomization were performed
with the use of several imputation methods to
account for missing primary-outcome data.
We used the Kaplan–Meier method to evaluate the primary and secondary outcomes. The
primary outcome was analyzed with the use of a
log-rank test with a two-sided significance level
of 0.05. A Cox proportional-hazards regression
model was used to estimate hazard ratios with
95% confidence intervals. We used a z-test statistic for the between-group comparison of the
number of cases of gastric cancer divided by the
total person-time accumulated. Statistical analyses were conducted with the use of SAS software,
version 9.4 (SAS Institute), and R software, version
3.5.0 (R Foundation for Statistical Computing).
R esult s
Participants
From November 2004 through December 2011,
a total of 3100 persons were screened; 1239 did
not meet inclusion criteria, including 963 (31.1%)
who were excluded because they did not have
H. pylori infection. An additional 23 declined
to participate. Therefore, 1838 participants underwent randomization; 917 were assigned to
receive treatment for H. pylori infection, and
921 were assigned to receive placebo (Fig. 1).
The baseline characteristics of these participants were well-balanced between the groups
(Table 1 and Table S3). After the exclusion of
162 participants (3 in whom gastric cancer was
detected at the baseline endoscopy, 1 who did
not have H. pylori infection, 8 who did not start
the trial regimen, and 150 who had no followup data), a total of 1676 participants — 832 in
the treatment group and 844 in the placebo
group — were included in the modified intention-to-treat population for the analysis of the
primary outcome (Table S4). The baseline characteristics of the 162 excluded participants
were similar to those of the participants in the
modified intention-to-treat population (Tables
S5 and S6). The median duration of follow-up
for the assessment of the primary outcome was
9.2 years (interquartile range, 6.2 to 10.6;
maximum, 14.1), and the median duration of
follow-up for the assessment of overall survival was 10.2 years (interquartile range, 8.9
to 11.6).
Primary Outcome
Gastric cancer developed in 10 of 832 participants (1.2%) in the treatment group and in 23 of
844 (2.7%) in the placebo group (P=0.03 by logrank test) (Fig. 2). All cases of gastric cancer
were detected by means of the surveillance endoscopies, and no cases of gastric cancer were
found to have been missed when data were
compared with the national database. The hazard ratio for the development of gastric cancer in
the treatment group as compared with the placebo group was 0.45 (95% confidence interval
[CI], 0.21 to 0.94). The number needed to treat
to prevent one case of gastric cancer was 65.7
(95% CI, 35.1 to 503.8) over the duration of the
trial. (The characteristics of the diagnosed cases
of gastric cancer are provided in Table S7.)
Among the 33 participants in whom gastric cancer developed, 30 had stage I disease (90.9%),
and 3 had stage II disease (9.1%).
Several sensitivity analyses that included all
1838 participants who underwent randomizaThe New England Journal of Medicine
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n engl j med 382;5 nejm.org January 30, 2020 431
Gastric Cancer and H. pylori Treatment
tion resulted in findings that were similar to
those of the primary analysis and showed the
effectiveness of H. pylori treatment in preventing
gastric cancer (Table S8). In an intention-to-treat
analysis that used imputed data from the National Cancer Incidence Database, the hazard
ratio for development of gastric cancer with
treatment as compared with placebo was 0.42
(95% CI, 0.20 to 0.89) (Fig. S2).
Analysis According to H. pylori Eradication
Status
H. pylori eradication status was evaluated in 1587
participants during the follow-up period. Eradication was confirmed in 551 of 786 participants
(70.1%) in the treatment group and in 57 of 801
participants (7.1%) in the placebo group. H. pylori
infection persisted in the remaining 979 participants (Table S9).

1838 Underwent randomization
3100 Participants were assessed for eligibility
917 Were assigned to receive
H. pylori treatment
921 Were assigned to receive
placebo
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432 n engl j med 382;5 nejm.org January 30, 2020
T h e n e w e ng l a nd j o u r na l o f m e dic i n e
Of the 33 cases of gastric cancer, 28 developed in the 979 participants (2.9%) with persistent infection, and 5 developed in the 608 participants (0.8%) in whom the infection was
eradicated (hazard ratio for gastric cancer with
eradicated infection as compared with persistent
infection, 0.27; 95% CI, 0.10 to 0.70) (Fig. 3).
(Characteristics of the gastric cancers according
to follow-up H. pylori eradication status are provided in Table S10.) The incidence of gastric
cancer was lower among participants in whom
H. pylori infection was eradicated than among
participants with persistent infection (0.94 cases
vs. 3.41 cases per 1000 person-years).
Of the 10 cases of gastric cancer that developed among participants in the treatment group,
5 cases (50.0%) developed in participants with
persistent infection, and 5 (50.0%) developed in
participants with confirmed eradication (Fig.
S3). The results of a combined analysis of the
risk of gastric cancer according to trial-group
assignment and follow-up H. pylori eradication
status are provided in Figure S4. The incidence
of gastric cancer among participants in the
treatment group who had persistent infection
was similar to the incidence among participants
in the placebo group with persistent infection.
Overall Survival
Death occurred in 16 of 917 participants (1.7%)
in the treatment group and in 18 of 921 (2.0%)
in the placebo group. No significant difference

* Plus–minus values are means ±SD. Data are shown for the intention-to-treat population, which included all participants
who underwent randomization. Percentages may not total 100 because of rounding.
† In the placebo group, 1 participant had a mother and also offspring with gastric cancer, and 1 had a sibling and also
offspring with gastric cancer; 39 participants in the treatment group and 36 in the placebo group had 2 or more siblings with gastric cancer.
‡ Symptoms included those associated with gastroesophageal reflux disease or mild nonulcer dyspepsia.
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n engl j med 382;5 nejm.org January 30, 2020 433
Gastric Cancer and H. pylori Treatment
in overall survival rates was found between the
trial groups (Fig. S5). The causes of death did
not differ between the groups (Table S11). In
the treatment group, 6 participants died from
other organ cancers, 1 died from cardiovascular disease, and 9 died from other causes. In
the placebo group, 7 participants died from
other organ cancers, 4 died from cardiovascular
disease, and 7 died from other causes. Death
from gastric cancer was not observed in either
group.
Incidence of Adenoma
The incidence of gastric adenoma was similar in
the two groups. Gastric adenomas developed in
14 participants (1.7%) in the treatment group
and in 13 (1.5%) in the placebo group (Fig. S6
and Table S12).
Adverse Events
The safety analysis included 1746 participants;
98.5% of the participants took more than 75% of
the assigned trial pills (Table S13). Drug-related
adverse events were more common in the treatment group than in the placebo group (53.0% of
participants in the treatment group and 19.1% in
the placebo group had at least one adverse event;
P<0.001), but the severity was usually mild. Taste
alteration, nausea, diarrhea, and abdominal pain
were common in the treatment group (Table 2).
Discussion
In this prospective, randomized trial involving
first-degree relatives of patients with gastric
cancer, the risk of gastric cancer was 55% lower
among those who received H. pylori eradication
treatment than among those who received placebo, during a median follow-up of 9.2 years. Of
note, the risk of gastric cancer was 73% lower
among persons in whom H. pylori eradication
was achieved than among those in whom infection was persistent. Adverse events were common in the treatment group, but the severity was
usually mild.
A meta-analysis of six randomized trials involving healthy, asymptomatic participants with
H. pylori infection showed that the risk of gastric
cancer was approximately 34% lower among
those who received treatment than among those
in the control groups.6 One large study that
evaluated gastric cancer as the primary outcome

Placebo
H. pylori
treatment

Persistent
infection
Eradicated
infection
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T h e n e w e ng l a nd j o u r na l o f m e dic i n e
concluded that the incidence of gastric cancer
was similar in the treatment group and the placebo group (7 cases in the treatment group and
11 in the placebo group; P=0.33), which may
have been the result of the underpowered design, despite the 7.5-year follow-up of 1630 participants.24 Another large study (the Shandong
Intervention Trial) involving 2258 participants
showed that the risk was 39% lower with H. pylori
treatment than with placebo over an extended
follow-up of 15 years; the between-group difference in risk was not significant during the initial
7.3-year follow-up.25,26 Results of long-term followup (22 years) in the same study showed a higher
difference in risk (52% lower in the treatment
group).27 The results of these studies emphasize
that trials of prevention of gastric cancer by treatment of H. pylori infection require many participants who are followed for a long period of
time, as is the case in an ongoing randomized
trial involving more than 90,000 participants.28
We were able to conduct this trial with a somewhat smaller sample size because the incidence
of gastric cancer among first-degree relatives of
patients with gastric cancer was high, and the
participants had high adherence to the trial
regimen. Sensitivity analyses that used imputation methods for missing data from participants
who were lost to follow-up robustly supported
our conclusion.
In this trial, the risk of gastric cancer was
55% lower among participants assigned to the
group that received treatment for H. pylori infection than among those assigned to the placebo
group and 73% lower among participants in
whom H. pylori eradication was confirmed than
among those who had persistent infection. These
results are similar to those of our previous trial
in patients with early gastric cancer (the risk of
gastric cancer was 50% lower in the treatment
group and 68% lower among participants in
whom H. pylori was eradicated).5 In the current
trial and in our previous trial, the risk of gastric
cancer was lower by 18 percentage points in the
analysis according to eradication status than in
the analysis according to the assigned group;
this finding is most likely the result of the persistent risk in the cases of eradication failure.
The 30% H. pylori eradication failure rate of
clarithromycin-containing triple therapy in our trial
was similar to data from a Korean meta-analysis.29 In contrast to previous trials in China,24,25
our trial did not test the success of eradication
therapy in the treatment group because we
wanted to maintain strict blinding. Subgroup
analyses of the Shandong Intervention Trial suggested a risk reduction even in cases of eradication failure.30 However, the results of the current
trial, along with those of our previous trial,5
showed that the risk of gastric cancer among
participants in whom infection was not eradi

* Data are shown for the safety population, which included all participants who
underwent randomization and received at least one dose of H. pylori treatment
or placebo. Adverse events were graded according to the National Cancer
Institute Common Terminology Criteria for Adverse Events, version 3.0.
† P values were calculated with the use of Pearson’s chi-square test or Fisher’s
exact test.
‡ In the group that received treatment for H. pylori infection, grade 3 adverse
events included nausea (in 2 participants), diarrhea (in 3 participants), and
abdominal pain (in 2 participants); 5 of the 7 participants took all prescribed
treatment tablets. Grade 3 diarrhea developed in 1 participant in the placebo
group who took all the placebo tablets.
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n engl j med 382;5 nejm.org January 30, 2020 435
Gastric Cancer and H. pylori Treatment
cated was similar in the treatment group and in
the placebo group. Our data emphasize that
eradication success should be confirmed, as the
“test–treat–test” approach recommends.31
In a meta-analysis, mortality from gastric cancer was about 33% lower among participants who
received treatment for H. pylori infection than
among those who did not — a finding similar
to the 34% lower incidence of gastric cancer
among treated participants.6 An unexpected finding from a more recent meta-analysis was a 12%
increase in all-cause mortality after H. pylori
treatment.32 This potential risk should be clearly
addressed before treatment of H. pylori infection
is applied generally as the primary prevention
strategy. In our trial, the clarithromycin-containing triple therapy was not associated with an
increase in death from any cause or death from
any specific causes. Of note, no death from gastric cancer was reported in either group, presumably because of the detection of disease in
its early stages. In previous trials, which adopted
4-year to 5-year intervals for surveillance endoscopy, death from gastric cancer was reported even
in the H. pylori treatment groups.24,25 In contrast,
in our trial, which used a 2-year surveillance
interval, we detected all gastric cancers at a curable stage (all within stage II).33 The National
Cancer Screening Program in Korea recommends
a 2-year interval for endoscopies in persons 40
years of age or older, which could reduce mortality from gastric cancer by about 81% if the procedure is performed three or more times.34
Screening intervals shorter than every 2 years
seem unnecessary because stage-specific prognosis of gastric cancer in patients with a family
history of gastric cancer has been shown to be
similar or better than the prognosis in patients
with no family history of gastric cancer.35
The results of this trial showed that treatment of H. pylori infection did not result in a
lower incidence of gastric adenoma than placebo.
This finding is similar to that of our previous
trial involving patients with early gastric cancer;
in that trial, the incidence of adenoma was almost equal in the two groups (8.2% in the treatment group and 8.4% in placebo group).5 Together, our trials suggest that the preventative
effect of H. pylori treatment is not preceded by a
decrease in the incidence of adenoma, and the
adenoma–carcinoma sequence is not the pathway activated by H. pylori in the development of
gastric cancer.
The main advantage of our trial is that the
incidence of gastric cancer was evaluated as the
primary outcome in a large-scale, long-term trial.
We confirmed outcome data obtained from active surveillance with data from the national
databases. The trial has several limitations. First,
it was performed at a single center in South
Korea. However, the fact that the Korean population is of the same ethnic group and that there
is little geographic variation in the incidence of
gastric cancer may support the generalizability
of the findings to the rest of South Korea.36 Because family history is a consistent risk factor
worldwide, our results may be globally applicable.9,37 Second, an ethical issue can be raised
about conducting a trial with the use of placebo.
However, the national health insurance system
of South Korea does not currently cover H. pylori
therapy in our trial population. We provided
eradication therapy to all participants who still
had H. pylori infection at the end of the trial.
Third, we did not evaluate the genetic susceptibility of the participants to gastric cancer or the
bacterial virulence factors of H. pylori, which may
be risk factors for gastric cancer.
In conclusion, treatment of H. pylori infection
reduced the risk of gastric cancer in first-degree
relatives of patients with gastric cancer.
A data sharing statement provided by the authors is available
with the full text of this article at NEJM.org.
Supported by grants (0410450, 0710340, 1010190, 1310280,
1610180, 1910270) from the National Cancer Center, South Korea.
No potential conflict of interest relevant to this article was
reported.
Disclosure forms provided by the authors are available with
the full text of this article at NEJM.org.
We thank the family members of the patients with gastric
cancer for participating in the trial; the members of the data and
safety monitoring board; the trial collaborators for contributions to the conduct of this trial; the staff of the Korea Central
Cancer Registry for access to the Korea National Cancer Incidence Database; Jeil Pharmaceutical for manufacturing and supplying lansoprazole placebos; Hanmi Pharmaceutical for clarithromycin placebos; and Chong Kun Dang Pharmaceutical for
amoxicillin placebos. A list of members of the data and safety
monitoring board and the trial collaborators is provided in the
Supplementary Appendix.
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436 n engl j med 382;5 nejm.org January 30, 2020
Gastric Cancer and H. pylori Treatment
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