Gastric Cancer

Editor

CHIN HUR

GASTROINTESTINAL ENDOSCOPY
CLINICS OF NORTH AMERICA
www.giendo.theclinics.com

Consulting Editor
CHARLES J. LIGHTDALE

July 2021  Volume 31  Number 3

 Gastric Cancer

Contributors

CONSULTING EDITOR

CHARLES J. LIGHTDALE, MD
Professor of Medicine, Division of Digestive and Liver Diseases, Columbia University
Medical Center, New York, New York, USA

EDITOR

CHIN HUR, MD, MPH

Director, Healthcare Innovations Research and Evaluation (HIRE), Professor, Columbia
University, Department of Medicine, Columbia University Irving Medical Center, New York,
New York, USA

AUTHORS

ANDREW CANAKIS, DO
Department of Medicine, Boston University School of Medicine, Boston Medical Center,
Boston, Massachusetts, USA

CHARLOTTE K. CHING, MD
Internal Medicine Resident, Vagelos College of Physicians and Surgeons, Department of
Medicine, Columbia University Irving Medical Center, New York, New York, USA

SOO-JEONG CHO, MD, PhD

Associate Professor, Department of Internal Medicine and Liver Research Institute, Seoul
National University Hospital, Seoul National University College of Medicine, Seoul, Korea

ANDREW HSU, MD
Chief Fellow, Division of Hematology/Oncology, The Warren Alpert Medical School of
Brown University, Lifespan Cancer Institute, Rhode Island Hospital/The Miriam Hospital,
Providence, Rhode Island, USA

ROBERT J. HUANG, MD, MS

Division of Gastroenterology and Hepatology, Stanford University, Stanford, California, USA

JOO HA HWANG, MD, PhD

Division of Gastroenterology and Hepatology, Stanford University, Stanford, California, USA

HAEJIN IN, MD, MPH, MBA

Associate Professor of Surgery, Associate Professor of Epidemiology and Population
Health, Department of Surgery, Montefiore Medical Center, Departments of Surgery, and
Epidemiology and Population Health, Albert Einstein College of Medicine, New York, New
York, USA

MANAMI INOUE, MD, PhD

Chief, Division of Prevention, Center for Public Health Sciences, National Cancer Center,
Tokyo, Japan
iv Contributors

HWOON-YONG JUNG, MD, PhD, AGAF

Department of Gastroenterology, University of Ulsan College of Medicine, Asan Medical
Center, Asan Digestive Disease Research Institute, Seoul, Korea

FAY KASTRINOS, MD, MPH

Associate Professor of Medicine, Herbert Irving Comprehensive Cancer Center,
Columbia University Medical Center, Division of Digestive and Liver Diseases, Columbia
University Irving Medical Cancer, Vagelos College of Physicians and Surgeons, New York,
New York, USA

BOKYUNG KIM, MD
Clinical Fellow, Department of Internal Medicine and Liver Research Institute, Seoul
National University Hospital, Seoul National University College of Medicine, Seoul,
Korea

GA HEE KIM, MD, PhD

Department of Gastroenterology, University of Ulsan College of Medicine, Asan Medical
Center, Asan Digestive Disease Research Institute, Seoul, Korea

JUDITH KIM, MD
Post-doctoral Fellow, Department of Medicine, Division of Digestive and Liver Diseases,
Columbia University Irving Medical Center, New York, New York, USA

RAYMOND KIM, MD
Division of Gastroenterology and Hepatology, University of Maryland Medical Center,
University of Maryland School of Medicine, Baltimore, Maryland, USA

THERESA H. NGUYEN, MD
Clinical Post-doctoral Fellow, Section of Gastroenterology and Hepatology, Department
of Medicine, Baylor College of Medicine, Houston, Texas, USA

RICHARD M. PEEK, Jr, MD

Division of Gastroenterology, Hepatology, and Nutrition, Vanderbilt University Medical
Center, Nashville, Tennessee, USA

ALEXANDER G. RAUFI, MD
Assistant Professor of Medicine, Division of Hematology/Oncology, The Warren Alpert
Medical School of Brown University, Lifespan Cancer Institute, Rhode Island Hospital/The
Miriam Hospital, Providence, Rhode Island, USA

SHEILA D. RUSTGI, MD
Assistant Professor of Medicine, Herbert Irving Comprehensive Cancer Center, Columbia
University Medical Center, Division of Digestive and Liver Diseases, Columbia University
Irving Medical Cancer, Vagelos College of Physicians and Surgeons, New York, New
York, USA

SHAILJA C. SHAH, MD, MPH

Division of Gastroenterology, Hepatology, and Nutrition, Vanderbilt University Medical
Center, Nashville, Tennessee, USA; Veterans Affairs San Diego Healthcare System,
University of California, San Diego, La Jolla, California, USA

IAN SOLSKY, MD, MPH

Department of Surgery, Montefiore Medical Center, New York, New York, USA
 Contributors v

AARON P. THRIFT, PhD

Assistant Professor, Section of Epidemiology and Population Sciences, Department of
Medicine, Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine,
Houston, Texas, USA

TIMOTHY CRAGIN WANG, MD

Division Chief, Department of Medicine, Division of Digestive and Liver Diseases,
Columbia University Irving Medical Center, New York, New York, USA
 Gastric Cancer

Contents

Foreword: Turning a Spotlight on Gastric Cancer xiii

Charles J. Lightdale

Preface: Gastric Cancer: An Update on the Rapidly Changing Characteristics and

Evolving Opportunities for Interventions xv
Chin Hur

Gastric Cancer Epidemiology 425

Aaron P. Thrift and Theresa H. Nguyen
In the United States, the incidence of gastric cancer has decreased over
the past five decades. However, despite overall decreasing trends in inci-
dence rates of gastric cancer, rates of noncardia gastric cancer among
adults aged less than 50 years in the United States are increasing, and
most cases of gastric cancer still present with advanced disease and
poor resultant survival. Epidemiologic studies have identified the main
risk factors for gastric cancer, including increasing age, male sex, non-
White race, Helicobacter pylori infection, and smoking. This article sum-
marizes the current epidemiologic evidence with implications for primary
and secondary prevention of gastric cancer.

Public Health Interventions for Gastric Cancer Control 441

Manami Inoue
Despite its generally decreasing trend in incidence, gastric cancer remains
the fifth-most common cancer worldwide. Gastric cancer has substantially
declined over the past century, thanks to decreases in risk factors such as
Helicobacter pylori infection, tobacco smoking, and salt-preserved food
intake. These decreases have resulted from natural interventions and
population-based intervention strategies. H pylori eradication for infected
patients has potential as a prevention strategy for those at high risk, but
warrants a longer follow-up period. The ongoing increase in obesity prev-
alence may cause an increase in cardia gastric cancer, especially in West-
ern populations, and should be carefully monitored.

Helicobacter pylori and Gastric Cancer 451

Judith Kim and Timothy Cragin Wang
Helicobacter pylori is present in approximately one-half of the world’s pop-
ulation. There are significant differences in prevalence based on region,
age, race/ethnicity, and socioeconomic status. H pylori is the most com-
mon cause of infection-related cancers. Studies have demonstrated the
relationship between H pylori infection and gastric adenocarcinoma and
mucosa-associated lymphoid tissue lymphoma. H pylori has features
and enzymatic properties allowing it to survive in the acidic stomach envi-
ronment, and has specific virulence factors that promote an increased risk
viii Contents

of gastric pathology. Eradication of H pylori is first-line therapy for mucosa-

associated lymphoid tissue lymphoma and decreases the risk of gastric
adenocarcinoma.

Inherited Predisposition to Gastric Cancer 467

Sheila D. Rustgi, Charlotte K. Ching, and Fay Kastrinos
Approximately 10% of patients with gastric cancer show familial aggregation
and up to 3% are related to various inherited cancer syndromes. There are
multiple germline pathogenic variants and cancer syndromes associated
with an increased risk of gastric cancer. Appropriate assessment of familial
and genetic risk may allow a personalized approach to gastric cancer preven-
tion through screening and risk-reducing surgeries. The ability to better identify
carriers with pathogenic genetic variants associated with gastric cancer
before a diagnosis of cancer requires effective genetic risk assessment and
testing, followed by optimal screening and surveillance recommendations or
prophylactic surgery to further reduce the associated morbidity and mortality.

Endoscopic Screening and Surveillance for Gastric Cancer 489

Bokyung Kim and Soo-Jeong Cho
Gastric cancer is one of the most common cancers worldwide. Gastric
cancer is a multifactorial disease, and the incidence varies widely by
geographic region, with half of new cases occurring in East Asia.
Population-based nationwide screening for gastric cancer has been imple-
mented in some Eastern Asian countries such as South Korea and Japan.
In these countries, endoscopic screening decreased gastric cancer mor-
tality. Endoscopic screening seems to be a cost-effective modality in
countries with high incidence of gastric cancer. However, the usefulness
of population-based screening has not yet been proved in countries with
low incidence of gastric cancer.

Improving the Early Diagnosis of Gastric Cancer 503

Robert J. Huang and Joo Ha Hwang
Video content accompanies this article at http://www.giendo.
theclinics.com.

Gastric cancer (GC) remains a leading cause of cancer morbidity and mor-
tality worldwide. Outcomes from GC remain poor, especially in Western
nations where cancer diagnosis is usually at advanced stages where cura-
tive resection is not possible. By contrast, nations of East Asia have adop-
ted methods of population-level screening with improvements in stage of
diagnosis and survival. In this review, the authors discuss the epidemi-
ology of GC in Western populations, highlight at-risk populations who
may benefit from screening, overview screening modalities, and discuss
promising approaches to early GC detection.

Chemoprevention Against Gastric Cancer 519

Shailja C. Shah and Richard M. Peek Jr.
Gastric cancer is the fifth most common cause of cancer and the third
leading cause of cancer-related deaths globally. The number of gastric
 Contents ix

cancer-related deaths is projected to increase, attributable primarily to the

expanding aging population. Prevention is a mainstay of gastric cancer
control programs, particularly in the absence of accurate, noninvasive mo-
dalities for screening and early detection, and the absence of an infrastruc-
ture for this purpose in the majority of countries worldwide. Herein, we
discuss the evidence for several chemopreventive agents, along with pu-
tative mechanisms. There remains a clear, unmet need for primary chemo-
prevention trials for gastric cancer.

Endoscopic Advances for Gastric Neoplasia Detection 543

Andrew Canakis and Raymond Kim
This article explores advances in endoscopic neoplasia detection with
supporting clinical evidence and future aims. The ability to detect early
gastric neoplastic lesions amenable to curative endoscopic submucosal
dissection provides the opportunity to decrease gastric cancer mortality
rates. Newer imaging techniques offer enhanced views of mucosal and
microvascular structures and show promise in differentiating benign
from malignant lesions and improving targeted biopsies. Conventional
chromoendoscopy is well studied and validated. Narrow band imaging
demonstrates superiority over magnified white light. Autofluorescence im-
aging, i-scan, flexible spectral imaging color enhancement, and bright im-
age enhanced endoscopy show promise but insufficient evidence to
change current clinical practice.

Endoscopic Resection of Gastric Cancer 563

Ga Hee Kim and Hwoon-Yong Jung
Video content accompanies this article at http://www.giendo.
theclinics.com.

With improvements in the early detection of early gastric cancer (EGC) and
advances in therapeutic techniques, endoscopic resection (ER) for EGC
has become widely adopted in East Asian and Western countries. Endo-
scopic submucosal dissection has higher rates of en bloc, complete,
and curative resections with lower rates of local recurrence than that of
endoscopic mucosal resection. ER is a minimally invasive method with
low morbidity that provides excellent outcomes. ER for EGC is a safe,
effective method, preserving organ function and thus maintaining the pa-
tient’s quality of life, and is recognized as the first-line treatment of EGC in
selected patients.

Surgical Treatment for Gastric Cancer 581

Ian Solsky and Haejin In
Video content accompanies this article at http://www.giendo.
theclinics.com.

Surgery is an essential component of curative-intent treatment strategies

for gastric cancer. However, the care of each patient with gastric cancer
must be individualized based on patients and tumor characteristics. It is
important that all physicians who will be caring for patient with gastric can-
cer understand the current best practices of surgical management to
x Contents

provide patients with the highest quality of care. This article aims to pro-
vide this information while acknowledging areas of surgical management
that are still controversial.

Advances in Systemic Therapy for Gastric Cancer 607

Andrew Hsu and Alexander G. Raufi
Gastric cancer represents a major global health problem. Approximately
half of patients are diagnosed with early stage disease and surgical resec-
tion is potentially curative. The addition of combination chemotherapy,
with or without radiotherapy, to surgery has been shown to improve out-
comes. In metastatic disease, combination chemotherapy in the form of
2- or 3-drug regimens has been used. The aim of this chapter is to summa-
rize currently approved systemic treatment options for gastric cancer and
to highlight several promising treatments currently under investigation.
 Gastric Cancer xi

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 Gastric Cancer

Foreword
Tu r n i n g a S p o t l i g h t o n G a s t r i c
Cancer

Charles J. Lightdale, MD
Consulting Editor

Gastric adenocarcinoma is a common and highly lethal cancer worldwide. The disease
is of lower incidence in the United States and other western countries. The lower inci-
dence is probably related in part to the decreasing incidence of gastric Helicobacter
pylori infections in the west. A reverse effect of the decline in H pylori in the west
has been the dramatic rise in Barrett’s esophagus and esophageal adenocarcinoma
primarily affecting white men. Adenocarcinoma of the stomach, on the other hand,
excluding esophagogastric junction cancer, more commonly occurs in blacks, His-
panics, and Asians, creating health disparities in western countries. As immigration
has led to more diversity in western populations, there is an increasing need to pay
attention to the relatively “neglected” adenocarcinomas of the stomach.
A fascinating finding is that the precursor to gastric adenocarcinoma on pathology is
intestinal metaplasia, the same type of tissue that characterizes Barrett’s esophagus.
On pathology examination, the incomplete type of intestinal metaplasia has the highest
potential for malignant transformation in the stomach. The distribution of intestinal
metaplasia in the stomach, usually distal in patients with H pylori infection, can be
patchy and irregular and difficult to identify on endoscopy. Another challenge is that
the surface area of the stomach is much larger than the tubular esophagus and takes
longer to thoroughly examine. The earliest changes of dysplasia and intramucosal can-
cer, often subtle, pale, flat, or slightly raised or depressed lesions, can also be very
difficult to find. Random biopsies by the dozens can still miss these lesions.
Endoscopists in high-incidence regions have in recent decades trained their eyes to
detect these lesions with experience and training not yet widely available in the
west. The newest endoscopes with high-resolution white light and electronic chro-
moendoscopy with magnification have been clearly an advance in examination of
the stomach for detection of intestinal metaplasia and early neoplasia.

Gastrointest Endoscopy Clin N Am 31 (2021) xiii–xiv

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xiv Foreword

Dr Chin Hur, the Editor for this issue of the Gastrointestinal Endoscopy Clinics of
North America, is an internationally recognized expert in cancer screening and preven-
tion for gastrointestinal cancers. He has assembled an outstanding group of experts to
create an issue that shines a bright spotlight on gastric cancer, providing a compre-
hensive state-of-the-art review. I urge all general gastroenterologists and gastrointes-
tinal endoscopists to read this issue. It is time for us to up our game for the prevention,
early detection, and treatment of adenocarcinoma of the stomach.

Charles J. Lightdale, MD
Division of Digestive and Liver Diseases
Columbia University Irving Medical Center
161 Fort Washington Avenue
New York, NY 10032, USA
E-mail address:
cjl18@cumc.columbia.edu
 Gastric Cancer

Preface
G a s t r i c Ca n c e r :
An Update on the Rapidly
Changing Characteristics and
Evolving Opportunities for
Interventions

Chin Hur, MD, MPH

Editor

Gastric cancer (GC), specifically gastric adenocarcinoma, is the fifth most common
cancer and the third leading cause of cancer death globally and has been categorized
as a neglected cancer by the World Health Organization.1,2 Usually diagnosed at
advanced stages, GC has a 5-year survival rate of w30%.3 In the United States, there
are stark disparities, with blacks, Hispanics, and Asians having a nearly 2-fold greater
risk of developing or dying from GC compared with whites,4 reflecting differences in
risk factors, such as Helicobacter pylori infection and smoking, as well as access to
primary prevention5 and care.6 Several factors are changing the landscape of GC pre-
vention, including a better understanding of the disease’s natural history,7–9 new evi-
dence on prevention from prospective studies,10–14 and anticipated results from
ongoing randomized controlled trials.15 As early GC detection can improve survival
by allowing for curative surgical or noninvasive endoscopic resection,16 new targeted
approaches to GC prevention have the potential to markedly improve population
health and reduce GC disparities within the United States.
Although H pylori has been the primary focus of global GC prevention efforts to
date,1,2 substantial variation by subpopulation in H pylori prevalence in the United
States and the world has accentuated the need to optimize H pylori screen-and-treat
interventions for vulnerable groups.17–20 Early detection of GC or precancerous lesions
can further reduce GC burden. For example, surveillance of individuals with gastric

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1052-5157/21/ª 2021 Published by Elsevier Inc.
xvi Preface

intestinal metaplasia (IM), a precursor lesion with a high progression risk to gastric
neoplasia, is currently recommended in many countries.21,22 However, as gastric IM
is often asymptomatic, most of the 5% to 10% of US adults with this condition remain
undiagnosed.9,23 In addition, an increase in GC incidence among younger individuals
has been observed, particularly in young women.24–27 A critical need exists to identify
effective and cost-effective strategies to address these clinical challenges in the
United States, as well as globally.
I would like to express my gratitude to Dr Charlie Lightdale for providing me the op-
portunity to serve as a guest editor for this issue of Gastrointestinal Endoscopy Clinics
of North America. I am deeply indebted to all the authors who have written superb ar-
ticles that distill the current state of the spectrum of GC knowledge ranging from
biology to epidemiology and therapy. To our readers, we hope and trust that our ef-
forts have produced a useful resource for clinical care, research, and cancer control
interventions.

Chin Hur, MD, MPH

Director, Healthcare Innovations Research
and Evaluation (HIRE)
Professor, Columbia University
Department of Medicine
Columbia University Irving Medical Center
622 W 168th Street, PH9-105C
New York, NY 10032, USA
E-mail address:
Chin.hur@columbia.edu

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21. Pimentel-Nunes P, Libanio D, Marcos-Pinto R, et al. Management of epithelial pre-
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22. Banks M, Graham D, Jansen M, et al. British Society of Gastroenterology guide-
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23. Sonnenberg A, Lash RH, Genta RM. A national study of Helicobactor pylori infec-
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G a s t r i c C a n c e r Ep i d e m i o l o g y
a, b
Aaron P. Thrift, PhD *, Theresa H. Nguyen, MD

KEYWORDS
 Incidence  Survival  Risk factors  Genetics  Environment

KEY POINTS
 Globally, gastric cancer remains the fifth most common cancer and the third leading
cause of cancer-related mortality.
 In the United States, despite overall decreasing rates over the past five decades, inci-
dence of noncardia gastric cancer is increasing among adults less than 50 years.
 Helicobacter pylori is the main cause of gastric cancer, accounting for approximately 89%
of distal gastric cancer cases worldwide.
 Population-based programs of screening and surveillance and H pylori screening and
eradication hold greatest promise for reducing the burden of gastric cancer.

INTRODUCTION

Gastric cancer is the fifth most common cancer worldwide and the third leading cause
of cancer-related mortality.1 There are two main topographic types of gastric cancer:
cardia gastric cancer (arising in the area of the stomach adjoining the esophagogastric
junction) and noncardia gastric cancer (arising from more distal regions of the stom-
ach). The epidemiology of the two topographic types is distinct. Furthermore, accord-
ing to the Lauren classification, there are two histologic types of gastric cancer:
intestinal and diffuse. Both histologic subtypes are associated with Helicobacter pylori
infection. The diffuse type contains diffuse carcinoma cells that lack cohesion and
invade tissues independently or in small clusters. The intestinal type of adenocarci-
noma forms glands or tubules lined by epithelium with cohesion among tumor cells
that resemble the intestinal mucosa. The intestinal type is the most frequent type
found in high gastric cancer incidence populations. A prolonged precancerous pro-
cess occurs before the development of the intestinal type of adenocarcinoma, known
as the Correa cascade, with well-defined, consecutive stages.2 The process is initi-
ated with H pylori infection causing chronic active gastritis. With sustained infection
for decades, gastric mucosal inflammation may lead to glandular loss, known as
chronic atrophic gastritis. Atrophy typically first occurs in the incisura angularis and

a
Section of Epidemiology and Population Sciences, Department of Medicine, Dan L Duncan
Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA; b Baylor
Clinic, 6620 Main Street, MS: BCM620, Room 110D, Houston, TX, 77030, USA
* Corresponding author. Baylor College of Medicine, One Baylor Plaza, MS: 307, Room 621D,
Houston, TX 77030.
E-mail address: aaron.thrift@bcm.edu

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426 Thrift & Nguyen

then extends over time to the anterior and posterior gastric walls. Atrophy is then
replaced with intestinal metaplastic cells, initially with small intestinal complete pheno-
type, then eventually to large intestinal (incomplete or colonic) phenotype. Following
incomplete intestinal metaplasia, dysplasia then develops (first low grade, then high
grade), after which invasive carcinoma is the final stage. This article describes the
descriptive epidemiology of gastric cancer, its main risk factors, and opportunities
and challenges for primary and secondary prevention.

INCIDENCE AND MORTALITY

Worldwide Trends
According to GLOBOCAN estimates, there were 1,033,701 new cases of gastric cancer
worldwide and 782,685 deaths related to gastric cancer in 2018.3 Gastric cancer was
the fifth-most commonly diagnosed cancer type in 2018 (representing 5.7% of all can-
cer cases diagnosed) and was responsible for 8.2% of all deaths from cancer in 2018,
making it the third-most common cause of cancer-related death after lung (18.4% of
deaths) and colorectal (9.2% of deaths) cancers.3 In 2018, the global age-
standardized incidence and mortality rates for gastric cancer were 11.1 and 8.2 per
100,000, respectively. Gastric cancer incidence rates increase with increasing age
and are two-fold to three-fold higher for men than women. Gastric cancer was the fourth
most commonly diagnosed cancer type in men (incidence rate, 15.7 per 100,000) and
the seventh most commonly diagnosed cancer type in women (incidence rate, 7.0
per 100,000) in 2018.3 Recent studies examining global trends in incidence and mortal-
ity rates for gastric cancer have confirmed a continued decline worldwide4–6; however,
these studies also highlight the global variability in incidence and mortality rates and dif-
ferences in secular trends. Approximately 86% (885,119 of 1,033,701) of new gastric
cancer cases in 2018 occurred in regions with high and very high Human Development
Index. Environmental factors likely explain this, particularly H pylori infection because
highly virulent strains of H pylori are found in Eastern and South Eastern Asia, regions
with high Human Development Index level and where 64% (657,254 cases) of new
gastric cancer cases were diagnosed in 2018 (Fig. 1).1,7 The highest incidence rates
for gastric cancer are observed in Eastern Asia (32.1 per 100,000 men; 13.2 per

Fig. 1. Worldwide age-standardized incidence rate per 100,000 for gastric cancer in 2018. (From
GLOBOCAN 2020; Graph production: IARC (http://gco.iarc.fr/today) World Health Organization.)
 Gastric Cancer Epidemiology 427

100,000 women), Central and Eastern Europe (17.1 per 100,000 men; 7.5 per 100,000
women), and South America (12.7 per 100,000; 6.9 per 100,000 women), whereas the
lowest incidence rates are observed in North America (5.6 per 100,000 men; 2.8 per
100,000 women) and Africa (w5 per 100,000 men and 3–4 per 100,000 women).1 There
has been a steady decline in incidence and mortality rates for gastric cancer in Western
populations since the middle of the twentieth century. In Japan and Korea, countries
with historically high gastric cancer incidence rates, delayed but similar decreasing
trends have been observed in recent years.8 The highest mortality rates for gastric can-
cer are observed in Eastern Asia (15.9 per 100,000).1 High mortality rates are also
observed in Central and Eastern Europe and South America, whereas lowest mortality
rates for gastric cancer are seen in Northern America (1.8 per 100,000).1

United States Trends

The epidemiology of gastric cancer in the United States has changed dramatically
over time,9 with a linear decline in incidence rates in recent decades.10,11 For the pur-
pose of this review, the most recent data were analyzed from the US National Cancer
Institute’s Surveillance, Epidemiology, and End Results (SEER) nine registries12
(covering approximately 10% of the US population) in which 89,066 cases of invasive
gastric cancer (defined using International Classification of Diseases for Oncology,
Third Edition, site codes C160–C169 and histology type, excluding 9050–9055,
9140, and 9590–9992) were diagnosed between 1975 and 2017. Gastric cancer inci-
dence rates decreased from 11.7 per 100,000 in 1975 to 6.6 per 100,000 in 2017
(Fig. 2). During that period, incidence of gastric cancer decreased at a rate of
1.49% per year (average annual percent change [AAPC], 1.49%; 95% confidence
interval [CI], 1.43% to 1.55%). Among all gastric cancer cases in the SEER data-
base diagnosed between 1975 and 2017, 61.4% were in men. Between 1975 and

Fig. 2. Age-adjusted incidence rates of gastric cancer in the United States, 1975 to 2017.
(From Surveillance, Epidemiology, and End Results (SEER) Program (www.seer.cancer.gov)
SEER*Stat Database: Incidence - SEER Research Data, 9 Registries, Nov 2019 Sub (1975-
2017) - Linked To County Attributes - Time Dependent (1990-2017) Income/Rurality, 1969-
2017 Counties, National Cancer Institute, DCCPS, Surveillance Research Program, released
April 2020, based on the November 2019 submission.)
428 Thrift & Nguyen

2017, gastric cancer incidence rates in the United States decreased in men (AAPC,
1.70%; 95% CI, 1.64% to 1.77%) and women (AAPC, 1.34%; 95% CI,
1.21% to 1.47%). The lifetime risk of gastric cancer in the United States is approx-
imately 1 in 95 men and 1 in 154 women.10
Incidence rates for gastric cancer in the United States increase with increasing age,
with, historically, low rates of gastric cancer among adults aged less than 50 years.10
However, although rates of noncardia gastric cancer in the United States continue to
decrease among adults aged greater than or equal to 50 years, the incidence of non-
cardia gastric cancer among persons aged less than 50 years is increasing.13–15 In
addition to established sex disparities, incidence rates for gastric cancer vary among
different ethnic groups within the United States.10 Compared with non-Hispanic
Whites, incidence rates for gastric cancer are two-fold higher among Hispanics,
non-Hispanic Blacks, and Asian and Pacific Islanders in the United States.10 Divergent
secular trends in gastric cancer rates by cancer stage at diagnosis between non-
Hispanic Whites and Hispanics aged less than 50 years have also been reported in
the United States.10,11 Among non-Hispanic Whites, rates of localized-stage noncar-
dia gastric cancer increased by 5.28% (95% CI, 3.94%–6.64%) per year between
2001 and 2014. Conversely, during the same period, the rates of regional- and
distant-staged noncardia gastric cancer among non-Hispanic Whites aged less than
50 years decreased and remained unchanged, respectively. By contrast, there was
a significant increase in distant-staged noncardia gastric cancers among Hispanics
aged less than 50 years (AAPC, 1.78%; 95% CI, 0.66%–2.91%).14
Geographic differences in overall gastric cancer incidence rates and trends over
time have been observed in the United States.15 Data from the US Cancer Statistics
registry (covering 100% of the US population in 2015)16 show that the highest inci-
dence rates for gastric cancer in 2001 to 2002, 2006 to 2007, and 2011 to 2012
were found in Hawaii (14.4, 10.6, and 9.1 per 100,000, respectively), whereas by
2016 to 2017 the highest rates were found in New York (8.7 per 100,000). In 2001 to
2002, 12 of the 50 states had incidence rates less than or equal to 5.7 per 100,000;
this number increased to 22 states by 2016 to 2017. By contrast, the number of states
with incidence rates greater than 8.4 per 100,000 decreased from seven states
(Hawaii, Alaska, New York, Rhode Island, New Jersey, Connecticut, Louisiana) in
2001 to 2002 to one (New York) by 2016 to 2017 (Fig. 3).
For gastric cancer cases in the SEER 18 registries,17 median relative survival has
increased from 10.3 months in 2000 to 17.6 months for persons diagnosed in 2016.
Overall 5-year observed survival rates increased from 18.8% for patients diagnosed
with gastric cancer in 2000 to 28.4% for patients diagnosed in 2012. The greatest abso-
lute improvement in survival trends occurred in patients with gastric cancer diagnosed
with localized disease. Approximately 46% of patients diagnosed with localized gastric
cancer in 2000 survived 5 years after their diagnosis, whereas the 5-year observed sur-
vival rate for patients diagnosed with localized gastric cancer in 2012 was 61% (Fig. 4).
However, one-third of patients with gastric cancer are still diagnosed with distant-stage
disease and there has been little improvement in 5-year survival rates for these patients
(2.3% for patients diagnosed in 2000 vs 5.4% for those diagnosed in 2012).

RISK FACTORS
Helicobacter pylori Infection
Chronic infection with H pylori is the main cause of gastric cancer, accounting for
approximately 89% of distal gastric cancer cases worldwide.18 In 1994, the Interna-
tional Agency for Research on Cancer classified H pylori as a class I carcinogen for
 Gastric Cancer Epidemiology 429

Fig. 3. State-level heat maps showing age-adjusted incidence rates of gastric cancer in the
United States, 2001 to 2017. (From National Program of Cancer Registries and Surveillance,
Epidemiology, and End Results SEER*Stat Database: NPCR and SEER Incidence - U.S. Cancer
Statistics 2001-2017 Public Use Research Database, 2019 Submission (2001-2017), United
States Department of Health and Human Services, Centers for Disease Control and Preven-
tion and National Cancer Institute. Released June 2020. Accessed at www.cdc.gov/cancer/
uscs/public-use.)

noncardia gastric cancer and reconfirmed this classification in 2009.19 Most H pylori
infections are acquired during childhood and, once established, usually persist for
life unless treated. There is substantial regional variation in prevalence,20 with highest
prevalence in Central and South America and in parts of Asia and Eastern Europe, re-
gions with highest rates of gastric cancer.20 A stronger effect of H pylori on the risk of
noncardia gastric cancer is observed among individuals with the CagA-positive H py-
lori strain compared with the CagA-negative strain.21 Likely because of a reduced bac-
terial load in severe corpus atrophy, positive low CagA antibody titers may confer
higher risk for noncardia gastric cancer (relative risk [RR], 3.9; 95% CI, 2.1–7.0) than
high antibody titers (RR, 2.0; 95% CI, 1.3–3.2).22 Geographic variation in noncardia
gastric cancer incidence may be explained by global variability in the prevalence of
CagA-positive H pylori strains, and by functional differences in CagA tyrosine phos-
phorylation sites between Eastern and Western CagA-positive H pylori strains.23
430 Thrift & Nguyen

Fig. 4. Five-year survival rates for gastric cancer in the United States, 2000 to 2012, by stage
at diagnosis (localized, regional, and distant stage). (From Surveillance, Epidemiology, and
End Results (SEER) Program (www.seer.cancer.gov) SEER*Stat Database: Incidence - SEER
Research Data, 18 Registries, Nov 2019 Sub (2000-2017) - Linked To County Attributes -
Time Dependent (1990-2017) Income/Rurality, 1969-2018 Counties, National Cancer Insti-
tute, DCCPS, Surveillance Research Program, released April 2020, based on the November
2019 submission.)

Studies show that the CagA EPIYA-D in East Asian strains of H pylori bind to the pro-
oncogenic SHP2 phosphatase two-fold more strongly than the CagA EPIYA-C in
Western strains.24 However, a case-control study found that the odds of noncardia
gastric cancer in CagA seropositives was higher in non-Japanese Brazilians (odds ra-
tio [OR], 4.5; 95% CI, 2.6–7.9) than in Japanese Brazilians (OR, 2.1; 95% CI, 1.2–3.6),
which may reflect geographic variations in the frequency rather than oncogenic poten-
tial of CagA-positive H pylori strains.25
Cigarette Smoking
In 2002, International Agency for Research on Cancer concluded that there was suf-
ficient evidence for a causal relationship between smoking and gastric cancer.26 In a
meta-analysis, compared with never smoking, current smoking was associated with
increased risk of cardia gastric cancer (RR, 1.87; 95% CI, 1.31–2.67; nine studies)
and noncardia gastric cancer (RR, 1.60; 95% CI, 1.41–1.80; nine studies).27 A recent
pooled analysis of data from 10,290 gastric cancer cases and 26,145 control subjects
in the Stomach Cancer Pooling Project (StoP) found that current smokers had 25%
higher risk of gastric cancer compared with never smokers (OR, 1.25; 95% CI,
1.11–1.40).28 Smoking conferred increased risk regardless of tumor location; howev-
er, the magnitude of association seemed stronger for cardia gastric cancer than non-
cardia gastric cancer. Risk increased linearly with increasing number of cigarettes per
day (P for trend <0.01) and duration of smoking (P for trend <0.01). Importantly, this
study found evidence that, among ever smokers, gastric cancer risk declined with
increased years of smoking cessation (P for trend <0.01). Gastric cancer risk in former
smokers became similar to that of never smokers after 10 years of smoking
 Gastric Cancer Epidemiology 431

cessation.28 Other forms of tobacco use have been associated with an increased risk
of gastric cancer, although this has not been consistent across studies.29

Excess Body Weight

Studies examining the association between excess body weight and gastric cancer
risk have reported conflicting results. A meta-analysis of 13 cohort and three case-
control studies found that obesity (body mass index [BMI] 30 kg/m2; OR, 1.13;
95% CI, 1.03–1.24) was associated with a modest increased risk for gastric cancer.30
When examined separately by tumor location, obesity was associated with increased
risk for cardia gastric cancer (OR, 1.61; 95% CI, 1.15–2.24) but not noncardia gastric
cancer (OR, 0.83; 95% CI, 0.68–1.01).30 Notably, a meta-analysis of 10 cohort studies
found that excess body weight (using the World Health Organization classification of
overweight and obese) was associated with an increased risk of gastric cancer in non-
Asians (BMI 25; OR, 1.24; 95% CI, 1.14–1.36), but not in Asians (OR, 1.17; 95% CI,
0.88–1.56).31 Using the Asia-Pacific classification system of obesity (BMI 25 kg/m2),
a meta-analysis of seven Asian cohort studies found that obesity was associated with
only 3% increased risk of gastric cancer (RR, 1.03; 95% CI, 1.01–1.06).32

Dietary Factors
There is strong evidence that diet influences risk of cancer; however, reported asso-
ciations of dietary factors with gastric cancer are conflicting. These variations might
reflect true differences in exposure–disease outcome associations but might also
be a result of inherent challenges in the design and conduct of nutritional epidemiology
studies. For example, when stratified by study design, a meta-analysis found that red
meat was associated with increased risk for gastric cancer in 24 case-control studies
(RR, 1.67; 95% CI, 1.36–2.05) but there was no association in four cohort studies (RR,
1.14; 95% CI, 0.97–1.34).33 Similarly, increased white meat consumption was associ-
ated with lower risk of gastric cancer when assessed in population-based case-con-
trol studies (RR, 0.75; 95% CI, 0.61–0.93; nine studies) but not in cohort studies (RR,
0.85; 95% CI, 0.63–1.16; five studies).34 There is, however, stronger evidence
for processed meat. In a meta-analysis, high consumption of processed meat was
associated with increased risk for gastric cancer whether assessed in cohort (RR,
1.21; 95% CI, 1.04–1.41; seven studies) or case-control (RR, 2.17; 95% CI, 1.51–
3.11; 12 studies) studies.34 When stratified by anatomic subtype, high processed
meat consumption conferred increased risk for noncardia gastric cancer but not car-
dia gastric cancer. Given the association between a diet high in processed meats and
increased risk of noncardia gastric cancer, attention has been placed on nitrates and
nitrites, and, in particular, N-nitrosodimethylamine (NDMA), a type of nitrosamine pro-
duced by chemical reactions of nitrates and nitrites. NDMA occurs in dietary foods as
a food additive often used in processed meats and is a potential carcinogen.35 A meta-
analysis of seven cohort and four case-control studies found that those with the high-
est NDMA consumption had 34% increased risk of gastric cancer compared with
lowest intake (RR, 1.34; 95% CI, 1.02–1.76).36 A nonlinear trend toward gastric cancer
risk was seen with increasing NDMA intake greater than 0.12 mg/day (P for nonlinearity
<0.001).
High salt intake has been hypothesized to promote gastric mucosal damage, hyper-
gastrinemia, and cell proliferation, and several prospective studies have been per-
formed to evaluate the relationship between salt intake and risk of gastric cancer.37
A meta-analysis of seven cohort studies found that high salt intake was associated
with 68% higher risk of gastric cancer compared with low intake (RR, 1.68; 95% CI,
1.17–2.41).38 Stratified analysis was not performed for anatomic subtype of gastric
432 Thrift & Nguyen

cancer in the meta-analysis; however, a large case-control study from Portugal found
that high salt intake (>3960.1 mg/day) was associated with increased risk of noncardia
gastric cancer (OR, 2.26; 95% CI, 1.27–4.04) compared with low intake (<3067.5 mg/
day), whereas no association was found for cardia gastric cancer.39 Although these
data suggest that salt intake is a risk factor for gastric cancer, only one study in the
meta-analysis adjusted for H pylori infection, and the positive association may be
caused by confounding because those ethnicities with high prevalence of H pylori
infection may also have diets high in salt.38,40
Decreasing trends in the incidence of gastric cancer has been hypothesized to be
partly caused by the increased availability of fresh fruit and vegetables. A meta-
analysis of six cohort studies found an inverse relationship with high white vegetable
consumption versus low (RR, 0.67; 95% CI, 0.47–0.95), but no association was seen
with total vegetables and gastric cancer risk (22 studies; RR, 0.98; 95% CI, 0.91–1.05)
and stratified by cardia and noncardia cancer.41 Total fruit consumption was found to
be inversely associated with risk of gastric cancer in pooled analysis of 30 cohort
studies (RR, 0.93; 95% CI, 0.89–0.98); however, this was not seen in pooled analyses
stratified by cardia (RR, 1.08; 95% CI, 0.93–1.26; seven studies) and noncardia (RR,
0.98; 95% CI, 0.82–1.16; seven studies).41

Alcohol Consumption
Alcohol may affect gastric cancer cell proliferation42 and has been examined as a risk
factor for gastric cancer with inconsistent results. A meta-analysis of 23 cohort studies
published through 2016 found some evidence for a modest increased risk of gastric
cancer associated with ever alcohol consumption (RR, 1.17; 95% CI, 1.00–1.34;
I2 5 79.6%).43 Among alcohol drinkers, risk increased by 7% with every 10 g/day
increment in alcohol consumption (RR, 1.07; 95% CI, 1.02–1.12).43 Likewise, a
meta-analysis of 56 case-control and 17 cohort studies also reported increased risk
of gastric cancer with high alcohol consumption (vs low; RR, 1.25; 95% CI, 1.15–
1.37) with a curvilinear dose-response.44 Notably, subgroup analysis for type of
alcohol demonstrated increased risk of gastric cancer with high consumption of
beer (RR, 1.13; 95% CI, 0.98–1.39) and liquor (RR, 1.22; 95% CI, 1.06–1.40), but
not wine. When stratified by anatomic subtype, there was a significant
association between high alcohol consumption and risk of noncardia gastric cancer
(18 studies; RR, 1.19; 95% CI, 1.01–1.40) but not cardia gastric cancer (15 studies;
RR, 1.16; 95% CI, 0.98–1.39).44 In pooled analyses of data from StoP, heavy alcohol
drinking (>6 drinks/day) conferred increased risk for cardia (OR, 1.61; 95% CI, 1.11–
2.34) and noncardia (OR, 1.28; 95% CI, 1.13–1.45) gastric cancer.45

Medications
Nonsteroidal anti-inflammatory drugs (NSAIDs), including nonselective NSAIDs
(aspirin), have been proposed as potential chemopreventive therapy for gastric cancer
given increased cyclooxygenase-2 expression found in gastric cancer tissue.46 A
meta-analysis of 24 studies demonstrated that any NSAID use was associated with
22% lower risk of gastric cancer compared with never use (RR, 0.78; 95% CI, 0.72–
0.85).47 For every 2 years of incremental NSAID use, gastric cancer risk decreased
by 11% (RR, 0.89; 95% CI, 0.83–0.96). Aspirin alone was also inversely related to
gastric cancer risk (RR, 0.70; 95% CI, 0.62–0.89). In subgroup analysis for anatomic
subtype, any NSAID use was associated with lower risk of noncardia gastric cancer
(RR, 0.70; 95% CI, 0.59–0.84), with evidence for a dose–response relationship (per
2-year increments; RR, 0.83; 95% CI, 0.72–0.96; P for linear trend <0.01), but not
associated with cardia gastric cancer.47 However, a meta-analysis of nine randomized
 Gastric Cancer Epidemiology 433

controlled trials found no statistically significant association between NSAID use and
gastric cancer risk (RR, 0.84; 95% CI, 0.65–1.10).48
Statins (HMG CoA reductase inhibitors), one of the most widely used medications
for hyperlipidemia, have also been proposed as chemopreventive therapy, because
studies have shown that statins have antiproliferative, proapoptotic, antiangiogenic,
and immunomodulatory effects in human gastric cancer–derived cell lines.49 A
meta-analysis of six case-control studies demonstrated an inverse relationship be-
tween statin use and risk of gastric cancer (OR, 0.83; 95% CI, 0.76–0.90;
I2 5 0%).50 Pooled analysis of three case-control studies found a dose-duration
response with long statin duration use (2 years of daily use) having more chemopre-
ventive effect (OR, 0.35; 95% CI, 0.16–0.76) than short statin duration use (<2 years of
daily use; OR, 0.73; 95% CI, 0.51–1.05).50 Another meta-analysis of 26 randomized
controlled trials found that statin use was associated with 27% lower risk of gastric
cancer (RR, 0.73; 95% CI, 0.58–0.92), which was attenuated but remained significant
after excluding subjects with diabetes (RR, 0.85; 95% CI, 0.80–0.91).51

Genetics
Although most gastric cancers are sporadic, risk of gastric cancer is up to 10-fold higher
in persons with a family history of gastric cancer.52 Gastric cancer may also develop as
part of a familial cancer syndrome, such as hereditary diffuse gastric cancer syndrome,
Lynch syndrome (in particular patients with an MLH1 or MSH2 mutation),53 familial
adenomatous polyposis, Peutz-Jeghers syndrome, and Li-Fraumeni syndrome.54

Other
Up to 10% of gastric cancers are attributed to less common causes, including infec-
tion with Epstein-Barr virus (EBV), autoimmune gastritis, and Ménétrier disease. A
recent international pooled analysis of 15 studies reported that approximately 8% of
gastric cancers harbor EBV,55 but there is insufficient epidemiologic evidence of a
clear etiologic role for EBV in gastric carcinogenesis.19

PREVENTION

Gastric cancer maintains a high case fatality rate of 75% throughout most of the
world56 and is a main contributor to global disability-adjusted life-year burden.57
Mass screening for gastric cancer is generally not included in national strategies for
cancer prevention because of high cost; decreasing incidence; and a lack of data
on whom, when, and how to screen. To date, the clinical practice of gastric cancer
prevention has focused on screening and surveillance and H pylori screening and
eradication. However, incorporating multiple risk factors into a clinical prediction
rule could lead to more efficient selection for screening of patients at risk for gastric
cancer. Several models have been developed58; however, none of these models is
perfect and they require further examination in larger, external populations before clin-
ical implementation is recommended.59

Primary Prevention with Helicobacter pylori Screening and Eradication

A systematic review and meta-analysis of six international randomized controlled trials
found that adults who have tested positive for H pylori and received
eradication therapy had 34% lower risk of developing incident gastric cancer
compared with H pylori–positive control subjects who received placebo or no therapy
(RR, 0.66; 95% CI, 0.46–0.95)60; corresponding to a number needed to treat to prevent
one gastric cancer of 124 (95% CI, 78–843).60 A phase 3 randomized controlled trial in
434 Thrift & Nguyen

school-aged H pylori–naive children reported successful prevention of H pylori infec-

tion with a prophylactic oral H pylori vaccine (vaccine efficacy, 71.8%).61 A large
community-based intervention trial in China demonstrated that H pylori eradication
is feasible and acceptable; however, eradication was not uniformly achieved in the
population.62
These studies show that under conditions of low bacterial burden and acute infec-
tion, persistent H pylori infection can be prevented, and eradication of H pylori may
lead to reduced incidence of gastric cancer. Additionally, under various assumptions
about effectiveness and costs, population-based screening and eradication of H py-
lori has been shown to be cost-effective.63,64 In particular, for geographic regions
with high gastric cancer burden, population-based H pylori serology screening is
cost-effective when performed in persons aged greater than 50 years. There is
some evidence that population-based H pylori serology screening is cost-effective
for populations with gastric cancer rates as low as 4.2 per 100,000.64 Further
studies are needed to establish whether screening in high-risk subpopulations
residing in countries with low gastric cancer incidence, such as the United States,
is cost-effective.65

Secondary Prevention with Screening and Surveillance

Upper gastrointestinal endoscopy studies have shown the highest detection rates
among the screening modalities and are considered the gold standard for the diag-
nosis of gastric cancer.66 Although the available evidence shows that endoscopic
population screening is cost-effective in areas with high gastric cancer burden,64
further studies are needed to evaluate the impact of this technique before recom-
mending its broad use as a primary screening test.67 Upper gastrointestinal series
has continuously been analyzed as a rivaling modality for cancer detection but has
not shown clear benefits over endoscopy.68
Several countries have implemented national screening programs. For example, in
South Korea, the Korean Gastric Cancer Association and National Cancer Center
established national guidelines for gastric cancer screening in 2001. These guidelines
recommend biennial gastric cancer screening via upper endoscopy or upper gastro-
intestinal series for men and women aged greater than or equal to 40 years, which
started in 2002.69 In 2013, the Japanese government approved insurance coverage
for a gastric cancer prevention program that includes H pylori screening and treatment
(primary prevention) and post–H pylori treatment surveillance (secondary prevention
for people with atrophic gastritis).70 In the United States, there are no population-
based mass screening programs aimed at reducing the incidence of gastric cancer.

FUTURE DIRECTIONS

Biomarkers for screening and risk triaging and clinical prediction rules that combine
these biomarkers with established clinical and lifestyle factors for risk stratification
need to be derived, optimized, and then validated in external populations. Future
biomarker studies should aim to state the a priori plan for building statistical models;
consider interactions, transformations, and splines; refrain from categorizing predic-
tors; use and report model coefficients; aim for external validation; use informed
and a priori stated criteria for desired sensitivity and specificity; and assess model per-
formance by incorporating population disease risk. Finally, at the public health level
and clinically, risk communication should be a central feature of research and
implementation.
 Gastric Cancer Epidemiology 435

SUMMARY

Further improvements in screening, treatment, and early diagnosis are needed for
gastric cancer, which remains the third most common cause of cancer-related mortal-
ity worldwide. Although mass screening strategies could be beneficial, current modal-
ities are not yet readily implementable in organized screening settings. Conversely,
because the population risk (based on histology) can change rapidly, and H pylori
eradication is effective, population-based programs of screening and treatment of H
pylori may hold greatest promise for reducing the burden of gastric cancer.61

CLINICS CARE POINTS

 Although rates of noncardia gastric cancer in the United States continue to decrease among
adults aged 50 years, the incidence of noncardia gastric cancer among persons aged less
than 50 years is increasing, particularly among Hispanics, non-Hispanic Blacks, and Asian and
Pacific Islanders.
 Chronic infection with H pylori is the main cause of gastric cancer, accounting for
approximately 89% of distal gastric cancer cases worldwide, and data demonstrate that
eradicating H pylori reduces the incidence of gastric cancer.
 Although studies show that endoscopic population screening is cost-effective in areas with
high gastric cancer burden, further studies are needed before recommending the broad
use of upper endoscopy as a primary screening test in the United States and other low-
incidence countries.

DISCLOSURE

The authors have nothing to disclose.

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P u blic Heal t h I n t er venti o ns
f o r G a s t r i c C a n c e r C o n t ro l
Manami Inoue, MD, PhD

KEYWORDS
 Gastric cancer  Risk factor  Prevention  Intervention

KEY POINTS
 Gastric cancer incidence has decreased substantially over the past century, by decreases
in Helicobacter pylori infection, tobacco smoking and salt-preserved food intake.
 Helicobacter pylori eradication for infected patients has potential as a prevention strategy
for those at high risk but warrants a longer follow-up period.
 The increase in obesity prevalence may cause an increase in cardia gastric cancer, espe-
cially in Western populations, and should be carefully monitored.

INTRODUCTION AND BACKGROUND

Despite the generally decreasing trend in incidence, gastric cancer still contributes to the
global burden of cancer, remaining the fifth-most common cancer worldwide with more
than 1 million incident cases in 2018.1 Gastric cancer incidence is characterized by large
geographic variation, with high rates in East Asia, Eastern Europe, and some South Amer-
ican countries, which in turn provides insights into how to approach risk factors and primary
prevention of gastric cancer. Gastric cancer can be divided by anatomic origin into 2 sub-
types, cardia and noncardia, which share some risk factors, but have others that are specific
to each. Noncardia gastric cancer is more common than cardia gastric cancer in East Asian
populations, where gastric cancer rates are generally high, whereas cardia gastric cancer is
more common in Western populations. These differences again provide important clues to
the differences in etiology of these 2 cancer subtypes.
The most important risk factor for gastric cancer is Helicobacter pylori (H pylori)
infection, particularly for noncardia gastric cancer. The prevalence of H pylori varies
widely by geographic area, socioeconomic status, and birth cohort.2 Generally, coun-
tries and regions with high gastric cancer rates tend to have a high seroprevalence of
H pylori infection. The recent global reduction in gastric cancer is attributed in large
part to a decrease in H pylori infection. This decline in H pylori has coincided with a
decrease in the incidence of noncardia gastric cancer and an increase in the incidence
of cardia gastric cancer.3 Stated differently, H pylori is a significant risk factor for

Conflict of Interest: None declared.

Division of Prevention, Center for Public Health Sciences, National Cancer Center, 5-1-1 Tsukiji,
Chuo-ku, Tokyo 104-0045, Japan
E-mail address: mnminoue@ncc.go.jp

Gastrointest Endoscopy Clin N Am 31 (2021) 441–449

https://doi.org/10.1016/j.giec.2021.03.002 giendo.theclinics.com
1052-5157/21/ª 2021 Elsevier Inc. All rights reserved.
442 Inoue

noncardia gastric cancer, but is inversely associated with the risk of cardia gastric
cancer.4
However, a decrease in gastric cancer was evident in many countries even before
this bacterium was discovered. This finding suggests that gastric cancers result from a
variety of environmental causes, both related and unrelated to H pylori infection, and
that both directed and nonspecific interventions impacting these causes might have
led to this decline. Here, the risk factors of gastric cancer and its population-level pre-
vention are discussed.

RISK FACTORS OF GASTRIC CANCER

With the increasing importance of evidence-based cancer prevention approaches,

various international bodies have continued a series of risk factor assessments over
recent decades that use both systematic review and meta-analysis. From the current
evidence base, H pylori infection and tobacco smoking are known causes of gastric
cancer, with sufficient evidence for categorization as group 1 carcinogens by the In-
ternational Agency for Research on Cancer (IARC).5 Apart from these 2 factors, the
Continuous Update Project of the World Cancer Research Fund (WCRF) summarizes
the most recently updated evaluation of risk factors for gastric cancer.3 In its project
report focusing on gastric cancer, the panel judged that high consumption of alcoholic
drinks (>45 g ethanol/d) and foods preserved by salting is a probable cause of gastric
cancer and that a greater amount of body fat or a higher body mass index (BMI) is a
probable cause of cardia gastric cancer. Nonstarchy vegetables, allium vegetables,
and fruit, judged in its previous 2007 report as probably decreasing this risk,6 have
been downgraded owing to limited evidence. The updated report states that there
is only limited evidence to suggest that consumption of grilled (broiled) or barbecued
(charbroiled) meat and fish increases the risk of gastric cancer or consumption of pro-
cessed meat increases the risk of noncardia gastric cancer, or that low consumption
of fruit increases the risk of gastric cancer or low consumption of citrus fruit increases
the risk of cardia gastric cancer. Table 1 summarizes the risk factors for gastric
cancer.

H PYLORI INFECTION

H pylori is, above all others, the most important cause of gastric cancer, especially
noncardia gastric cancer. The acquisition of H pylori infection generally occurs during
childhood, usually before 5 years of age. Infection status is, therefore, strongly sug-
gested to depend on environmental hygiene during childhood and eating behavior,
such as mouth-to-mouth feeding. Such lifestyle factors during infancy greatly reflect
the infection rate in adulthood.2 It is notable that, in Japan, where gastric cancer
has been the most common cancer for the last century, the prevalence of H pylori
infection has decreased with a birth cohort effect,2,7 peaking at approximately 70%
to 80% for those born around 1930 to 1940 and decreasing with age to reach approx-
imately 5% for those born around 2000, with no substantial change of infection rate
during the lifetime for each birth cohort (Fig. 1). This finding implies that gastric cancer
prevention strategies confer generational effects. Countries with a similar experience
should consider risk-stratified approaches to gastric cancer prevention over the next
few decades. A decreasing trend has also been observed in Korea, suggesting the
importance of H pylori infection management at a younger age.8 Although screen-
and-treat strategies are recommended in communities at high risk of gastric cancer,
their use in children and adolescents is controversial, and further evidence is awaited.9
Going forward, improvements in hygiene and socioeconomic conditions will foster a
 Health Interventions for Gastric Cancer Control 443

Table 1
Summary of risk factors for gastric cancer

Evidence Level Risk Factor (Positive Association)

Strong evidence Convincing/ H pylori infection (noncardia)
established cause Tobacco smoking
Probable Body fatness (cardia)
Alcoholic beverages (intake
above 45 g of ethanol per day)
Food preserved by salting
Limited evidence Limited—suggestive Processed meat (noncardia)
Grilled (broiled) or barbecued
(charbroiled) meat and fish
Low fruit intake
Low citrus fruit intake (cardia)

Data from Refs.3,17,18

substantial decrease in the overall prevalence of H pylori infection in all age groups
and even in countries with a high prevalence of infection, eventually reaching the level
of a rare event and leading to an overall decrease in gastric cancers.
H pylori eradication for infected individuals has been considered a possible preven-
tive measure for gastric cancer, despite incurring side effects such as gastroesopha-
geal reflux disease and antibiotic resistance.10 The effectiveness of eradication is
considered dependent on whether it can reverse precancerous lesions, such as atro-
phic gastritis or intestinal metaplasia, before the point of no return, namely the irrevers-
ible point of progression to gastric cancer.11 One meta-analysis indicated that
eradication of H pylori is not effective in patients with intestinal metaplasia and
dysplasia.12 Accordingly, eradication of H pylori at an early stage is considered effec-
tive in preventing gastric cancer onset by inhibiting the progression of these precan-
cerous lesions. A recent Cochrane systematic review assessed the effectiveness of H

80%

70%

60%

50%

40%

30%

20%

10%

0%
1905

1910

1915

1920

1925

1930

1935

1940

1945

1950

1955

1960

1965

1970

1975

1980

1985

1990

1995

2000

Year of birth

Fig. 1. Declining trends in the prevalence of H pylori infection by birth year in a Japanese
population (meta-regression analysis of 170,752 Japanese participants). (Adapted from
Wang C, Nishiyama T, Kikuchi S et al. Changing trends in the prevalence of H. pylori infec-
tion Japan (1908-2003): a systematic review and meta-regression analysis of 170,752 individ-
uals. Sci Rep. 2017;7(1):15491; with permission.)
444 Inoue

pylori eradication among healthy, asymptomatic individuals in the general population

in decreasing the incidence of gastric cancer. The results provided moderately certain
evidence that eradication decreases the incidence of gastric cancer and mortality in
healthy, asymptomatic infected Asian individuals; however, the authors noted that
these results cannot necessarily be extrapolated to other populations.13 An earlier sys-
tematic review mentioned that large-scale eradication has been performed mostly for
benign conditions in Japan, where the effects of eradication in preventing gastric can-
cer are conceivably greater than would be seen in multinational, mixed populations
with differing screening quality and disease progression.14 To date, most studies
investigating the incidence of gastric cancer after H pylori eradication had relatively
short periods of about 10 years, and whether the effect extends beyond 10 years re-
mains unclear.15 A study in Japan with follow-up beyond 10 years reported that pa-
tients with mild to moderate gastric atrophy at baseline had a greater risk of
developing diffuse-type gastric cancer with longer follow-up and that endoscopic sur-
veillance should be continued accordingly beyond 10 years after cure of H pylori, irre-
spective of the severity of gastric atrophy.16 Additional studies with long follow-up
periods are required.

TOBACCO SMOKING

From the current evidence base, tobacco smoking is a known cause of gastric can-
cer,17 with sufficient evidence for categorization as a group 1 carcinogen by the
IARC.18 A systematic review and meta-analysis of prospective studies showed a
significantly increased risk for both men and women and both cardia and noncardia
gastric cancer in Asians, Europeans, and Americans. Compared with those who never
smoked, current smokers had a 1.2- to 1.9-fold increased risk of gastric cancer, in a
dose-responsive manner.19 There was insufficient evidence for different risks between
cardia and noncardia subsites, or by histologic type. It was also estimated that 16.5%
of gastric cancers among male patients and 1.9% among female patients were attrib-
utable to tobacco smoking globally in 2020, having decreased from respective 2012
estimates of 19.5% and 3.0%, respectively.20
Several mechanisms are suggested to explain the specific effect of tobacco smoking
on gastric cancer. Nicotine, nitrosamines, and other nitroso compounds in cigarette
smoke affect gastric physiology.21 Also, tobacco smoking is related to an increased
risk of transition to dysplasia and intestinal metaplasia and to a delay in both stomach
emptying and alcohol absorption.22 Tobacco smoking increases the risk of gastro-
esophageal reflux disease, which is associated with cardia gastric cancer.23
Because active and secondhand smoking are known to increase the risk of major
diseases, including many sites of cancer, prevention of active and secondhand smok-
ing has long been targeted as both global and national health policies, and many coun-
tries have already regulated tobacco smoke.24 Obviously, tobacco smoking is a major
risk factor for cancer. Measures to prevent smoking will prevent not only the target
gastric cancer but also other smoking-related cancers.

ALCOHOL CONSUMPTION

The WCRF has summarized the most updated evaluation of risk factors for gastric
cancer in its Continuous Update Project.3 In the project report, the panel judged
that greater consumption of alcoholic beverages is a probable cause of gastric cancer,
based on evidence for intake of greater than 45 g ethanol/d (approximately 3 drinks
per day).
 Health Interventions for Gastric Cancer Control 445

A nonlinear dose–response meta-analysis showed that daily consumption of 45 g of

ethanol and above particularly and significantly increased the risk of gastric cancer.
No difference was observed between cardia and noncardia gastric cancers.
Alcoholic beverages and the acetaldehyde associated with their consumption are
classified in the IARC monograph evaluation as group 1 carcinogens to humans.5
Ethanol is fat soluble and acts as a solvent, enhancing the penetration of carcinogens
into cells, causing damage to the gastric mucosa.25 Its metabolite acetaldehyde can
have a local toxic effect, which may be related to the occurrence of gastric cancer. The
pathogenic effect of ethanol in causing gastric mucosal damage is associated with
disruption of the balance of gastric mucosal defense and external invasion. Genetic
polymorphisms, such as alcohol dehydrogenase-2 polymorphism, are more common
in Japanese and East Asian populations26 and influence susceptibility to alcohol.3
To prevent gastric cancer, a decrease in alcohol consumption to less than 45 g/
d may be effective,3 albeit that no consumption at all is recommended considering to-
tal cancer prevention.27

SALT-PRESERVED FOODS

Salt intake in general terms is known to be associated not only with gastric cancer, but
also with hypertension and stroke.28 These diseases were historically the 2 most com-
mon conditions in Japan. Interestingly, although the amount of salt intake tends to be
associated with an increased risk of stroke, the intake of highly salt-concentrated pre-
served foods instead increases the risk of gastric cancer.29 The WCRF concluded that
greater consumption of salt-preserved foods is a probable cause of gastric cancer.3
Highly salt-concentrated preserved foods are irritating to the delicate lining of the
stomach, which makes H pylori infection more likely or more severe and leads to
gastric cancer.30
Salt reduction indicates both a decrease in the amount of salt intake and in the
intake of highly salt-concentrated preserved foods. Salt-preserved foods in general
were more commonly consumed before the availability of refrigeration.31,32 The
dissemination of refrigeration about a century ago had a major impact on the decrease
in gastric cancer mortality in some developed countries. In addition, the expansion of
industrial refrigeration in both storage and transportation resulted in an increased
intake of fresh food.31,32 It also decreased the need for salting and pickling, which
are positively associated with gastric cancer. Home refrigeration increased the shift
from salt preservation to frozen storage.32 In Japan, the number of households with
electric refrigerators increased rapidly after 1960, a trend that was strongly inversely
correlated with gastric cancer decline.31
Bolstering this natural unplanned triumph through the widespread adoption of
refrigeration,31 many countries such as in Finland and the UK have adopted
population-based salt reduction strategies.33 These interventions have proved effec-
tive in terms of both health and financial cost.30 These countries based their strategies
on a gradual and sustained decrease in the amount of salt added to food by food man-
ufacturers, plus a sustained mass media campaign aimed at encouraging dietary
change within households and communities. In contrast, countries in which consump-
tion derives mostly from salt added during cooking or from sauces require public
health campaigns to encourage consumers to use less salt.
Japan has achieved a decrease in salt consumption at the community level. In the
late 1950s, deaths from stroke in Japan were the highest in the world. It became
apparent that salt consumption was particularly high in the northern regions and
that the number of strokes in different parts of the country was directly related to
446 Inoue

the amount of salt consumption. The Japanese government initiated a campaign to

reduce salt intake, which proved effective over the following decade. A consequent
decrease in blood pressure was seen in both adults and children, along with a sub-
stantial decreased in stroke mortality30 and eventually in gastric cancer incidence
and mortality. Beginning in the 1970s, Finland aimed to decrease salt intake in the
whole population in collaboration with the food industry. In the following 30 years,
salt intake has been decreased by one-third, and cardiovascular disease and gastric
cancer mortality has substantially declined.30 More recently, in the UK, the Consensus
Action on Salt and Health, a nongovernmental organization, and the Food Standards
Agency, a quasigovernmental organization, developed a program for voluntary salt
reduction in 2003 in collaboration with the food industry that has resulted in a reduc-
tion of salt intake in the UK population.34 Cost estimates reveal that a decrease in salt
intake is equally or more cost effective to tobacco control in terms of decreasing car-
diovascular disease, the leading cause of death and disability worldwide.33 Overall, it
is evident that a modest reduction in population-level salt intake worldwide would
result in a major improvement in public health, owing not only to the prevention of can-
cer, but also to that of other major diseases.

BODY FATNESS

Greater body fatness, as marked by BMI, was not recognized as a risk factor for
gastric cancer until recent risk assessments. A meta-analysis by the WCRF of the rela-
tive risk of gastric cancer by anatomic subsite showed a 23% increase in risk of cardia
gastric cancer per 5 kg/m2 increase in BMI (relative risk, 1.23; 95% confidence inter-
val, 1.07–1.40), although no significant association was observed with noncardia
gastric cancer (relative risk, 0.93; 95% confidence interval, 0.85–1.02 per 5 kg/m2 in-
crease in BMI). This effect of greater body fatness was especially apparent in men and
non-Asians.
Obesity may introduce inflammation of the stomach lining via tumor necrosis factor-
a, IL-6, and monocyte chemoattractant protein-1. According to the increasing cardia
gastric cancer rate in Western populations, accumulating evidence suggests that
greater body fatness or higher BMI are probable causes of cardia gastric cancer.35
This status of greater body fatness or obesity as probable risk factors for cardia
gastric cancer but not noncardia gastric cancer is notable. In some reports, the overall
decrease in gastric cancer in these decades is mainly attributable to a decline in non-
cardia gastric cancer.36,37 There are exceptions, however, in which cardia gastric can-
cer has been absolutely or relatively increasing in countries with previously low rates,
such as the United States.38,39 The burden of gastric cancer attributed to higher BMI
was not high in regions with a high overall gastric cancer rate. The current global
pattern shows that cardia gastric cancer rates are similar to or higher than noncardia
rates in populations with a low noncardia gastric cancer incidence.40
Obesity is increasing globally41,42 and will positively affect cardia gastric cancer
incidence. This is particularly evident in Western populations, in which gastric cancer
rates are conventionally low. As with tobacco smoking and alcoholic beverage con-
sumption, prevention strategies targeting obesity impact not only gastric cancer,
but also many other major diseases. Decreasing the obesity burden requires a com-
bined approach of individual interventions and changes in the environment and soci-
ety.43 At the same time, the trend in cardia gastric cancer should also be monitored,
namely not only regarding the relative proportion but also the absolute rate in both high
and low gastric cancer incidence countries.
 Health Interventions for Gastric Cancer Control 447

SUMMARY AND PERSPECTIVES

Gastric cancer has substantially declined over the past century, thanks to decreases
in risk factors such as H pylori infection, tobacco smoking, and salt-preserved food
intake resulting from both general improvements in hygiene and food storage after
the dissemination of refrigeration and population-based intervention strategies,
including prevention of tobacco smoking, decreases in salt intake, and obesity con-
trol. H pylori eradication for infected subjects has potential as a prevention strategy
for those at high risk, but warrants a longer follow-up period. The ongoing increase
in obesity may cause increases in cardia gastric cancer, especially in Western popu-
lations, and this possibility should be carefully monitored in both Western and Asian
populations.

ACKNOWLEDGMENT

The author have received grant from National Cancer Center Research and Develop-
ment Fund (grant number 2021-A-16) and from Practical Research for Innovative Can-
cer Control, Japan Cancer Research Project, Japan Agency for Medical Research and
Development (grant number 20CK0106561h0001).

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H e l i c o b a c t e r p y l o r i and
Gastric Cancer
Judith Kim, MD*, Timothy Cragin Wang, MD

KEYWORDS
 Helicobacter pylori  Gastric cancer  Gastric adenocarcinoma  MALT lymphoma

KEY POINTS
 Helicobacter pylori prevalence varies based on geography, age, race/ethnicity, and socio-
economic status.
 Multiple case-control and prospective studies in humans and animal models have inves-
tigated the relationship between H pylori and gastric cancer.
 The mechanism for H pylori–associated gastric carcinogenesis is complex, and likely in-
volves the interaction of bacterial factors, host factors, and environmental factors.
 Eradication of H pylori decreases the risk of gastric cancer, although population-based
screening and treating is not recommended universally.

INTRODUCTION

Helicobacter pylori is a spiral shaped, gram-negative bacterium and the most com-
mon chronic bacterial infection in humans. This bacterium is present in approxi-
mately one-half of the world’s population, although there is significant variation
based on region, age, race/ethnicity, and socioeconomic status.1,2 H pylori is asso-
ciated with multiple gastrointestinal diseases, including gastritis, peptic ulcer dis-
ease, and gastric cancer. The vast majority of patients are asymptomatic,
although about 10% develop peptic ulcer disease, 1% to 3% develop gastric adeno-
carcinoma, and 0.1% develop mucosa-associated lymphoid tissue (MALT) lym-
phoma. In 1994, H pylori was recognized as a class I carcinogen in 1994 by the
World Health Organization and International Agency for Research on Cancer based
on the growing evidence establishing the role of H pylori in gastric carcinogenesis.3
Since then, numerous preclinical studies have shown the direct carcinogenicity of H
pylori in susceptible animal species. The bacterium is considered a necessary but
insufficient cause of gastric cancer; only a minority of H pylori–infected individuals
develop cancer. Disease pathogenesis likely represents a complex interaction

Department of Medicine, Division of Digestive and Liver Diseases, Columbia University Irving
Medical Center, New York, NY, USA
* Corresponding author.
E-mail address: jk3848@cumc.columbia.edu

Gastrointest Endoscopy Clin N Am 31 (2021) 451–465

https://doi.org/10.1016/j.giec.2021.03.003 giendo.theclinics.com
1052-5157/21/ª 2021 Elsevier Inc. All rights reserved.
452 Kim & Wang

between bacterial, host, and environmental factors that has been the subject of
intense investigation since the discovery of H pylori.

EPIDEMIOLOGY

H pylori is ubiquitous, but its distribution is heterogenous throughout the world. The
prevalence of infection is greater in developing countries than developed countries.
The wide variation in international and national prevalence is likely related to risk fac-
tors such as socioeconomic status, level of hygiene, and household crowding.4–6 The
transmission of H pylori is most likely person to person via the fecal–oral or oral–oral
route.7 Children are often infected by strains identical to their parents, suggesting
transmission within families in early childhood.8
In developing countries, H pylori prevalence can reach more than 80% in older
adults.1,9 The incidence of H pylori infection has generally decreased over time with
improving sanitation and standards of living in many countries. In Japan, the preva-
lence of H pylori infection has drastically decreased with rising economic status. Older
generations born in the 1950’s have a prevalence greater than 80%, decreasing to
10% for those born in the 1990s and 2% for those born after 2000.10 In the United
States, the prevalence of H pylori is estimated to be 30% to 40%, which has been
decreasing steadily over time since World War II. However, in the last decade, there
has been a significant increase in gastric cancer in patients under the age of
40.11,12 Furthermore, there is significant variation among different ethnic groups.
Blacks and Hispanics have a higher prevalence of infection compared with non-
Hispanic Whites.1,6,13 Asians in the United States also have much higher rates of H py-
lori infection compared with Whites.14,15

H PYLORI AND GASTRIC ADENOCARCINOMA

The association between H pylori and the development of noncardia gastric cancer
has been well-established. The majority of those infected with H pylori remain asymp-
tomatic, but an estimated 1% to 3% develop gastric adenocarcinoma and 0.1%
develop MALT lymphoma. Approximately 90% of all gastric cancers can be attribut-
able to H pylori.1 It is considered the most common cause of infection-related cancers,
representing 5.5% of the cancer burden.16
About 90% of gastric tumors are adenocarcinomas. Gastric adenocarcinoma is
further classified into 2 main histologic types, intestinal or diffuse type. H pylori is asso-
ciated with both subtypes of gastric cancer, although it is more frequently associated
with and better characterized in the development of intestinal adenocarcinoma.17 In-
testinal type-tumors are characterized by corpus-dominant gastritis with gastric atro-
phy and intestinal metaplasia, whereas diffuse type are characterized by gastritis
throughout the stomach without atrophy. Intestinal tumors are more common than
diffuse cancers, comprising 82% of gastric adenocarcinomas in the United States.18
There has been a marked decline in intestinal-type gastric cancers in the past 50 years,
correlating to improved sanitation and food preservation, in addition to the decreasing
prevalence of H pylori.18,19 In contrast, the incidence of diffuse type cancers in West-
ern countries has been increasing, particularly in young (<40 year old) individuals,
largely in women with tumors in the gastric corpus.20,21
The stepwise development of intestinal-type adenocarcinoma, also known as the
Correa cascade, has been well-described (Fig. 1).22 Chronic inflammation leads to
the transition of normal mucosa to chronic gastritis, which can further develop into
atrophic gastritis, intestinal metaplasia, dysplasia, and finally cancer. H pylori infection
is the best studied trigger that can lead to chronic active gastritis in this pathway. This
 Helicobacter pylori and Gastric Cancer 453

Fig. 1. Correa cascade for gastric intestinal adenocarcinoma.

chronic inflammation leads to the destruction of parietal and chief cells of the stom-
ach, resulting in achlorhydria and atrophic gastritis. The loss of parietal and chief cells,
which normally secrete signals that modulate the growth and differentiation of the
gastric progenitors, leads to the proliferation and accumulation of undifferentiated
gastric progenitor cells as well as intestinal metaplasia. Intestinal metaplasia is a pre-
malignant lesion that harbors the undifferentiated progenitors that can give rise to
dysplasia and carcinoma.23–25 An in vivo study in 1998 using Mongolian gerbils helped
to directly demonstrate that H pylori induces gastric adenocarcinoma.26 In this study,
long-term inoculation with H pylori resulted in intestinal metaplasia and then adeno-
carcinoma in 37% of the infected animals, whereas no significant changes were found
in the uninfected cohort. Similar studies were carried out in mice (INS-GAS), demon-
strating directly the carcinogenicity of H pylori.27
Two landmark studies in 1991 established the relationship between H pylori and
gastric adenocarcinoma in humans. Parsonnet and colleagues28 performed a nested
case-control study from a cohort of 128,992 patients in California. In this study, 109
patients with histologically confirmed gastric adenocarcinoma were matched with
control patients. Serum samples were tested for IgG antibodies to H pylori. The au-
thors found that 84% of the patients with gastric cancer had previously been infected
with H pylori as compared with 61% of the matched control subjects. Prior infection
with H pylori was associated with 3.6 times the odds of gastric adenocarcinoma
than no infection (odds ratio [OR], 3.6; 95% confidence interval [CI], 1.8–7.3).28
Nomura and colleagues29 performed a nested case-control study from a cohort of
11,148 Japanese American men in Hawaii. One hundred nine patients with histologi-
cally confirmed gastric cancer cases were identified and matched with 109 controls.
Of the patients with gastric cancer, 94% had H pylori antibodies in the serum
compared with the matched control subjects. Prior H pylori infection was associated
with a 6.0 times odds for gastric cancer compared with no H pylori infection (OR, 6.0;
95% CI, 2.1–17.3).29
In 2001, one of the largest prospective long-term study evaluating the development
of gastric cancer in H pylori infected patients was published. This study followed 1526
Japanese patients with duodenal ulcers, gastric ulcers, gastric hyperplasia, or non-
ulcer dyspepsia, of which 1246 had H pylori infection. After a median duration of
follow-up of 7.8 years, 36 patients in the infected group and none in the noninfected
group developed gastric cancer (P<.001).30 Numerous subsequent studies worldwide
have affirmed this relationship, establishing H pylori as a primary factor in the patho-
genesis of gastric cancer.6,31–34

H PYLORI INFECTION AND MUCOSA-ASSOCIATED LYMPHOID TISSUE LYMPHOMA

Another important role of H pylori is in the pathogenesis of MALT lymphoma. The first
evidence for this association came from histopathological assessment of patients
infected with H pylori. Lymphoid tissue is absent from the normal gastric mucosa,
454 Kim & Wang

but is seen in patients with H pylori–associated gastritis.35,36 H pylori triggers T-cell–

mediated, B-cell expansion through the CD40 pathway. The chronic proliferation of
B cells and chronic inflammation induces additional oncogenic events that leads to
development of MALT lymphoma.37
In a 1991 cohort study, 92% of 110 patients with gastric MALT were found to have H
pylori infection. Subsequent trials showed that eradication of H pylori infection led to a
regression of gastric MALT lymphoma.38,39 One meta-analysis including 34 studies
with 1271 patients with MALT lymphoma found that gastric lymphoma remission
was achieved in 77.8% of 1250 patients who were successfully cured of H pylori infec-
tion.39 Although rare case reports have noted regression of extragastric MALT lym-
phoma lesions, gastric MALT lymphoma is the only malignancy for which antibiotics
are the first choice of therapy with curative intent.

MECHANISM OF H PYLORI

The molecular mechanism by which H pylori induces gastric cancer is not completely
understood, but is likely a combination of virulence factors, host genetic predisposi-
tion, and environmental factors.
H pylori was first discovered in patients with gastritis in 1982 by J. Robin Warren and
Barry Marshall, who were awarded the Nobel Prize in Physiology or Medicine for their
work.40 H pylori are unique bacteria that have adapted to survive in the harsh, acidic
environment of the stomach. H pylori has multiple characteristics that allow it to sur-
vive in the stomach.41 Its spiral shape and flagella optimize its motility, allowing pas-
sage through the mucosa to the gastric epithelium. Bacterial surface adhesins
recognize and bind to host receptors on gastric epithelial cells. H pylori produces
the enzyme urease, which hydrolyzes gastric urea to form ammonia. Ammonia neu-
tralizes gastric acid, allowing the bacterium to penetrate the gastric mucosa, and
damages epithelial cells. Urease also stimulates inflammatory cells leading to further
cellular injury.42 H pylori produces more catalase enzyme than most other bacteria,
which is an antioxidant that neutralizes reactive oxygen metabolites produced by in-
flammatory cells and may help the organism to survive in the inflamed mucosa. These
diverse characteristics allow H pylori to reach close proximity to the gastric epithelium
and subsequently deliver bacterial factors that modulate its activity to cause cellular
damage. H pylori isolates demonstrate significant genetic diversity and strain-
specific properties are thought to contribute to the ability to cause a variety of
diseases.43
Two virulence factors, cytotoxin-associated antigen A (CagA) and vacuolating cyto-
toxin (VacA), are the best defined and associated with an increased risk of gastric pa-
thology. CagA is a bacterial protein that is associated with cell injury and more severe
gastrointestinal disease.44,45 Virulent strains of H pylori encode cag pathogenicity is-
land, which expresses a type IV secretion system that allows for the injection of viru-
lence factors like CagA into the host target cells. CagA has multiple effects on gastric
epithelial cells, including increasing cell proliferation, decreasing cell apoptosis, and
altering cell polarity, which all promote tumor development.
Infection with cagA-positive H pylori strains compared with cagA-negative strains
are associated with an increased risk for development of gastric adenocarcinoma.
One meta-analysis of 16 studies with 2284 gastric cancer cases and 2770 matched
controls evaluated the relationship between cagA positivity and gastric cancer.46 H
pylori infection was associated with a 2.28-fold increased risk of gastric cancer (OR,
2.28; 95% CI, 1.71–3.05). In H pylori–positive populations, cagA seropositivity
increased the risk for noncardia gastric cancer (OR, 2.01; 95% CI, 1.21–3.32). These
 Helicobacter pylori and Gastric Cancer 455

results suggest that patients with cagA-positive strains of H pylori are at a greater
risk for developing gastric cancer than cagA-negative strains. In 2008, the first study
demonstrated a potential causal link between cagA and carcinogenesis in vivo
through the generation of transgenic mice expressing CagA throughout the body
or predominantly in the stomach. The functional overexpression of phosphorylated
CagA-induced gastric epithelial hyperplasia, as well as rare adenocarcinomas of
the stomach and small intestine indicating the potential directly oncogenicity of
CagA.47
VacA is another important virulence factor that promotes the formation of acidic
vacuoles in the cytoplasm of gastric epithelial cells. VacA acts as a urea transporter
that can increase the permeability of the gastric epithelium to urea and so optimizes
urease activity.48 VacA also induces apoptosis and disrupts the epithelial cell tight
junctions to cause cellular collapse. In addition, VacA acts as an immunosuppressant
that inhibits T-cell proliferation and alters the host immune response thereby enabling
the persistent colonization of the stomach by H pylori. All H pylori strains contain vacA
genes, but certain allelic forms of VacA, such as s1/m1, are associated with an
increased risk of developing peptic ulcer disease and gastric cancer.48,49
Early on, H pylori was thought to colonize primarily the gastric pits. More recently,
the potential relationship between H pylori and stem cells in disease development
has been investigated. Studies by Sigal and colleagues50 using quantitative confocal
microscopy and 3-D reconstruction of gastric glands have shown that H pylori colo-
nizes deep in the stomach glands may interact directly with progenitor cells in gastric
glands, thereby impacting carcinogenesis. H pylori can directly activate and induce
proliferation Lgr51 cells, thus expanding the stem cell compartment, in part through
upregulation of R-spondin-3 in stromal cells. However, H pylori tends to disappear
in late-stage gastric preneoplasia, and there has been no evidence to date that
cagA is present dysplastic gastric glands. Patients with gastric cancer and H pylori
infection overexpress leucine-rich repeat-containing G-coupled receptor 5 cells,
which comprise both stem and secretory cells in the gastric antrum, and seem to
have antimicrobial activity.51 H pylori–infected patients also have been found to
have increased DNA damage in leucine-rich repeat-containing G-coupled receptor
cells.52,53 H pylori–related inflammation can also lead to recruitment of bone
marrow–derived stem cells to the gastric mucosa.54,55 Finally, more recently, mouse
models of Helicobacter infection have revealed the Helicobacter sp. can activate
CCK2R1 antral stem cells and induce symmetric cell division that predisposes to
antral carcinogenesis.56

HOST FACTORS AND H PYLORI

H pylori elicits a strong inflammatory and immune response from its host. Certain host
gene polymorphisms in cytokines have been associated with an increased suscepti-
bility to noncardia gastric adenocarcinoma. IL-1ß, which is a proinflammatory cytokine
and inhibitor of gastric acid secretion, is upregulated by the presence of H pylori.
Proinflammatory genotypes of the IL-1 loci that upregulate IL-1ß concentrations
have been associated with an increased likelihood of gastric cancer.57 Enhanced
IL-1ß concentrations lead to an inhibition of acid secretion and increase the spread
of H pylori–induced inflammation from the antrum to the corpus of the stomach. Proin-
flammatory genotypes of tumor necrosis factor a and IL-10 were also associated with
an increased risk of noncardia gastric adenocarcinoma.58 The host immune response
is likely the major factor that influences the risk of developing gastric cancer, as IL-1ß
–driven inflammation alone can induce gastric cancer, even in the absence of
456 Kim & Wang

Helicobacter infection,59 indicating a complex interaction between genetic and bacte-

rial factors in disease carcinogenesis.

ENVIRONMENTAL FACTORS AND H PYLORI

Significant geographic variations in the incidence of gastric cancer suggest that envi-
ronmental factors impact H pylori and gastric carcinogenesis. High dietary salt intake
has been associated with an increased risk of gastric cancer in prospective cohort
studies.60,61 In 1 study, a higher median urine salt excretion level was correlated
with an increased mortality rate of stomach cancer.62 In vitro and in vivo studies
have also described mechanisms by which salt may influence gastric carcinogenesis.
The cultivation of H pylori in high-salt conditions leads to alterations in the proteome,
including increased expression of CagA.63,64 In 1 study, Mongolian gerbils infected
with wild-type cagA1 H pylori strains fed a high-salt diet all developed gastric adeno-
carcinoma compared with one-half of the animals fed a regular diet. Those fed the
high-salt diet had more severe gastric inflammation, increased parietal cell loss,
increased gastric expression of IL-1ß, and increased cagA transcription compared
with those on a regular diet.65
Ascorbic acid, an important dietary antioxidant, has also been associated with H py-
lori and gastric cancer. It is thought to decrease the risk of cancer by decreasing the
formation of carcinogenic nitrites in the stomach and limit damage from free radicals
and reactive oxygen species.22,66 Lower levels of ascorbic acid are seen in patients
with H pylori, whereas the eradication of H pylori increases these levels.67 Ascorbic
acid ingestion has been associated with a decreased risk of gastric cancer in case-
control studies.68–70 However, studies on the impact of vitamin C supplementation
on H pylori eradication and gastric cancer have shown conflicting results.66,71,72
Furthermore, in mouse models of Helicobacter infection, vitamin C supplementation
does not protect vitamin C–deficient mice from H pylori–induced gastritis and gastric
cancer.73 In contrast, supplementation with folic acid does prevent Helicobacter-
associated gastric cancer in mice, possibly through increasing global DNA methyl-
ation and thus decreasing inflammation.74

DIAGNOSIS OF H PYLORI

There are multiple tests to diagnose active H pylori infection, either invasive with upper
endoscopy or noninvasive (Table 1). There are 4 diagnostic tests that can be per-
formed with upper endoscopy. Gastric biopsies for histology taken at the antrum
and body of the stomach can diagnose H pylori infection as well as associated gastric
pathology. The sensitivity and specificity of histology for diagnosis are approximately
95% and 99%, respectively.75 Gastric biopsy urease testing can also be performed to
test for the production of ammonia. The sensitivity and specificity for biopsy urease
testing are about 90% and 95%, respecitvely.76 Gastric biopsies can also be obtained
for bacterial culture and antibiotic sensitivity testing. Bacterial culture has a high spec-
ificity, approaching 100%, but a lower sensitivity of 85% to 95% because H pylori is
difficult to culture.76 Biopsy for culture and sensitivity should be performed for patients
with persistent H pylori infection after 2 courses of antibiotic treatment. Quantitative
polymerase chain reaction testing on gastric biopsies can detect low amounts of bac-
teria. Polymerase chain reaction testing has a high specificity and sensitivity (>95%),
but its use is limited by higher cost.76
Noninvasive tests for active H pylori infection are urea breath testing and stool an-
tigen testing. The urea breath test detects for the hydrolysis of urea by H pylori to pro-
duce carbon dioxide and ammonia. The sensitivity and specificity for this test are both
 Helicobacter pylori and Gastric Cancer 457

Table 1
Diagnostic tests for H pylori infection

Test Strengths/Weaknesses Estimated Sensitivity and Specificity

Biopsy histology High accuracy, requires 95%, 99%75
invasive endoscopy
Biopsy urease High accuracy, requires 90%, 95%76
testing invasive endoscopy
Biopsy bacterial High specificity, but lower 100%, 85%–95%76
culture sensitivity as difficult to
culture, requires invasive
endoscopy
Biopsy polymerase Expensive, requires 95%, 95%76
chain reaction invasive endoscopy
Urea breath test Noninvasive 95%, 95%77
Stool antigen assay Noninvasive, less expensive 94%, 97%78
Serology antibody Indicates either active 85%, 79%79
testing or prior infection

approximately 95%.77 The stool antigen assay is another option that tests for the pres-
ence of bacterial antigen, which indicates active infection. The sensitivity and speci-
ficity are, respectively, estimated to be 94% and 97%.78 Serology testing for H
pylori IgG antibodies can also be performed, although a positive result can be inter-
preted as either active or prior infection. The sensitivity and specificity for serology
testing have been estimated as 85% and 79%, respectively.79

H PYLORI ERADICATION

Antibiotic eradication of H pylori infection can decrease the risk of gastric cancer. A
meta-analysis of 24 studies including 715 incidence gastric cancers among a total
of 48,064 patients assessed the effects of antibiotic eradication on gastric cancer
risk.80 Patients with H pylori eradication had a lower incidence of gastric cancer
than those who did not receive treatment (pooled incidence rate ratio, 0.53; 95%
CI, 0.44–0.64). The benefits of antibiotic eradication increased in populations with
higher baseline cancer incidence. The relative risk for gastric cancer with H pylori
treatment in low, intermediate, and high incidence regions were 0.80, 0.49, and
0.45, respectively.
A randomized controlled trial in 2020 from South Korea investigated whether treat-
ment to eradicate H pylori decreases the risk of gastric cancer in people with a family
history of gastric cancer.81 One thousand eight hundred thirty-eight patients with first-
degree relatives with gastric cancer were randomized to receive either eradication
therapy with antibiotics or placebo. During a median follow-up of 9.2 years, the treat-
ment of H pylori infection significantly decrease the risk of gastric cancer compared
with placebo in patients with a family history of gastric cancer.
It is important to recognize that the antibiotic regimens used in these studies are not
specific for H pylori, but in fact result in broad decreases and alterations in the gut
microbiome. In late stages of gastric disease, H pylori colonization decreases and
even disappears, and it has been hypothesized the bacterial overgrowth by non–H py-
lori species can contribute to gastric cancer progression. Indeed, the absence of
commensal flora in H pylori–infected INS-GAS mice prevents progression to high-
grade dysplasia/gastric cancer,82 whereas the additional colonization with a restricted
458 Kim & Wang

commensal microbiota (eg, Schaedler’s flora) is able to restore progression to high-

grade dysplasia.83 These observations on the importance of commensal bacteria
was supported by human studies by Li and colleagues,84 show showed that antibiotic
eradication treatment was able to reduce gastric cancer incidence, even in the
absence of H pylori elimination. Thus, antibiotics prevent gastric cancer through ef-
fects on both H pylori and commensal bacteria.

OPTIMAL TIMING OF H PYLORI ERADICATION

Lee and associates85 examined the efficacy of H pylori eradication in preventing the
progression of gastritis to gastric cancer in H pylori infected transgenic mice. H pylori
eradication at 8, 12, and 22 weeks after infection decrease the severity of dysplasia
(P<.01) compared with untreated mice. The development of neoplasia was prevented
by H pylori eradication at 8 weeks (P<.001) and less effectively at 12 and 22 weeks
(P<.05). H pylori eradication seems to be most effective at preventing cancer when
given at an earlier point in the course of the infection.85
In 2004, a prospective randomized controlled trial of 1630 healthy carriers of H pylori
infection from China were randomly assigned to receive H pylori eradication or pla-
cebo.86 All patients had an endoscopy at the start of the trial. There were 18 cases
of gastric cancer that developed during the 7.5-year follow-up, with no difference be-
tween subjects who received eradication or treatment (P 5 .33). However, in the sub-
group of patients who did not have any precancerous lesions (gastric atrophy,
intestinal metaplasia, and dysplasia) on initial presentation, no patient who received
H pylori eradication developed cancer compared with those who received placebo
(0 vs 6; P 5 .02). Earlier eradication may be more effective in preventing H pylori–asso-
ciated gastric cancer.
There has been controversy regarding whether H pylori eradication is effective at
stopping carcinogenesis in patients who already have advanced precursor lesions,
such as atrophic gastritis or intestinal metaplasia. Atrophic gastritis with or without in-
testinal metaplasia has often been considered the point of no return, regardless of H
pylori treatment. However, several studies have shown that H pylori eradication can
lead to the regression of precancerous lesions, such as atrophic gastritis and intestinal
metaplasia.72,87,88 In addition, H pylori eradication can prevent metachronous gastric
cancers as well. Patients with early gastric cancers are thought to be at high risk for
subsequent gastric cancers owing to advanced glandular atrophy in the stomach. In
1 study published in 2018, 396 patients who underwent endoscopic resection of early
gastric cancer or high-grade adenoma received either H pylori eradication or pla-
cebo.89 During a median follow-up of 5.9 years, 14 patients developed metachronous
cancers compared with 27 in the placebo group (hazard ratio, 0.50; 95% CI, 0.26–
0.94). In addition, in a subgroup of 327 patients who underwent endoscopic biopsy
at the 3-year follow-up, more patients in the treatment group had an improvement
in the atrophy grade than in the placebo group (48.4% vs 15.0%; P<.001).

POPULATION-BASED H PYLORI SCREENING AND TREATMENT

Although H pylori eradication decreases the risk of preneoplastic lesions and gastric
cancer, population-based screening and treatment is not universally recommended
owing to its cost.90 However, in high-risk populations, screening and treatment may
be cost-effective in high-risk populations91,92 and is recommended by Asian and Eu-
ropean guidelines given the clinical and economic benefits of gastric cancer preven-
tion.93–95 Other outcomes such as peptic ulcer and lymphoma prevention are
additional benefits that would make H pylori eradication more cost effective.
 Helicobacter pylori and Gastric Cancer 459

Given the evolutionary cohabitation of H pylori with humans, it has been postulated
that there may be some protective benefits with infection. H pylori infection has been
associated with a lower incidence of gastroesophageal reflux disease and gastric and
esophageal cardia cancers. H pylori has also been negatively associated with asthma
and other allergic diseases.96,97 Another potential concern for population-based treat-
ment is the risk of increasing antibiotic resistance.
The International Agency for Research on Cancer has recommended that countries
should explore the possibility of introducing population-based H pylori screen-and-
treat programs based on disease burden and cost effectiveness.97 Guidelines in the
United States recommend that all patients with a positive test for H pylori be offered
treatment, but state that there is insufficient evidence to support routine testing for and
treatment of H pylori in asymptomatic individuals.98

SUMMARY

H pylori is present in approximately one-half of the world’s population and is thought to

have coevolved with humans. There are significant differences in prevalence based on
region, age, race/ethnicity, and socioeconomic status. The vast majority of infected in-
dividuals remain asymptomatic, but H pylori can cause multiple gastrointestinal dis-
eases, including gastritis, peptic ulcer disease, and gastric cancer. It is the most
common cause of infection-related cancers, representing 5.5% of the world cancer
burden. Several case-control and prospective studies have demonstrated the relation-
ship between H pylori infection and gastric adenocarcinoma and MALT lymphoma.
The molecular mechanism by which H pylori induces gastric cancer is not
completely understood but is likely a combination of virulence factors, host genetic
predisposition, and environmental factors. H pylori isolates demonstrate significant
genetic diversity and strain-specific properties are thought to contribute to the ability
to cause a wide variety of diseases of differing severity in its hosts. H pylori has
numerous features and enzymatic properties that allow it to survive in the acidic envi-
ronment of the stomach, and has specific virulence factors, such as cagA and vacA,
that promote an increased risk of gastric pathology. However, host inflammatory re-
sponses are likely the major factor driving gastric cancer progression, modified in
part by dietary factors that may also contribute to H pylori–induced gastric carcino-
genesis. Finally, similar to other cancers, the host non–H pylori microbiome is likely
to be a critical factor but at present requires further study.
The eradication of H pylori is the first-line therapy for MALT lymphoma. The eradica-
tion of H pylori also decreases the risk of developing gastric adenocarcinoma, and the
benefits may be increased in populations with a higher baseline cancer incidence.
Population-based screening and treatment is not universally recommended owing to
its cost, although it may be beneficial in populations at high risk for gastric cancer. Given
the heterogeneity of H pylori infection and gastric cancer incidence, screening programs
should be considered based on disease risk and cost effectiveness.

CLINICS CARE POINTS

 H pylori is present in 50% of the world’s population though most are asymptomatic without
clinical disease.
 The prevalence of H pylori is higher in developing countries than developed countries,
although there is significant variation depending on socioeconomic factors and race/
ethnicity.
460 Kim & Wang

 H pylori is considered a type I carcinogen by the World Health Organization and is a primary
factor in the pathogenesis of gastric adenocarcinoma and MALT lymphoma.
 H pylori related carcinogenesis is likely a combination of bacterial properties, host genetic
factors, and environmental risk factors.
 H pylori are unique bacteria with special characteristics and virulence factors that lead to
disease pathogenesis.
 There are various methods for the diagnosis of H pylori, including invasive by upper
endoscopy and noninvasive tests.
 The eradication of H pylori likely decreases the risk of initial and recurrent gastric cancer and
is recommended in all patients who test positive for infection.

DISCLOSURE

The authors have nothing to disclose.

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I n h e r i t e d Pred i s p o s i t i o n to
Gastric Cancer
Sheila D. Rustgi, MDa,b,c, Charlotte K. Ching, MD, MAc,d, Fay Kastrinos, MD, MPHa,b,c,*

KEYWORDS
 Gastric cancer  Genetic testing  Hereditary diffuse gastric cancer
 Lynch syndrome

KEY POINTS
 Approximately 10% of gastric cancer cases involve familial aggregation and up to 3% are
related to an inherited cancer syndrome.
 Several pathogenic variants and cancer syndromes, including hereditary diffuse gastric
cancer, Lynch syndrome, and gastric adenocarcinoma and proximal polyposis syndrome,
are associated with increased risk of gastric cancer.
 Appropriately identifying patients for genetic counseling and testing for pathogenic germ-
line variants informs the patient’s and the family members’ risks of gastric and other can-
cers and guides appropriate surveillance and treatment.

INTRODUCTION

Gastric cancer, notably gastric adenocarcinoma, is the fifth most common cancer
diagnosed worldwide.1 In the United States, it is highly lethal, with a median 5-year
survival rate of only 32%.1,2 Although most cases are sporadic, up to 10% of gastric
cancers show familial aggregation and arise in individuals with a strong family history
of the malignancy, and up to 3% are related to an inherited cancer syndrome.3–5 There
are multiple germline pathogenic variants and cancer syndromes that are associated
with an increased risk of gastric cancer.6–8
Although family history of gastric cancer is a risk factor for gastric cancer, it is not
always clear whether this is caused by shared environmental factors, a genetic predis-
position, or a multifactorial cause that may include these factors and others. For
example, a recent prospective study found that eradication of the carcinogen Helico-
bacter pylori decreases the risk of gastric cancer among patients with a first-degree
relative with gastric cancer.9
In the United States, screening for gastric cancer is not recommended because of
its low prevalence in the general population. However, a recent systematic review

a
Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York,
NY, USA; b Division of Digestive and Liver Diseases, Columbia University Irving Medical Cancer,
New York, NY, USA; c Vagelos College of Physicians and Surgeons, New York, NY, USA;
d
Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA
* Corresponding author. 161 Fort Washington Avenue, Suite 862, New York, NY 10032.
E-mail address: Fk18@columbia.edu

Gastrointest Endoscopy Clin N Am 31 (2021) 467–487

https://doi.org/10.1016/j.giec.2021.03.010 giendo.theclinics.com
1052-5157/21/ª 2021 Elsevier Inc. All rights reserved.
468 Rustgi et al

suggests that screening patients at high risk for gastric cancer, whether because of
precancerous conditions such as intestinal metaplasia, family history, or known ge-
netic mutations, may be cost-effective.10

HISTOLOGY

The most common and worldwide histologic classifications for gastric cancer are the
Lauren and World Health Organization (WHO) classifications. Classically, there are 2
histologic subtypes of gastric cancer, first described by Lauren11 in 1965, the diffuse
and intestinal types. The diffuse type is characterized by poorly cohesive cells, highly
invasive disease, and occasionally signet cells, so named for their similarities to signet
rings on histology because the mucus pushes the nucleus to the edge of the cell.12
These abnormal cells infiltrate the stroma either alone or in small groups, leading to
a population of scattered tumor cells. This cancer type more often affects young
women. Furthermore, peritoneal spread before the identification of a precursor lesion
is common and therefore has a worse prognosis. In contrast, the intestinal type in-
cludes cohesive gland formations and is often associated with intestinal metaplasia.
Unlike diffuse gastric cancer, intestinal tumors grow along broad cohesive fronts to
form an exophytic mass and are more associated with lymphatic or vascular invasion.
These tumors occur more commonly in the elderly and male patients, and affect the
antrum. The 2 subtypes are thought to progress through different carcinogenic
pathways.
In 2010, the WHO system also created a histopathology classification system that
was more detailed than the Lauren classification and based on morphologic charac-
teristics, including 4 subtypes (papillary, tubular, mucinous, and poorly cohesive).
However, the prognostic relevance of both classification systems has been controver-
sial and insufficient to guide therapy. Using updated analytical techniques, the Cancer
Genome Atlas Research Network has developed a new classification system based
on comprehensive analysis of 295 primary gastric cancers: tumors positive for
Epstein-Barr virus, microsatellite unstable tumors, genomically stable tumors, and tu-
mors with chromosomal instability.13 This classification system may be important for
identifying possible therapeutic targets.

INHERITED CANCER SYNDROMES ASSOCIATED WITH GASTRIC CANCER

Several cancer predisposition genes are associated with an increased risk of gastric
cancer. Original reports related to gastric cancer risks associated with various
inherited cancer syndromes relied heavily on data derived largely from familial cancer
registries worldwide. Earlier gastric cancer risk estimates may therefore be subject to
ascertainment bias and overestimation, given that patients were often identified and
selected for genetic testing based on young-onset gastric cancer and an increased
number of gastric cancer cases among relatives. With advances in next-generation
sequencing technologies, germline genetic testing has expanded to include the simul-
taneous testing of multiple cancer susceptibility genes, and additional genotype-
phenotype correlations have been elucidated. As a result, the prevalence of inherited
gastric cancer and its associated risk among numerous cancer syndromes have been
redefined.

HEREDITARY DIFFUSE GASTRIC CANCER

Hereditary diffuse gastric cancer (HDGC) is an autosomal dominant inherited cancer

syndrome in which affected patients across multiple generations develop poorly
 Inherited Predisposition to Gastric Cancer 469

differentiated diffuse signet ring cell carcinoma at a young age, as well as lobular
breast cancer in women.14 HDGC is caused by inactivating germline mutations in
CDH1 (E-cadherin) where the most common cause of second CDH1 allele inactivation
is promoter methylation.
The clinical criteria to identify individuals at risk for HDGC has evolved over the last
20 years. Original clinical criteria were based on high burden of diffuse gastric cancer
among multiple family members, often defined by young ages of cancer onset, or
lobular breast cancer in a family with diffuse gastric cancer. However, less than
50% of individuals who fulfilled the original clinical criteria were identified as germline
carriers of pathogenic variants in the CDH1 gene.15 Most recently, the International
Gastric Cancer Linkage Consortium (IGCLC) revised recommendations based on in-
dividual and clinical criteria to determine eligibility for germline testing16 (Table 1). In
addition, genetic testing could be considered in patients with bilateral or familial
lobular breast cancer diagnosed before the age of 50 years, patients with diffuse
gastric cancer and cleft lip/palate, and those with precursor lesions for signet ring
cell carcinoma.3,17 One study using registry data from the Netherlands found that
the addition of these criteria increased sensitivity to 89% in identifying patients with
pathogenic germline CDH1 mtuations.18

Genetic Alteration
A mutation in the gene for E-cadherin, a cell adhesion protein that normally acts as a
tumor suppressor gene, was first described in 1998 in 3 Maori families from New Zea-
land.19 Since then, this mutation has been well documented in multiple affected fam-
ilies from many different ethnic backgrounds.20–23 A second germline truncating allele
in CTNNA1 has been described in families who meet the clinical testing criteria for
diffuse gastric cancer but without obvious mutation in the CDH1 gene.24 The remain-
ing allele was silenced in patients with cancer or signet ring cells. This gene encodes
alpha-E-catenin, which functions in the same protein as E-cadherin.

Table 1
Hereditary diffuse gastric cancer testing criteria

Patients with a  Two or more patientsa with gastric cancer, at

family history of: least 1 of whom has confirmed DGC
 One or more cases of DGC at any age and
1 or more cases of lobular breast cancer in
a patient <70 y old in different family membersa
 Two cases of LBC before age 50 y
Patient with  DGC diagnosed before age 50 y
personal history of:  DGC at any age in individuals of Maori ethnicity
 DGC at any age in individuals with a personal or
family history (first degree) of cleft lip/cleft palate
 DGC and LBC, both diagnosed before age 70 y
 Bilateral LBC, diagnosed before 70 y
 Gastric in situ signet ring cells and/or pagetoid spread
of signet ring cells in individuals <50 y old

Abbreviations: DGC, diffuse gastric cancer; LBC, lobular breast cancer.

a
Patients and family members are first-degree or second-degree relatives of each other
Adapted from the International Gastric Cancer Linkage Consortium practice guidelines. Blair VR,
et al. Hereditary diffuse gastric cancer: updated clinical practice guidelines. Lancet Oncol. 2020
Aug;21(8):e386-e397. doi: 10.1016/S1470-2045(20)30219-9. PMID: 32758476; PMCID: PMC711
6190. Reprinted with permission of Elsevier, Inc.
470 Rustgi et al

Gastric Cancer Risks

With the advent of multigene panel testing and the increased uptake of this testing, partic-
ularly among women and families with breast cancer, the frequency of pathogenic vari-
ants in CDH1 being detected has also increased, even among families without report of
gastric cancer. A recent study describes the phenotype of CDH1 mutation carriers in a
cohort of 26,936 patients who had undergone germline genetic testing25; a total of 20 pa-
tients had mutations in CDH1 detected, whereas 13 did not meet IGCLC clinical criteria
for CDH1 testing. Of those with pathogenic CDH1 variants, 19 patients had a personal
history of cancer, including breast cancer (both ductal and lobular), colon, and gastric
cancers. Notably the 3 patients who underwent gastrectomy had evidence of diffuse
gastric cancer on resection despite not meeting the diagnostic testing criteria.
The penetrance of gastric cancer and breast cancer is important when counseling
affected patients. Earlier lifetime estimates of gastric cancer risk among CDH1 carriers
were as high as 67% for men and 83% for women but were derived from families that
met the original, more stringent clinical criteria for HDGC and thereby were subject to
ascertainment bias. Reported estimates among CDH1 mutations were also subject to
overestimation because of a common haplotype suggestive of a founder effect from
Newfoundland, with an associated 40% risk of gastric cancer in affected men by
age 75 years and 63% in women.22
In more recent studies where CDH1 mutation carriers were identified through multi-
gene panel testing, the lifetime risk of gastric cancer by age 80 years has been re-
ported to be lower at 37.2% to 42%26 in men and approximately 33% for women,27
with as few as 33% of carriers meeting clinical criteria for HDGC.27 With respect to
the risk of lobular breast cancer among female carriers of pathogenic variants in the
CDH1 gene, a recent study reported a lifetime risk of 42% by the age of 80 years,28
and, in a study of female carriers not ascertained based on fulfillment of clinical criteria
for HDGC, the lifetime risk of lobular breast cancer was 55%.27

Endoscopic Surveillance and Surgical Management

Patients with pathogenic variants in the CDH1 mutation and HDGC are advised to un-
dergo prophylactic gastrectomy.17 Patients who are symptomatic by the time diffuse
gastric cancer is detected often have widely invasive disease and poor prognosis, with
only 10% having possibly curable disease through surgical resection.29 Many patients
have microscopic foci of cancer on resected specimens; ideally, surgery should occur
in the dormant period before the carcinoma proliferates and spreads.30 Prophylactic
gastrectomy is a morbid procedure that demands a significant lifestyle change, and
the discussion and timing are individualized. In general, most patients are recommen-
ded to undergo this surgery by age 30 years or based on the family history of gastric
cancer onset. Multiple studies of carriers who undergo prophylactic gastrectomies
suggest they are very efficacious. One of the largest studies, of 41 patients with
CDH1 mutation who underwent prophylactic gastrectomy, found that 85% had 1 or
more foci of signet cell gastric cancer.31 Barriers to undergoing surgery included pa-
tient age, positive beliefs about endoscopic surveillance, close relatives who had
negative surgical experiences, and fertility concerns and life stress. In contrast, facil-
itating factors included availability of social support, trust in health care providers, un-
derstanding associated risk, negative beliefs about surveillance and history of
abnormal results, family-related factors, and positive attitude toward surgery.32
The diffuse nature of the disease, where there are no clear visual lesions to identify, limits
endoscopic surveillance by esophagogastroduodenoscopy (EGD) and the identification
of precursor or early-stage, treatable cancer.33 In patients who opt to not undergo
 Inherited Predisposition to Gastric Cancer 471

prophylactic gastrectomy, annual endoscopic surveillance is recommended at an expert

center with multiple random biopsies following the Cambridge Protocol3,17 in order to
possibly identify microscopic foci of signet cells. Careful examination with extensive
washing, inflation, and deflation to assess distensibility is recommended, as well as treat-
ment of H Pylori, if detected. In addition to random biopsies, endoscopists should look for
pale spots to biopsy because prior reports have correlated these areas to the presence of
signet ring cell carcinoma.34 Any suspicious findings, lesions, or abnormal biopsy results
should prompt referral for gastrectomy. One study of patients who were undergoing sur-
veillance found that 16 of 29 developed cancer and underwent gastrectomy within a me-
dian of 5 months.35 Therefore, the primary recommendation is for prophylactic
gastrectomy in identified CDH1 carriers and strong consideration in individuals that
meet clinical criteria for an HDGC kindred.16,17 Endoscopy is reserved for those who
refuse prophylactic gastrectomy or are physically unfit to undergo the surgery.16,17,34

INTESTINAL-TYPE ADENOCARCINOMA

Most hereditary syndromes associated with gastric adenocarcinoma are of the intes-
tinal type. The lifetime risk of gastric cancer varies by syndrome and must be weighed
against competing risk from other cancers (Tables 2 and 3). In addition, the gastric
cancer risks may be underestimated in some syndromes, where ascertainment of
cases may have been for other malignancies (ie, Lynch syndrome and familial adeno-
matous polyposis [FAP]).

LYNCH SYNDROME

Lynch syndrome is a prevalent hereditary cancer syndrome that affects 1 in 300 Ameri-
cans, many of whom are unaware of their diagnosis.6 The most common malignancy
associated with Lynch syndrome is colorectal cancer; however, endometrial, ovarian,
gastric, small bowel, ureter, and renal pelvic cancers are also Lynch-associated cancers.
Lynch syndrome has been associated with pathogenic variant in 1 of 4 DNA
mismatch repair genes (MLH1, MSH2, MSH6, and PMS2), as well as EPCAM, which
causes epigenetic silencing of the MSH2 gene.36,37 When a second mutation occurs in
the normally functioning allele, the mismatch repair gene no longer repairs DNA and
malignancies can occur, which are frequently associated with microsatellite instability.
However, the penetrance and lifetime cancer risks vary by the specific mismatch
repair gene mutation and it is well appreciated that pathogenic MSH2 gene variants
are more frequently associated with extracolonic malignancies.
Overall, Lynch syndrome is classically described as a colorectal cancer syndrome,
reflecting the highest cumulative cancer risk for these patients. One large observa-
tional multicenter study of 3119 patients followed for a total of 24,475 years, including
many cancer survivors, found that the lifetime risk of cancer varied by underlying mu-
tation, with MLH1 being highest risk followed by MSH2 and MSH6, with PMS2 muta-
tions being significantly lower risk than the other mutations.38 The cumulative risks for
colorectal cancer were 46%, 43%, and 15% in MLH1, MSH2, and MSH6 carriers; for
endometrial cancer, 43%, 57%, and 46%; for ovarian cancer, 10%, 17%, and 13%;
for upper gastrointestinal cancers, 21%, 10%, and 7%; for urinary tract cancers,
8%, 25%, and 11%; for prostate cancer, 17%, 32%, and 18%; and for brain tumors,
1%, 5%, and 1%, respectively.
Gastric Cancer Risks
Lynch syndrome carriers have up to a 10% lifetime risk of gastric cancer.6,39,40 The
burden of risk varies substantially by genotype, being near 10% for individuals with
472 Rustgi et al

Table 2
Genetic syndromes associated with gastric cancer

Gene
Gene Syndrome Predominant Cancers Function Gastric Cancer Risk
CDH1, HDGC Gastric, female Tumor 33% women,
CTNNA1 lobular breast suppressor 42% men,
37.2% overall26,27
67% men,
83% women
by age 80 y in
HDGC families108
MLH1 Lynch syndrome Colorectal, Mismatch 5%–7%6,38,40,43
endometrial, repair
ovarian, urothelial,
gastric, small bowel,
biliary, brain
MSH2 Lynch syndrome Colorectal, Mismatch 0.2%–9%38,40,43,109
endometrial, repair
ovarian, urothelial,
gastric, small bowel,
biliary, brain
MSH6 Lynch syndrome Colorectal, Mismatch <1%–7.9%6,42,109
endometrial, repair
ovarian, urothelial,
gastric, small bowel,
biliary, brain
PMS2 Lynch syndrome Colorectal, Mismatch Inadequate
endometrial, repair data6,109
ovarian
APC Familial Colorectal Tumor 1%–2%56–58
adenomatous suppressor
polyposis
APC Gastric Gastric, colorectal Tumor Inadequate
promoter adenomatous suppressor data110
1B and proximal
polyposis
syndrome
STK11 Peutz-Jeghers Female breast, Tumor 29%73,74
syndrome colorectal, stomach, suppressor
small intestine,
cervical, testicular,
pancreatic
TP53 Li-Fraumeni Female breast, soft Tumor 5%–10%111
syndrome tissue sarcoma, suppressor
osteosarcoma,
colorectal,
adrenocortical
carcinoma, leukemia,
brain and central
nervous system
tumors
SMAD4/ Juvenile polyposis Colorectal, small Tumor 21%78,79,85
BMPR1A syndrome intestine suppressor
 Inherited Predisposition to Gastric Cancer 473

Table 3
Inherited cancer syndrome and gastric cancer surveillance recommendations

Recommended Age of Initiation

Syndrome Screening Modality (y)a Interval
HDGC EGD before 30 Annual
prophylactic
gastrectomy;
continued if
prophylactic
gastrectomy
is not pursued
Lynch syndrome EGD 1 H pylori 30 Every 1–5 y
testing
Familial EGD with dedicated 25–30 Pending ampullary
adenomatous ampullary examination and
polyposis examination and polyp pathology
random sampling results
of fundic gland
polyps
Gastric EGD before Personalized based Annual
adenocarcinoma prophylactic on
and proximal gastrectomy; affected family
polyposis continued if members’ ages of
syndrome prophylactic polyp onset
gastrectomy
is not pursued
Peutz-Jeghers EGD Once age 8 If polyps present
syndrome Restart age 18 repeat every 3 y
Li-Fraumeni EGD 25 or 5 y before the Every 2–5 y
syndrome earliest known
gastric cancer in
the family
Juvenile polyposis EGD 12 Every 1–3 y
syndrome
Familial intestinal EGD No No
gastric cancer recommendations recommendations
a
Initiate 5 to 10 y before youngest age of gastric cancer diagnosis in family.
Derived from National Comprehensive Cancer Network guidelines, International Gastric Cancer
Linkage Consortium, the American College of Gastroenterology, the United States Multi-Society
Task Force, the European Society for Medical Oncology, the American Society for Clinical Oncology,
and the Mallorca Group.

MLH1 and MSH2 mutations, but may be similar to population level risk (w1% in the
United States) for patients with PMS2 mutations.38,39,41–44 The average age of
onset of gastric cancer for the former patients is usually in the early 50s. Most
data for gastric cancer risk are derived from family cancer registries where most
subjects were ascertained predominantly for their personal and/or family histories
of colorectal cancer; history of gastric cancer may not have been reliably captured
and could potentially be underestimated. In contrast, data on gastric cancer esti-
mates from certain European family cancer registries may overestimate lifetime
risk because there are particular founder mutations where gastric cancer is more
consistently observed.39
474 Rustgi et al

Endoscopic Evaluation and Surveillance

Multiple societies have developed recommendations for gastric cancer screening for
individuals with Lynch syndrome.6,41,45–49 However, these recommendations are
based on limited evidence and mostly on expert consensus. Most guidelines recom-
mend esophagogastroduodenoscopy (EGD) and H pylori testing as the preferred mo-
dalities, with initiation at age 30 years, with the exception of the National
Comprehensive Cancer Network (NCCN) guidelines, which recommend starting at
age 40 years. Surveillance recommendations also vary from annually to every 5 years.
For example, the NCCN guidelines recommend EGD every 3 to 5 years for patients at
high risk.6,48 Risk factors for these patients are similar to those for the general popu-
lation, such as male sex, older age, first-degree relative with gastric cancer, Asian
ethnicity, residing in or immigrating from countries with high incidence of gastric can-
cer, autoimmune gastritis, gastric intestinal metaplasia, and gastric adenomas. In 1
study of 73 individuals with Lynch syndrome–associated gene mutations and 32 family
members without Lynch syndrome, there was no significant difference in occurrence
of H pylori, intestinal metaplasia, or gastritis between the 2 groups.50 Risk factors spe-
cific to Lynch syndrome carriers include carrying an MLH1 or MSH2 pathogenic
variant.6 More research is needed to determine the optimal age of initiation, surveil-
lance technique, and intervals between examinations.

FAMILIAL ADENOMATOUS POLYPOSIS

FAP is an autosomal dominant hereditary polyposis syndrome caused by germline

mutations in the adenomatous polyposis coli (APC) gene. The classic form of FAP is
clinically defined by the presence of 100 or more synchronous colorectal adenomas.
Attenuated FAP is a less severe entity, defined as the presence of fewer than 100
adenomatous polyps.51
FAP has been identified worldwide and is estimated to affect between 2.29 and 3.2
per 100,000 births.45,52–54 FAP may be suspected either when the patient has a rela-
tive with the syndrome and mutation or in patients with the clinical phenotype. De novo
cases of FAP account for approximately 25% of all newly diagnosed cases, where
there is absence of family history. The carcinogenic pathway of FAP is shared with
sporadic colon cancer where a loss of function in both APC alleles is highly penetrant
and causes polyp development in childhood and colorectal cancer in young adult-
hood.55 Patients with FAP have about 100% lifetime risk of colon cancer unless pre-
vented either through endoscopic clearing of polyps or colectomy. Patients with FAP
also have increased risk of duodenal or ampullary cancer, desmoid tumors, papillary
thyroid cancer, adrenal adenomas, and osteomas of the bone.45 Children are at risk of
hepatoblastoma until about the age of 5 years, and screening with alpha-fetoprotein
and ultrasonography is recommended until the age of 7 years. Other nonmalignant
extraintestinal manifestations include congenital hypertrophy of the retinal pigmented
epithelium and epidermoid cysts.

Gastric Cancer Risk, Endoscopic Evaluation, and Surveillance

The data on the risk of gastric cancer for individuals with FAP are evolving. The pres-
ence of benign fundic gland polyps is common and well documented, although ade-
nomas in the stomach are rare. The incidence of gastric cancer in Western patients
with FAP was thought to be about the same as the population risk, or 0.6%.56,57 How-
ever a recent study of 767 patients with FAP who underwent upper endoscopy in a he-
reditary cancer clinic cohort reports a dramatic increase in gastric cancer.58 Between
1979 and 2016, 10 patients were diagnosed with gastric adenocarcinoma, 9 of whom
 Inherited Predisposition to Gastric Cancer 475

were diagnosed in the last 4 years of the study, and 8 of the 10 had low-grade or high-
grade dysplasia on previous EGD. Given the difficulty in identifying carcinoma among
dense polyposis, these investigators then developed a prospective study to identify
endoscopic features that might predict cancer.59 Using polyp color, pit pattern, sur-
face architecture, and appearance under high-definition white light and narrow-
band imaging, the endoscopists were able to identify high-risk polyps with sensitivity
of 79% and specificity of 78.8%.
Current guidelines for endoscopic evaluation of the upper gastrointestinal tract have
predominantly focused on surveillance of the duodenum for adenomatous polyposis,
more so than for gastric adenomas. Endoscopic surveillance is recommended to
begin at the age of 25 to 30 years and includes dedicated evaluation of the ampulla
of Vater in the duodenum. Random sampling of fundic gland polyps is recommended
when encountered and, for patients with cancer or high-grade dysplasia (not low
grade), surgical consultation is recommended. The interval for endoscopic surveil-
lance is otherwise recommended based on duodenal polyposis using the Spigelman
criteria. However, if the risk of gastric cancer continues to increase among FAP car-
riers, recommendations for gastric cancer surveillance may need to be defined.

GASTRIC ADENOCARCINOMA AND PROXIMAL POLYPOSIS SYNDROME

Gastric adenocarcinoma and proximal polyposis syndrome (GAPPS) is a rare hered-

itary gastric cancer condition characterized by proximal gastric polyposis and
increased risk of early-onset, intestinal-type adenocarcinoma, in the absence of colo-
rectal polyposis. It is a novel, autosomal dominant condition that was first described in
2012,60 with the associated variant elucidated in 2016,61,62 which involves the pro-
moter 1B region of the APC gene. Fundal gland polyps (FGPs) are the sentinel features
of the GAPPS phenotype; however, a dysplasia- adenoma-adenocarcinoma
sequence has been reported in the development of the malignant phenotype of
GAPPS. A diagnosis of GAPPS is made by the presence of FGPs sparing the antrum
and lesser curvature of the stomach, the absence of colonic and duodenal polyposis,
an autosomal dominant inheritance pattern, and the exclusion of other gastric polyp-
osis syndromes, as well as chronic use of PPIs.63 The unique noninvolvement of the
antrum in patients with GAPPS, coupled with the absence of a colonic polyposis
phenotype, is an important clinical feature that distinguishes GAPPS and FAP. Family
members at risk should undergo germline mutation testing for the presence of APC
promotor 1B variants to initiate timely endoscopic evaluation and surveillance, in addi-
tion to other preventive strategies, including timing of risk-reducing surgery.

Gastric Cancer Risk, Endoscopic Evaluation, and Surveillance

The lifetime risk of gastric cancer in individuals with the GAPPS syndrome
remains undefined because the natural history of GAPPS is not yet clearly defined.
The rate of malignant transformation is unknown and endoscopic surveillance in car-
riers and family members with gastric polyposis and any grade of dysplasia on biopsy
and polypectomy specimens may miss invasive cancer in other areas of the stomach.
Heterogeneity in the impact of the individual primary promotor variants, along
with differences in the frequency and type of second-hit events, and any underlying
perturbations of the APC promotor 1A are likely drivers of the malignant phenotype,
including rate of progression toward invasion and metastasis. The interindividual het-
erogeneity within GAPPS requires a personalized approach to family members at risk
and affected by the phenotype. There are disconcerting reports that do not support
prolonged endoscopic surveillance because it is common for individuals to present
476 Rustgi et al

with disease by the third to fourth decade of life, and even as early as the late
teens.60,62,63 The endoscopic appearance can include confluent, carpetlike involve-
ment with limited disruption of the mucosa, and presence of adenomatous lesions
can be used to triage patients to undergo total gastrectomy, although data from larger
case series for this rare condition are lacking. Nonetheless, the concerns of adequate
sampling via endoscopic biopsies in the face of hundreds of heterogenous polypoid
lesions, which may include FGPs with different degrees of dysplasia, adenomas, or
mixed histology polyps, pose significant challenges and justify expedited referral to
clinical genetics, surgery, and surgical oncology. Total gastrectomy should be consid-
ered in all patients with GAPPS with fundal gland polyposis and the presence of
dysplasia on gastric biopsy or polypectomy specimens who are able to undergo major
surgery.
Similar to gastric cancer, there is an incomplete understanding of other organs at
risk for cancer. Colonic involvement in GAPPS has been described, and an
increased incidence of colonic adenomas justifies inclusion of colonoscopic
screening and surveillance into the routine work-up of patients with GAPPS.64 How-
ever, the interval for surveillance is guided by the initial findings in carriers and may
not be intensive for colorectal cancer prevention. It is thought that the mild colonic
phenotype generally involves fewer than 20 total small, hyperplastic polyps or small
adenomas in GAPPS carriers and is caused by an incomplete protection of APC
promotor 1A activity.62

PEUTZ-JEGHERS SYNDROME

Peutz-Jeghers syndrome (PJS) is an autosomal dominant syndrome caused by germ-

line mutations in STK11 tumor suppressor gene. PJS is estimated to occur in between
1 in 50,000 and 1 in 200,000 live births.65 It is characterized by early onset of gastro-
intestinal polyposis and cancers and mucocutaneous pigmentation, commonly at the
vermilion border of the lips.66,67 On histology, the polyps are hamartomatous polyps
and occur most frequently in the stomach, small bowel, and colon, where 1 study esti-
mated that 50% to 64% of patients had luminal tract polyps.68 Patients may present at
an early age with anemia, bleeding, obstruction, or intussusception caused by the
polyps. One-third of patients have symptoms by age 10 years and 50% by age
20 years.68
PJS can be diagnosed clinically with if any of the following criteria are present69,70: 2
or more histologically confirmed Peutz-Jeghers (PJ) polyps; any number of PJ polyps
in an individual who has a close relative with PJS; characteristic mucocutaneous
pigmentation in an individual who has a family history of PJS in a close relative; or
any number of PJ polyps in an individual who also has characteristic mucocutaneous
pigmentation. In individuals who fulfill the aforementioned clinical criteria, 94% are
found to carry the STK11 mutation.66,70–72 PJS can also occur de novo in up to
one-quarter of patients.71

Gastric Cancer, Endoscopic Evaluation, and Surveillance

The lifetime risk of gastric cancer in PJS is near 29%,73,74 but may be overestimated
because of ascertainment bias because most individuals and families with PJS were
originally enrolled in family cancer registries for management of polyposis, and gastric
cancer may not have been consistently reported. Several malignancies are associated
with PJS and carriers have a high burden of cancer risk75; by age 70 years, PJS car-
riers have an 81% risk of developing cancer. A systematic review of multiple studies
suggests the lifetime risks of cancer in PJS are 39% for colorectal, 29% for gastric,
 Inherited Predisposition to Gastric Cancer 477

13% for small bowel, 24% to 54% for breast, 21% for ovarian, 10% to 23% for cer-
vical, 9% for uterine, 9% for testicular, 7% to 17% for lung, and 11% to 36% for
pancreatic cancers.76
Several expert groups, including the American College of Gastroenterology (ACG),
the NCCN, and the Mallorca group, have put forth recommendations for surveillance
for these patients.6,45,66 The Mallorca group and ACG recommend EGD, capsule
endoscopy, and colonoscopy starting at age 8 years.45,66 If polyps are found, surveil-
lance should be continued every 3 years; if not, then repeat testing with all 3 modalities
is recommended at age 18 years. Endoscopic management of polyps is recommen-
ded when feasible, with surgical consideration for advanced neoplasia and cancer,
complications related to polyposis, or when disease burden is not amenable to endo-
scopic interventions.65,77

JUVENILE POLYPOSIS SYNDROME

Juvenile polyposis syndrome (JPS) is a rare autosomal dominant condition character-

ized by multiple hamartomatous polyps throughout the gastrointestinal tract, predom-
inantly the colorectum (98% of cases), followed by the stomach (14%), jejunum and
ileum (7%), and duodenum (7%). Its incidence is between 1 in 100,000 and 1 in
160,000 individuals78 and it is associated with germline mutations in the SMAD4 or
bone morphogenetic protein receptor type-1A (BMPR1A) genes; both genes are
related to the transforming growth factor-beta (TGF-beta) signaling pathway, involved
with cell growth, differentiation, and apoptosis.78,79 Clinical manifestations are typi-
cally seen by the third decade of life79 and most often include gastrointestinal bleeding
and anemia, and occasional abdominal pain, diarrhea, and prolapsed rectal polyps.
SMAD4-related JPS has been linked to hereditary hemorrhagic telangiectasia; mani-
festations of this overlap syndrome include mucocutaneous telangiectasias, arteriove-
nous malformations, and epistaxis.80
A clinical diagnosis of JPS can be made if 1 of the following criteria are met
more than 5 juvenile polyps of the colorectum, multiple juvenile polyps in other
parts of the gastrointestinal tract, or any number of juvenile polyps in a person
with a known family history of juvenile polyps. Germline mutations in either
SMAD4 or BMPR1A have been identified in approximately 40% to 60% of JPS
cases, the remainder of which are thought to be caused by de novo mutations.81
JPS is considered highly penetrant, with 1 study of 34 SMAD4 mutation–positive
individuals showing that 97% developed colorectal polyps and 68% developed
gastric polyps.82 Several genotype-phenotype correlations have been established.
For example, individuals with recurrent 10q22q23 deletions affecting the BMPR1A
gene have a more severe phenotype, with earlier onset of juvenile polyps and
larger polyp burden.83,84 In addition, individuals with SMAD4 mutations are more
likely to have significant polyposis of the upper gastrointestinal tract and a higher
risk for gastric cancer.85

Gastric Cancer Risks

The gastrointestinal cancer risk in JPS is thought to arise from malignant transforma-
tion of the adenomatous components present in juvenile polyps.78,79,86 Although
generally limited by small sample sizes, studies have shown the incidence of gastric
cancer in JPS to be between 11% and 29% in patients with gastric polyps.78,79,85
In 1 study of 44 patients with clinical JPS from 30 kindreds, the average age of gastric
cancer diagnosis was 56 years (range, 21–73 years); notably, all affected individuals
had SMAD4 mutations.85 Similar findings were observed in another study of 80
478 Rustgi et al

unrelated patients with clinical or suspected JPS, which found that all 7 cases of
gastric cancer were in families with SMAD4 mutations.87 Interestingly, although histo-
logic analysis showed predominantly intestinal gastric cancer, 1 case of the diffuse
subtype was identified, suggesting that the gastric cancer risk in JPS may not be
exclusively related to malignant transformation of juvenile polyps.

Endoscopic Evaluation and Surveillance

Screening for gastric cancer involves upper endoscopy every 1 to 3 years beginning at
age 12 years, or earlier if symptoms occur.45 Surveillance should be repeated every 1
to 3 years, depending on polyp burden, and polyps 5 mm or larger should be removed.
Although JPS is a hamartomatous polyposis syndrome, up to 75% of patients have
mixed polyp types, including inflammatory, hyperplastic, and adenomatous polyps,
the last of which is thought to predispose to malignant transformation.88
Complete or partial gastrectomy is indicated if cancer, high-grade dysplasia, or pol-
yposis cannot be adequately controlled endoscopically. Given that upper gastrointes-
tinal involvement tends to correspond with more severe disease in JPS, particularly in
SMAD4 mutation carriers, continued endoscopic monitoring for polyp recurrence
postgastrectomy is likely needed, but clear surveillance recommendations are
lacking.89

LI-FRAUMENI SYNDROME

Li-Fraumeni syndrome (LFS) is a rare autosomal dominant hereditary cancer syndrome

associated with germline mutations in the tumor protein p53 gene (TP53). A wide spec-
trum of malignancies is seen in LFS, the most common being breast cancer (27%–31%
of cases), followed by soft tissue sarcomas (17%–27%), osteosarcomas (3%–16%),
brain tumors (9%–14%), adrenocortical carcinomas (6%–13%), and leukemias (2%–
4%),90–92 which are common in childhood or early adulthood. However, a variety of
gastrointestinal malignancies are also associated with LFS, including gastric and colo-
rectal cancers. In addition to the excess of early-onset cancers seen in LFS, carriers
have a 40% to 49% risk of developing a second cancer, with a median onset of 10 years
after the first cancer diagnosis. The 2 major classification systems used to identify pa-
tients who should undergo molecular testing for LFS are the classic LFS criteria and the
Chompret criteria. Combined, these 2 approaches have been shown to confer a 95%
sensitivity and 52% specificity in detecting patients with TP53 mutations.92

Gastric Cancer Risk, Endoscopic Evaluation, and Surveillance

LFS is considered highly penetrant, with a 70% or higher lifetime risk of cancer in men
and a 90% or higher lifetime risk of cancer in women.93,94 Gastric cancer is an uncom-
mon manifestation of LFS and lifetime risk estimates are not well established.94–96
When observed in LFS, gastric cancer almost always presents at an earlier age than
in the general population. Among 429 cancer-affected individuals from 62 TP53
mutation–positive families, 21 (4.9%) patients from 14 families (22.6%) had a diag-
nosis of gastric cancer.97 Notably, the mean and median ages at gastric cancer diag-
nosis were 43 and 36 years, respectively, which was significantly younger than the
median age at diagnosis in the general population at 68 years. On pathology, both in-
testinal and diffuse gastric cancer were identified, with 50% of the tumors located in
the proximal stomach.
With the goal of early tumor detection and reduction of cancer-related and
treatment-related morbidity and mortality, proposals for clinical surveillance of TP53
mutation carriers have been made by the NCCN and the American Association for
 Inherited Predisposition to Gastric Cancer 479

Cancer Research (AACR). For breast cancer, diagnostic screening with breast MRI is
recommended annually starting at age 20 years; the addition of contrast-enhanced
MRI and mammogram is still debated.98 For colorectal cancer, diagnostic screening
with colonoscopy is recommended every 2 to 5 years starting at age 25 years, or 5
to 10 years before the earliest known colorectal cancer in the family, whichever comes
first. Whole-body MRI has been invoked as a useful surveillance tool with associated
survival benefits in LFS patients; however, rates of false-positive findings that required
further evaluation have been as high as 29.9%, indicating the need for controlled
studies assessing relative risks and benefits.98–100
Screening for gastric cancer is recommended with upper endoscopy every 2 to
5 years starting at age 25 years, or 5 years before the earliest known gastric cancer
in the family.101 However, these recommendations are based on expert opinion
because there is a paucity of data on the use and value of endoscopic evaluation
for gastric cancer in LFS. A potential limitation in endoscopic screening may be related
to the evaluation of diffuse-type gastric cancer because endoscopic findings are
frequently normal in patients with this subtype, which is typically diagnosed on pathol-
ogy following gastrectomy.33

FAMILIAL INTESTINAL GASTRIC CANCER

Familial gastric cancer describes families with intestinal-type gastric cancer in the
absence of polyposis or a pathogenic germline mutation associated with this malig-
nancy.102,103 Although the rates of gastric cancer differ worldwide, it is clear that family
history of gastric cancer is an independent risk factor, as supported by multiple case-
control studies that report general risk ratios of 1.5 to 3.5.104 Although the presence of
first-degree relatives with intestinal-type gastric cancer is a strong and consistent risk
factor for gastric cancer, the pathogenic mechanisms behind this familial aggregation
are unclear. The possible causes for familial clustering include bacterial factors, envi-
ronmental factors, or a combination thereof. Among individuals with a family history,
current or past H pylori infection and having 2 or more first-degree affected relatives
are associated with an increased risk of developing gastric cancer. H pylori eradica-
tion is an important preventive strategy in first-degree relatives of patients with gastric
cancer, particularly those in their 20s and 30s, where early eradication could prevent
the progression to intestinal metaplasia and reduce the synergistic risk in individuals
with both H pylori infection and a family history.105 In addition, no specific single nucle-
otide polymorphism has been shown to be associated with familial clustering of
gastric cancer. Ongoing genome-wide association studies that incorporate environ-
mental and modifiable risk factors may increase the understanding of the pathogen-
esis of gastric cancer among patients with family history.
In addition, familial intestinal gastric cancer (FIGC) has been defined as having a
high burden of gastric cancer in the family. Clinically, patients meet criteria if there
are 2 first-degree or second-degree relatives with gastric adenocarcinoma, where 1
had been diagnosed before age 50 years. Alternatively, 3 or more first-degree or
second-degree relatives diagnosed at any age are included. In a single center study
of 50 patients from FIGC kindreds, both germline and tumor testing was performed
and compared with HDGC and sporadic cases to evaluate for genetic causes poten-
tially underlying a monogenic or an oligogenic/polygenic inheritance pattern.106 FIGC
probands developed gastric cancer at least 10 years earlier, tumors more often dis-
played microsatellite instability, and there were significantly more somatic common
variants than sporadic tumors. The investigators concluded that FIGC is likely a poly-
genic gastric cancer predisposing to disease and proposed that any family presenting
480 Rustgi et al

2 patients with gastric cancer, 1 confirmed on intestinal histology, independently of

age, and with or without colorectal cancer, breast cancer, or gastric ulcers in other
family members, could be considered FIGC.106
Although endoscopic surveillance is expected to benefit individuals with a family
history of gastric cancer, further large-scale, prospective studies are warranted to
evaluate the cost-effectiveness and optimal time point for endoscopy in individuals
with FIGC. At present, there are no clear surveillance recommendations, and further
studies are needed to better describe and understand families with this gastric cancer
history.

GENETIC TESTING

Next-generation sequencing has led to the development of multigene panel tests,

allowing providers to simultaneously test for multiple germline mutations associated
with malignancy. For families with a history of multiple cancers, many of which overlap
between known inherited cancer syndromes, multigene panel testing allows the
increased identification of pathologic variants.107 However, increased germline ge-
netic testing for multiple cancer susceptibility genes also leads to the identification
of more variants of unknown significance or pathogenic variants whose associated
risks and clinical implications are not yet known. Genetic counseling is therefore
necessary to determine which testing is appropriate and for interpreting testing results
to guide patients and at-risk family members with cancer screening and preventive
strategies, including risk-reducing, prophylactic surgeries. If a germline mutation is
identified in an inherited cancer predisposition gene of which gastric cancer is but 1
manifestation, family members can benefit from earlier and enhanced screenings for
gastric cancer, in addition to the other associated malignancies.
Referral for genetic counseling and testing is recommended for individuals diag-
nosed with gastric cancer who meet several clinical criteria related to personal and/

Fig. 1. Genetic risk assessment for individuals with gastric adenocarcinoma. aGAPPS caused
by pathogenic variant in APC promoter 1B and prophylactic gastrectomy recommended.
b
Germline genetic testing for the newly identified pathogenic variant is recommended
for all at-risk family members (cascade genetic testing).
 Inherited Predisposition to Gastric Cancer 481

or family cancer history (Fig. 1). Once a pathogenic variant is identified in the individ-
uals with gastric cancer, at-risk family members benefit from genetic testing for the
newly detected familial variant, a process referred to as cascade testing. This
approach is cost-effective in identifying individuals unaffected by cancer but at high-
est risk of developing malignancy caused by a pathogenic germline variant and who
can benefit the most from cancer prevention and early detection strategies.

SUMMARY

Appropriate assessment of familial and genetic risk for gastric cancer development
may allow a personalized approach to gastric cancer prevention through screening
and risk-reducing surgeries. The ability to better identify carriers with pathogenic ge-
netic variants associated with gastric cancer before a diagnosis of cancer requires
effective implementation of strategies for genetic risk assessment and testing, fol-
lowed by optimal screening and surveillance recommendations to further reduce
the morbidity and mortality.

CLINICS CARE POINTS

 Gastric cancer is associated with several germline pathogenic variants associated with
inherited cancer syndromes.
 Patients with identified pathogenic variants in the CDH1 gene should be considered for
prophylactic gastrectomy, the timing of which can be as early as age 30 years and may
vary based on presence or absence of family history of diffuse gastric cancer, burden of this
cancer among multiple relatives, and/or abnormal findings detected on surveillance
endoscopy.
 The management of CDH1 carriers without family history of gastric cancer is evolving with
respect to timing of prophylactic gastrectomy and the limitations of surveillance endoscopy.
 Patients with inherited cancer syndromes associated with intestinal-type gastric cancer
benefit from gastric cancer screening by upper endoscopy, with age of initiation and
interval recommendations tailored to the specific syndrome and/or pathogenic variant and
its associated gastric cancer risk.
 The term FIGC may be used to describe those patients with a significant family history of
gastric cancer who do not carry an associated pathogenic variant or meet clinical criteria
for inherited cancer syndromes.
 Genetic testing and identification of germline pathogenic variants in select individuals with
gastric cancer allows at-risk family members to undergo genetic testing with the benefit of
cancer screening and preventive strategies for carriers of the familial variant.

DISCLOSURE

The authors have nothing to disclose.

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virulence, and genetic susceptibility. Eur J Gastroenterol Hepatol 2011;23(5):
411–7.
106. Carvalho J, Oliveira P, Senz J, et al. Redefinition of familial intestinal gastric can-
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determine risk of colorectal cancer. Gastroenterology 2020;158(2):389–403.
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E n d o s c o p i c Sc re e n i n g an d
S u r v eilla n c e f o r G as t r i c
Cancer
Bokyung Kim, MD, Soo-Jeong Cho, MD, PhD*

KEYWORDS
 Screening  Surveillance  Gastric cancer  Upper gastrointestinal endoscopy

KEY POINTS
 The value of screening asymptomatic individuals for gastric cancer depends on the inci-
dence, screening methods, and management of gastric cancer.
 Upper gastrointestinal endoscopy is increasingly preferred as a screening method for
gastric cancer.
 Population-based nationwide endoscopic screening of gastric cancer decreased gastric
cancer mortality in countries with high incidence rates, such as South Korea and Japan.
 Endoscopic surveillance is targeted to high-risk individuals with gastric premalignant le-
sions, family history of gastric cancer, and previous history of gastric cancer, but no stan-
dardized recommendations have been established.

INTRODUCTION

Gastric cancer is one of the most common cancers worldwide.1,2 The incidence of
gastric cancer varies widely by geographic region, with half of new cases occurring
in East Asia.3 The value of screening asymptomatic individuals for gastric cancer de-
pends on the incidence, screening methods, and management of gastric cancer.4
Population-based national screening for gastric cancer has been implemented in
some countries with a high incidence of gastric cancer, such as South Korea and
Japan.5 Two main modalities for gastric cancer screening are upper gastrointestinal
endoscopy and upper gastrointestinal series (UGIS). Several studies have reported
higher detection rates of gastric cancer with upper intestinal endoscopy compared
with UGIS, and gastrointestinal endoscopy has been increasingly used in screening
for gastric cancer in recent years.4,6–8 Some observational studies suggest that gastric
cancer screening has contributed to detection of cancer in early stages and an overall
decline in gastric cancer mortality.9–17 In terms of surveillance, endoscopic

Department of Internal Medicine and Liver Research Institute, Seoul National University Col-
lege of Medicine, 103 Daehak-ro, Jongno-gu, Seoul 03080, Korea
* Corresponding author.
E-mail address: crystal522@daum.net

Gastrointest Endoscopy Clin N Am 31 (2021) 489–501

https://doi.org/10.1016/j.giec.2021.03.004 giendo.theclinics.com
1052-5157/21/ª 2021 Elsevier Inc. All rights reserved.
490 Kim & Cho

surveillance in high-risk subgroups such as individuals with gastric premalignant le-

sions or family history of gastric cancer is expected to be beneficial but standard sur-
veillance strategies are lacking.18–26 This review aims to discuss current evidence and
strategies for endoscopic screening and surveillance for gastric cancer.

GASTRIC CANCER INCIDENCE AND MORTALITY

Every year, approximately one million people are diagnosed with gastric cancer world-
wide.1,2 It is one of the most common cancers, and the incidence is highly geograph-
ically heterogeneous. Incidence rates are the highest in East Asia, Central Asia,
Eastern Europe, and South America, whereas the lowest rates are in North America,
North Africa, and East Africa.1–3 Although the incidence and mortality of gastric cancer
has decreased over a few decades, it remains the fifth most commonly diagnosed
cancer and third leading cause of cancer mortality.2,27–29 The decline of the incidence
and mortality of gastric cancer is likely attributable to reduction of Helicobacter pylori
infection, changes in food preservation, and better diagnostic and treatment op-
tions.30–32 Notably, the 5-year survival rates are exceptionally high in South Korea
and Japan, reported as 60.3% to 76.5%, compared with the worldwide range of
around 20% to 40%.33–36 One of the most important factors that can explain these dif-
ferences is the implementation of population-based national screening program for
detection of gastric cancer in the 2 countries.

SCREENING AND SURVEILLANCE MODALITY

The ideal modality for gastric cancer screening should be safe, simple, validated, and
cost-effective. Several modalities including upper gastrointestinal endoscopy, UGIS,
and blood tests such as H pylori serology, pepsinogen (PG), microRNA, and serum
trefoil factor have been proposed for screening methods.7,37–43 The 2 main modalities
for gastric cancer screening are upper gastrointestinal endoscopy and UGIS, as they
enable visualization of the gastrointestinal tract.
Upper gastrointestinal endoscopy allows direct visualization of the gastric mucosa,
and biopsy can be performed at suspicious sites for the diagnosis of premalignant le-
sions as well as gastric cancer. Recently, advanced endoscopic imaging techniques
such as narrow band imaging, autofluorescence imaging, magnification endoscopy,
and confocal laser endomicroscopy have been increasingly used for diagnosis.44–47
UGIS, also known as barium meal, allows identification of malignant gastric ulcers
and infiltrating lesions including some early gastric cancers. It was used as the initial
tool for gastric cancer screening from the early 1960s in Japan and showed reduction
in gastric cancer mortality by 40% to 60% in case-control studies.13,48 Recent studies
have reported higher sensitivity in cancer detection with upper gastrointestinal endos-
copy compared with UGIS. A study from Japan reported the detection rate of gastric
cancer by upper gastrointestinal endoscopy to be 2.7- to 4.6-fold higher than that of
UGIS.4,7 Two Korean studies showed the probability of detecting gastric cancer with
upper gastrointestinal endoscopy was 2.9- to 3.8-fold higher than that of UGIS.6,8 In
recent years, upper gastrointestinal endoscopy has been increasingly used for gastric
cancer screening and has become the primary modality for screening in South Korea
and Japan.42,49 The reported sensitivities and specificities of upper gastrointestinal
endoscopy and UGIS in the National Cancer Screening Program of South Korea
and Japan are summarized in Table 1.6,8,52,53
However, it should be noted that the cost of upper gastrointestinal endoscopy is
quite low in these countries (approximately 40 US dollars in South Korea). In most
other countries, upper gastrointestinal endoscopy is an expensive procedure, which
 Screening for Gastric Cancer 491

Table 1
Sensitivity and specificity of upper gastrointestinal endoscopy and upper gastrointestinal
series in the National Cancer Screening Program of South Korea and Japan

Follow- Upper Gastrointestinal Endoscopy UGIS

up Positive Positive
Period Sensitivity Specificity Predictive Sensitivity Specificity Predictive
Author (y) (%) (%) Value (%) (%) (%) Value (%)
Lee 1 59.0 96.3 6.1 42.1 89.8 0.8
et al,8
2010
Choi 1 69.0 96.0 6.2 36.7 96.1 1.7
et al,6
2012
Hamashima 1 88.6 85.1 - 83.1 85.6 -
et al.,52
2013

Data from Refs.6,8,50,51

makes the implementation of national screening program difficult, along with the need
for additional experienced endoscopists and potential complications.52,53

NATIONAL SCREENING PROGRAM OF GASTRIC CANCER

Screening for gastric cancer has been introduced in several East Asian countries with
a high incidence of gastric cancer. At present, Korea and Japan are the only countries
that have implemented population-based nationwide gastric cancer screening pro-
gram. In Singapore and Taiwan, screening program is mainly targeted at high-risk
populations.4 Many other countries do not have nationwide screening programs for
gastric cancer, especially in areas with low incidence rates of gastric cancer including
United States and most Europe countries.

South Korea
South Korea has the highest incidence of gastric cancer in the world.2 It was the first
country to introduce upper gastrointestinal endoscopy as a nationwide gastric cancer
screening method. The National Cancer Screening Program (NCSP) was launched in
1999 by the Ministry of Health and Welfare in South Korea. NCSP has provided bien-
nial screening for gastric cancer with upper gastrointestinal endoscopy or UGIS for in-
dividuals aged 40 years and older.54 The participation rates for gastric cancer
screening increased from 7.40% in 2002 to 45.40% in 2011. In terms of screening mo-
dality, upper gastrointestinal endoscopy has been increasingly used compared with
UGIS, from 31.15% in 2002 to 72.55% in 2011.49 In addition, quality assurance is
required based on the law, and the screening results are collected to the national can-
cer registry.
Since the NCSP began, the risk of death from gastric cancer has decreased by 47%
with upper gastrointestinal endoscopy.10 In South Korea, cost of upper gastrointes-
tinal endoscopy is similar to that of UGIS. Considering the low cost of upper gastroin-
testinal endoscopy, the high incidence of gastric cancer, and the effect in reducing
gastric cancer mortality, upper gastrointestinal endoscopy seems to be the most
cost-effective modality of gastric cancer screening in South Korea.8,42
492 Kim & Cho

Japan
Japan was the first country to introduce nationwide gastric cancer screening program.
It was initially introduced in Miyagi Prefecture with UGIS in 1960. In 1983, nationwide
gastric cancer screening program with UGIS was adopted for individuals aged 40
years and older.38 In 2015, upper gastrointestinal endoscopy was added to the Jap-
anese guideline for gastric cancer screening.55 In the updated guideline released in
2018, population-based nationwide screening is recommended for individuals aged
50 years and older with upper gastrointestinal endoscopy or UGIS.56,57 The participa-
tion rate of gastric cancer screening in Japan differs largely among the municipalities
and has been reported to increase from 20.7% to 26.7% after the introduction of up-
per gastrointestinal endoscopy as a screening method.57,58 The cost for upper gastro-
intestinal endoscopy in Japan is around $112 US dollars. As in South Korea, upper
gastrointestinal endoscopy is increasingly preferred as screening modality compared
with UGIS in Japan.57,59 The Japanese government collects the results of cancer
screening and publishes a summary every year.

Other Countries
In Taiwan, gastric cancer screening program has been implemented in Matsu Island,
where gastric cancer incidence is relatively high. In 1995, screening program with up-
per gastrointestinal endoscopy was recommended to individuals with low serum level
of PG (<30 ng/mL).60 In 2004, Taiwanese Ministry of Health initiated population-based
H pylori eradication program, which provided upper gastrointestinal endoscopy and H
pylori eradication for individuals who were tested positive for C-urea breath test.61
In Singapore, gastric cancer screening is targeted at high-risk groups rather than
population-based nationwide screening. A cost-benefit study of endoscopic
screening for gastric cancer in Singapore concluded that endoscopic screening was
cost-effective in moderate- to high-risk groups such as Chinese men aged 50 to
70 years.4,62
China has no nationwide screening program but has adopted gastric cancer
screening for high-risk groups in some regions with high incidence of gastric cancer.
In 2008, two-step screening program including upper gastrointestinal endoscopy was
adopted in high-risk regions in China, including Wuwei, Linqu and Zhuanghe, by the
Central Financial Transfer Payment Projects.63,64

EFFECTIVENESS OF SCREENING PROGRAM OF GASTRIC CANCER: MORTALITY

REDUCTION

To date, no randomized controlled trial has been conducted regarding the effect of
gastric cancer screening on mortality and is difficult to conduct. Several case-
control studies and cohort studies were performed in Japan, South Korea, and
China.10,65–74 In a recent meta-analysis including 4 case-control studies and 6 cohort
studies in Asia, which comprised about 34,000 individuals, endoscopic screening for
gastric cancer was associated with 40% reduction of gastric cancer mortality (Fig. 1).
There was no association between endoscopic screening and the incidence of gastric
cancer.74 Although significant heterogeneity between the included studies and
possible confounding effect by H pylori, the investigators concluded that upper
gastrointestinal endoscopy for gastric cancer screening may reduce the risk of gastric
cancer mortality in Asian countries.74 Several case-control studies and cohort studies
conducted in Japan reported a 31%–79% reduction in mortality of gastric cancer in
individuals screened with upper gastrointestinal endoscopy.65,66,68,69,71,72 The largest
study was conducted in South Korea as a nested case-control study with 27,290
 Screening for Gastric Cancer 493

Fig. 1. Forest plot of reduction of gastric cancer morality after endoscopic screening. ID,
identification. (From Zhang X, Li M, Chen S, et al. Endoscopic Screening in Asian Countries
Is Associated With Reduced Gastric Cancer Mortality: A Meta-analysis and Systematic Re-
view. Gastroenterology. 2018;155(2):347 to 354 e349; with permission.)

individuals aged 40 years or older.10 The study analyzed the effect of NCSP with upper
gastrointestinal endoscopy and UGIS on gastric cancer mortality and compared the
effect between 2 different screening modalities. The risk for gastric cancer mortality
was reduced by 47% for ever-screened individuals with upper gastrointestinal endos-
copy compared with individuals who were never screened. Interestingly, endoscopic
screening showed a dose-dependent effect in gastric cancer mortality. In individuals
who underwent endoscopy twice, gastric cancer mortality was reduced by 68% and in
individuals who underwent endoscopy 3 times or more, gastric cancer mortality was
reduced by 81%. Also, analysis of time interval from the last screening date to the
diagnosis date of gastric cancer showed the effect in mortality reduction remained sig-
nificant even in intervals of 48 months or more. Individuals who were ever screened
with UGIS only did not show significant reduction in gastric cancer mortality.

ISSUES AND CONCERNS OF SCREENING PROGRAM

Screening Interval
The interval of gastric cancer screening is important in the aspect of medical cost and
the risk of gastric cancer progression. Short intervals may warrant early detection, but
problems such as patient compliance, medical cost, and lack of facilities arise. Long
screening intervals may be economical, but risk of gastric cancers detected in
advanced stage cannot be excluded. A study of 2362 patients that aimed to evaluate
the effect of endoscopic screening interval on overall survival of patients with gastric
cancer concluded that endoscopic evaluation with 1 to 3 years interval before gastric
cancer diagnosis reduced overall mortality of patients with gastric cancer.75 The study
also conducted a spline analysis and confirmed a U-shaped relationship between the
endoscopic screening interval and the mortality risk and concluded that screening in-
terval of 32 months seems to be associated with the lowest overall mortality (hazard
ratio, 0.65; 95% confidence interval 0.52–0.81).75
494 Kim & Cho

Cost-effectiveness
Cost-effectiveness analysis was conducted in several countries including United
States. In United States, one study evaluated the incremental cost-effectiveness ratio
(ICER) of one-time screening of gastric cancer at the age of 50 years and concluded
that the ICER for screening remained high.76 Another study reported that endoscopic
screening is cost-effective for Asian Americans, especially for Japanese, Korean, and
Chinese Americans aged 50 years or older in the United States.77
In South Korea, several studies regarding cost-effectiveness were conducted, as
the Korean government requires such studies as a report of the NCSP program. Until
now, 3 studies reported the screening program to be cost-effective, and endoscopic
screening was a more cost-effective strategy compared with UGIS.8,42,78 One study
using time-dependent Markov model comparing different screening methods and in-
tervals concluded that annual endoscopy was most cost-effective in men aged 50–
80 years and biennial endoscopy was most cost-effective in women aged 50–
80 years.8 Similarly, one Japanese study reported upper gastrointestinal endoscopy
to be the best method for detecting early gastric cancer and the most cost-effective
strategy compared with other screening methods including UGIS.7

Missed Cancers and Endoscopic Quality

Missed cancer rates vary by country, with 2% to 10% in Western populations and
20% to 40% in Eastern Asia. Differences in gastric cancer incidence, indication,
and adoption of screening programs may have contributed to the discrepancy.79 A
recent Japanese study reported that an endoscopist with experience in less than
500 cases of upper gastrointestinal endoscopy was associated with 3-fold increased
risk of missed gastric cancer.80 A recent Korean study reported that observation time
of longer than 3 minutes or more increased the detection rate of early gastric cancer
and gastric dysplasia compared with observation time of less than 3 minutes.81 The
European Society of Gastrointestinal Endoscopy (ESGE) quality improvement initiative
recommended several performance measures including procedure time of minimum
7 minutes for the first diagnostic upper gastrointestinal endoscopy.82

SURVEILLANCE IN HIGH-RISK POPULATION

Although screening programs in South Korea and Japan are known to be effective in
reducing mortality and are cost-effective, it should be noted that the cost of upper
gastrointestinal endoscopy is low and the incidence of gastric cancer is high in these
countries. Such nationwide population-based screening programs would be difficult
to apply in others countries with low incidence of gastric cancer or with limited medical
resources. Therefore, in many other countries, upper gastrointestinal endoscopy is
targeted to high-risk population as a surveillance strategy. Currently, however, no
standardized international recommendations have been established.

Atrophic Gastritis, Intestinal Metaplasia, and Gastric Dysplasia

Atrophic gastritis and intestinal metaplasia are well known as the precursor lesions of
gastric cancer.83 Chronic inflammation of gastric mucosa is known to trigger a
sequence of chronic active gastritis, atrophic gastritis, intestinal metaplasia,
dysplasia, and gastric adenocarcinoma.84 Thus, surveillance of gastric cancer is
considered to be important in patients with gastric atrophy, intestinal metaplasia,
and dysplasia.
A multidisciplinary group in Europe including the ESGE published management
guidelines for precancerous conditions and lesions in the stomach (MAPS) in 2012.
 Screening for Gastric Cancer 495

The guidelines emphasize surveillance in high-risk groups with gastric atrophy, intes-
tinal metaplasia, and dysplasia. Suggested surveillance interval varies according to
the degree and extent of atrophy and intestinal metaplasia and grade of dysplasia,
which ranges from 6 months to 3 years. However, this guideline does not address
screening methodologies in general populations.85
On the contrary, a recent guideline on management of gastric intestinal metaplasia
published by the American Gastroenterological Association suggests against routine
use of endoscopic surveillance in patients with gastric intestinal metaplasia. The
guideline suggested patients with gastric intestinal metaplasia at higher risk for gastric
cancers, such as patients with family history of gastric cancer, ethnic minorities, or pa-
tients with extensive gastric intestinal metaplasia, may elect for surveillance.19
In Japan, a recent recommendation suggested 1- to 2-year surveillance in patients
with gastric atrophy.86 Another study reported the usefulness of surveillance using risk
stratification by H pylori serology in combination with PG test results and recommen-
ded 1-year surveillance for H pylori-negative and PG-positive cases.40

Family History
Individuals with family history of gastric cancer are associated with higher risk of
gastric cancer with odds ratio ranging from 2 to 10.87 However, there was no definite
endoscopic surveillance guidelines of family members of patients with sporadic
gastric cancer. A small portion of gastric cancer is related to hereditary syndromes.
In family members of hereditary diffuse gastric cancer, annual endoscopic surveillance
with high-definition endoscope is recommended in individuals who did not receive
gastrectomy.88

Surveillance for Metachronous Gastric Cancer

Patients with history of gastric cancer treated with surgery or endoscopic resection
have a risk for cancer development in the remnant stomach. Previous studies have re-
ported the incidence of metachronous gastric cancer of about 3% to 4% per
year.80,89,90 In a Japanese guideline, the interval of endoscopic surveillance after
endoscopic resection of gastric cancer was recommended to be annual or biannual.91
Several other studies recommend the endoscopic follow-up interval to be within
3 months for the initial follow-up, 6 months, and then 12 months.80,92

SUMMARY

Gastric cancer is one of the most common cancers worldwide. The incidence varies
widely by geographic region, with half of new cases occurring in East Asia.
Population-based nationwide screening for gastric cancer is implemented in some
Eastern Asian countries with high incidence of gastric cancer including South Korea
and Japan. Upper gastrointestinal endoscopy is increasingly preferred as a screening
method. Endoscopic screening for gastric cancer decreased the mortality of gastric
cancer and the effect on mortality reduction was superior to UGIS. Endoscopic
screening is a cost-effective screening modality in countries with high incidence of
gastric cancer and an interval of 1 to 3 years seems optimal. To reduce missed can-
cers and improve screening quality, sufficient procedure time and endoscopic expe-
rience should be achieved. In countries with low incidence of gastric cancer,
surveillance targeted to high-risk population such as individuals with atrophy, intesti-
nal metaplasia, gastric dysplasia, family history of gastric cancer, and previous history
of gastric cancer should be considered.
496 Kim & Cho

CLINICS CARE POINTS

 Population-based endoscopic screening of gastric cancer decreased gastric cancer mortality

in countries with high incidence of gastric cancer such as South Korea and Japan. In these
countries, endoscopic screening is a cost-effective modality. However, the benefit and cost-
effectiveness of population-based screening is uncertain in countries with low incidence of
gastric cancer.
 Sufficient procedure time and endoscopic experience should be achieved to reduce missed
cancers and improve screening quality.
 In countries with low incidence of gastric cancer, surveillance targeted to high-risk
population such as individuals with atrophy, intestinal metaplasia, gastric dysplasia, family
history of gastric cancer, and previous history of gastric cancer should be considered.

DISCLOSURE

This study was supported by grants from the National Research Foundation of Korea
(#NRF-2019R1A2C1009923), the Korean College of Helicobacter and Upper Gastro-
intestinal Research Foundation (#KCHUGR - 202002001), and the SNUH research
fund (#03-2020-0370).

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 Screening for Gastric Cancer 501

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Improving t h e Ear l y
Diagnosis of Gastric Cancer
Robert J. Huang, MD, MS*, Joo Ha Hwang, MD, PhD

KEYWORDS
 Helicobacter pylori  Intestinal metaplasia  Endoscopic screening  Early detection
 Cancer stage  East Asia

KEY POINTS
 Patients are diagnosed with gastric cancer at more advanced stages and have overall
lower survival in the United States compared with East Asia.
 Observational data from Japan and South Korea, nations with national gastric cancer
screening programs, show that endoscopic screening may improve gastric cancer
mortality.
 In the United States high-risk racial/ethnic groups (Alaskan Natives, American Indians,
Asians, Blacks, Hispanics), first-generation immigrants form high-incidence regions,
and individuals with a family history may benefit from screening.
 Individuals with intestinal metaplasia, particularly extensive or histologically severe dis-
ease, may benefit from endoscopic surveillance.
 A video of use of chromoendoscopy to enhance detection of gastric intestinal metaplasia
accompanies this article.

Video content accompanies this article at http://www.giendo.theclinics.com.

INTRODUCTION

Every year 1.2 million persons are diagnosed with and 860,000 persons die from
gastric cancer (GC) worldwide,1 making GC the fifth leading cause of cancer incidence
and third leading cause of cancer mortality, respectively.2 Outcomes from GC in most
of the world remain poor, including in the United States (US). In the US, GC afflicts
27,000 each year3 and carries a dismal prognosis (5-year survival of 27%).4 These sta-
tistics reflect the fact that most of the GCs in the US are diagnosed at advanced
stages,4 where curative resection is unlikely. Strategies to improve the early diagnosis
of GC are therefore crucial to improving survival.

Division of Gastroenterology and Hepatology, Stanford University, 300 Pasteur Drive, Alway
Building M211, Stanford, CA 94305, USA
* Corresponding author.
E-mail address: rjhuang@stanford.edu

Gastrointest Endoscopy Clin N Am 31 (2021) 503–517

https://doi.org/10.1016/j.giec.2021.03.005 giendo.theclinics.com
1052-5157/21/ª 2021 Elsevier Inc. All rights reserved.
504 Huang & Hwang

GCs are classified as cardia or noncardia based on the anatomic location of origin
within the stomach. Cardia GCs, which share risk factors and natural history with
esophageal adenocarcinomas, constitute approximately one-quarter of GCs world-
wide.5 Noncardia GCs constitute three-quarters of GCs worldwide, have witnessed
improvements in outcomes following adoption of screening programs in nations of
East Asia,6,7 and are the focus of this review.

HELICOBACTER PYLORI AND CORREA’S CASCADE

Development of noncardia GC has been linked, in multiple epidemiologic studies, with

infection with the gram-negative, microaerophilic organism H pylori (Hp).8,9 Worldwide
Hp prevalence rates range from less than 40% in industrialized nations of Western
Europe and North America to greater than 70% in areas of South America, Africa,
Eastern Europe, and East Asia.10 Hp infection is associated with a 3-fold increase in
lifetime odds of development of noncardia GC; moreover, Hp is believed responsible
for 75% to 95% of all GC cases worldwide.11,12 Colonization with Hp induces a state
of chronic inflammatory insult that leads to a cascade of mucosa perturbations,
termed Correa’s cascade (Fig. 1).13 In Correa’s cascade, chronic gastritis is followed
by progressive atrophy of the oxyntic or antral gastric mucosa and then eventual
replacement by intestinal mucosa consisting of Paneth, goblet, and absorptive cells.
Intestinal metaplasia (IM) of the stomach is an important precursor lesion in the
pathway to GC,14–17 and regional prevalence of IM correlates closely with incidence
of GC worldwide.18 Even with decreasing prevalence of Hp, with the secular aging
of the global population GC cases and deaths are expected to climb well into the
twenty-first century.19,20

GASTRIC CANCER SCREENING AND OUTCOMES IN EAST ASIA

The incidence of GC is significantly higher in nations of East Asia compared with the
US. Although the incidence of GC is roughly 6 per 100,000 in the US, it is approxi-
mately 28 per 100,000 in Japan and 34 per 100,000 in South Korea. Yet although inci-
dence of GC is much higher in these countries, survival from GC is also higher
compared with the US or Western Europe (Fig. 2). Five-year observed survival from
GC exceeds 60% in both South Korea and Japan, compared with less than 30%
for the US and Western Europe.21,22 These differences in survival are due in large
part to differences in stage of diagnosis. Although nearly 60% of GCs are diagnosed
at a surgically or endoscopically curable stage in South Korea and Japan, fewer than a
quarter of GCs are diagnosed at such stages in the West.4,23–25
In Japan, a national screening program for GC was first introduced in 1983. This
program consisted of radiography-based screening of all adults older than or equal
to 40 years, with endoscopic examination performed on individuals with abnormal
radiographic results.26 Based on the results of several rigorous observational studies,
the national screening program was amended in 2016 to allow for either endoscopic or
radiographic screening for adults older than or equal to 50 years on a biennial basis.26

Fig. 1. Proposed carcinogenic cascade induced by Helicobacter pylori (Hp) and other envi-
ronmental insult. Patients with atrophic gastritis, intestinal metaplasia, and dysplasia remain
at increased risk for gastric cancer even following Hp eradication.
 Improving the Early Diagnosis of Gastric Cancer 505

Fig. 2. Left panel depicts 5-year observed survival following gastric cancer diagnosis in East
Asia (South Korea, Japan) and Western nations (United States and Europe). Right panel de-
picts the proportion of all gastric cancers diagnosed at localized stage based on United
States National Cancer Institute summary staging. (Data from Refs.4,23–25)

Although endoscopic screening is rapidly being adopted throughout Japan, radio-

graphic screening is still the predominant screening modality in most prefectures.27
South Korea initiated a biennial screening program consisting of either endoscopic
or radiographic screening for adults older than or equal to 40 years in 2002.28 In prac-
tice, endoscopic screening has been the predominant modality practiced in South Ko-
rea due to patient preference. Since the initiation of the national screening program,
the proportion of GCs diagnosed as early GC (defined as tumor with invasion limited
to mucosa or submucosa) has increased from 39% in 2001 to 73% in 2016.29 More-
over, observed 5-year survival has increased from 46% to 75%.29

EFFICACY AND SAFETY OF SCREENING MODALITIES

Radiographic Screening
Radiographic screening involves the ingestion of a contrast agent (often barium)
and subsequent fluoroscopic imaging of the gastric lumen. Contrast radiography
allows for the detection of luminal pathology including ulcers, polyps, and masses.
However, compared with modern endoscopy, radiography has both limited sensi-
tivity and specificity.30 Cancer registry data suggest that the sensitivity of radio-
graphic screening ranges from 60% to 80% and specificity from 80% to 90%.6 It
should also be noted that for early GC (where a luminal prominence or depression
may be minimal), the sensitivity of radiography has been reported to be significantly
lower (14%–36%).31,32
The efficacy of radiographic screening has been assessed in several observational
studies, including both cohort and case-control studies,26 although notably no ran-
domized controlled trial has been conducted comparing radiographic screening
with standard of care. From cohort studies from Japan33,34 comparing radiographic
screening with no screening over long-term follow-up (11–13 years), receiving radio-
graphic screening was associated with both reductions in GC-specific mortality (rela-
tive risk 0.52–0.54) as well as all-cause mortality (relative risk 0.71–0.83). However,
during the period of these studies radiography was also a standard test for assess-
ment of gastrointestinal symptoms, introducing the possibility of confounding by indi-
cation. Moreover, receipt of subsequent screening (such as by endoscopy) in the
follow-up period was not ascertained possibly causing overestimation of the effect
size. The safety profile of radiographic screening is generally favorable, with mild
risk of constipation or ileus and rare cases of aspiration pneumonia.6 In a report of
more than 3 million radiographic screening procedures performed, only a single death
was attributed to an adverse event related to screening.26 Radiation exposure from
506 Huang & Hwang

photofluorographic screening is in the range of 0.6 mSv (by comparison a standard

chest radiograph exposure is approximately 0.1 mSv).
As a relatively safe and inexpensive modality, radiography may continue to serve a
role for GC screening in resource-limited settings. However, as the primary motivation
for screening is to improve the detection of early stage cancers, radiography has
limited utility compared with modern, high-resolution gastrointestinal endoscopy.
Moreover, when an abnormality is detected through radiography, a confirmatory up-
per endoscopy is required for visualization and tissue acquisition.

Endoscopic Screening
Since 2001 in South Korea and 2016 in Japan,29 endoscopic screening has been
offered as an alternative modality to radiographic screening. Endoscopic screening of-
fers several advantages to radiographic screening, including the ability to directly visu-
alize the gastric mucosa and tissue sampling of abnormal-appearing tissue or visible
lesions. Compared with radiographic screening, endoscopic screening demonstrates
both better sensitivity and specificity.26,35 This increased sensitivity is especially
important for early GCs that demonstrate only subtle mucosal changes and that
may not have an elevated or depressed component visible on contrast radiography.
Techniques to enhance mucosal contrast have been developed to improve detection
of subtle lesions, such as narrow-band imaging and chromoendoscopy (Video 1). In
narrow-band imaging, conventional white light is filtered into defined wavelengths in
order to maximize absorption by hemoglobin, as well as limit penetration of light
beyond the mucosal surface. Given this shorter wavelength, the resulting “blue” light
penetrates less deeply than conventional white light and may improve contrast of the
mucosal surface. Chromoendoscopy also serves to amplify contrast of mucosal le-
sions through the use of dye-based staining of the gastric mucosa with biologically
compatible agents such as acetic acid or methylene blue.36,37 Application of dilute
acetic acid can modify the optical properties of the epithelium by slightly altering
the pH or by reversibly altering the structure of cellular proteins to reflect white light.
Methylene blue is actively absorbed by small intestinal epithelium but not normal
gastric epithelium, enhancing contrast between metaplastic and normal gastric
epithelium. Chromoendoscopy may improve the delineation of surface irregularities,
which in turn may improve the diagnosis and staging of early GCs.38 Early GC detec-
tion may allow for opportunities for endoscopic resection through endoscopic submu-
cosal dissection (ESD, Fig. 3). For GCs confined to the mucosa or proximal
submucosa (with invasion depth of <500 microns) and without lymph node involve-
ment, ESD offers similar cure rate and fewer rates of adverse events compared with
surgical gastrectomy based on retrospective series from East Asia.39,40
The efficacy of endoscopic screening in decreasing cancer-specific mortality has
been evaluated in observational studies form East Asia. A systematic review and
meta-analysis of the protective effect of endoscopic screening on cancer-specific
mortality identified 10 studies (6 cohort studies and 4 case-control studies) from South
Korea, Japan, and China.41 Receipt of endoscopic screening was associated with an
approximate 40% reduction in risk for GC-specific mortality in the pooled estimate,
with a robust protective effect found compared both against no-screening and radio-
graphic screening controls.41 When reviewing the existing evidence in support of
endoscopic screening, the Japanese Guideline Development Group initially found
inadequate observational data to justify population-level endoscopic screening in
2008.6,42 However, based on the results of numerous high-quality observational
studies published after 2008, the Japanese guidelines were amended to favor endo-
scopic screening in 2018 with an evidence score of 21 (moderate-quality case-control
 Improving the Early Diagnosis of Gastric Cancer 507

Fig. 3. Top left panel depicts a subtle, flat, erythematous lesion, which was biopsied to be
gastric adenocarcinoma. Use of narrow-band imaging (top right) enhances visualization
and delineation of the lesion. This lesion was staged as an early gastric cancer (tumor inva-
sive to no deeper than mucosa or submucosa) and removed by endoscopic submucosal
dissection (bottom left). En bloc resection specimen (bottom right) confirmed tumor
confined to mucosal layer, without lymphovascular invasion and with negative lateral and
deep margins consistent with curative resection.

and cohort studies with a low risk for bias, confounding or chance, and a moderate
probability that the relation is causal).26 Notably, the primary endpoint of these studies
has been GC-specific mortality (as opposed to overall mortality). Currently no random-
ized controlled trial data exist for the benefits of endoscopic screening.
In the US and Europe most upper endoscopies are performed under sedation (either
moderate or deep). The risk of cardiopulmonary events related to sedation has been
estimated to be between 1 in 170 and 1 in 10,000, with the higher range of estimates
incorporating minor events (such as changes in oxygen saturation or heart rate).43 The
Japanese Association of Gastroenterological Cancer Screening has found an overall
rate of complications of 87 per 100,000 for endoscopic screening and 43 per
100,000 for radiographic screening.26

Serologic Screening
Hp-induced inflammation begins in the antrum and proceeds upward to the corpus
with chronic infection. Human pepsinogens are classified into 2 biologically distinct
types, pepsinogen I and pepsinogen II. As inflammation proceeds toward the corpus
with chronic Hp infection, levels of pepsinogen I (produced by chief cells in the corpus)
decrease, whereas levels of pepsinogen II remain more constant.44 As such, a
508 Huang & Hwang

decreased level of pepsinogen I and decreased pepsinogen I/II ratio may indicate
advanced atrophic gastritis.44 Serum pepsinogens in combination with Hp IgG anti-
body have been evaluated as noninvasive screening tools in East Asian cohorts.45–47
However, use of these markers demonstrate significant limitations including a high de-
gree of heterogeneity in reported testing characteristics between populations,
differing cutoff points, and variability based on proton pump inhibitor use.48,49 These
methods are not currently used for population-level screening in either South Korea or
Japan. Their use may also be limited in Western populations, which differ in preva-
lence of Hp infection, proton pump inhibitor therapy use, and rates of autoimmune
atrophic gastritis.49,50

GASTRIC CANCER SCREENING IN THE UNITED STATES

At-risk Populations
In the US, GC survival is poor (5-year observed survival of 27%) and most of the can-
cers are diagnosed at regional or distant stages.4 Although overall incidence of GC is
modest among the general population (w6 per 100,000), certain high-risk racial
(Asians, Alaskan Indians, American Indians, Blacks/African Americans) and ethnic
(Hispanics) groups may face significantly higher risk (Fig. 4). Very high-risk subgroups
such as Japanese and Korean Americans face an incidence 6- to 8-fold higher than
non-Hispanic Whites.51 Beyond race and ethnicity, Americans at increased risk for
GC include those with a family history or with cancer-predisposing syndromes, recent
immigrants from high-incidence regions of the world, those with a history of Hp infec-
tion, and those with precancerous changes of the stomach.29 It behooves both clini-
cians and policy makers to be cognizant of high-risk groups and to offer appropriate
counseling for the role of preventative strategies such as GC screening.
IM is a critical precursor lesion to GC, and prevalence of IM in populations correlates
with GC incidence. In the US, the prevalence of IM has been estimated to be between
5% and 10% of the general population.52,53 High-risk subgroups including certain
racial and ethnic minorities may have IM prevalence several-fold higher.54,55 Within
the US, there seems to be a close association between prevalence of IM with

Fig. 4. Crude incidence of gastric cancer in United States (per 100,000; Y-axis) plotted by age
group (X-axis). Asians, Blacks, Hispanics, and American Indian/Alaskan Natives face a several-
fold increased risk compared with non-Hispanic Whites. (Data from the Surveillance, Epide-
miology, and End Results (SEER) Program (www.seer.cancer.gov) Research Data (1973-2015),
National Cancer Institute, DCCPS, Surveillance Research Program released in April 2018
based on the November 2017 submission.)
 Improving the Early Diagnosis of Gastric Cancer 509

incidence of GC within racial subgroups (Table 1). These data suggest that all racial
and ethnic groups are at risk for GC once IM has developed. Although gastritis and
atrophy may reverse and normalize following Hp eradication, IM often persists.56,57
Moreover, long-term clinical follow-up suggests that patients with IM remain at
increased risk for GC even after eradication of Hp.58,59
The annual rate of progression onto GC from IM is estimated to be approximately
0.25%.60 However, this aggregation of risk does not capture the variability of presen-
tation in IM histologic severity or topographic distribution. In order to estimate histo-
logic severity, scoring systems such as the operative link for gastritis assessment
(OLGA)61 for atrophic gastritis and the operative link for gastric IM (OLGIM) for IM
have been developed (Fig. 5).62 OLGA and OLGIM rely on both an assessment of
the topographic extent of disease as well as the percentage of glandular involvement
from each biopsy location using a visual-analogue scale.63 The resultant stage score,
ranging from 0 (no IM or no atrophy) to 4 (severe, extensive IM or atrophy), has been
validated in several observational studies as risk-stratification tools for progression
onto subsequent GC.64–67 Use of the OLGA and OLGIM systems depends on consis-
tent sampling of multiple locations of the stomach (including antrum, incisura, and
corpus/body) in a systematic manner termed the “Sydney Protocol.”63 Another prom-
ising method of histologic risk stratification is through distinguishing complete IM from
incomplete IM. Complete IM is characterized by well-defined goblet cells and a well-
developed brush border, whereas in incomplete IM mucin droplets of varying sizes
and shapes can be found and there is an absence of a brush border.68 In specialized
centers where mucin staining is available, complete IM will be found to display pre-
dominantly small intestinal phenotypic markers such as MUC2 and sucrase, whereas
incomplete IM only selectively or incompletely expresses small intestinal markers but
may express gastric phenotypic markers such as MUC5AC and large intestinal pheno-
typic markers such as Das-1.69

Current Recommendations
Recommendations for GC screening or precancerous lesion surveillance by US-
based professional societies are depicted in Table 2. Currently, the American Society
of Gastrointestinal Endoscopy (ASGE) has recommended endoscopic screening for
GC in first-generation immigrants from high-risk regions (ie, Japan, China, Russia,
and South America) older than 40 years, in particular if there is a family history of
GC in a first-degree relative.70 Regarding surveillance of patients with precancerous
lesions, the ASGE recommends surveillance of patients with atrophic gastritis or IM
when there is increased risk of GC due to ethnic/racial background, positive family his-
tory, or extensive anatomic distribution of disease.14,70 By contrast, the American
Gastroenterological Association (AGA) recommends against the routine use of

Table 1
Estimated prevalence of intestinal metaplasia and incidence of gastric cancer in racial/ethnic
groups in the United States

Racial/Ethnic Group Prevalence of IM (%) Incidence of GC References

4,21,52,54
Non-Hispanic Whites 7–9 6–8 per 100,000
4,21,55
Non-Hispanic Black 21 11 per 100,000
4,21,54,55
Hispanics 12–30 11 per 100,000
51,54
Chinese 26 15 per 100,000
51,54
Koreans 40 45 per 100,000
510 Huang & Hwang

Fig. 5. Scoring of gastric precancerous lesions using the Operative Link systems. In these
scoring systems, biopsies from the gastric antrum and body are individually scored for de-
gree of atrophic gastritis and intestinal metaplasia using a visual-analogue scale (none,
mild, moderate, marked). A summary stage for both atrophy and intestinal metaplasia is
then assigned.

endoscopic surveillance in patients with IM but clarifies that this is a conditional

recommendation based on very low-quality evidence.71 The AGA guidelines further
state that “Patients with IM at higher risk for GC who put a high value on potential
but uncertain reduction in GC mortality, and who put a low value on potential risks
of surveillance endoscopies, may reasonably elect for surveillance.” The AGA guide-
lines identify patients with IM at higher risk for GC as those with incomplete IM, those
with extensive IM, and those with a family history of GC. The AGA guidelines also iden-
tify patients at overall increased risk for GC including racial/ethnic minorities and im-
migrants from high-incidence regions. Notably neither the ASGE nor the AGA have
made recommendation on the optimal interval for surveillance of IM if this strategy
is pursued.

FUTURE SCREENING MODALITIES

Promising biomarkers currently under development or validation may revolutionize

early GC detection and prevention. MicroRNAs (miRNAs) are small, noncoding mole-
cules involved in biological processes including cell-cycle progression and apoptosis.
Given their stability, presence in blood, and role in numerous pathways, miRNAs have
been evaluated as potential biomarkers for GC. Five miRNAs have shown particular
promise as screening tests for GC: miR-2172–74 (inhibitor of tumor suppressor genes),
miR-106a75,76 (cell proliferation signal), miR-106b77,78 (inhibitor of apoptosis), miR-
22373,79 (cell proliferation and invasion), and miR-42180–82 (apoptosis resistance).
Notably, these miRNAs have mostly been evaluated in cohorts from East Asia where
the prevalence of Hp and incidence of GC is much higher. Additional prospective vali-
dation studies are required before translation of miRNAs to clinical practice.
Risk stratification of IM may also be improved through use of molecular markers. In
a prospective cohort study of high-risk Singaporean Chinese patients, IM biopsy sam-
ples with shortened telomeres and chromosomal aberrations were found to be asso-
ciated with subsequent progression to either dysplasia or frank carcinoma. By
 Table 2
Guidelines issued by United States professional societies

Society Year Recommendation

Gastric Cancer Screening
American Society of Gastrointestinal Endoscopy70 2015 Endoscopic screening for gastric cancer in first-generation immigrants from
high-risk regions (eg, Japan, China, Russia, and South America) may be
considered for those aged 40 y, particularly if there is a family history of
gastric cancer in a first-degree relative
Surveillance of Intestinal Metaplasia (IM)
American Society of Gastrointestinal Endoscopy14,70 2015 Endoscopic surveillance in patients with gastric atrophic gastritis or IM
coupled with an increased risk of gastric cancer because of racial/ethnic
background, extensive anatomic distribution, or family history
American Gastroenterological Association71 2019 Recommends against routine use of endoscopic surveillance in patients with
IM. Conditional recommendation, very low quality of evidence

Improving the Early Diagnosis of Gastric Cancer

Patients with IM at higher risk for gastric cancer who put a high value on
potential but uncertain reduction in gastric cancer mortality, and who put
a low value on potential risks of surveillance endoscopies, may reasonably
elect for surveillance
Patients with IM specifically at higher risk of gastric cancer include those
with
 Incomplete vs complete IM
 Extensive vs limited IM
 Family history of gastric cancer
Patients at overall increased risk for gastric cancer include
 Racial/ethnic minorities
 Immigrants from high-incidence regions

Existing recommendations from United States–based professional societies regarding screening of gastric cancer or surveillance of precancerous lesions such as IM.

511
512 Huang & Hwang

contrast, IM with normal-like epigenetic patterns were associated with stability or

regression.65 Although requiring validation, such a molecular signature for IM progres-
sion may serve as a valuable tool to allow for focused and highly personalized strate-
gies of surveillance while also avoiding unnecessary endoscopies in low-risk subjects.

SUMMARY

GC remains a devastating disease for the 27,000 Americans diagnosed each year.
Compared with East Asia, survival from GC in the US and Europe is lower, reflecting
a later stage of diagnosis. In high-incidence nations of East Asia, national screening
programs have been adopted. An emerging body of observational data suggests
that endoscopic screening may prevent GC-specific mortality in targeted populations.
There exist high-risk populations within the US who may benefit from targeted
screening, including racial/ethnic groups (American Indians, Alaska Indians, Asians,
Blacks, Hispanics), first-generation immigrants from high-incidence regions, and
those with a family history of GC. Individuals diagnosed with IM, particularly extensive
IM or histologically severe IM, may benefit from endoscopic surveillance. Emerging
molecular technologies may help to identify high-risk individuals who should be
screened, as well as stratify IM for risk of cancer progression.

CLINICS CARE POINTS

 Racial/ethnic minorities and first-generation immigrants are at increased risk for GC and may
benefit from endoscopic cancer screening.
 Patients diagnosed with incomplete, extensive, or severe IM should be offered endoscopic
surveillance.
 Use of narrow-band imaging and chromoendoscopy during endoscopy can improve the
detection of GC.

DISCLOSURE

RJH is supported by the National Cancer Institute of the National Institutes of Health
under Award Number K08CA252635. The content is solely the responsibility of the au-
thors and does not necessarily represent the official views of the National Institutes of
Health.

SUPPLEMENTARY DATA

Supplementary data related to this article can be found online at https://doi.org/10.

1016/j.giec.2021.03.005.

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C h e m o p re v e n t i o n A g a i n s t
Gastric Cancer
a,b, a
Shailja C. Shah, MD, MPH *, Richard M. Peek Jr, MD

KEYWORDS
 Gastric neoplasm  Helicobacter pylori  Aspirin
 Nonsteroidal anti-inflammatory drugs  Chemoprevention

KEY POINTS
 Helicobacter pylori eradication remains the mainstay form of chemoprevention against
noncardia gastric adenocarcinoma.
 However, the observations that the incidence of non-H. pylori associated gastric cancer is
rising, and gastric cancer still develops in people after H. pylori eradication highlights the
importance of investigations defining other effective chemopreventive agents.
 To date, many agents including aspirin, non-steroidal anti-inflammatory drugs, metformin,
statins, and alpha-difluoromethylornithine have been investigated in their role as chemo-
preventive agents in gastric cancer.
 Future randomized controlled clinical trials particularly for high-risk populations, such as
people with gastric preneoplastic mucosal changes are needed in order to provide guid-
ance on how to position the use of these agents for gastric cancer prevention.

BACKGROUND

Gastric cancer is the fifth most common cancer and third leading cause of cancer-
related mortality globally, accounting for approximately 1 million new cases annually
and more than 780,000 cancer-related deaths.1 Prevention and early detection are
two foundational pillars for addressing the substantial burden of gastric cancer. Early
detection provides the opportunity for potentially curative resection if gastric cancer is
diagnosed before submucosal invasion. However, except in the few countries where

Grant support: S.C. Shah is funded by a 2019 American Gastroenterological Association

Research Scholar Award and Veterans Affairs Career Development Award under award number
ICX002027A-01. R.M. Peek is funded by the NIH/NCI through the following awards: R01
DK58587, R01 CA 77955, P01 116087. The content is solely the responsibility of the listed au-
thors and does not necessarily represent the official views of the funding agencies listed.
Writing assistance: None.
a
Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, Vanderbilt
University Medical Center, 1030C MRB IV, 2215 Garland Avenue, Nashville, TN 37232-0252, USA;
b
Veterans Affairs Tennessee Valley Health System, Nashville Campus, Nashville, TN, USA
* Corresponding author.
E-mail address: shailja.c.shah@vumc.org

Gastrointest Endoscopy Clin N Am 31 (2021) 519–542

https://doi.org/10.1016/j.giec.2021.03.006 giendo.theclinics.com
1052-5157/21/Published by Elsevier Inc.
520 Shah & Peek

endoscopic screening for gastric cancer occurs, gastric cancer is most often diag-
nosed in the advanced stages, which is when symptoms present and prompt a diag-
nostic evaluation. Unfortunately, there are no curative options for advanced stage
disease and the 5-year survival rates are dismal at best. The vast majority of countries,
including the United States, do not screen for gastric cancer. Focused efforts on
gastric prevention, therefore, are key and represent the mainstay in these countries.
Attention to primary, secondary, and tertiary gastric cancer prevention, even in those
countries where gastric cancer screening does occur, decreases the downstream
health and economic burden associated with a gastric cancer diagnosis.
Cancer risk determinants can be divided into modifiable (eg, diet, smoking) and
nonmodifiable (eg, genetics, age) factors. Accordingly, interventions aimed at cancer
risk attenuation and prevention are focused on altering modifiable factors; for
example, via smoking cessation and nutritional education programs. Chemopreven-
tion is a critical adjunct, because these interventions alone are rarely sufficient. Che-
moprevention in the form of Helicobacter pylori eradication already forms the
foundation for gastric cancer prevention. However, the benefit is significantly attenu-
ated once more advanced gastric mucosal changes have occurred, because the risk
of gastric cancer persists despite H pylori eradication. As described elsewhere in this
article, H pylori eradication therapy decreases but does not eliminate the risk of meta-
chronous cancer (tertiary prevention), thus suggesting that there is a field effect that
persists even in the absence of ongoing H pylori infection. Further complicating the
picture is that there is an increase in observed non–H pylori associated noncardia
gastric adenocarcinoma in some populations, particularly as the prevalence of H pylori
decreases.2 For these reasons, chemopreventive agents aside from H pylori eradica-
tion alone should likewise be considered tenets to any successful gastric cancer con-
trol program.
In this article, we will discuss chemopreventive agents for intestinal-type noncardia
gastric cancer, with a predominant focus on H pylori eradication therapy and nonste-
roidal anti-inflammatory drugs (NSAIDs), including aspirin, because these agents have
the strongest and largest body of supporting data. Other putative chemopreventive
agents are discussed within the context of both clinical and experimental data.

Mechanisms
Having an in-depth understanding of the pathogenesis of intestinal-type noncardia
gastric adenocarcinoma (NCGA), along with modifying factors, is foundational to che-
moprevention research and the discovery of effective chemopreventive agents. NCGA
develops as a stepwise progression from chronic nonatrophic gastritis to atrophic
gastritis, intestinal metaplasia, and dysplasia, before the final malignant transforma-
tion in a very small proportion of individuals.3,4 The most common trigger for this
so-called Correa cascade is chronic infection with H pylori. Three nested case-
control studies, all published in 1991, demonstrated that people with H pylori infection
had a significant 3-fold to 6-fold higher likelihood of developing gastric cancer
compared with individuals without H pylori infection.5–7 Accordingly, the World Health
Organization and International Agency for Research on Cancer classified H pylori as a
definite biological carcinogen. A meta-analysis published by the Helicobacter and
Cancer Collaborative Group in 2001 with 10 additional years of data confirmed these
findings.8 Even though only a small percentage of individuals infected with H pylori
(<1%–3%) will have malignant complications, this number still represents a massive
burden of preventable disease because H pylori is estimated to infect more than
one-half the global population; indeed, approximately 90% of NCGA are attributable
to H pylori infection.9–11 Other environmental triggers for the inflammation–
 Chemoprevention Against Gastric Cancer 521

preneoplasia–neoplasia sequence, including chronic bile reflux, high dietary con-

sumption of salt and nitrites, the non–H pylori microbiome and metabolic byproducts,
and autoimmunity, can act independently or potentiate the pathologic effects of H
pylori.12
The complex interactions between these triggers, along with underlying host ge-
netic factors and microbial factors, including H pylori strain–specific factors, together
lead to a field effect of gastric mucosal changes; however, the exact molecular and
genetic underpinnings remain unclear. Depending on ongoing insults, progression
may or may not occur. DNA damage, as the downstream consequence of ongoing
inflammation and subsequent oxidative stress, is a fundamental process in gastric
carcinogenesis, even in the absence of H pylori. One study in a Mongolian gerbil
experimental model demonstrated that administering a diet containing a potent anti-
oxidant derived from canola oil (4-vinyl-2,6-dimethoxyphenol) resulted in a substan-
tially lower incidence of gastric adenocarcinoma, even though the H pylori bacterial
density was not changed.13 Similar findings were replicated in transgenic mice, where
administration of 4-vinyl-2,6-dimethoxyphenol was associated with significantly lower
levels of cyclo-oxygenase (COX)-2, IL-1B, and IL-12B expression and significantly
lower likelihood of spontaneous gastric tumor development.14 Collectively, these
data confirm that inflammation severity, not just H pylori infection alone, is likely the
more important factor in NCGA pathogenesis and underscores the importance of che-
mopreventive strategies apart from simply H pylori eradication alone.

H pylori Eradication Treatment as Chemoprevention Against Gastric Cancer

H pylori typically persists for the lifetime of the host unless eradicated with antibiotics
and high-dose acid suppression for a set duration. Before the formal discovery of H
pylori by J. Robin Warren and Barry Marshall in the late 1970s,15 the environmental
trigger for the Correa cascade was unknown and was thought most likely to be dietary.
Several subsequent studies unequivocally confirmed that chronic H pylori infection led
to chronic gastritis with or without continued progression along the carcinogenic
cascade.6–8,16
Since that time, several observational and interventional studies evaluating the ef-
fect of H pylori eradication versus no eradication on gastric cancer incidence have
been published, albeit with mixed results, because some studies have yielded null
findings. The mixed results likely reflect differences in study population, design, length
of follow-up, presence of preneoplastic lesions at the time of H pylori eradication, the
exposure measure (eg, H pylori eradication treatment but without subsequent confir-
mation testing as the exposure group vs H pylori eradication treatment and confirmed
successful eradication as the exposure group), outcome measures (eg, some studies
analyzed changes in atrophic gastritis or gastric intestinal metaplasia as surrogate
markers, and not gastric cancer incidence per se), and the reference population (eg,
general population as the reference group vs individuals with H pylori infection but
who received placebo/no treatment, or unsuccessful treatment as the reference
group), among others. Prospective large population-based studies are no longer likely
to be performed, especially in countries with low to intermediate gastric cancer inci-
dence, owing to cost and logistical barriers, not to mention ethical considerations.17
The long sojourn time between H pylori infection and gastric cancer occurrence and
the overall rarity of gastric cancer on a population level are leading barriers for such
studies. For chemoprevention trials, follow-up should ideally extend past 10 years.
Thus, even in a high-risk population, the estimated sample size to detect a 50%
decrease over 10 years between an H pylori eradicated versus noneradicated group
would be more than 17,000 per group.18 Ethical considerations provide another
522 Shah & Peek

formidable barrier because, even though only a minority of individuals with H pylori will
develop malignant complications, we are not able to definitively predict who will or will
not progress; this line of reasoning forms the rationale for the recommendation of most
major medical societies to universally eradicate H pylori when diagnosed. Thus, with-
holding eradication treatment or providing a placebo treatment for a known carcin-
ogen would be unethical.17 Notably, in countries where H pylori eradication therapy
is still not universally recommended, such as in South Korea, randomized controlled
trials (RCTs) of H pylori eradication versus no eradication have continued to be con-
ducted; these studies have provided risk reduction estimates in distinct high-risk pop-
ulations, including those with family history of gastric cancer19 or prior history of
gastric cancer20,21 (discussed elsewhere in this article), although the ethics of these
studies has been questioned. The same group that published these referenced
studies is currently conducting an RCT of H pylori eradication therapy versus placebo
to investigate the effect of H pylori eradication on gastric cancer incidence in the gen-
eral population (HELPER study, NCT02112214); the anticipated completion date for
this 10-year follow-up study is 2029.
Multiple retrospective cohort studies have been published, the majority in Asian-
Pacific countries, analyzing the association between H pylori eradication treatment
and primary prevention of gastric cancer.22 Important differences across studies are
those already listed elsewhere in this article, with the major differences including vari-
ability with respect to H pylori eradication regimens (most used clarithromycin-based
regimens), rigor with respect to H pylori diagnosis determination, whether or not H py-
lori eradication confirmation testing was performed (and modality), reference groups,
study time period, and duration and completeness of follow-up, as well as the baseline
demographics of the cohort itself (eg, several studies had a greater than 70% male
predominance, with variability in the mean age at study entry).22 Moreover, most of
these studies were not designed to separately analyze outcomes according to the
presence or absence of symptoms or the presence or absence of gastric pathology,
such as gastric or duodenal ulcers or already existing gastric (pre)neoplasia; or, this
factor was analyzed in a limited fashion. Notwithstanding, a meta-analysis of cohort
studies published before May 2015 demonstrated that H pylori eradication treatment
was associated with a pooled 48% lower risk (incidence rate ratio, 0.52; 95% confi-
dence interval [CI], 0.41–0.64) of incident gastric cancer, which was not significantly
different compared with the pooled estimate for RCTs (incidence rate ratio, 0.60;
95% CI, 0.44–0.81) (P 5 .34 by meta-regression).22 There was a trend toward greater
benefit with a longer duration of follow-up after eradication (P 5 .06), but this differ-
ence was not statistically significant; the mean follow-up for the included studies
ranged from 24 to 121 months. This meta-analysis also supported prior studies sug-
gesting that the benefit of H pylori eradication for primary prevention is greater in pop-
ulations with a higher gastric cancer incidence compared with a lower incidence. It
should be emphasized, however, that this meta-analysis included only 2 studies con-
ducted outside of the Asian-Pacific region, and one was conducted in Colombia,23 a
country with a high gastric cancer incidence; thus, only 1 study was from a country
with a low to intermediate incidence of gastric cancer (Finland).24 Of note, the Finnish
study, which was conducted from 1986 to 1998, used a decrease in H pylori serum
antibody titers as a surrogate for H pylori eradication, which may have led to
misclassification.
Since the publication of that meta-analysis, 2 retrospective cohort studies from
Western populations (Sweden, the United States) were published, both with different
study designs.25,26 The population-based retrospective cohort study from Sweden
(2005–2012) compared the incidence of NCGA in patients who received H pylori
 Chemoprevention Against Gastric Cancer 523

eradication treatment to the general Swedish population as the reference group.26 The
majority of individuals were 18 to 59 years old, and the mean follow-up time for this
study was only 3.7 years (maximum, 7.5 years; minimum not specified, but presum-
ably 1 year). Details regarding the H pylori positivity rate in the general population
comparator group, as well as the presence of symptoms or gastric pathology, and
whether or not individuals had received H pylori treatment before study entry were
not available or provided in the study. The exposure group included patients with
gastric pathology based on International Classification of Disease codes, including
gastric ulcers, duodenal ulcers, and atrophic gastritis. Moreover, eradication confir-
mation testing was not universally performed after H pylori treatment and thus H pylori
eradication cannot be confirmed in the primary exposure group; acknowledging this
limitation, the authors did conduct a separate analysis among individuals who
received more than 1 prescription of H pylori treatment during follow-up. Notwith-
standing, after correction of an error in the statistical analysis,27 the authors reported
that, among 95,176 Swedish individuals who received H pylori eradication therapy,
0.1% (n 5 69) developed NCGA over 351,018 person-years of follow-up time. The
age- and sex-standardized risk of gastric cancer in the H pylori treated group
compared with the general population decreased with increasing time since eradica-
tion therapy, such that the risk was 4.2-fold higher (95% CI, 3.04–5.66) and 3.1-fold
higher (95% CI, 1.88–4.76) after 1 to 3 years and 3 to 5 years of follow-up, respectively.
After 5 to 7.5 years of follow-up, however, the rate in the H pylori treated group was not
significantly different compared with the general population (standardized incidence
ratio, 2.06; 95% CI, 0.75–4.48); however, this finding was based on only 6 cases of
NCGA.27 There was a higher risk of NCGA among those with persistent H pylori infec-
tion, as indicated by at least 2 courses of eradication treatment during follow-up (stan-
dardized incidence ratio, 10.5; 95% CI, 3.82–22.8), compared with individuals who
received only 1 course of H pylori treatment during follow-up (standardized incidence
ratio, 2.38; 95% CI, 1.80–3.10).
One recently published retrospective cohort study conducted in United States vet-
erans included a limited secondary analysis investigating the impact of H pylori erad-
ication treatment among those with confirmed H pylori who also had subsequent H
pylori testing to evaluate the success of treatment.26 It was not stated whether pa-
tients were symptomatic or had known gastric (pre)neoplasia. Notably, only 2.2% of
the starting cohort (n 5 8020 of 371,813) had sufficient data available to be included
in this secondary analysis. Based on this restricted sample of patients who had confir-
matory testing, which is subject to bias, the authors did demonstrate that successful H
pylori eradication was associated with a 76% lower likelihood (standardized hazard ra-
tio, 0.24; 95% CI, 0.15–0.41) of distal gastric cancer compared with unsuccessful H
pylori eradication. The follow-up time specifically for this subanalysis was not pro-
vided. Other methodological limitations need to be considered when interpreting the
findings of this study28; for example, approximately 70% (n 5 258,362 of 371,813)
of the cohort were deemed to have H pylori exposure based solely on prescriptions
for anti–H pylori therapy without confirmatory laboratory testing identified in the med-
ical record.
Multiple RCTs have also been published that compare H pylori eradication versus
no eradication and the subsequent incidence of gastric cancer, and thus complement
the observational evidence provided from cohort studies. Unfortunately, there is a
similar dearth of evidence from low or intermediate risk populations from Western
countries. Recently, the Cochrane Gut Group updated their systematic review and
meta-analysis, which was published in 2015, that compared the incidence of gastric
cancer in asymptomatic individuals from the general population randomized to H
 524
Table 1
RCTs evaluating the association between H pylori eradication and gastric cancer

Shah & Peek

First Author,
Publication year Country/Region Study Population Intervention Follow-up Outcome Measures
Choi et al,19 2020 Korea, single center Participants with a family 1. Lansoprazole 30 mg, Median duration of 1. Incident gastric cancer
history of gastric Amoxicillin 1g, Clarithromycin follow-up was 9.2 y 2. Overall survival
cancer, n 5 1826 500 mg BID  7 d (IQR, 6.2–10.6) and 3. Incident gastric
randomized (n 5 1587 2. Placebo  7 d 10.2 y (IQR, 8.9–11.6) adenoma
evaluated for H pylori H pylori eradication 5 70.1% for incident gastric
eradication) cancer and overall
survival, respectively
Correa et al23 2000 Colombia, 2 Participants with 1. Bismuth 262 mg, amoxicillin Cited analysis, 6 y. 1. Progression of
Correa et al,106 2001 communities in confirmed histologic 500 mg, metronidazole 375 mg Note: multiple points of preneoplastic lesions
Narino Province diagnoses of gastric TID  14 d follow-up have been (based on histologic
preneoplasia, n 5 976  With or without dietary published to date, score, and global
randomized (n 5 852 in supplements with the most recent a assessment).
intention to treat; 2. Placebo 16-y analysis.107  Gastric cancer
n 5 631 complete case  With or without dietary outcome published
analyses); age 29–69, supplements separately108
mean 51.1 y; 46.1% H pylori eradication 2. Relative risk of
male rate 5 58.0% progression, no change,
regression of histologic
lesions
Leung et al,34 2004 China, 11 villages in Participants with vs 1. Omeprazole 20 mg, amoxicillin Cited analysis, 5 y 1. Histologic outcomes at
Yantai County, without dyspepsia, 1g, clarithromycin 500 mg BID  Note: 10-y follow-up 2 and 5 y (subsequently,
Shandong who underwent upper 7d also published.108 8 and 10 y)
Province endoscopy with biopsy. 2. Placebo  7 d
n 5 587 randomized H pylori eradication
(34% with gastric rate 5 55.6%
preneoplasia at
baseline); age 35–75 y,
mean, 52.0 y; 47.8%
male
Note: 33.7% with
preneoplasia at
baseline
Saito et al 2005 Japan, 145 centers Participants were healthy 1. Lansoprazole 30 mg, amoxicillin Follow-up stated as 1. Histologic regression or
(abstract only; full volunteers with H 1.5 g, clarithromycin 400 mg “4 y” progression of atrophy
study not pylori infection. once daily  7 d by at least 1 grade
published as of n 5 629 randomized; 2. No eradication (Note: did not report on
Feb. 2020) age 20–59 y, mean not H pylori eradication gastric cancer
reported rate 5 74.4% incidence, although this
was a priori planned
outcome)
Wong 200432 China, 7 villages in Participants undergoing 1. Omeprazole 20 mg, amoxicillin/ Follow-up time, 7.5 y 1. Incidence of gastric
Changle Country, screening endoscopy clavulanic acid 750 mg, cancer
Fujian Province (age 35–65 y, mean metronidazole 400 mg BID  2. Incidence in those with
42.2 y). n 5 2423 14 d vs without
evaluated, and 2. Placebo  14 d premalignant lesions
n 5 1628 with H pylori H pylori eradication
infection but without rate 5 83.7%
endoscopic lesions (eg,
peptic ulcer) were
randomized
Note: 37.7% with

Chemoprevention Against Gastric Cancer

premalignant lesions at
baseline (gastric
atrophy, intestinal
metaplasia, gastric
cancer)
Wong et al,30 2012 China, 12 villages Participants with H pylori 1. Omeprazole 20 mg, amoxicillin Follow-up time, 5 y 1. Gastric cancer
Linqu County, infection and 1g, clarithromycin 500 mg BID  2. Regression or
Shandong advanced gastric 7d progression of gastric
Province lesions (severe chronic a. PLUS placebo BID, OR premalignant lesions
atrophy, intestinal b. PLUS celecoxib
metaplasia, dysplasia); 2. Placebo
age 35–64 y, mean 53 y 3. Celecoxib 1 placebo
n 5 1024 randomized, H pylori eradication rate 5 63.5%
2  2 factorial design
ALL participants had

(continued on next page)

525
 526
Shah & Peek
Table 1
(continued )
First Author,
Publication year Country/Region Study Population Intervention Follow-up Outcome Measures
premalignant lesions at
baseline
You et al,33 2006 China, 13 villages Participants were 1. Omeprazole 20 mg, Amoxicillin Follow-up time, 14.7 y 1. Prevalence of dysplasia
Linqu County, selected randomly and 1g BID  14 d a. with or without Note: multiple points of or gastric cancer
Shandong underwent upper vitamin or garlic follow-up have been 2. Prevalence of other
Province endoscopy, n 5 2258 supplementation published to date, precancerous lesions
participants 2. Placebo  vitamin or garlic with the most recent a (severe chronic atrophic
randomized; age 35–64 supplementation 22-y analysis.82 gastritis, intestinal
y, mean 46.8 y  “Vitamins” 5 vitamin C, E, metaplasia)
2  2  2 factorial design selenium 3. Average ‘severity’ score
Note: H pylori confirmed  Garlic 5 garlic oil and Kyolic
via serologic testing aged garlic extract
64% had preneoplastic
lesions at baseline

Abbreviation: BID, 2 times per day; IQR, interquartile range; TID, 3 times per day.
Data from Refs.19,23,29,30,32–34,82,106–108
 Chemoprevention Against Gastric Cancer 527

pylori eradication therapy versus no therapy. Their comprehensive literature search

through February 2, 2020, identified 7 distinct baseline RCTs (ie, no overlapping study
populations) that met the full inclusion criteria. Six of these RCTs were performed in
Asian countries, and the seventh was performed in Colombia.19,23,29–34 No RCTs
analyzing H pylori eradication versus no eradication on gastric cancer incidence
have been conducted in countries with populations at low or intermediate risk for
NCGA. Table 1 provides descriptions of these base RCTs, which resulted in a number
of subsequent publications that are organized in the full Cochrane Review.29 Based on
meta-analysis of 8323 individuals in these 7 RCTs (modified intention to treat),
compared with placebo or no treatment, H pylori eradication treatment was associ-
ated with a significant 46% lower risk (relative risk [RR], 0.46; 95% CI, 0.40–0.72) of
incident gastric cancer on 4 to 22 years of follow-up time; the number needed to treat
to have 1 person benefit was 72 (95% CI, 55–118). There was no significant heteroge-
neity observed across the studies. The quality of evidence was downgraded from high
to moderate for this primary analysis based on a few important considerations. First,
although 4 studies were deemed low risk of bias, 2 were deemed high risk and 1 was at
unclear risk. Second, the H pylori eradication regimens used in these 7 studies varied;
indeed, many of these studies started enrolling before 1994, which is when proton-
pump inhibitors became more widely available. Last, some studies used a factorial
design, with some arms including H pylori eradication therapy and vitamin supplemen-
tation, for example; as such, it was sometimes not possible to isolate fully whether the
observed relative risk reduction in gastric cancer was wholly attributable to H pylori
eradication. Based on meta-analysis of the 4 RCTs (n 5 6301) that reported on gastric
cancer-related mortality, randomization to H pylori eradication therapy versus no ther-
apy/placebo was associated with a significant 49% lower risk of gastric-cancer
related mortality (RR, 0.61; 95% CI, 0.40–0.92) on follow-up ranging from 7 to 22 years,
with a number needed to treat to benefit of 137 (95% CI, 89–667).

Concomitant gastric preneoplasia

As described elsewhere in this article, one of the leading mechanisms underlying the
chemopreventive effect of H pylori eradication treatment is that successful eradication
of H pylori substantially decreases and ideally eliminates persistent inflammation.
Indeed, the majority of individuals with H pylori nonatrophic gastritis and nonsevere
atrophic gastritis will have normalization of these mucosal changes after successful
H pylori eradication. The return of normal gastric mucosa also restores gastric acid
production and facilitates the restoration of the normal gastric microbiota,35 which
likely also contributes to the beneficial effect of H pylori eradication in these early,
reversible mucosal stages. However, if there are severe mucosal changes present,
including severe gastric atrophy with or without gastric intestinal metaplasia, studies
suggest that the benefit of H pylori eradication treatment, even with confirmed erad-
ication of H pylori organisms, is attenuated and potentially even null. The presence
of gastric intestinal metaplasia has been considered the first irreversible stage in the
Correa cascade and the earliest point of no return, although a handful of cohort studies
have challenged this notion of irreversibility.36 Our understanding of the chemopreven-
tive effects of H pylori eradication once preneoplastic gastric mucosal changes have
developed is limited at best and largely reflects the difficulty in conducting robust clin-
ical studies to investigate this question with rigor. As such, most studies have included
mixed populations with or without gastric preneoplastic changes—under which non-
metaplastic and metaplastic gastric atrophy both qualify.
A few studies have provided some insight, however. The authors of the updated
Cochrane meta-analysis of RCTs cited elsewhere in this article conducted a subgroup
528 Shah & Peek

analysis of 3425 individuals who had gastric preneoplasia at baseline and demon-
strated that there was no difference in gastric cancer incidence between those ran-
domized to H pylori eradication treatment versus placebo or no treatment; 2.4% of
participants randomized to treatment (42 of 1734 participants) compared with 3.4%
of participants randomized to placebo or no treatment (57 of 1691 participants) devel-
oped gastric cancer on follow-up.29 It should be noted, however, that the authors
included dysplasia (grade not specified) as a preneoplastic mucosal change. A recent
comprehensive systematic review with meta-analysis that was focused specifically on
the natural history and outcomes of gastric intestinal metaplasia reported that, among
individuals with confirmed gastric intestinal metaplasia and no higher grade pathol-
ogy, H pylori eradication treatment versus placebo was associated with a 17% higher
risk of progression (RR, 1.17; 95% CI, 1.01–1.36) to more advanced histology (mod-
erate certainty in evidence), although the authors noted that the estimate was largely
driven by data from 1 trial, the Shandong Interventional Trial.33,36 This same trial
though had conflicting results in another analysis, because H pylori eradication treat-
ment in individuals with confirmed gastric intestinal metaplasia was also associated
with regression to improved histology.33,36,37 For the outcome of gastric cancer inci-
dence specifically, H pylori eradication treatment versus placebo was associated with
a significantly decreased risk in patients with or without gastric intestinal metaplasia
(RR, 0.68; 95% CI, 0.48–0.96) on follow-up ranging from 4 to 16 years; however,
when limited to only individuals with gastric intestinal metaplasia, there was similarly
no substantial benefit on follow-up ranging from 5 to 12 years (RR, 0.76; 95% CI,
0.36–1.61).17 Importantly, the data informing these meta-analyses were drawn primar-
ily from 3 main RCTs, 2 from China and 1 from Colombia. The findings were somewhat
driven by 1 large RCT from the Fujian Province, China with 7.5 years of follow-up; in
this study, compared with placebo, the eradication of H pylori was associated with
a decreased risk of gastric cancer only in individuals without precancerous lesions (at-
rophy, intestinal metaplasia, or dysplasia) at the outset, but there was no difference
between the treatment and placebo groups when the analysis included individuals
with precancerous lesions, including dysplasia.
Despite the conflicting evidence, H pylori eradication as chemoprevention for
gastric cancer among individuals with gastric intestinal metaplasia (and other prema-
lignant mucosal pathology) is still recommended by most international guidelines.38–41
Because these individuals remain at risk of gastric cancer despite H pylori eradication,
most international medical societies also suggest ongoing endoscopic surveillance for
early detection of neoplasia, although the recommendations remain mixed in the
absence of high-quality evidence derived from RCTs. Importantly, this finding under-
scores the need for more studies to better define mechanisms driving neoplastic pro-
gression in the absence of ongoing H pylori infection, such as the role of the non–H
pylori microbiome and metabolites. Indeed, a better understanding of these mecha-
nisms will help to inform the identification of adjunctive chemopreventive agents to
ideally reverse these mucosal abnormalities and restore normal gastric mucosa, or
at least halt further progression.

H pylori eradication for gastric cancer prevention in specific populations

Family history of gastric cancer. H pylori and family history of gastric cancer are the 2
strongest risk factors for gastric cancer. Approximately 10% of gastric cancers
demonstrate familial aggregation. Having a family history of gastric cancer in a first-
degree relative compared with no family history is associated with an approximately
3-fold higher risk of gastric cancer, although this risk varies from 2-fold up to 10-
fold higher in case-control studies, depending on the ethnic group and country of
 Chemoprevention Against Gastric Cancer 529

origin.42 In addition to sharing genetics, family members share environmental expo-

sures, behaviors, and cultural practices, as well as dietary habits and preferences.
Furthermore, family members can share the same strains of H pylori as well as develop
similar host immune responses to chronic H pylori infection; they may also have a
greater susceptibility to infection.43–47 To this end, studies have demonstrated that in-
dividuals who have a family history of gastric cancer more often have H pylori infection
and more often demonstrate precancerous gastric mucosal changes that are more se-
vere compared with individuals without a family history. Although there are guideline
recommendations for endoscopic screening in individuals with a family history of
gastric cancer in a first-degree family member, there is a notable dearth of studies
analyzing strategies for chemoprevention in this high-risk population. One recent
double-blind, placebo-controlled RCT from South Korea, in which 1838 first-degree
relatives of individuals with gastric cancer were randomized to H pylori treatment
versus placebo, demonstrated that H pylori eradication treatment was associated
with a 55% decreased risk of incident gastric cancer (hazard ratio [HR], 0.45; 95%
CI, 0.21–0.94) during a median follow-up of 9.2 years, based on the modified
intention-to-treat analysis (n 5 1676).19 Gastric cancer occurred with significantly
lower frequency in those with successful H pylori eradication compared with those
with persistent infection (0.8% vs 2.9%; HR, 0.27; 95% CI, 0.10–0.70).19 There is a
relative consensus globally for recommending a test and treat strategy for H pylori
as a chemopreventive measure among individuals with a positive family history of
gastric cancer,41,48 but recommendations are mixed in some Western countries,
namely the United States,49,50 owing to lack of high-quality evidence supporting this
practice.

Metachronous gastric cancer (tertiary prevention). To date, there have been at least 3
RCTs of H pylori eradication versus no eradication for reducing the risk of metachro-
nous gastric cancer, with 2 studies20,51 reporting a decreased risk of subsequent
gastric cancer and a third study52 demonstrating no statistically significant difference
in the incidence of metachronous gastric cancer in those who were randomized to H
pylori treatment versus no treatment (P 5 .15). Several observational studies have also
been performed, with overall mixed results, either demonstrating a benefit or a null as-
sociation, which likely reflects sample size considerations and significant differences
in study design. Notably, no studies outside of Asia have investigated the effect of H
pylori eradication for tertiary chemoprevention. A meta-analysis of 10 studies,
including both RCTs and cohort studies that were published before May 2015, demon-
strated that, compared with the reference group, H pylori eradication was associated
with 54% lower risk of metachronous gastric cancer (RR, 0.46; 95% CI, 0.35–0.60).22
The duration of follow-up for these studies ranged from a minimum of 24 months to a
maximum of 58 months. A third RCT published in 2018 (and, thus, not included in the
previously referenced meta-analysis) with median follow-up of 5.9 years, reported
that, compared with placebo, H pylori eradication therapy was associated with a sig-
nificant 50% decrease in the risk of metachronous gastric cancer (HR, 0.50; 95% CI,
0.26–0.94) based on a modified intention-to-treat analysis; moreover, among individ-
uals who had baseline atrophy of the corpus lesser curvature, those who received H
pylori eradication treatment more often had improvement in atrophy grade at 3 years
compared with individuals who received placebo (48.4% vs 15.0%; P<.001).20
These data, coupled with the observation that the vast majority of individuals with
NCGA have background preneoplastic mucosal changes at diagnosis, provide further
evidence for the field effect that occurs within the context of chronic H pylori exposure.
Moreover, multiple studies in the past decade have confirmed that ongoing H pylori
530 Shah & Peek

infection may lead to genome instability and aberrant gene expression as a result of H
pylori–mediated epigenetic changes and dysregulated DNA repair, among other
potentially carcinogenic events.53 Taken together, these data do lend support to the
strategy of treatment of H pylori in the presence of gastric premalignant mucosal
changes. However, the extrapolation of these data outside of the populations included
in these studies is problematic, given the variability in and interaction between host
genetic risk and H pylori strain specific virulence that might characterize other diverse
populations. Thus, although H pylori eradication therapy for tertiary prevention of
gastric cancer seems reasonable, studies are needed across diverse populations,
especially low to intermediate risk populations from Western countries.
Collectively, these data suggest there is insufficient evidence to support broad
population-based testing and treatment of H pylori as a screening strategy in popula-
tions with a low incidence of gastric cancer, but this might be reasonable for higher risk
populations, including those residing within countries that are overall low risk based on
population aggregation.48,54 Several questions remain when considering how to best
translate the current evidence into clinical practice, particularly among high-risk pop-
ulations residing in otherwise low-risk geographic regions; for example, determining
the optimal age for H pylori screening and treatment because gastric premalignant
changes are more frequent in older individuals who have greater cumulative H pylori
exposure, as well as determining how to balance the desire for chemoprevention
with the increasing rates of H pylori eradication failure and antibiotic resistance.

Aspirin and Nonsteroidal Anti-inflammatory Drugs as Chemoprevention Against

Gastric Cancer
Aspirin and nonaspirin NSAIDs have both been investigated extensively for their role in
cancer prevention, with their protective effect appearing most relevant for adenocar-
cinomas.55 The daily intake of aspirin or nonaspirin NSAIDs has been associated with
risk reductions of up to 63% in colorectal cancer and up to nearly 40% for breast, lung,
and prostate adenocarcinomas. The exact molecular basis of this chemopreventive
effect is not fully elucidated and likely varies depending on the cancer location, cancer
phenotype, and individual characteristics, such as host genetic composition and envi-
ronmental contributors. That said, several biologically plausible hypotheses have been
proposed, the majority of which are COX dependent, although COX-independent
pathways also seem to be relevant. NSAIDs, including aspirin, inhibit COX-1 and
COX-2 production. The inhibition of COX-2 seems to be most relevant in chemopre-
vention against malignancies of the gastrointestinal tract, namely, colorectal and (non-
cardia) gastric cancers. Several studies have consistently demonstrated that COX-2
levels are significantly higher in gastrointestinal malignancies; indeed, higher COX-2
expression is observed in gastric cancer tissue compared with tissue samples ob-
tained from normal gastric mucosa in the same individual. This finding suggests a
role for increased prostaglandin biosynthesis and COX-2 overexpression in carcino-
genesis, as well as lymphovascular invasion and metastasis.55 COX-2 is involved in
several other pathways that, when dysregulated, are also implicated in carcinogen-
esis; these pathways include promotion of angiogenesis and cell proliferation, as
well as inhibition of apoptosis. NSAIDs including aspirin, presumably through
blockade of COX-2, have antitumor growth effects, including the inhibition of angio-
genesis and the upregulation of mediators leading to apoptosis (eg, activation of cas-
pase-3).56–58 Aspirin and nonaspirin NSAIDs might also exert chemopreventive benefit
through COX-independent pathways, including activation of nuclear factor-kB, acti-
vated protein 1, Wnt-ß-catenin, and extracellular signal-regulated kinase, among
 Chemoprevention Against Gastric Cancer 531

others.59–62 Some of these pathways exert important roles in H pylori–induced gastric

carcinogenesis, adding a further layer of complexity.
Numerous cohort and case control studies, along with several meta-analyses,
analyzing the association between aspirin and nonaspirin NSAIDs and risk of gastric
cancer, have been published to date. The results are generally consistent and demon-
strate an inverse association between regular NSAID use and the risk of noncardia
gastric cancer. Notably, the protective association for noncardia gastric cancer
does seem to be driven more so by aspirin, with the data for nonaspirin NSAID use
generally demonstrating a lesser risk attenuation or a null association. Again, these
mixed findings may relate more to study design considerations such as rigor of the
statistical analysis with respect to confounder adjustment and exposure misclassifica-
tion, particularly because NSAIDs can be obtained over the counter in most countries.
Many studies that analyzed nonaspirin NSAIDs did not adjust for aspirin use, which is
important because some studies have demonstrated as high as 56% overlap between
nonaspirin NSAID users and aspirin users.63 At least 2 studies have analyzed the as-
sociation according to histology of noncardia gastric cancer, both with congruent find-
ings that the risk reduction was stronger for intestinal-type, compared with diffuse-
type histology, which tends to have a greater genetic predisposition as opposed to
the former, where environmental factors are key drivers.63,64
Most studies report a risk reduction for noncardia gastric cancer among regular
aspirin users of approximately 20% to 50%, although these values vary depending
on the definition of regular use (typically at least once weekly), the duration of use,
the rigor of the analysis, the completeness of the data, and other population charac-
teristics, including geography and H pylori status. One of the most recently published
meta-analyses, which analyzed 33 studies from Asia, Europe, and North America and
included nearly 2 million individuals, demonstrated that the use of aspirin at least
monthly was associated with a 16% to 26% significantly lower risk of noncardia
gastric cancer.65 Based on a meta-analysis of 3 studies, aspirin use compared with
nonuse was also associated with a significantly lower risk of gastric cancer-related
mortality. Another recent meta-analysis of both any NSAID use, aspirin only, and
nonaspirin NSAID use reported significant 30% (RR, 0.70; 95% CI, 0.59–0.84), 36%
(RR, 0.64; 95% CI, 0.53–0.78), and 26% (RR, 0.74; 95% CI, 0.60–0.93) respective re-
ductions in the risk of noncardia gastric cancer; whereas, none were associated with
cardia gastric cancer.66 Subgroup analyses demonstrated consistent findings irre-
spective of study design (cohort vs case control).
Individual studies conducted in populations with a higher gastric cancer risk,
including those conducted in Asia and among individuals with H pylori exposure,
have generally demonstrated greater risk decreases with regular aspirin use versus
nonuse. One large territory-wide study from Hong Kong, which included 63,605 indi-
viduals with H pylori infection who were successfully eradicated between 2003 and
2012, demonstrated that regular aspirin use (at least once weekly) compared with
no use or infrequent use was associated with a significantly reduced risk of gastric
cancer (HR, 0.30; 95% CI, 0.15–0.61) on follow-up out to a median of 7.6 years (inter-
quartile range, 5.1–10.3 years). A greater decrease in risk was observed with
increasing aspirin frequency, dose, and duration of use (all P trends <.001).62 The
risk reduction associated with aspirin doses of less than 100 mg was 62% (HR,
0.38; 95% CI, 0.18–0.79) versus 85% in users of aspirin 100 mg or higher (HR, 0.15;
95% CI, 0.03–0.65), although the CI was wider in the latter group owing to smaller
sample size (n 5 4607 [8%] vs 1725 [3%]). The mechanisms underlying the greater
magnitude of risk reduction observed in this cohort of H pylori eradicated individuals
compared with cohorts with mixed H pylori infected and uninfected individuals are not
532 Shah & Peek

well defined. NSAID use has been demonstrated to decrease H pylori proliferation and
enhance the antimicrobial effect of anti–H pylori treatment, as well as attenuate poten-
tial H pylori–induced carcinogenic pathways; indeed, H pylori infection is associated
with increased prostaglandin synthesis and COX-2 expression, which might be
blocked by NSAID consumption.67–71 The chemopreventive benefit of NSAID use,
especially aspirin, after H pylori has been eliminated, however, has been incompletely
investigated. It is likely that many participants in the referenced study from Hong
Kong62 already had underlying gastric premalignant mucosal changes; whether regu-
lar NSAID use decreases the likelihood of malignant transformation, which is known to
occur even after successful H pylori eradication,36 is undetermined. Notably, 1 RCT of
rofecoxib 25 mg/d versus placebo in individuals with histologically confirmed intestinal
metaplasia and successful H pylori eradication reported no significant difference in the
frequency of intestinal metaplasia regression or in the severity of intestinal metaplasia
after 2 years of follow-up.72 It is possible that NSAIDs, including aspirin, are more rele-
vant with respect to the prevention of actual malignant transformation, as opposed to
earlier phases of progression. This remains an important area of investigation because
there are limited options for gastric cancer risk attenuation in this high-risk population,
save perhaps interval endoscopic surveillance, which is costly and has limitations.
Although these data are overall promising, particularly for aspirin, evidence from
RCTs is needed to guide positioning of NSAIDs as chemopreventive agents against
gastric cancer. The most pressing knowledge gaps that need to be bridged include
defining the high-risk populations who might benefit most from NSAID chemopreven-
tion and in whom there is minimal harm; the minimum effective dose, frequency, and
duration of use needed for benefit; and the ideal drug (eg, aspirin vs selective COX-2
inhibitors, such as celecoxib, which have fewer adverse gastrointestinal effects
compared with nonselective agents), which should also consider individual comorbid-
ities (eg, cardiovascular risk, bleeding risk). To date, no RCTs have been conducted
analyzing NSAID use and gastric cancer incidence or mortality as the primary
outcome. One related RCT was conducted using the Women’s Health Study cohort.
In this study, nearly 40,000 women age 45 years or older who were generally healthy
were randomly assigned to every other day aspirin 100 mg or placebo and were fol-
lowed for the outcome of an invasive cancer diagnosis at any site. Over an average
follow-up of 10 years, there was no significant association between aspirin use and
the risk of invasive gastric cancer.73 However, this study was likely underpowered
for gastric cancer because only 20 cases occurred (cardia vs noncardia not specified);
the population is also a low-risk population for gastric cancer, because the Women’s
Health Study recruited female health professionals and the overall demographic
included less than 10% non-White races/ethnicities.74 A secondary analysis of individ-
ual level data from 8 eligible RCTs where study participants were randomized to daily
aspirin versus no aspirin and originally followed for the primary outcome of cardiovas-
cular events, demonstrated the potential benefit of regular use of aspirin for chemo-
prevention and decreasing the risk of cancer-related mortality. Among 23,535
participants randomized to aspirin use, there was a lesser all-cancer mortality,
including gastrointestinal cancers specifically (HR, 0.46; 95% CI, 0.27–0.77), after
5 years of follow-up. For cancers overall, the benefit was greater with longer duration
of aspirin use, but aspirin doses in excess of 75 mg did not impact the risk estimates.
For gastric adenocarcinoma specifically (cardia vs noncardia not specified), there was
a lower risk of death only after 10 to 20 years of follow-up (HR, 042; 95% CI, 0.23–
0.79). Competing risk of death is certainly a consideration in this study; the cancer inci-
dence was not reported.
 Chemoprevention Against Gastric Cancer 533

a-Difluoromethylornithine as Chemoprevention Against Gastric Cancer in Patients

with Gastric Preneoplasia
Polyamines have been implicated in gastric carcinogenesis. These effectors, which
are generated by ornithine deoxycarboxylase, have been associated with disruption
of DNA repair mechanisms and inducing DNA damage, as well as altering the host im-
mune response in gastric tissue. The expression of ornithine deoxycarboxylase in the
gastric mucosa is part of the host innate immune response to H pylori infection.75,76
Treatment with a-difluoromethylornithine (DFMO), which is an inhibitor of ornithine
deoxycarboxylase, has been demonstrated to directly reduce H pylori virulence and
attenuate risk of gastric dysplasia and carcinoma in Mongolian gerbils via a decrease
in polyamine concentration in gastric tissue and abrogating polyamine-driven oxida-
tive stress.76 At least in experimental studies, DFMO also enhances DNA repair and
decreases apoptosis-resistant cells with DNA damage; in this way, DFMO directly im-
pacts genome stability in H pylori–infected gastric mucosa.75–78 As such, DFMO has
been proposed as a chemopreventive agent specifically in H pylori–associated gastric
carcinogenesis and human trials are ongoing. Studies have demonstrated a chemo-
preventive effect of DFMO (in combination with sulindac) with respect to colorectal ad-
enoma recurrence, which is hypothesized to be via a similar mechanism of polyamine
inhibition.79–81

Other Chemopreventive Agents Against Gastric Cancer

Several other medications and dietary interventions have been investigated for their
chemopreventive effects against gastric cancer, mostly with mixed findings and
without high-quality data. Studies of nutritional intakes and cancer risk are inevitably
difficult to conduct in a rigorous manner owing to the large sample sizes and long
follow-up time that are needed, not to mention the challenges with respect to residual
confounding, accurate exposure assessment, and determining the level of sustained
dietary modification that is needed for an effect. This said, dietary interventions are
attractive as chemoprevention, owing to the fact that they are generally safe, cost
effective, and feasible. As such, certain dietary interventions might have an adjunctive
role in addition to other lifestyle modifications that are known to decrease noncardia
gastric cancer (as well as the risk of other cancer types). Dietary interventions include
limiting the consumption of salted foods, high nitrite foods, processed foods, and red
meats, and increasing the consumption of fresh vegetables and fruits, particularly cit-
rus fruits and those high in beta-carotene, vitamin C, and antioxidants, and possibly
garlic and allium vegetables. Garlic and its derivatives have antioxidant, antimicrobial,
and immunomodulatory properties, among other benefits.82 Studies have demon-
strated that garlic is associated with a decreased risk of metachronous colorectal ad-
enomas, and possibly also gastric cancer.82–84 Calcium and magnesium might also
have benefit in decreases noncardia gastric cancer risk.85 Curcumin has been inves-
tigated in mechanistic studies, but clinical data are limited. Clinical and experimental
data suggest a possible benefit of green tea and ginseng consumption.86–90 Selenium,
which is an essential trace element that is consumed in the diet, has also been inves-
tigated as a chemopreventive agent in gastric cancer given its antioxidant properties,
in addition to anti-inflammatory, proapoptotic, and antiangiogenic properties.91
One RCT from Linqu County, Shandong Province of China randomly assigned 2258
H pylori seropositive individuals to H pylori treatment, vitamin supplementation, garlic
supplementation, or placebo (2  2  2 factorial design) and 1107 H pylori seroneg-
ative individuals to vitamin supplementation, garlic supplementation, or placebo
(2  2 factorial design). The vitamin supplementation intervention included the
534 Shah & Peek

administration of vitamin C, vitamin E, and selenium for 7.3 years (1995–2003),

whereas the garlic supplementation intervention included administration of garlic
extract and oil over this same time period. Notably, H pylori treatment was amoxicillin
1 g and omeprazole 20 mg 2 times per day for 2 weeks and it is not stated whether or
not nonserologic testing and confirmation of eradication was performed. The authors
did report excellent compliance among participants. Based on 22 years of follow-up,
H pylori treatment (odds ratio [OR], 0.48; 95% CI, 0.32–0.71), and vitamin supplemen-
tation (OR, 0.64; 95% CI, 0.46–0.91), but not garlic supplementation (OR, 0.81; 95%
CI, 0.57–1.13) were associated with reduced incidence of gastric cancer. All 3 inter-
ventions, compared with placebo, were associated with a significantly decreased
gastric cancer–related mortality; however, the effects of vitamin supplementation on
gastric cancer incidence and garlic supplementation on mortality generally occurred
later, and only after 14.7 years of follow-up. Separate analyses were not conducted
for noncardia versus cardia, but the authors noted that the majority of gastric cancers
were noncardia.82 Other RCTs of dietary interventions with or without concomitant H
pylori eradication treatment have been conducted in other high-risk populations.23
The coadministration of vitamins and antioxidants with H pylori eradication therapy
does seem to have a greater chemopreventive effect compared with eradication treat-
ment alone.29 The factorial design of some of these trials, however, make it difficult to
isolate the effect, if even present, of any singular exposure. Also complicating this field
are the baseline risk of gastric cancer in the study population and the modifying effects
of other environmental, cultural, and nongenetic factors, including nutritional defi-
ciencies, as well as genetic factors; these factors limit generalizability. These findings
do warrant exploration in other high-risk populations for the primary reasons stated
elsewhere in this article—dietary modifications are generally safe, low-cost, and sus-
tainable interventions that can be implemented on a larger scale, and might have other
off-target benefits related to risk reduction of other disease pathology.
Metformin and statins have also been investigated clinically for their chemopreven-
tive effects for gastric cancer based on supportive data from experimental studies.
Metformin decreases gastric cancer cell viability, invasion, and migration via downre-
gulation of COX expression, as well as through downregulation of hypoxia inducible
factor 1a, pyruvate kinase M2, phosphatidylinositol 3-kinase/protein kinase b, and
poly (ADP-ribose) polymerase expression.92–95 By inhibiting phosphatidylinositol 3-ki-
nase/protein kinase b and poly (ADP-ribose) polymerase pathways specifically, met-
formin also induces cell cycle arrest and apoptosis in gastric cancer cells. There are
numerous observational studies, the majority of which are limited to individuals with
type 2 diabetes (indication bias), which analyze the association between metformin
and gastric cancer incidence. Collectively, the conclusions are mixed, with some
studies, including large population-based studies, demonstrating null findings,
whereas others demonstrate a protective effect.96–101 These inconsistent data relate
to significant differences in study design with respect to the study population, the rigor
of the statistical analysis, including confounder adjustment and assessment of the
exposure, such as new user versus prevalent user designs, as well as variable ac-
counting of immortal time bias,102 and preclude strong conclusions. Many studies
did not adjust for relevant medications including aspirin, NSAIDs, statins, and insulin,
or other relevant confounders such as H pylori exposure, smoking, and body mass in-
dex. One recent meta-analysis that included eligible cohort studies published through
October 2019 demonstrated that using 8 cohort studies with approximately 1.2 million
type 2 diabetics, metformin use was associated with 21% decrease in gastric cancer
risk (HR, 0.79; 95% CI, 0.62–1.00); separate estimates were not provided for noncar-
dia versus cardia gastric cancer.96 Meta-analyses of the studies that analyzed
 Chemoprevention Against Gastric Cancer 535

sulfonylurea derivatives and noninsulin antidiabetic agents demonstrated a null asso-

ciation with gastric cancer incidence. Geographic differences seem to be relevant,
because the magnitude of the protective association was amplified when meta-
analysis was limited to the 3 studies from Asian populations only (HR, 0.54; 95% CI,
0.38–0.78), but the benefit was significantly attenuated when limited to the 5 studies
from Western populations (HR, 0.99; 95% CI, 0.99–0.99). One recent cohort analysis
conducted among diabetic patients from Hong Kong who were successfully eradi-
cated for H pylori demonstrated that metformin use was associated with a significantly
lower risk of gastric cancer compared with nonusers, and there was a trend toward an
increased benefit with increasing duration and dose of metformin.99 The authors also
conducted a propensity score adjustment, as well as repeated their analysis using
time varying covariates and lag time analysis with similar findings.102,103
There is also biological plausibility underlying a hypothesized chemopreventive ef-
fect of statins for gastric cancer, but high-quality and consistent clinical data are lack-
ing.104,105 Well-conducted RCTs among specific high-risk populations are needed to
adjudicate the findings presented herein regarding aspirin, NSAIDs, metformin, and
statin use, among other putative chemopreventive agents to establish their effective-
ness, or lack thereof, in noncardia gastric cancer. Despite otherwise promising data at
least for aspirin and metformin, these cannot yet be recommended outside of their pri-
mary indications.

SUMMARY

There is ample evidence of the benefit of H pylori eradication in primary chemopreven-

tion against intestinal-type noncardia gastric cancer when eradication occurs before
the development of advanced preneoplastic mucosal changes. There might still be
benefit thereafter, but the data are overall mixed and the benefit seems to be attenu-
ated at best. Experimental as well as clinical data support other agents as primary
chemoprevention, all with biological plausibility and the majority already used clinically
for benign conditions. Although the largest body of evidence is available for NSAIDs,
particularly aspirin, there are still no RCTs analyzing primary prevention of gastric can-
cer as the outcome. Dietary modifications as chemoprevention in gastric cancer also
show promise and are particularly attractive given their favorable safety profile. Unfor-
tunately, despite the substantial burden of gastric cancer globally, little progress has
been made to rigorously analyze chemopreventive agents. To move the needle for-
ward, the research agenda should ideally be focused on primary prevention trials,
as well as on investigations aiming to personalize the selection of chemoprevention
agents in high risk individuals. Several major knowledge gaps persist, including
defining the role of agents, such as aspirin or metformin, as chemoprevention after
H pylori eradication in individuals who have developed gastric preneoplasia, as well
as identifying the age at which these interventions are most beneficial in specific pop-
ulations. Another challenge remains in identifying effective chemoprevention for non-H
pylori–associated gastric cancer. Focused investigation is needed in the face of an
expanding aging population and the projected increase in gastric cancer-related
deaths so that we can appropriately position gastric cancer chemopreventive agents
in the armamentarium of gastric cancer control programs.

CLINICS CARE POINTS

 Several randomized controlled trials have confirmed that chemoprevention
through H. pylori eradication is associated with a reduced risk of noncardia
gastric adenocarcinoma; however, the chemopreventive benefit is significantly
536 Shah & Peek

attenuated in patients who have already developed gastric premalignant

mucosal changes.
 Additional studies are especially needed to define underlying mechanisms of
neoplastic progression following H. pylori eradication and in patients without
H. pylori to help target discovery of chemoprevention agents.
 Several case-control and cohort studies support an association between aspirin
and potentially non-aspirin non-steroidal anti-inflammatory drugs and noncardia
gastric cancer.
 This review describes the current literature surrounding several posited chemo-
preventive agents for gastric cancer, and provides a critical appraisal of the cur-
rent evidence.

DISCLOSURES/CONFLICT OF INTEREST STATEMENT

The authors have no potential conflicts (financial, professional, nor personal) that are
relevant to this article.

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Endoscopic Advances for
G a s t r i c Ne o p l a s i a D e t e c t i o n
a b,
Andrew Canakis, DO , Raymond Kim, MD *

KEYWORDS
 Gastric neoplasia  Image enhancement endoscopy  Narrow band imaging
 Blue laser imaging  i-scan  Flexible spectral imaging color enhancement
 Probe-based confocal laser  Endocytoscopy

KEY POINTS
 Advances in endoscopic gastric neoplasia detection provides clinicians with the opportu-
nity to decrease mortality rates through early detection of subtle lesions and targeted
biopsies.
 The validated classification system used with narrow band imaging is able to predict and
correlate endoscopic gastric findings with histopathologic diagnoses.
 Further multicenter studies with supporting clinical evidence, standardized definitions,
and adequate training are needed before these newer modalities are routinely used in
practice.
 Decision model analyses are needed to determine if these modalities can improve detec-
tion rates while reducing costs and unnecessary biopsies.

INTRODUCTION

Gastric cancer (GC) is the third most common cause of cancer-related death world-
wide and represents a major health burden because of its high incidence and mortality
rates,1 with more than 700,000 related deaths annually.2 The multistep progression to-
ward GC includes well-defined stages from chronic active gastritis, chronic atrophic
gastritis, gastric intestinal metaplasia (GIM), dysplasia, and ultimately invasive carci-
noma.3 Endoscopic screening and surveillance strategies are now proving critical in

Conflict of Interest Statement: A. Canakis has no potential conflicts (financial, professional, or

personal) that are relevant to the content presented in this article. R. Kim is a consultant to
Medtronic.
a
Department of Medicine, Boston University School of Medicine, Boston Medical Center, 72
East Concord Street, Evans 124, Boston, MA 02118, USA; b Division of Gastroenterology &
Hepatology, University of Maryland Medical Center, University of Maryland School of Medicine,
22 South Greene Street, Baltimore, MD 21201, USA
* Corresponding author.
E-mail address: rkim@som.umaryland.edu
Twitter: @AndrewCanakis (A.C.)

Gastrointest Endoscopy Clin N Am 31 (2021) 543–561

https://doi.org/10.1016/j.giec.2021.03.007 giendo.theclinics.com
1052-5157/21/Published by Elsevier Inc.
544 Canakis & Kim

reducing mortality and costs, especially because when patients are symptomatic they
are usually diagnosed at an advance stage with a dismal 5-year survival rate.4,5 How-
ever, in Japan, the implementation of a national GC screening program has improved
the 5-year survival rate to more than 60%,6 and in Korea a 47% reduction of GC mor-
tality was reported by endoscopic screening. It has been shown that the main driver of
cost is diagnosing gastric neoplasia in a curable stage and preventing advanced-
staged disease and mortality.7 Fortunately, the prolonged time interval over several
years before final malignant transformation, coupled with identifiable preneoplastic
stages on histopathology provides a massive opportunity for early detection of gastric
neoplasia via endoscopic screening.4 As such, GC is being increasingly recognized as
a preventable and curable cancer, especially in light of expanding availability and
experience with effective, endoscopic therapeutic options, such as endoscopic sub-
mucosal dissection (ESD).4,8
In this context, advances in endoscopic gastric neoplasia detection have rapidly
evolved, and now provides clinicians with the opportunity to decrease mortality rates
through early detection of subtle lesions. Although white light endoscopy (WLE) is
currently the primary method for detecting lesions, its macroscopic, diagnostic limita-
tions and poor histopathologic correlation have led to the development of newer tech-
nologies that improve mucosal and microvascular visualization.9 In this article, we
explore image-enhancement endoscopy (IEE) methods, such as chromoendoscopy
(CE), narrow band imaging (NBI), blue light imaging, i-scan technology, flexible spec-
tral imaging color enhancement (FICE), and a few more (Table 1).

DISCUSSION
Conventional Chromoendoscopy
CE uses dye-based staining techniques to aid in the visualization and detection of
mucosal irregularities during endoscopy to improve the yield of targeted biopsies.10
CE can either be applied through staining directed at a suspicious lesion or blindly
by voluminously spraying and screening the entire area of interest.11 There are three
types of stains used (absorptive, contrast, and reactive stains) with different transient
properties that can enhance the mucosal topography and delineate anatomic borders.
(1) Absorptive stains (ie, methylene blue, acetic acid, crystal violet, and Lugol) have dif-
ferential absorptive properties based on cell type, and in the case of methylene blue,
the dye is absorbed by intestinal epithelial cells, and not the epithelia of squamous or
gastric mucosa.10,11 (2) Contrast, or nonabsorptive stains (ie, indigo carmine), do not
react with the cells; instead the dye accentuates the topography, mucosal surface,
and border of a lesion by accumulating in the grooves and crevices of a mucosal
lesion.10,12 (3) Reactive stains, such as Congo red and phenol red, change color during
a chemical reaction when it comes into contact with acidic and alkaline environments
on the surface, respectively. Congo red can detect ectopic sites of excessive acid pro-
duction, whereas phenol red can detect Helicobacter pylori infection within the
stomach.11,12
The CE equipment is widely available, easy to use, inexpensive, and safe. However,
this technique can often lengthen procedure times, add to staff burden, and requires
extensive experience to interpret staining patterns.13,14 Yet, its application in the clin-
ical setting has shown promise in detecting early GC (EGC).15 A meta-analysis of 10
studies, including 699 patients with 902 lesions, found that compared with standard
WLE, CE exhibited higher detection rates for EGC and premalignant lesions.16 It is
important to highlight that only two of the studies in this analysis used methylene
blue, whereas the majority examined indigo carmine, the most commonly used stain.
Table 1
Summary of advances in endoscopic techniques

Techniques Company Manufacture Technology How It Works

Conventional chromoendoscopy — Absorptive stains (methylene blue, acetic During an endoscopy, the topical
acid, crystal violet, Lugol); contrast application of specialized
stains (indigo carmine); reactive stains biodegradable stains or dyes are
(Congo red, phenol red) deployed to the area of interest to
improve the enhancement of tissue
characterization
Autofluorescence imaging Olympus Evis Exera II/III processors, Video System A trimodal video processor enables real-
Center (CV-260SL) time detection of natural tissue
fluorescence that combines
autofluorescence signals with green
light to create false color images via a
special rotary filter
Narrow band imaging Olympus Evis Exera II/III processors, Video System Real-time images are captured with a
Center (CV-260SL, CV-290) special optical filter (narrow bands of
415 nm and 540 nm) that illuminates
mucosal surfaces at specific
wavelengths to create greater contrast
images between vascular and mucosal
structures
Flexible spectral imaging color Fujifilm EPX-4400 system, VP-4400HD and VP- Video processor imaging, reconstruction

Gastric Neoplasia Detection

enhancement 4450HD processors, XL-4400 and XL- technology that generates
4450 light source reconfigured pixilated images of a
single wavelength to create enhanced
color images of vascular and surface
tissue
Blue laser imaging Fujifilm VP-4450HD processor, XL-4450 HD light Computerized processing system that
source, L590 series endoscopes uses a combination of white (450 nm)
and blue light (410 nm) laser sources to
create mucosal surface pattern images

(continued on next page)

545
 546
Canakis & Kim
Table 1
(continued )
Techniques Company Manufacture Technology How It Works
Probe-based confocal laser Pentax Probe: Cellvizio 100 Series System with Low-power, laser tissue illumination that
endomicroscopy Confocal Miniprobes; GastroFlex UHD creates high-magnification, high-
Miniprobe resolution images with tissue
Endoscope: Pentax ISC-1000 system with fluorescence using exogenous contrast
EC3870CIK scope agents
i-scan digital contrast Pentax EPK-i5000 and EPK-i7000 HD processor, Software-based, digital post-processing
Series I and 90K gastroscopies imaging system that provides
combinations of surface, contrast, and/
or tone enhancement
Endocytoscopy Olympus Probe-based system (XEC-300, XEC-120) Fixed-focus, high-power objective lens
with CLV-180 light source and CV-180 allows for real-time visualization of
video processor cellular structures
Integrated endoscope system (XGIF-
Q260EC1,XCF-Q260EC1) with a CLV-
260SL light source and CV-260SL video
processor
Near-infrared Raman spectroscopy Multiple companies Four major components: (1) laser systems An optical vibrational technique that uses
(eg, Nd:YAG and diode laser), (2) near infrared light to detect the
collection optics, (3) Raman scattering of monochromatic light (and
spectrophotometers, and (4) detectors photon absorption) to characterize
(deep-depletion charge-couple or biomolecular tissue changes
charge-injection devices)
 Gastric Neoplasia Detection 547

A few studies have suggested that when methylene blue is absorbed by colonocytes17
and esophageal18 cells there is a risk of oxidative DNA damage when exposed to white
light, which is not seen with indigo carmine.
Still, methylene blue has shown promise in detecting premalignant gastric lesions.19
In a study of 136 patients by Dinis-Ribeiro and colleagues,20 methylene blue was
shown to have a diagnostic accuracy of 84% and 83% when detecting GIM and
dysplasia, for which the study proposed a classification system based on these find-
ings. A few years later Areia and colleagues21 externally validated and reproduced
these findings in a multicenter study of 42 subjects with premalignant lesions. Another
prospective study of 33 patients, with prior biopsies showing GIM, demonstrated the
advantage of CE over conventional endoscopy with 40 and 16 positive biopsies of pre-
malignant lesions detected, respectively.22
Although there are limited studies examining methylene blue for gastric neoplasia
detection, indigo carmine is widely used, and in combination with acetic acid,
numerous studies have shown its ability to accurately detect dysplasia and
EGC.23–27 Taking advantage of the contrast changes when acetic acid is used, one
study was able to differentiate grades of neoplasia based on the dynamic changes
in the whitening with time.28 In response to this, a subsequent group attempted to
classify neoplastic changes into five categories,29 and later showed acetic acid’s su-
periority over conventional endoscopy in characterizing staining patterns with EGC
changes.23 In an effort to enhance this effect, indigo carmine was added to an acetic
acid mixture and when compared with conventional endoscopy it showed better re-
sults in defining lateral borders of GC (67% vs 84%).27 Before ESD, one prospective
of 108 EGC lesions found that the accuracy of delineating EGC margins in WLE, acetic
acid, and acetic acid plus indigo carmine was 50%, 76%, and 91%, respectively.30 In
this context, current clinical evidence supports the use of this modality when CE is
used.

Autofluorescence Endoscopy
Autofluorescence endoscopy (AFI) uses the fluorescent properties of gastric tissue to
create real-time endoscopic images that generates blue and green light from tissue
illumination.31 By taking advantage of fluorophores (eg, collagen, flavins, and porphy-
rins) and their ability to emit fluorescent light at certain wavelengths, AFI can capture
normal, metaplastic, and dysplastic changes accordingly.32,33 In autofluorescence,
shorter wavelength light interacts with the fluorophores, which then emit light at longer
wavelengths in the submucosal layer.33
The utility of AFI in detecting gastric neoplasia is unclear because of conflicting ev-
idence in the literature, and it is not typically used in routine practice.34–38 A prospec-
tive study of 51 patients with 91 gastric lesions compared WLE with AFI in detecting
gastric neoplasia, and found AFI was less sensitive (64% vs 74%) and specific (49%
vs 83%).34 Furthermore, of the 39 biopsy-proven neoplastic lesions, 22 were detected
by WLE and AFI, whereas only seven were seen by WLE and five by AFI alone. The
same group conducted another study of 62 patients with 47 biopsy-proven neoplastic
lesions using trimodal imaging endoscopy, which added NBI and AFI to WLE, and
found that they were able to increase detection rates by 13%, although AFI alone still
displayed lower detection rates compared with WLE.35 Although these two studies by
Kato and colleagues34,35 did not show promising results for EGC, So and col-
leagues38 conducted a randomized prospective study comparing trimodal imaging
endoscopy with WLE in 64 patients and found that there were improved detection
rates for GIM when using trimodal imaging endoscopy (68% vs 34%). To explore
the role of AFI in surveillance following ESD, Imaeda and colleagues37 investigated
548 Canakis & Kim

242 surveillance endoscopies and found that WLE missed five EGC lesions, which
were all detected by AFI.
In the context of conflicting data, AFI is unlikely to be a stand-alone modality
because of its high false-positive rate and inconsistent autofluorescence pattern for
EGC.31,36 Additionally, the low-resolution image quality, nonspecific indirect detection
of dysplasia, and inability to examine deeper tissue further hinders its use.32

Narrow Band Imaging

NBI has emerged as an accurate and reliable technique in identifying EGC by optically
filtering white light. Since its introduction in 2005 it has become the most widely used
IEE technology. The system is activated by a button on the endoscope, which powers
a filter located between the xenon lamp and red-green-blue rotatory filter.10,11 This en-
ables narrow band blue (415 nm) and green (540 nm) light to generate false color im-
ages on the endoscopy monitor for which 100-fold magnification is possible.10
Because hemoglobin is a chromophore, blue and green light are absorbed and then
reflected at different depths resulting in enhanced visualization of the superficial capil-
lary network (green light) and deeper subsurface vasculature (blue light).10,11,39
NBI has been well validated as a tool that correlates endoscopic gastric findings
with histopathologic diagnoses when used with magnifying endoscopy.39 As such,
magnifying endoscopy with NBI (ME-NBI) can characterize EGC tissue based on
microvascular patterns and surface microstructures, for which Yao and colleagues40
introduced a widely used classification system that can enhance diagnostic accuracy.
This systematic classification system is defined by the presence or absence of a
demarcation line (DL), between the lesion and surrounding noncancerous mucosa,
and an irregular microvascular pattern within the lesion itself.40 Using these two find-
ings, the group was able to prospectively differentiate benign and cancerous lesions
with a sensitivity, specificity, and accuracy of 93%, 99%, and 99%, respectively.40 A
simple diagnostic algorithm has been introduced for the endoscopist to follow when
encountering suspicious lesions.41
Furthermore, ME-NBI has been able to predict and correlate the vascular histologic
findings of intralobular and corkscrew pattern with differentiated and undifferentiated
carcinoma, respectively.42,43 ME-NBI has also shown promise when looking at smaller
gastric lesions, and one study of 362 patients with depressed lesions less than 10 mm
found that variations in microvessel shape had a diagnostic accuracy of 92%.44 When
compared with CE, ME-NBI demonstrated a higher sensitivity (78% vs 44%), speci-
ficity (82% vs 93%), and diagnostic accuracy (88% vs 70%) in identifying lesions
less than or equal to 5 mm.45 As Table 2 illustrates, ME-NBI has been properly inves-
tigated in EGC as a reliable modality to detect microvascular and mucosal patterns.

Magnified White Light Versus Narrow Band Imaging

There have been a multitude of studies comparing NBI with WLE. A randomized
controlled trial showed that ME-NBI was more accurate in diagnosing cancer in small
depressed lesions.46 When comparing the 40 GCs (20 in each group), the accuracy
(90% vs 65%) and specificity (94% vs 68%) were statistically significant and greater
in the ME-NBI cohort; when using the modalities together the accuracy and specificity
improved to 97%. Another prospective randomized trial of 353 patients with EGC,
showed that WLE alone had marginal accuracy (65%), specificity (68%), and sensi-
tivity (40%) findings.47 However, when applying ME-NBI after WLE, the accuracy,
specificity, and sensitivity markedly improved to 97%, 97%, and 95%, respectively.
Another group also illustrated the superiority ME-NBI over WLE when using a triad-
 Table 2
Summary of studies looking at NBI and early gastric cancer detection

M-NBI M-NBI M-NBI

Sensitivity Specificity Accuracy
Author, Year Country Study Design Number of Gastric Lesions (Type) (C-WLI), % (C-WLI), % (C-WLI), %
Kanesaka et al,44 2015 Japan Post hoc analysis, multicenter 343 (40 cancer, 303 benign) a
25; 55; 13; 70 a
90; 24; 99; 95 a
83, 28, 89, 92
prospective
Fujiwara et al,45 2015 Japan Single center, retrospective 103 (32 cancer, 71 noncancerous) 78 92.9 88.3
Yao et al,94 2014 Japan Multicenter, prospective 371 (20 cancer, 351 noncancerous) 85.7 99.4 98.1
Yamada et al,47 2014 Japan Post hoc analysis, multicenter, M-NBI group: 177 (20 cancer, 155 95 (40) 97 (68) 97 (65)
prospective, RCT noncancerous)
Ezoe et al,46 2011 Japan Multicenter, prospective, RCT M-NBI group: 177 (20 cancer, 157 60 (40) 94.3 (67.9) 90.4 (64.8)
noncancerous)
Kato et al,48 2010 Japan Single center, prospective, 201 (14 cancer, 187 noncancerous) 92.9 (42.9) 94.7 (61) —
comparative

Gastric Neoplasia Detection

Yao et al,95 2007 Japan Single center, prospective, blinded 158 (14 cancer, 144 gastritis) 92.9 99.3 98.7

Abbreviations: C-WLI, conventional white-light imaging; M-NBI, magnifying narrow band imaging; RCT, randomized controlled trial.
a
Microvascular findings based were characterized by dilation, tortuosity, difference in caliber, and variation in shape (% listed in that order).

549
550 Canakis & Kim

based diagnosis of disappearance of fine mucosal structure, microvascular dilation,

and heterogeneity in detecting superficial GC.48
Many of these promising studies suggest that ME-NBI is an accurate tool that may
enable clinicians to avoid unnecessary biopsies while improving targeted biopsies and
serving as a potential method to make an optical diagnosis. One comparative meta-
analysis of 14 studies with more than 2000 patients, found that the pooled sensitivity,
specificity, and area under curve for EGC when using ME-NBI was 86%, 96%, and
96%, respectively.49 These findings were influenced by the type and size of the lesion,
where depressed lesions less than 10 mm in diameter exhibited lower sensitivities.
Yet, the specificity for these small depressed lesions remained high and still outper-
formed WLE. Another meta-analysis of 2153 gastric lesions echoed these findings
and found that ME-NBI was superior to WLE in terms of sensitivity (83% vs 48%),
specificity (96% vs 67%), and area under curve (96% vs 62%).50 Once again these
were promising results; however, this was a prospective randomized multicenter
study of 579 patients that found no statistical difference in the GC detection rates be-
tween the ME-NBI (7/286) and WLE (3/293).51

Narrow Band Imaging’s Role in Endoscopic Submucosal Dissection

ESD now offers clinicians with the chance to obtain complete curative resection in
cases of EGG. The defining features of successful ESD are the ability to determine
the horizonal margins and depth of the lesion, a finding that is enhanced by the appli-
cation of ME-NBI. One of the first comparative studies between indigo carmine CE and
ME-NBI, showed the higher diagnostic accuracy of ME-NBI (97% vs 78%) in delin-
eating EGC tumor margins.52 As Table 3 shows, similar findings have been reported
in other comparative studies favoring the utility of ME-NBI in determining the horizonal
extent of EGC lesions. However, it is important to highlight that one randomized
controlled study by Nagahama and colleagues53 reported similar margin delineation
rates between ME-NBI and indigo carmine CE (88% vs 86%). Despite this finding
most studies to date have favored the use of ME-NBI.
Briefly, in terms of defining the invasion depth for EGC, the main diagnostic
approach is conventional endoscopy and endoscopic ultrasound; however, some
studies have shown that roughly 20% of patients undergoing such evaluations may
not be eligible for ESD because of the diagnostic limitations.39 ME-NBI has been
shown to improve the diagnostic yield of differentiated EGC based on the presence
or absence of microvascular structures and patterns.54,55 It is interesting to mention
that a recent artificial intelligence (AI) study compared WLE, NBI, and CE using indigo
carmine and found that each method was highly accurate in predicting invasion depth
but there was no significant difference in accuracy between each system.56 Another
study compared an AI computer-aided system using ME-NBI with 11 experts in diag-
nosis EGC and found that the AI system was equivalent to and better than several ex-
perts.57 At this point in time further studies are needed to clarify the role of NBI and AI
in serving as supplementary tools when approaching ESD.

Limitations of Narrow Band Imaging

Although there are promising advantages of this technology, there are a few limitations
of NBI to highlight. First, the significant experience needed to effectively use this sys-
tem is time consuming, and accurately identifying horizontal margins before ESD can
also to procedure times and endoscopy costs.39 Second, in the stomach darker imag-
ing of distant lesions is limited when examining a broader area.58 Last, its reliability in
delineating undifferentiated cancers is limited, and should be limited to differentiated
type GC until further data results.39,55 At this point in time, most of the data are
 Gastric Neoplasia Detection 551

Table 3
Comparative studies of NBI using endoscopic submucosal dissection in EGC lesions

Total
Number
of EGC
Study Lesions
Design Comparative (# in M-NBI
Author, Year (Country) Modality Group) Accuracy (%)
Nagahama et al,53 2018 Multicenter, Indigo 343 (175) M-NBI: 88
RCT carmine CE CE: 85.7
(Japan)
Asada-Hirayama et al,96 2016 Single Indigo 109 (58) M-NBI: 89.4
center, carmine CE CE: 75.9
prospective
(Japan)
Nagahama et al,97 2011 Single Indigo 350 (62) M-NBI: 72.6
center, carmine CE CE: 81.1
case
series
(Japan)
Kiyotoki et al,52 2010 Single Indigo 83 (38) M-NBI: 97.4
center, carmine CE CE: 77.8
RCT
(Japan)

Abbreviations: CE, chromoendoscopy; EGC, early gastric cancer; M-NBI, magnifying narrow band
imaging.

primarily from high-prevalence regions; however, its generalization to low-prevalence

regions has to be approached with caution.

Flexible Spectral Imaging Color Enhancement and Bright Image Enhanced

Endoscopy Using Blue Laser Imaging
Flexible spectral imaging color enhancement
FICE was introduced in 2005 as an IEE system that mathematically processes endo-
scopic images at dedicated wavelengths without the need for an optical filter.58 Using
a computed spectral estimation technique, endoscopists can view reconfigured high-
resolution contrast images without magnification or compromising on brightness. As
such, this optical band imaging system can differentiate malignant and normal mu-
cosa based on surface pattern enhancement influenced by neoplastic laminar blood
flow and structural distortion.58
There are only a few studies looking at the reliability of FICE as a screening tool in
detecting EGC. The first study to demonstrate the clinical utility of FICE was conduct-
ed in Japan in which Osawa and colleagues59 prospectively identified 96% (26/27
cases) of depressed-type EGC. Shortly afterward, the same group conducted a pro-
spective study, where they examined 81 lesions with elevated-type EGC, and were
able to easily identify DLs using FICE without magnification in the background of whit-
ish atrophic mucosa.60 These findings were validated in a retrospective study by Mouri
and colleagues,61 who found that setting the wavelength at 530 nm enhanced EGC
visualization in close to 50% of cases studied. Although these results are promising,
one meta-analysis showed that there are still insufficient data and differing pattern def-
initions for neoplasia to aggregate the results for FICE.62 Furthermore, comparative
studies against other modalities are still needed and require further investigation.
552 Canakis & Kim

Bright image enhanced endoscopy using blue laser imaging

Blue laser imaging (BLI) evolved as an adaptive technologic method that combines
narrow band laser light and white light to produce enhanced color images of deep
mucosal microvasculature and superficial microtubule patterns.58 Serving as a
computer-based CE system, BLI enables distant high-resolution vascular contrast
detection during a screening endoscopy.63 As such, boundaries of malignant lesions
are identified and magnified. The added advantage of distant light dark imaging and
the ability to examine mucosal microstructures makes BLI more appealing when
comparing it with NBI.63 The characteristics between BLI and FICE are seen in
Table 4.
As a newer technology there are only a handful of GC studies to date.63–66 Kaneko
and colleagues64 measured and compared observable distances of GC between BLI
and NBI, for which they demonstrated the ability of BLI to identify 14 GC lesions at a
further distance (27 mm vs 16 mm). At distance of 40 mm, only one lesion was
detected by NBI, whereas six were observed using BLI. In a prospective study
analyzing 127 gastric lesions (32 cancerous and 95 noncancerous), a group in Japan
showed that the accuracy (92% vs 72%), sensitivity (94% vs 47%), and specificity
(92% vs 80%) of BLI was notable higher when compared with WLE.65 Similar findings
were also reported in another comparative study of EGC lesions.63 Recently, a ran-
domized controlled study of 122 gastric lesions with clear DL seen on BLI were
compared with and without biopsy confirmation, and the researchers showed that bi-
opsy confirmation may not be needed when DL are identified by BLI.66 Further
comparative studies are needed to define the role of BLI in clinical practice and its po-
tential to increase the efficacy of ESD.
Probe-Based Confocal Laser Endomicroscopy
Probe-based confocal laser endomicroscopy (pCLE) is a new endoscopic technique
that enables real-time high-resolution microscopic imaging.67 This imaging modality
uses confocal probes that are passed along the accessory channel whereby laser light
is focused at a certain tissue depth, reflected, and then refocused through a pinhole
via the same lens. This specific method of tissue illumination creates images at the
cellular and microvascular level, which offers clinicians the ability to make an optical
biopsy in real time.68 This technology is exciting because it has the potential to
decrease biopsy-related costs and adverse events, while at the same time offering

Table 4
Descriptions and comparisons between flexible spectral imaging color enhancement and blue
laser imaging

Flexible Spectral Imaging Color

Enhancement Blue Laser Imaging
Color Blue-green-red Blue-green
information
Light source Xenon laser Laser
Processor Fujinon VP-4450HD, VP-4400HD Fujinon VP-4450 HD
Wavelengths/ Divides white light into 3 Two different laser wavelengths;
images wavelengths to create color- laser light (410 nm) and white
enhanced image light (450 nm) combine to
produce images
Viewing Bright images  magnification Bright images with a contrast
characteristics mode and bright mode
 Gastric Neoplasia Detection 553

the potential to make informed real-time treatment decisions.69 To advance the appli-
cation of pCLE, the Miami Classification was introduced in 2009 as a way to implement
a standardized classification system for its diagnostic use.69 The routine use of this
method is hindered by its well-documented learning curve for image interpretation
that depends on experience and adequate training.70
Although pCLE is a promising technique there are only a few studies examining GC.
To compare pCLE with WLE, Park and colleagues71 demonstrated the superiority of
pCLE in undifferentiated-type GCs. Another study of 20 resected or biopsied lesions
found that pCLE made an accurate diagnosis in 19/20 cases.68 Favorable results were
also seen in two meta-analysis, which reported sensitivities and specificities ranging
from 85% to 91% and 99%, respectively.67,72 Lastly, a recent prospective,
pathologist-blinded study compared pCLE with standard biopsies in 74 lesions (21
gastric and 53 esophageal) and reported comparable results.73 Although these limited
studies show the potential for pCLE, larger randomized studies are needed to solidify
its clinical reliability for GC detection.

I-Scan
Introduced in 2007, i-scan is a new technology that uses the reflective proprieties of
mucosal surfaces to create real-time, multichannel images using special processing
technology.9 There are three modes for this method (ie, surface enhancement,
contrast enhancement, and tone enhancement) that mathematically process white
light images by the press of a button on the endoscope, enabling endoscopists to
simultaneously view two or more modes at the same time.74 These special functions
allow for enhanced screening detection of early gastric lesions. Briefly, surface
enhancement and contrast enhancement provide light-dark contrast and add blue co-
lor in dark areas, respectively.74 As such, these algorithms use pixel luminance infor-
mation to provide enhancement of depressed areas and surface architecture.9,74 The
last method, tone enhancement, is able to process individual components of red-
green-blue light frequencies to create a detailed reconfigured color image that en-
hances detailed mucosal structures.9,74
Although this technology is exciting, there are currently limited data to support its
routine use for diagnosing gastric neoplasia. Li and colleagues75 conducted one of
the first prospective studies using i-scan where they examined 43 patients with small
(<1 cm) superficial gastric lesions. In comparing all three modes, surface enhance-
ment and tone enhancement displayed a slightly higher diagnostic yield than contrast
enhancement. Overall, when comparing i-scan readings with the gold standard of his-
tology, its value was limited in neoplasia detection. The study reported a specificity of
77% and a positive predictive value of 50%.75 Similar findings were demonstrated in
another study that compared i-scan with WLE in 10 patients with gastric neoplasia, in
which the accuracy of WLE (92%) and i-scan (91%) were comparable.76 Conse-
quently, more experience and head-to-head studies are needed with i-scan
technology.

Endocytoscopy
Initially developed in 2003, endocytoscopy (ECS) has evolved as an in vivo magnifica-
tion technology that provides ultrahigh microscopic imaging with a 520 magnifica-
tion power.77 Through contact light microscopy, ECS enables visualization at the
individual cellular level where a high-powered lens projects a magnified image using
intraprocedural staining.78 As such, GC is identified, and there has been favorable
interobserver agreement between pathologists and endoscopists.77 However, there
are limited data on GC detection, especially because image quality is hindered by
554 Canakis & Kim

poor dye staining from gastric secretions.79 One of the first studies examined 28
gastric lesions and reported a sensitivity of 56% and specificity of 89%.80 A larger
study of 100 lesions reported favorable results (regardless of expertise) for which
the sensitivity, specificity, and accuracy were 78%, 93%, and 87%, respectively.81
Another group showed that the “enlarged nuclear sign” could aid in EGC diagnosis
with similar interobserver sensitivities (83%–87%), specificities (85%–95%), and ac-
curacies (84%–91%).78 The high accuracy of ECS has shown promise, but larger
blinded studies are still needed to determine if it can provide additional advantage
to conventional endoscopy and NBI.78,79
The intersection of ECS and AI with machine learning has also been explored, with
promising results.82,83 In one study by Hirasawa and colleagues,82 endoscopic images
of 67 GC lesions were detected with an overall sensitivity of 92%, and 99% when look-
ing at lesions with diameters more than 6 mm. The lesions missed by the AI system
were all superficially depressed. Another study by Zhu and colleagues83 found that
this deep learning application outperformed their endoscopists, with higher accuracy
and specificity rates, when detecting the invasion depth of GC. These studies provide
a glimpse of what these future technologies can provide, whereby improved diag-
nostic methods and efficient workflow can reduce costs and better identify patients
for ESD.77

Near-Infrared Raman Spectroscopy

Raman spectroscopy measures the inelastic scattering of monochromatic light with a
1.8-mm endoscopic probe that process molecular vibrations when it comes into direct
contact with tissue.84 As such, molecular features of cellular components and
biochemical tissues (ie, proteins, lipids, glycoproteins, and DNA) are analyzed and
identified.84 In combination with a near-infrared laser, this modality can penetrate
deeper levels of tissues via photon absorption with less interference to provide endo-
scopists with detailed molecular fingerprints that can differentiate neoplastic
changes.85
There have been numerous studies exploring the diagnostic ability of near-infrared
Raman spectroscopy (NIR) to identify GC changes.86–93 In an early study of 76 gastric
samples (21 histologically proven dysplasia), Teh and colleagues91 found that specific
spectral ranges of dysplasia were seen from 1200 to 1500 cm 1 and 1600 to
1800 cm 1 with a peak at 1450 cm 1. Using these spectral patterns in a diagnostic
algorithm based on principal component analysis and linear discriminant analysis,
they reported a sensitivity and specificity of 95% and 91%, respectively.91 A subse-
quent study by the same group reported similar findings when detecting GC and noted
that Raman peaks at 875 cm 1 and 1745 cm 1 were the most significant intensities to
differentiate normal and GC tissues.93 In a larger study of 1277 in vivo Raman spectra
acquired from 83 patients, Bergholt and colleagues86 further confirmed the ability of
NIR to detect intestinal-type adenocarcinoma with sensitivity of 85% and specificity
of 96%. Additionally, this method has also been able to differentiate benign versus
malignant gastric ulcers.87
These studies show that Raman spectroscopy is a quick, noninvasive way to make
an accurate and early diagnosis of gastric neoplasia. What is even more exciting is that
NIR has also been able to discriminate between differentiated and undifferentiated GC
at early and advance stages with accuracies ranging from 93% to 98%.90 Yet, there
are currently no studies comparing Raman spectroscopy with other endoscopic
detection techniques. The advancements of NIR have propelled this technology to
the forefront of GC diagnostic studies, although there are a few limitations to highlight.
Because this method detects molecular structures, there are instances where two
 Gastric Neoplasia Detection 555

similar molecules (eg, arachidonic and eicosapentaenoic acid) may be indistinguish-

able.88 There are also times where it is sensitive to process interference from pressure
changes or during heating when the sample can be damaged.88 However, these lim-
itations have not hindered the rapid advances of NIR where a noninvasive, reagent free
tissue diagnosis is feasible and accurate.

SUMMARY

With advancement of techniques for endoscopic detection of gastric neoplasia clini-

cians are now provided with the opportunity to decrease mortality rates through the
early detection of subtle lesions and subsequent targeted biopsies. In this article we
reviewed various IEE methods including CE, AFI, NBI, ME-NBI, FICE, BLI, pCLE,
i-scan, ECS, and NIR and their available scientific data. Despite the recent evolution
of these technologies, most of these image-enhancing modalities still lack randomized
controlled studies to prove their benefit in detecting EGC compared with conventional
WLE. Because of the relative lack of comparative data, no specific GI organization rec-
ommends IEE for gastric malignancy screening at this time, nor do there exist algo-
rithms to select the appropriate IEE method.
There is, however, stronger evidence supported by multiple randomized controlled
studies that some of these newer technologies including ME-NBI and BLI with their su-
perior mucosal and microvascular visualization enhance therapeutic endoscopic
treatment outcomes by better delineating tumor margins.
It is hoped that the continued evolution of techniques and availability of data from
large-scale comparative studies will alleviate these limitations.

CLINICS CARE POINTS

 When screening for an early gastric cancer, WLE is the currently recommended standard.
 CE with indigo carmine or methylene blue is used for the detection of early gastric cancer.
 AFI is unlikely to be a stand-alone modality because of its high false-positive rate.
 Nonmagnified NBI has a potential to improve early gastric cancer detection but it has
limitations with its dark field view.
 When endoscopic resection of the early gastric cancer is performed with ESD, IEE including
CE, NBI, ME-NBI, and BLI can be used for a better delineation of the tumor margins.

DISCLOSURE

There are no relevant disclosures.

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Endoscopic Resection of
Gastric Cancer
Ga Hee Kim, MD, PhD, Hwoon-Yong Jung, MD, PhD, AGAF*

KEYWORDS
 Early gastric cancer (EGC)  Endoscopic submucosal dissection (ESD)
 Endoscopic mucosal resection (EMR)  Stomach

KEY POINTS
 Endoscopic resection is an established first-line treatment modality for selected early
gastric cancers.
 Compared with endoscopic mucosal resection, endoscopic submucosal dissection is
generally associated with higher rates of en bloc, complete, and curative resections
and lower rates of local recurrence.
 Long-term outcomes in terms of recurrence and death of tumors that fulfill both the abso-
lute and the expanded criteria are excellent. Endoscopic resection might be considered a
primary treatment modality, replacing radical gastrectomy.

Video content accompanies this article at http://www.giendo.theclinics.com.

INTRODUCTION

Endoscopic resection (ER) is recognized as a minimally invasive treatment strategy for

premalignant gastrointestinal lesions, superficial esophageal cancer (SEC), early
gastric cancer (EGC), and early colon cancer with low morbidity and mortality.1
EGC is a well-established indication for ER for patients in East Asian and Western
countries.2,3 Recently, advancements in endoscopic techniques, including magnifying
endoscopy and image-enhanced endoscopy, have enabled the diagnosis of superfi-
cial neoplasia.4 With improvements in the early detection of EGC and advances in
techniques used, ER has become widely performed. Several studies have reported
favorable clinical outcomes of ER that are comparable to those of surgical resection
(SR), with greater safety and sufficient oncologic outcomes.5–10 ER for EGC was su-
perior to SR and showed several advantages in terms of improving the patient’s qual-
ity of life. Therefore, ER became a standard treatment for tumors meeting the specific
criteria characteristic of very low risk of lymph node metastasis (LNM).11

Department of Gastroenterology, University of Ulsan College of Medicine, Asan Medical

Center, Asan Digestive Disease Research Institute, 88, Olympic-ro 43-gil, Songpa-gu, Seoul
* Corresponding author.
E-mail address: hwoonymd@gmail.com

Gastrointest Endoscopy Clin N Am 31 (2021) 563–579

https://doi.org/10.1016/j.giec.2021.03.008 giendo.theclinics.com
1052-5157/21/ª 2021 The Author(s). Published by Elsevier Inc. This is an open access article under
the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
564 Kim & Jung

In this review article, the authors aim to discuss the techniques, indications, long-
term follow-up results, clinical management, and adverse events of ER as treatment
for gastric cancer.

Indications for Endoscopic Resection

Previous guidelines used for determining the indications for ER as treatment for EGC
were established primarily based on the presumed risk of LNM observed in surgical
specimens.12 In addition, the traditional criteria for ER of EGC were established ac-
cording to the technical limitation of traditional endoscopic mucosal resection
(EMR) for removing gastric lesions larger than 2 cm in diameter en bloc.13 The absolute
indications for ER were as follows: (1) papillary or tubular (differentiated) adenocarci-
noma, (2) 2 cm in diameter, (3) no ulceration within the tumor, and (4) no lymphatic-
vascular involvement.14–16
Clinical observations have noted that the empirical indications for EMR are too strict
and lead to unnecessary surgery.17 Therefore, the expanded criteria for ER have been
proposed, especially in cases whereby a large en bloc resection could be accom-
plished using endoscopic submucosal dissection (ESD).18,19 With the accumulation
of experience and technical advances, the indications for ER have widened and
criteria have expanded, proposed for tumors with minimal risk of LNM. Previous
studies investigated the long-term outcomes of ER in EGC meeting the expanded indi-
cation criteria, and the results were comparable with those in patients meeting the ab-
solute indication criteria. The expanded indication included 4 discrete criteria: (1)
intramucosal differentiated tumor without ulcers, size greater than 2 cm; (2) intramu-
cosal differentiated tumor with ulcers, size 3 cm; (3) intramucosal undifferentiated tu-
mor without ulcers, size 2 cm; and (4) submucosal invasion less than 500 mm (sm1),
differentiated tumor, size 3 cm.14–16
According to a recent multicenter study conducted in Japan (JCOG0607) that
included patients with differentiated mucosal cancer measuring greater than 2 cm in
diameter without ulcers and those with differentiated mucosal cancer measuring
3 cm with ulcers, the 5-year overall survival (OS) in the enrolled patients was
97.0% (95% confidence interval [CI], 95.0% to 98.2%).20 Based on the updated
2018 Japanese Gastric Cancer Association (JGCA) guidelines, the absolute indica-
tions for ESD were as follows: (1) a differentiated-type adenocarcinoma without ulcer-
ative findings, in which the depth of invasion is clinically diagnosed as T1a and the
diameter is greater than 2 cm, and (2) a differentiated-type adenocarcinoma with ul-
cerative findings, in which the depth of invasion is clinically diagnosed as T1a and
the diameter is 3 cm.11 In addition, the expanded indication now considers an
undifferentiated-type adenocarcinoma without ulcerative findings, in which the depth
of invasion is clinically diagnosed as T1a and the diameter is 2 cm. As such, the use
of ESD for tumors that fulfilled these expanded criteria subcategories should be
considered along with the risk of performing SR, given the increased risk of LNM.
The number of patients undergoing ESD for EGC has continuously increased as a
result of the criteria expansion.

Principles of Endoscopic Resection

Endoscopic mucosal resection
The first EMR technique was introduced in 1984 in Japan,21 and various techniques
have been developed since. The EMR with a cap-fitted panendoscope method was
developed in 1992 for the resection of SEC and is directly applicable to the resection
of EGC.22 The technique uses a transparent plastic cap mounted to the tip of a stan-
dard endoscope. A snare is prelooped inside the groove of the inner aspect of the
 Endoscopic Resection of Gastric Cancer 565

distal part of the cap, thus allowing the operator to cut lesions that are suctioned into
the cap. Using this technique, intramucosal cancers of 2 cm or less in diameter can be
safely removed. The EMR technique using ligation, which was subsequently extended
to EMR using multiband ligation, uses band ligation to create a “pseudopolyp” by suc-
tioning the lesion into the banding cap and deploying a band underneath it.23 There is a
wide variety of EMR methods used in the clinical setting, but the basic steps in per-
forming this procedure are as follows (Fig. 1): (1) delineation of the lateral margin
with or without chromoendoscopy, (2) placement of markings using a brief burst of
electrocautery or argon plasma coagulation, (3) submucosal injection to lift the lesion,
and (4) resection of the lesion. Before the development of ESD, EMR with circumfer-
ential precutting (EMR-P) was the most effective method for cutting larger lesions in 1
piece.24 EMR-P for intramucosal cancers less than 2 cm may be considered an alter-
native to ESD (Video 1).25 However, larger-sized lesions (>2 cm) cannot be completely
resected by EMR at once, and piecemeal resection can potentially increase the risk of
local recurrence and cause inadequate histologic staging.26,27

Fig. 1. EMR-P. (A) Adenoma of about10 mm in size with high-grade dysplasia on the lesser
curvature side of the antrum. (B) Narrow band imaging (NBI) finding of adenoma and
circumferential marking. (C) After saline injection, an elevated lesion shows hyperemic
discoloration at the center. (D) Circumferential precutting using snare tip. (E) Cutting of sub-
mucosal tissue using a snare. (F) Tissue containing adenoma resected with by the EMR pro-
cedure after hemostasis. (G) Retrieved specimen. (H) NBI finding of resected specimen. The
final diagnosis of this 53-year-old patient was 2a type EGC with a 7  6-mm sized well-
differentiated adenocarcinoma, which invaded into lamina propria.
566 Kim & Jung

Endoscopic submucosal dissection

The ESD technique has been widely used to remove tumors greater than 2 cm in diam-
eter with acceptable complication rates and higher en bloc and complete resection
rates than conventional EMR. Using this technique, the submucosal layer is dissected
with through-the-scope endoscopic knives. ESD was first published in 1999 and can
be used for resection of large lesions en bloc and allows precise pathologic staging.28
Complete en bloc resection regardless of tumor size, location, and presence of
fibrosis is now possible.
The procedure is performed in the following order: identification of the lesion,
marking around the lesion, submucosal injection, mucosal incision, submucosal
dissection, and tissue retrieval (Fig. 2). Before performing ESD, endoscopic examina-
tion, including white-light imaging, narrow-band imaging, and chromoendoscopy, was
performed to determine the exact margin of the tumor. Mucosal markings were made
mainly by forced coagulation effect 3 to 5 mm outside apart from the border of the
lesion (Video 2). After placing several dots around the lesion, normal saline mixed
with epinephrine and methylene blue was injected into the submucosal layer. The so-
lution was repeatedly injected into the target mucosa until the layer was sufficiently
lifted and the tumor area appeared brown. This change is attributed to the thickness
of the tumor. A small incision was made using a needle knife followed by a circumfer-
ential precutting outside the marking. Submucosal dissection was performed from the
oral side, as the tumor was located in the distal location. If the tumor is located in the
proximal or middle stomach, dissection begins at the anal side. Various knives,
including insulation-tipped (IT), IT-2, hook, flex, triangle tip, flush and dual knives,
were used to dissect the submucosal layer parallel to the muscular layer until the
lesion was completely removed. The dissection is usually performed from the poste-
rior wall side to the dependent position. It is preferable to dissect the submucosal layer
located in a dependent position. Hemostasis was performed by applying hemostatic
forceps or hemoclips or using argon plasma coagulation to prevent delayed bleeding.
All nonbleeding visible vessels were coagulated after the completion of ER. The
resected tissue was stretched and fixed with a pin to ensure that all marked areas
have been removed before the resection. The tissues were then fixed in 10% formalin
solution and sent to the pathologists.

Endoscopic mucosal resection versus endoscopic submucosal dissection

The classical EMR method is easy to perform, has less complications, and is appli-
cable for small-sized lesions, although 1 treatment effect depending on the size of
the lesion has been reported. Moreover, the en bloc resection and complete resection
rates are greatly reduced. When the classical EMR method was used for lesions less
than 1 cm in size, the rate of complete resection was approximately 60% and
remained high, whereas the rate of complete resection of lesions greater than 2 cm
in size was low (20%–30%). Complete resection of lesions greater than 3 cm is difficult
to achieve.29 The success rate of conventional EMR was influenced by tumor size and
shape and decreased in patients with lesions of size greater than 2 cm, of depressed
type, and located along the lesser curvature or posterior wall of the body.27 In a meta-
analysis of 18 observational studies including 6723 lesions, patients who underwent
ESD had an increased incidence of en bloc resection (odds ratio [OR]: 9.00; 95%
CI: 6.66 to 12.17; P<.001), complete resection (OR: 8.43; 95% CI: 5.04–14.09;
P<.001), and curative resection (OR: 2.92; 95% CI: 1.85–4.61; P<.001) compared
with those who underwent EMR. Furthermore, ESD was associated with a lower
risk of local recurrence (OR: 0.18; 95% CI: 0.09–0.34; P<.001).30 There was no signif-
icant difference between ESD and EMR for the risk of bleeding (OR: 1.26; 95% CI:
 Endoscopic Resection of Gastric Cancer 567

Fig. 2. ESD. (A) Hyperemic flat elevated and depressed lesion of about 5  3 cm in size on
the greater curvature side of the antrum. (B) The tumor area is distinguishable under NBI
mode because the neoplasm has many vascular structures and is detected by NBI as dark
brown. (C) Endoscopic ultrasonography findings of this tumor. Scanned mucosal layer ap-
pears thickened and mixed hypoechoic, which is representative of the involved area. (D)
Marking. Circumferential marking around the tumor margin. Marking should be made at
3 to 5 mm outside apart from imaginary border. (E) Submucosal injection. During submuco-
sal injection of saline mixed with a small amount of methylene blue, tumor area can be
568 Kim & Jung

0.88–1.80; P 5 .203). The number of clinicians in centers outside of Asia who have
expertise and experience in performing ESD have increased, and ESD is the preferred
endoscopic treatment for patients with EGC based on certain published guidelines.

Clinical Management After Endoscopic Resection

When a lesion without lymphovascular invasion (LVI) and a negative surgical margin
meeting the absolute and expanded indication criteria is resected en bloc, it is consid-
ered a curative lesion.16,30,31 Metachronous gastric cancer may possibly develop
following ER, and the cumulative 3-year risk is approximately 5.9%.32 Regular surveil-
lance endoscopy every 6 to 12 months was recommended for patients who under-
went curative ER of EGC based on the absolute or expanded criteria for early
detection of metachronous gastric cancer. In addition, regular abdominopelvic
computed tomography scans at 6- to 12-month intervals were performed after cura-
tive ER of EGC for the detection of extragastric recurrence based on absolute and
expanded criteria. The patients were tested for Helicobacter pylori infection; if the
test yielded a positive result, appropriate treatment was provided to eradicate the
infection.33–35
Resected tumors that do not fulfill the following criteria were considered for noncur-
ative resection: (1) differentiated (well or moderately differentiated tubular or papillary)
intramucosal cancer measuring greater than 2 cm in diameter without ulcers (active or
scar), (2) differentiated mucosal cancer measuring less than 3 cm with ulcers (active or
scar), (3) undifferentiated (poorly differentiated tubular or poorly cohesive) mucosal
cancer measuring less than 2 cm without ulcers (active or scar), and (4) differentiated
mucosal cancer measuring less than 3 cm with subtle submucosal invasion
(<500 mm).16 LVI and positive vertical margins, which are confirmed after ER, are
also important reasons for the recommendation of an additional gastrectomy.16,31
Most studies that have investigated the long-term outcomes with or without additional
surgery in patients who did not meet the curative criteria for ER of EGC showed a sig-
nificant survival benefit.36–38

clearly seen as brown. This change is originated from the thickness of the tumor. (F) Precut-
ting. Circumferential cutting of the mucosa, including the marking spots. As can be appre-
ciated, there is sufficient free margin along the precut. (G–I) Submucosal dissection. (G)
After circumferential precutting, the submucosal layer is dissected from the oral side for
the distal location. If the tumor location is the proximal or middle stomach, dissection be-
gins from the anal side. (H) The direction of dissection is usually from the posterior wall
side to the dependent position. (I) It would be more comfortable to dissect the last submu-
cosa located in the dependent position. (J) Completion of submucosal dissection. (K) Hemo-
stasis. Coagulation of bleeding and nonbleeding exposed vessels to prevent delayed
bleeding. (L) Pinning of resected specimen. The retrieved specimen should be fixed using
pins, and all the marking spots and tissue orientation should be confirmed. The image
shows different numbers at the right side to keep proper orientation after resection. The
total procedure time for ESD was 37 min. The specimen size was 80  55 mm. (M) Specimen
after fixation in the formalin bag. The tumor margin usually can be seen after formalin fix-
ation. This lesion is a superficially depressed lesion, including several nondepressed foci. (N)
Mapping of specimen. Resected specimen is sliced at every 2- to 3-mm interval to make a
histopathological map. The final diagnosis was a 57  32-mm sized EGC, 2c12b, moderately
differentiated adenocarcinoma. The depth of invasion extends to the muscularis mucosae
(M3). All lateral and deep margins are free of tumor with no lymphovascular tumor
embolism.
 Endoscopic Resection of Gastric Cancer 569

Based on the updated 2018 JGCA guidelines, the technical terms related to the
curability of ER of EGC were revised: endoscopic curability (eCura) A to C-2. Curative
resection and expanded curative resection were changed to eCuraA and B. Noncur-
ative resection was divided into eCuraC-1 and C-2.11 The resection is classified as
endoscopic curability A (eCuraA) when all of the following conditions are fulfilled, pro-
vided that the cancer does not have ulcerative findings: en bloc resection, any tumor
size, histologically differentiated type-dominant, pT1a, negative horizontal and vertical
margins, and absence of LVI. The resection is classified as endoscopic curability B
(eCuraB) for histologically undifferentiated dominant type tumors when all of the
following conditions are fulfilled: no ulcerative findings, en bloc resection, pT1a, nega-
tive horizontal and vertical margins, no LVI, and tumor size 2 cm. The resection is
classified as endoscopic curability C-1 (eCuraC-1) when it is of histologically differen-
tiated type and fulfills the criteria for either eCuraA or eCuraB classification but was not
used to resect tumors en bloc or has positive horizontal margins. All other eCuraC re-
sections were subclassified as endoscopic curability C-2 (eCuraC-2). An exception
applies if cancer invasion is observed only at the horizontal resection margin
(eCuraC-1). Additional endoscopic management rather than SR is applied if histopath-
ological evaluation of endoscopically resected EGC specimen shows positive involve-
ment at the horizontal resection margin without any other findings compatible with
noncurative resection. Repeat ESD, close observation expecting a burn effect of the
initial ESD, and endoscopic coagulation using a laser or argon-plasma coagulator
rather than surgical gastrectomy fall under the category of eCuraC-1. The standard
management of eCuraC-2 is additional surgery; however, the clinicians’ decision
should consider the patient’s physical condition.11

Long-Term Outcomes
Many studies with long-term follow-up have identified ER as a favorable method for
curative resection of EGC with absolute indication.39 In the case of EGC with absolute
indication, the 5-year disease-specific survival rate is almost 100%. Therefore, the
data comparing outcomes in patients who underwent ER with those who had a gas-
trectomy suggest similar clinical outcomes.5 Several studies investigated the long-
term outcomes of ESD in EGC that met the expanded indication criteria, and the
results were comparable with those in patients meeting the absolute indication criteria
(Table 1).
No randomized trials have compared endoscopic and surgical management of
EGC. Recently, to validate the expanded indication criteria of ER, several studies

Table 1
Long-term outcomes of endoscopic resection for early gastric cancer

Number
of Patients FU Period En Bloc 5-y DFS 5-y OS 5-y DSS
Author, Publication Year (EMR/ESD) (mo) Resection (%) (%) (%) (%)
Shichijo et al,45 2020 0/214 88.8 99 NA 99.5 93.9
Kim et al,40 2018 0/697 59 99.1 87.9 96.6 90.6
Choi et al,41 2015 33/928 48.3 88.7 99.1 94.8 NA
Kosaka et al,42 2014 0/438 73 97.7 NA 83.1 100
Ahn et al,43 2011 534/833 32 86.1 NA 96.8 NA

Abbreviations: DFS, disease-free survival; DSS, disease-specific survival; FU, follow-up; NA, not
available.
570 Kim & Jung

compared the long-term outcomes of ER and SR, which reported favorable results for
ER (Table 2). Compared with SR, the benefits of ER included fewer complications and
a shorter length of hospital stay. ER preserves the stomach, thereby improving pa-
tients’ quality of life compared with SR.47 In a single-center prospective study by
Kim and colleagues,47 ER can provide better health-related quality-of-life benefits
for EGC patients than can SR, especially during the early posttreatment period. How-
ever, the 5-year cumulative metachronous recurrence rates after ER (5.8%–10.9%)
were significantly higher than those after SR (0.9%–1.1%).5,6 Metachronous gastric
cancer or local recurrence could be treated by ER if the lesion is detected early. There-
fore, more attention should be paid during surveillance endoscopy after ER.
The indications for ER include undifferentiated-type intramucosal EGC 2 cm in
diameter without ulceration or LVI.11,15 Instrumental and technical advancements,
such as the development of ESD, have enabled the resection of larger tumors. Conse-
quently, ER for undifferentiated EGC often results in the complete resection of the un-
differentiated intramucosal EGC greater than 2 cm in diameter with negative resection
margins and the absence of ulceration and LVI. In a recent multicenter study in Korea
conducted by Yang and colleagues,48 the risk of LNM or distant metastasis was 1%
for patients undergoing noncurative ER for undifferentiated EGC, with the tumor size
of greater than 2 cm as the only noncurative factor. The results of previous studies
were obtained by retrospective assessment of the patients’ medical records. Thus,
a prospective multicenter study with a high follow-up rate is required for a more pre-
cise evaluation of the long-term outcomes of gastric ESD.

Treatment Strategy for Noncurative Resection

The indication for endoscopic treatment of EGC is gradually expanding. Various other
factors may cause “noncurative resection,” unintended by the practitioner. According
to various previous studies, the incidence of noncurative resection after ER of EGC
was approximately 11.9% to 18.5%.49 The aim of ER for EGC is curative resection,
but unintended noncurative resection may occur because of various factors. Several
previous studies have analyzed the risk factors affecting noncurative resection in the
ER of EGC, including large tumor size, tumor location, and presence of ulcers and un-
differentiated tumors. In the case of noncurative resection, additional treatment is
required considering the risk of local recurrence and LNM, and the standard treatment

Table 2
Comparison of long-term outcomes between endoscopic resection and surgical resection for
early gastric cancer

No. of
Author, Patients FU Period R0 Resection 5-y DFS 5-y OS 5-y DSS
Publication Year ER/SR (mo) ER/SR (%) ER/SR (%) ER/SR (%) ER/SR (%) ER/SR
Lee et al,46 2018 522/522 52.7/59.2 NA 92.7/96.7 98.1/96.4 99.6/98.9
Quero et al,9 2020 64/73 23/21 88.1/100 74.9/72 77.7/71.8 NA
Fukunaga 181/127 42.9/64.2 NA NA 97.1/85.8 NA
et al,44 2017
Gong et al,10 2017 40/39 60.9 92.5/NA NA 93.9/97.3 NA
Pyo et al,8 2016 1290/1273 46 82.7/96.4 98/96.9 97.1/96.3 99.6/99.4
Choi et al,6 2015 261/114 74.9/78.1 85.8/NA 94.8/99.1 95.7/93.6 100/100
Choi et al,5 2011 172/379 81 NA NA 93.6/94.2 98.7/99.7

Abbreviation: No., number.

 Endoscopic Resection of Gastric Cancer 571

is gastrectomy with lymphadenectomy. Additional gastrectomy with lymph node

dissection is the standard treatment after noncurative ER.11,15,16,37 The rate of LNM
in patients who underwent additional gastrectomy after noncurative resection of ER
for EGC is 7.5% to 16.7%.50–52 Furthermore, if recurrence is observed when no addi-
tional treatment was provided after a noncurative ER, most patients do not achieve
long-term survival. In a recent study by Kim and colleagues,53 they developed a nomo-
gram to predict the status of LNM with the aim of avoiding unnecessary surgery. Multi-
variate analyses revealed that age, tumor size, lymphatic invasion, depth of invasion,
and histologic differentiation were all significant prognostic factors for LNM. Patients
with LVI or vertical margin positivity showed a survival benefit with additional curative
surgery.36,54 Thus, additional surgery should be selected in healthy, nonelderly
patients.
Otherwise, in some elderly patients and/or those with severe underlying diseases,
the advantages and disadvantages of additional surgery should be considered
when selecting the treatment strategy after noncurative ER.55 In elderly patients
with gastric cancer, it is necessary to evaluate not only the risk for LNM but also the
underlying conditions of the patient because heterogeneity in the aging process leads
to a diverse range of age-related declines in health and physical status among the
elderly.56,57 For reasons such as an increase in elderly patients because of the in-
crease in average life expectancy, underlying disease, poor general condition, or pa-
tient’s refusal of a gastrectomy, patients with noncurative resection may be treated
with redo ESD, argon plasma coagulation, or careful observation without further
treatment.58,59

Adverse Event
Bleeding
Post-ESD bleeding is difficult to predict and can be a potentially life-threatening
complication. Bleeding is the most common major complication of ER. Bleeding is
classified into immediate bleeding during ER and delayed bleeding after ER. Immedi-
ate bleeding can be defined as cases requiring blood transfusion, emergency surgery,
or vasopressor therapy in which the rate is less than 1%.60 The major factors affecting
intraoperative bleeding were tumor location (more often in the upper and middle thirds
than in the lower third) and tumor size (more often >2 cm in size).61 However, bleeding
can be successfully treated in most cases through coagulation of the bleeding vessels,
or placement of metallic clips for severe bleeding. In terms of postoperative bleeding,
the most acceptable definition is marked bleeding from the ER-related ulcers requiring
special measures for hemostasis; it is clinically noticed before endoscopy when the
hemoglobin level decreases by 2 g/dL, vital signs change, or either hematochezia or
massive melena is seen. It is reported that delayed bleeding occurs in 1.8% to
15.6% of cases.62–64 Delayed bleeding is associated with tumor location, larger tu-
mors (>40 mm), recurrent lesions, presence of ulcers, old age (80 years), longer pro-
cedure time, chronic kidney disease, liver cirrhosis, and the use of antithrombotic
agents.65–68 Delayed bleeding was reported to occur more frequently after ESD for le-
sions in the lower and middle thirds of the stomach compared with the upper third of
the stomach.69,70 Antral active peristalsis, and bile reflux might lead to a high inci-
dence of post-ESD bleeding in the lower stomach. Prophylactic hemostasis of visible
vessels on the postresection ulcer caused by ER of EGC may lower the risk of delayed
bleeding.70 In addition, proton pump inhibitors decrease the risk of symptoms and
complications associated with iatrogenic ulcers caused by ER of EGC.71,72 Several
randomized trials and a meta-analysis indicated that administering proton pump inhib-
itors significantly reduced the incidence of delayed bleeding compared with using a
572 Kim & Jung

histamine-2 receptor antagonist.71 A second-look endoscopy after ER may contribute

little to the prevention of delayed bleeding.73,74 The preventive coagulation of non-
bleeding visible vessels in second-look endoscopy after gastric ESD may contribute
little to the prevention of late delayed bleeding.70
With the increase in the use of antithrombotic agents, the management of these
drugs during the perioperative period remains a great concern. Patients receiving
antithrombotic agents have an increased risk of bleeding. However, discontinuing
the use of antithrombotic agents may lead to unexpected thrombotic events. In a
recent Korean propensity score matching study, So and colleagues65 reported con-
flicting results on the risk of bleeding after ESD for gastric neoplasms: delayed
bleeding rate in the continued use of antithrombotic agents group was higher than
that of the matched control group (15.9% vs 5.1%; OR: 3.55; 95% CI: 1.24–10.14;
P 5 .018). No thromboembolic events were observed in patients in the continuation
of antithrombotic agents group. In another study in Japan by Koh and colleagues,75
oral antithrombotic drug treatment was selected as an independent risk factor for
delayed but not early bleeding, according to the multivariate analysis (OR: 2.667;
95% CI: 1.231–5.776; P 5 .013). Interruption of antithrombotic drug treatment may
be adequate for preventing early post-ER bleeding; however, reinitiating antithrom-
botic agents is a significant independent risk factor for delayed post-ER bleeding.
Therefore, the post-ER bleeding risk for each agent must be analyzed individually.

Perforation
Perforation during ER with rates reportedly ranging from 1.2% to 9.6% can be conser-
vatively treated by complete endoscopic closure with endoclips.76,77 Delayed perfora-
tion because of artificial ulcers following ER is rare, reportedly 0.06% to 0.45% after
gastric ER; however, it can lead to serious conditions that often require emergency op-
erations.78 Perforations that occur in relation to ESD are classified into macroperfu-
sions and microperforations. A perforation is diagnosed when mesenteric fat or
intra-abdominal space is directly observed during the procedure (macroperforation)
or free air is found on a radiograph after the procedure without a visible stomach
wall defect during the procedure (microperforation). Immediate small perforations
can be successfully treated without surgery with a combination of endoscopic clipping
and broad-spectrum antibiotics.79 However, large perforations would require immedi-
ate surgery. Delayed perforation after ER may occur because of various factors, such
as tumor state (tumor depth, invasion status, and upper stomach), lesions in the
gastric tube, and the patient’s condition. The essential mechanism of delayed perfo-
ration after ESD was suggested to be electrical cautery during submucosal dissection
or repeated coagulation that caused ischemic change to the gastric wall, resulting in
necrosis.80 Recognizing delayed perforation in the differential diagnosis is important
when patients who have previously undergone ER for EGC show signs of peritoneal
irritation. Patients with delayed perforation who recovered with conservative manage-
ment were mostly those who developed adverse events before dietary intake and/or
received endoscopic intervention within 24 hours after onset.81

Other adverse events

The circumferential extent of the mucosal defect of greater than 75% of the circumfer-
ence of the lumen and longitudinal extent of greater than 5 cm were related to post-ER
stenosis with both cardiac and pyloric resections.82 Stenosis after gastric ER has been
reported to range from 0.7% to 1.9%.83 Several studies described the use of a steroid
(triamcinolone) solution for submucosal injection during ER.84 Balloon dilation is a
 Endoscopic Resection of Gastric Cancer 573

recognized standard treatment for benign strictures and is used as the primary treat-
ment for post-ER stenosis.85
According to a prospective study in Japan, ER procedures carry a moderate risk for
venous thromboembolism.86 In this study, D-dimer measurements were higher in pa-
tients with deep vein thrombosis (DVT) than in patients without DVT. D-dimer levels on
the day after ESD, in particular, may be associated with DVT in patients with ESD. Ac-
cording to the receiver operating characteristic curve analysis, the resulting cutoff
value of the D-dimer level on the day after ER was 1.9 mg/mL for ESD patients, with
superior association to pre-ESD or immediate post-ESD levels (sensitivity 83.3%;
specificity 79.6%).
The possibility of sedation-related adverse events, including pulmonary complica-
tions, may be increased when performing therapeutic endoscopy. In a single-center
retrospective study in Korea conducted by Gong and colleagues,87 the incidence of
aspiration pneumonia after ER for gastric neoplasms was 0.62%. In addition, old
age, smoking, and a longer hemostasis time were risk factors for the occurrence of
aspiration pneumonia after ER.

SUMMARY

ER is an effective treatment for EGC without metastasis because of the high en bloc
and complete resection and low local recurrence rate. With regard to its safety and ef-
ficacy, the indications for ER have broadened in the field of therapeutic endoscopy.
Long-term outcomes in terms of recurrence and death are excellent using both the ab-
solute and the expanded criteria. ER can preserve organ function with excellent main-
tenance of the patient’s quality of life. Therefore, ER may be positioned as a primary
treatment modality, replacing radical gastrectomy. To obtain these results, accurate
diagnosis, selection of patients, proper appreciation of technical aspects, and rational
strategy for follow-up are necessary. Thus, further technological advances in treat-
ment and outcomes of long-term follow-up under the expanded indications of ER
for EGC owing to the risk of LNM are expected in the next decade.

CLINICS CARE POINTS

 Endoscopic resection is recommended an established first-line treatment modality in both

absolute and selected expanded indication for early gastric cancer.
 The meticulous pathologic evaluation is needed to confirm the curability and to decide the
candidates taking additional gastrectomy with regional lymphadenectomy in the patients
with noncurative resection.
 To determine additional treatment strategy for noncurative resection, both aspects of the
underlying medical condition of the patient and the risk factors for lymph node metastasis
should be considered.

DISCLOSURE

The authors have nothing to disclose.

SUPPLEMENTARY DATA

Supplementary data to this article can be found online at https://doi.org/10.1016/j.

giec.2021.03.008.
574 Kim & Jung

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S u r g i c a l Tre a t m e n t f o r
Gastric Cancer
Ian Solskya, Haejin In, MD, MPH, MBA
a,b,c,
*

KEYWORDS
 Gastric cancer  Gastrectomy  Lymphadenectomy  Staging laparoscopy

KEY POINTS
 Staging laparoscopy is an important modality for patients with gastric cancer with stages
T1b or greater to evaluate for peritoneal spread when chemoradiation or surgery is
considered.
 The appropriate surgical procedure for gastric cancer is based on the lesion’s location:
subtotal gastrectomy is generally the procedure of choice for distal tumors, whereas total
gastrectomy is generally performed for proximal lesions in the upper third of the stomach.
 D2 lymphadenectomy is now supported as a critical part of a curative intent resection
given that gastric cancer spreads through lymphatics to regional lymph nodes.

Video content accompanies this article at http://www.giendo.theclinics.com.

INTRODUCTION

Regionality is an important theme when it comes to the surgical management of

gastric cancer. Not only does the location of gastric cancer and its extent of spread
dictate the operative plan but also, historically, the management of gastric cancer is
often thought of in terms of “Eastern versus Western” approaches. Incidence rates
in Eastern Asia are significantly higher than they are in North America.1 The greater
experience in treating gastric cancer in Asian institutions has led to differing manage-
ment practices in terms of screening and prevention as well as in treatment.2 In terms
of surgical management, Eastern surgeons have been pioneers and proponents of
minimally invasive techniques and more extensive lymph node dissections, which
have been controversial in Western institutions but are now being performed with
greater frequency. Despite some ongoing debate about the details of gastric cancer
management, what is agreed on is that surgery is an essential component of

a
Department of Surgery, Montefiore Medical Center, Albert Einstein College of Medicine,
1300 Morris Park Avenue Block Building #112, New York, NY 10461, USA; b Department of
Surgery, Albert Einstein College of Medicine, New York, NY, USA; c Department of Epidemi-
ology and Population Health, Albert Einstein College of Medicine, New York, NY, USA
* Corresponding author. Department of Surgery, Montefiore Medical Center, Albert Einstein
College of Medicine, 1300 Morris Park Avenue #112, New York, NY 10461.
E-mail address: hin@montefiore.org

Gastrointest Endoscopy Clin N Am 31 (2021) 581–605

https://doi.org/10.1016/j.giec.2021.04.001 giendo.theclinics.com
1052-5157/21/ª 2021 Elsevier Inc. All rights reserved.
582 Solsky & In

curative-intent treatment strategies. However, the care of each patient with gastric
cancer must be individualized and may require additional neoadjuvant or adjuvant
therapies, such as chemotherapy or radiation therapy. With the ongoing development
of new therapeutics, such as immunotherapy, and technologies, such as robotic sur-
gery, the future of gastric cancer care will continue to evolve and require the coordi-
nated teamwork of physicians with different medical and surgical expertise to
optimize patient outcomes. It is important that all physicians who will be caring for pa-
tients with gastric cancer understand the current best practices of surgical manage-
ment to provide patients with the highest quality of care. This article aims to provide
this information while acknowledging areas of surgical management that are still
controversial.

STAGING LAPAROSCOPY AS PART OF THE STAGING EVALUATION

Conventional staging for gastric cancer usually includes a physical examination, a

computed tomographic (CT) scan of the chest/abdomen/pelvis, and an endoscopic
ultrasound, which is performed in accordance with the TNM staging system of the
combined American Joint Committee on Cancer/Union for International Cancer Con-
trol (Table 1).3 Per National Comprehensive Cancer Network (NCCN) guidelines, the
performance of a staging laparoscopy with peritoneal washings is also indicated for
clinical stages T1b to evaluate for peritoneal spread when chemoradiation or surgery
is considered.4 Many experts follow these guidelines and support its use for locally
advanced disease and for patients being considered for neoadjuvant therapy but
not for those with early-stage disease.5 A staging laparoscopy is performed to directly
visualize the liver surface, peritoneum, and lymph nodes while allowing for the biopsy
of any worrisome lesions and the collection of peritoneal fluid for cytologic analysis.
Staging laparoscopy, with reported sensitivity of 86% and specificity of 100%, is su-
perior to radiographic studies for detecting metastatic disease and may detect radio-
graphically occult disease that can alter management in approximately 9% to greater
than 50% of patients with only localized disease on imaging.6–9 If metastatic disease is
identified, a patient may be spared from the performance of an unnecessary laparot-
omy, which has a morbidity of 13% to 23% and a mortality of 10% to 21%, whereas
staging laparoscopy has a morbidity of 0% to 2.5% and no reported mortality.7,10–13
During laparoscopy, peritoneal fluid can be collected and sent for cytology, which if
positive, upstages a patient to stage IV disease and is a poor prognostic sign predic-
tive of disease recurrence.9,14 Studies are ongoing to further delineate the role of sur-
gery and neoadjuvant strategies for individuals with positive cytology.15,16
When a patient is selected to undergo staging laparoscopy, it can be performed as a
one- or a 2-stage approach. In a one-stage approach, the staging laparoscopy is per-
formed concurrently at the same time as the planned surgical resection. In a 2-stage
approach, the staging laparoscopy is the only procedure performed to be followed at a
later date by a separate surgical resection if no metastatic disease is identified during
the staging laparoscopy. The advantage of the one-stage approach is that it involves
only 1 procedure and 1 anesthetic exposure. However, the disadvantage is that it can
add additional time and complexity to the case if there is uncertainty with a frozen sec-
tion biopsy or if there is a need for final pathology to confirm a worrisome finding. It is
also not possible to have cytology examined during a one-stage procedure. The
advantage of performing the staging laparoscopy separately in a 2-stage approach
is that it may identify patients who are more suited for a neoadjuvant approach.
Although a 2-stage approach requires the patient to be exposed a second time to
anesthesia for a definitive cancer operation, it is a more robust approach for ensuring
 Surgical Treatment for Gastric Cancer 583

Table 1
Eighth American Joint Committee on Cancer staging system for gastric adenocarcinoma

Primary tumor TX Primary tumor cannot be assessed

T0 No evidence of primary tumor
Tis Carcinoma in situ: intraepithelial tumor
without invasion of the lamina propria,
high-grade dysplasia
T1 Tumor invades the lamina propria,
muscularis mucosae, or submucosa
T1a Tumor invades the lamina propria or
muscularis mucosae
T1b Tumor invades the submucosa
T2 Tumor invades the muscularis propria
T3 Tumor penetrates the subserosal connective
tissue without invasion of the visceral
peritoneum or adjacent structures
T4 Tumor invades the serosa (visceral peritoneum)
or adjacent structures
T4a Tumor invades the serosa (visceral peritoneum)
T4b Tumor invades adjacent structures/organs
Regional nodes NX Regional lymph nodes cannot be assessed
N0 No regional lymph node metastasis
N1 Metastasis in 1 or 2 regional lymph nodes
N2 Metastasis in 3 to 6 regional lymph nodes
N3 Metastasis in 7 or more regional lymph nodes
N3a Metastasis in 7 to 15 regional lymph nodes
N3b Metastasis in 16 or more regional lymph nodes
Metastases M0 No distant metastasis
M1 Distant metastasis
Stage groupings 0 TisN0M0 IIIB T1N3bM0
(pathologic) IA T1N0M0 T2N3bM0
IB T1N1M0 T3N3aM0
T2N0M0 T4aN3aM0
IIA T1N2M0 T4bN1M0
T2N1M0 T4bN2M0
T3N0M0 IIIC T3N3bM0
IIB T1N3aM0 T4aN3bM0
T2N2M0 T4bN3aM0
T3N1M0 T4bN3bM0
T4aN0M0 IV Any T, any N, M1
IIIA T2N3aM0
T3N2M0
T4aN1M0
T4aN2M0
T4bN0M0

From Cameron J and Cameron A 2019. Current surgical therapy. 13th edition. p.102.

accurate staging. As the role of staging laparoscopy continues to be defined, it re-

mains underused in the United States: 1 study suggested that it was only performed
in 8% of older patients with gastric cancer.17
The uptake is likely higher at major cancer centers, where staging laparoscopy is
acknowledged as an important aspect of accurate staging.18 As further research elu-
cidates the value of neoadjuvant approaches and as more surgeons learn of its utility,
there may be a greater uptake of staging laparoscopy to rule out metastatic disease
and to obtain cytology to guide specific therapy (Video 1).
584 Solsky & In

SURGICAL APPROACH
Anatomy
Knowledge of the surgical anatomy of the stomach is important not only for the tech-
nical performance of gastric cancer surgery but also to help all providers understand
the physiologic changes that may be seen in patients after gastrectomy. Fig. 1 shows
the important anatomic structures and the relevant blood supply. Located in the left
upper quadrant of the abdomen, the stomach is adjacent to many important struc-
tures, including the left lateral lobe of the liver, the transverse colon, omentum,
pancreas, spleen, left kidney, left adrenal gland, and the diaphragm. The stomach
can be divided into 5 anatomic sections based on histology and function: (1) cardia
and gastroesophageal junction, (2) fundus, (3) body, (4) antrum, and (5) pylorus. The
cardia, the proximal stomach next to the lower esophageal sphincter, contains mucus
and endocrine cells. The fundus, adjacent to and rising above the cardiac opening,
contains parietal cells, chief cells, endocrine cells, and mucus cells. The body, be-
tween the fundus and antrum, contains cells similar to the fundus. The antrum, the
distal stomach separated from the body by the angular incisura, contains pyloric
glands, endocrine cells, mucus cells, and G cells. The pyloric sphincter, a muscular
valve separating the antrum from the duodenum, contains mucus cells and endocrine
cells. The lesser curve of the stomach is supplied by the left and right gastric arteries,
which branch off the celiac and common hepatic arteries, respectively. The greater
curvature is supplied by the right and left gastroepiploic arteries, which arise from
the gastroduodenal and splenic arteries, respectively. The fundus of the stomach is
supplied by the short gastric arteries, which also come off the splenic artery. Veins
parallel the arterial supply.19,20 The lymph node stations of the stomach have been
defined by the Japanese Research Society for the Study of Gastric Cancer and are
grouped into 16 stations according to location: 1 to 6 are perigastric and the others
are adjacent to major blood vessels, along the aorta, or behind the pancreas.21
Table 2 contains description of the lymph node stations.

Indicators of Resectability
Resection offers patients with gastric cancer the best chance for cure, but patients
must be appropriately referred for what can be a major procedure. Patients being
considered for resection must not have severe comorbidities that would prevent the
safe receipt of anesthesia. A gastric cancer is generally considered unresectable if
there are distant metastases, invasion of major vasculature such as the aorta, or
encasement of the hepatic artery or celiac axis. Involvement of the distal splenic artery

Fig. 1. Stomach anatomy and vasculature. (From Vishy Mahadevan, Anatomy of the stom-
ach, Surgery (Oxford), Volume 35, Issue 11, 2017, Pages 608-611, ISSN 0263-9319, https://
doi.org/10.1016/j.mpsur.2017.08.004. Accessed via https://www.sciencedirect.com/science/
article/pii/S0263931917301850.)
 Surgical Treatment for Gastric Cancer 585

Table 2
Anatomic definitions of lymph node stations

No. Definition
1 Right paracardial lymph nodes (LNs), including those along the first branch
of the ascending limb of the left gastric artery
2 Left paracardial LNs, including those along the esophagocardiac branch of
the left subphrenic artery
3a Lesser curvature LNs along the branches of the left gastric artery
3b Lesser curvature LNs along the 2nd branch and distal part of the right gastric
artery
4sa Left greater curvature LNs along the short gastric arteries (perigastric area)
4sb Left greater curvature LNs along the left gastroepiploic artery (perigastric
area)
4d Right greater curvature LNs along the 2nd branch and distal part of the right
gastroepiploic artery
5 Suprapyloric LNs along the 1st branch and proximal part of the right gastric
artery
6 Infrapyloric LNs along the first branch and proximal part of the right
gastroepiploic artery down to the confluence of the right gastroepiploic
vein and the anterior superior pancreatoduodenal vein
7 LNs along the trunk of left gastric artery between its root and the origin of its
ascending branch
8a Anterosuperior LNs along the common hepatic artery
8p Posterior LNs along the common hepatic artery
9 Celiac artery LNs
10 Splenic hilar LNs, including those adjacent to the splenic artery distal to the
pancreatic tail, and those on the roots of the short gastric arteries and
those along the left gastroepiploic artery proximal to its 1st gastric branch
11p Proximal splenic artery LNs from its origin to halfway between its origin and
the pancreatic tail end
11d Distal splenic artery LNs from halfway between its origin and the pancreatic
tail end to the end of the pancreatic tail
12a Hepatoduodenal ligament LNs along the proper hepatic artery, in the caudal
half between the confluence of the right and left hepatic ducts and the
upper border of the pancreas
12b Hepatoduodenal ligament LNs along the bile duct, in the caudal half
between the confluence of the right and left hepatic ducts and the upper
border of the pancreas
12p Hepatoduodenal ligament LNs along the portal vein in the caudal half
between the confluence of the right and left hepatic ducts and the upper
border of the pancreas
13 LNs on the posterior surface of the pancreatic head cranial to the duodenal
papilla
14v LNs along the superior mesenteric vein
15 LNs along the middle colic vessels
16a1 Paraaortic LNs in the diaphragmatic aortic hiatus
16a2 Paraaortic LNs between the upper margin of the origin of the celiac artery
and the lower border of the left renal vein

(continued on next page)

586 Solsky & In

Table 2
(continued )
No. Definition
16b1 Paraaortic LNs between the lower border of the left renal vein and the upper
border of the origin of the inferior mesenteric artery
16b2 Paraaortic LNs between the upper border of the origin of the inferior
mesenteric artery and the aortic bifurcation
17 LNs on the anterior surface of the pancreatic head beneath the pancreatic
sheath
18 LNs along the inferior border of the pancreatic body
19 Infradiaphragmatic LNs predominantly along the subphrenic artery
20 Paraesophageal LNs in the diaphragmatic esophageal hiatus
110 Paraesophageal LNs in the lower thorax
111 Supradiaphragmatic LNs separate from the esophagus
112 Posterior mediastinal LNs separate fro

Adapted from Japanese Gastric Cancer Association. Japanese classification of gastric carcinoma:
3rd English edition. Gastric Cancer 14, 101–112 (2011). https://doi.org/10.1007/s10120-011-0041-5.

is not a contraindication to resection, as the vessel can be taken en bloc along with the
stomach, spleen, and distal pancreas. The presence of bulky lymph nodes in the aor-
tocaval region, mediastinum, or the porta hepatis is considered distant disease and is
classified as stage IV.6 Concerning linitis plastica, extensive tumor infiltration of the
stomach resulting in a rigid thickened stomach, which is associated with poor prog-
nosis, there is some controversy as to whether this should be considered resectable
or not; however, in the era of neoadjuvant therapy, many surgeons would elect to pro-
ceed with resection if negative margins can be obtained.22–24 Of note, although pa-
tients with metastatic gastric cancer generally are not eligible for curative surgery,
this does not mean that these patients are excluded from surgical treatments, which
may be of benefit to some patients with complications, such as obstruction, bleeding,
or perforation (see later section on Palliative Interventions).

Preoperative Planning
The decision to pursue gastric cancer resection should occur with consultation of a
multidisciplinary tumor board to ensure that an appropriate multimodality treatment
strategy is planned. In the United States, neoadjuvant therapy is advocated by
NCCN guidelines and is increasingly pursued before surgical resection.4 Furthermore,
given that most resections will be performed under elective situations, it is critical for
patients to undergo preoperative medical assessments, as most of these patients are
older and present with comorbidities.25 As part of the workup, genetic counseling may
be indicated in cases whereby any genetic syndrome, such as hereditary diffuse
gastric cancer, familial adenomatous polyposis, or Peutz-Jeghers, is suspected.26
During the consent process for surgery, patients should be made aware not only of
the risks of surgery and its complications but also of complications related to anes-
thesia, the possibility of a prolonged intensive care unit course, and the potential
need for additional therapies, such as chemotherapy or radiation depending on the
surgical pathology.27 Before surgery, some surgeons will give patients a mechanical
bowel preparation or antibiotics for oral enteral decontamination, but there currently
are not enough data to support these practices as routine.28,29 At the time of surgery,
patients will receive antibiotic and venous thromboembolism prophylaxis.
 Surgical Treatment for Gastric Cancer 587

Total versus Partial Gastrectomy

Although endoscopic resection is proving to be a promising technique for early can-
cers, surgical gastrectomy remains the most frequently performed procedure for the
treatment of invasive gastric cancer. Currently, there are 2 main approaches that
can be used based on the gastric cancer’s location and characteristics: total gastrec-
tomy and partial gastrectomy, which is a broad term referring to any procedure not
removing the entire stomach (Fig. 2). It is important to note that these procedures
are sometimes performed for reasons outside of gastric cancer. However, in the
setting of gastric cancer, they must be performed adhering to oncologic principles,
including attention to surgical margins and appropriate lymph node dissection. As
such, for gastric adenocarcinoma in the distal stomach, smaller resections, such as
wedge resections or distal gastrectomy, generally are not appropriate, as they do
not allow for adequate lymphadenectomy.6 Subtotal gastrectomy, in which only the
fundus of the stomach is retained, is required to ensure the lymph nodes of the lesser
curvature are fully removed, and only well-vascularized viable stomach is remaining
because the ligation of the left gastric artery is required for a proper lymph node
dissection. Total gastrectomy, the removal of the entire stomach, is generally per-
formed for proximal lesions in the upper third of the stomach. Although proximal
gastric cancers can technically be approached with either a total gastrectomy or a
proximal partial gastrectomy, total gastrectomy is currently preferred because it is
associated with a much lower rate of reflux esophagitis when performed with a
Roux-en-Y reconstruction (2% vs >30%), a more complete lymph node dissection,
and fewer complications.30,31 However, the preference for total over proximal partial
gastrectomy is based on older data, and there are ongoing studies to further evaluate
these approaches (randomized clinical trial ongoing, KLASS 05 trial).32 Regarding
distal tumors, the literature has shown that there is no added survival benefit for
total gastrectomy compared with subtotal gastrectomy, which is why the latter less
aggressive approach is preferred.33,34 In some cases of local invasion, the removal
of adjacent organs may also be needed in order to perform a curative intent
procedure.
The general surgical steps involved in partial or total gastrectomy include the
following (Video 2):
1. Mobilization of the greater curvature with division of the left gastroepiploic. The
short gastric vessels are also divided for total gastrectomy, and omentectomy is
considered for advanced cancers.35
2. Infrapyloric mobilization with ligation of the right gastroepiploic vessels

Fig. 2. Total versus subtotal gastrectomy. (Illustrations by Michael Linkinhoker ª 2013 Johns
Hopkins University. All rights reserved)
588 Solsky & In

3. Suprapyloric mobilization with ligation of the right gastric vessels

4. Duodenal transection
5. D2 or D11 lymphadenectomy, with dissection of the porta hepatis, common he-
patic artery, left gastric artery, celiac axis, and splenic artery, and ligation of left
gastric vessels (based on location)
6. Gastric (or esophageal) transection
7. Reconstruction by loop or Roux-en-Y gastrojejunostomy (or Roux-en-Y
esophagojejunostomy)36
When preparing patients for total gastrectomy, it is important to prepare and drape
the chest in addition to the abdomen because of the possibility of needing to perform a
thoracotomy to obtain a clear proximal margin. For both procedures, intraoperative
frozen sections are generally performed to ensure that the cancer is fully removed.
Regarding partial gastrectomy, there are some variations developed by the Japanese
that are sometimes performed to limit postoperative syndromes that result from
altered gastric anatomy and physiology (see later discussion under Complica-
tions).37–40 Function-preserving techniques include those that preserve the pylorus
(pylorus-preserving segmental gastrectomy) and those that preserve the distal named
branches of the vagus nerves.37–40 These techniques are not widely described in
North American literature.

Optimal Surgical Margin

The goal of gastric resection for adenocarcinoma is to obtain a tumor-free resection
margin (R0) on pathologic examination because positive margins have been associ-
ated with worse outcomes.41 Another consideration is that gastric cancer has a ten-
dency for intramural spread.42 Although it was previously thought that a gross
margin of at least 5 cm was needed to obtain an R0 resection, this was based on older
data, and thus, there is ongoing debate as to the optimal margin, particularly in light of
increased use of neoadjuvant chemotherapy before resection.6 NCCN guidelines pre-
viously endorsed obtaining a margin 4 cm from the gross tumor, but now they simply
recommend “adequate gastric resection to achieve negative microscopic margins.”4
Although there are no randomized data to guide margin management, retrospective
studies have been performed and have suggested obtaining margins ranging from 2
to 6 cm.43,44 The 2018 Japanese Gastric Cancer Treatment Guidelines recommend
a gross resection margin of 2 cm for T1 tumors, 3 cm margin for T2 or deeper tumors
with an expansive growth pattern, and 5 cm for T2 or deeper tumors with an infiltrative
growth pattern.45 Ultimately, the operating surgeon must determine the appropriate
margin considering whether the risk of morbidity from further resection outweighs
the potential oncologic benefit. To identify whether the margin is adequate, intraoper-
ative frozen sections of the proximal and distal margins should be obtained in all pa-
tients undergoing potentially curative surgery. Based on the results of these frozen
sections, a wider excision may be necessary, as improved outcomes have been re-
ported with successful reexcision.46 However, experts recognize that it may be diffi-
cult to obtain a negative margin even with successive frozen sections.47 There is no
gold standard of care when it comes to positive frozen section margins, and manage-
ment is currently surgeon and institution dependent.

Extent of Lymph Node Dissection

Given that gastric cancer spreads through lymphatics to regional lymph nodes, cura-
tive intent resections must focus on adequate control of the lymph nodes for staging,
minimizing recurrence, and improving overall survival. The 16 lymph node stations
 Surgical Treatment for Gastric Cancer 589

defined by the Japanese Research Society for the Study of Gastric Cancer have been
grouped into a broader classification scheme that is used to describe the extent of
lymph node dissection based on the nodal stations to be removed. The extent of lym-
phadenectomy is categorized into D1, D11, D2, or D3, ranging from the minimal
required lymph nodes to a more extensive lymph node dissection. A D3 lymphadenec-
tomy is referred to as a superextended lymphadenectomy and includes a D2 lympha-
denectomy plus the removal of nodes within the root of mesentery and periaortic
regions (stations 1–16). The nodal stations that make up each lymph node removal de-
gree are defined by the type of gastrectomy conducted, which is in turn driven by the
location of the tumor (Fig. 3).6,45
The extent of lymph node dissection (D1 vs D2 vs D3) needed during a gastric can-
cer resection has been a topic of controversy. In Eastern countries, D2 lymphadenec-
tomy is considered standard of care. Western institutions have also started to adopt

Fig. 3. Lymph node stations. (From Japanese Gastric Cancer Association. Japanese gastric
cancer treatment guidelines 2018, 5th edition. Gastric Cancer 24, 1–21 (2021). https://doi.
org/10.1007/s10120-020-01042-y.)
590 Solsky & In

the recommendation that a D2 lymphadenectomy be performed. Current treatment

guidelines published by the NCCN, Cancer Care Ontario, and the European Society
of Surgical Oncology support the performance of a D2 lymph node dissection and
acknowledge that it is preferred over a D1 dissection when it can be safely per-
formed.4,48,49 Western institutions were slow adopters of the D2 dissection largely
because of the initial outcomes of 2 Western trials—the Dutch Gastric Cancer Group
Trial and the British Cooperative trial conducted by the Medical Research Council
trial—which showed that there was no improvement in overall survival with D2 as
compared with D1 lymph node dissection, but there was increased morbidity.50,51
However, these trials were criticized for including institutions lacking expertise in per-
forming D2 dissection as well as for incorporating routine splenectomy and distal
pancreatectomy as part of their procedures, which were thought to have impacted
the outcomes. Furthermore, 15-year data from the Dutch trial showed that a D2 lymph
node dissection as compared with a D1 dissection was associated with lower local
recurrence (12% vs 22%), regional recurrence (13 vs 19%), and gastric cancer–
related deaths (37% vs 48%) while still failing to show a difference in overall survival
(21% and 29%, P 5 .34).52 A meta-analysis comparing D1 and D2 lymphadenectomy
showed an improvement in disease-specific survival after D2 lymphadenectomy, but
there was an increase in postoperative mortality.53 It should be noted that although D2
is generally recommended as standard for optimal staging and treatment for most pa-
tients, in patients with early tumors, advanced age, poor functional status, and multi-
ple comorbidities, D1 or D11 dissections can be considered on a case-by-case
basis.6 The question of whether to perform a superextended D3 lymphadenectomy
has been less controversial, and it is not recommended outside of a select subset
of patients, as it has not been shown to have a survival benefit and may increase peri-
operative morbidity and mortality given its aggressive approach.53–55
Although D2 dissection is now supported by major institutions like the NCCN, this
does not mean that this recommendation is being followed in the United States. A
US randomized trial noted that 54% of patients underwent less than a D1 lymphade-
nectomy, whereas D1 or  procedures were performed in 36% and 10%, respec-
tively.56 Difficulty in documentation of removal by lymph node stations as well as a
desire to unify staging systems with other cancer sites resulted in changes to the N
stage of the American Joint Committee on Cancer (AJCC) staging system, which
was changed starting with the AJCC fifth edition to follow a numeric system instead
of one based on node distance from tumor location. As of the most recent AJCC
eighth edition, it required that least 16 lymph nodes be removed and examined at
the time of gastrectomy for adequate staging, which is used as a quality metric in
the United States in place of documentation of D2 dissection. Studies using number
of lymph nodes examined have similarly shown the inadequacy of US lymphadenec-
tomies reporting that less than one-third of US patients had 15 or more lymph nodes
removed during their procedures as was the recommendation in the AJCC fifth
through seventh editions.57,58
Failure to perform an adequate lymphadenectomy may not simply be due to a dif-
ference in philosophy, but it may also be that Western surgeons have not been
adequately trained how to do this complex procedure and may not be comfortable
performing it. The technical demands of performing a D2 lymphadenectomy are
well documented, and the literature points to a steep learning curve. Although Western
surgeons have reported the feasibility of performing this technique with good out-
comes, they have also acknowledged the importance of having these procedures per-
formed in specialized centers by individuals who have been adequately supervised
during the steep learning curve.59,60 In 1 study from Korea, it was reported that the
 Surgical Treatment for Gastric Cancer 591

learning curve for gastric cancer survival did not plateau until after a surgeon had per-
formed 100 operations.61
Thus, even though D2 dissection is now supported by Western institutions, training
will be required for surgeons to be proficient at this technique. Until that time, these
procedures should be performed at selected centers with surgeons with expertise
in performing this procedure, which is supported by a meta-analysis that shows the
relationship of outcomes after gastric cancer surgery with hospital and surgeon fac-
tors.62 Although there is still significant work that needs to be done in the West to
improve rates of D2 dissections, in the future, there may be other advancements in
the management of regional lymph nodes that will also have to be adopted. There is
growing interest in the use of sentinel lymph node biopsies for patients with early
gastric cancer as has been done for other types of cancer; however, this technique
has not been refined enough yet, and the data cannot yet support its use.63–67

Reconstructive Options
After a partial or total gastrectomy, it is necessary to reconstruct the gastrointestinal
(GI) tract. Different procedures have been devised to preserve duodenal continuity,
important for preventing loss of fat-soluble vitamins, and jejunal continuity, important
for preventing retrograde flow of jejunal contents that can occur when there is disrup-
tion in electrical activity initiated by the duodenal pacemaker.68 Some procedures also
include the construction of a gastric pouch to serve as a functional reservoir after gas-
trectomy. These different reconstructions have been devised to try to limit the effects
of postgastrectomy syndromes, but each generally has some degree of early or late
dumping because the pylorus is typically removed (see Complications in later
discussion).
After a partial gastrectomy, the most common reconstructive procedures are the
Billroth and Roux-en-Y reconstructions (Fig. 4). The Billroth I reconstruction anasto-
moses the remnant stomach to the duodenal stump in a primary end-to-end fashion,
which in turn preserves duodenal and jejunal continuity. This procedure, which re-
quires a tension-free anastomosis, is not feasible after subtotal gastrectomy or total
gastrectomy, which is commonly required for adequate tumor resection. The Billroth
II reconstruction anastomoses the remnant stomach to the proximal jejunum in an
end-to-side fashion, which preserves jejunal but not duodenal continuity. Gastritis
and dumping can be seen after this reconstruction, and it also tends to have some de-
gree of malabsorption of fat-soluble vitamins because of the loss of duodenal continu-
ity. The Roux-en-Y reconstruction anastomoses the remnant stomach to an

Fig. 4. Reconstruction options. (Illustrations by Michael Linkinhoker ª 2013 Johns Hopkins Uni-
versity. All rights reserved.)
592 Solsky & In

isoperistaltic roux limb of jejunum, whereas the proximal jejunum is anastomosed to

the distal roux limb in an end-to-side fashion; it is performed to divert the bilious
drainage away from the gastric remnant. The Roux-en-Y reconstruction results in
less reflux than in the Billroth reconstructions, but it can lead to gastric atony along
with the adverse effects of jejunal transection, which contributes to the “Roux syn-
drome” in which patients develop abdominal pain and vomiting.6,36 Although the pa-
tient’s anatomy and surgeon preference often dictate the type of reconstruction that is
performed, randomized trials seem to suggest that the Roux-en-Y reconstruction is
better tolerated overall and is associated with an improved quality of life compared
with the Billroth reconstructions.69–71
After a total gastrectomy, GI continuity can be restored with either a Roux-en-Y
reconstruction or a bowel interposition technique (jejunal or colon interposition). For
a Roux-en-Y approach, a surgeon may elect to perform a straight esophagojejunal
anastomosis, a looped esophagojejunal anastomosis, or a jejunal pouch construction,
which can be brought behind the colon (Hunt) or in front of the colon (Rodino).72 The
most prevalent reconstruction strategy and the one that is generally recommended is
the Roux-en-Y reconstruction.73,74 Despite some limited data, the literature also
seems to favor a jejunal pouch reconstruction, especially in patients who are antici-
pated to have a longer survival, as it has been associated with better functional out-
comes and improved quality of life.6,75–80

ADDITIONAL TECHNICAL CONSIDERATIONS

Minimally Invasive Techniques
Like all of surgery, gastric cancer surgery is trending toward the development of more
minimally invasive approaches. In addition to endoscopic techniques as described
previously, there are also laparoscopic and robotic approaches to gastrectomy, which
are gaining in popularity. Like most of gastric surgery, advances are primarily reported
in literature from Eastern institutions, but the benefits of these approaches are starting
to find their way into the practices and literature of Western institutions. Although an
open approach is still widely performed around the world, laparoscopic gastric resec-
tion when performed in experienced centers has been associated with a faster recov-
ery with less pain and fewer complications while allowing for comparable lymph node
retrieval.81–84 Laparoscopic gastrectomy is a well-established technique for treating
gastric cancer in Eastern countries and, in 2009, accounted for approximately one-
quarter of all gastric surgeries performed for cancer in Japan and South Korea.85
Many Eastern studies have been performed that show the benefit of a laparoscopic
technique to early gastric cancer81,83,86–89 and locally advanced gastric cancer.82,90–94
A 2016 meta-analysis concluded that laparoscopic gastrectomy resulted in less post-
operative morbidity, shorter hospitalization, and higher quality of life with no difference
in lymph nodes retrieved, mortality, cancer recurrence, and disease-free survival.95
Compared with Eastern countries, Western countries have less experience with lapa-
roscopic gastrectomy (performed in approximately 8%–23% of cases96,97), but it has
also been shown to be beneficial in Western cohorts.97–99 Although most of the afore-
mentioned studies are in regards to laparoscopic partial gastrectomy, total gastrec-
tomy can also be performed minimally invasively. It is a technically demanding
procedure, but when performed by a surgeon with advanced training in a high-
volume center, short- and longer-term outcomes are satisfactory.100–102
When deciding whether an open or minimally invasive approach should be taken,
ultimately the choice depends on several provider and patient factors. Laparoscopic
gastrectomy is a technically demanding procedure, especially when a D2
 Surgical Treatment for Gastric Cancer 593

lymphadenectomy and GI reconstruction are also performed, which requires an expe-

rienced surgeon who can be supported by staff and hospital resources to assist not
only intraoperatively but also in postoperative management. Studies suggest that 40
to 100 cases must be performed for a surgeon to be proficient in this technique.103–106
Regarding patient factors, the ideal patient is one with early gastric cancer who does
not have significant cardiopulmonary comorbidities, obesity, or previous upper
abdominal surgery, which may complicate a patient’s ability to receive pneumoperito-
neum and to have a safe dissection without encountering extensive intra-abdominal
adhesions. In addition, many bulky gastric cancers with local invasion into other or-
gans may not be best suited for a laparoscopic procedure. All these factors have to
be taken into consideration when deciding what type of surgery should be performed,
but the presence of these factors do not necessarily exclude a patient from a minimally
invasive approach.
Although Western countries are still catching up to their Eastern colleagues in terms
of laparoscopic gastric cancer management, the future of gastric cancer surgery may
trend toward robotic surgery, which has been an alternative minimally invasive tech-
nique since the early 2000s, yet still remains an emerging technology. In a meta-
analysis, robotic surgery was associated with less blood loss, less time to first flatus,
and greater lymph node yield than conventional laparoscopic gastrectomy, although
this study included no randomized trials.107 It also found that both approaches had
similar postoperative morbidity and mortality. As robotic technology becomes
cheaper and more prevalent, it is anticipated that it will take up a larger percentage
of the procedures performed for gastric cancer.

Drains and Feeding Tubes

Intraoperatively, some surgeons may elect to place drains and feeding tubes in gas-
trectomy patients, but in general, the literature does not support this practice, having
found no improvement in outcomes and a possible increase in complications with their
placement. However, there are some select patients in whom the placement of a small
bowel feeding tube can be justified: patients at the highest risk of anastomotic leak
and/or malnutrition, such as those undergoing total gastrectomy, and in those patients
in whom additional enteral feeding may decrease the time to adjuvant therapy.6
Although there are no strong recommendations regarding these feeding tubes (the
NCCN guidelines only recommend that they may be considered in select patients),
their placement still occurs in 24% to 32% of patients.4,108,109

Surgical Approach to Metastatic Disease

As new treatments emerge, providers are starting to question the oncologic dogma
that metastatic disease should only be treated with systemic therapy. There is some
evidence emerging to suggest that in some select patients a more aggressive surgical
approach may have some value. In recent years, literature has started to show that a
select group of patients with metastatic gastric cancer limited only to the peritoneum
without solid organ metastases may achieve a survival benefit by undergoing aggres-
sive cytoreductive surgery and heated intraperitoneal chemotherapy, but further
research is needed.110–113 Furthermore, when it comes to isolated solid organ metas-
tases, such as hepatic and pulmonary, there is some evidence to support the practice
of metastasectomy. Hepatic metastasectomy has been reported, but the occurrence
of isolated liver metastases is a rare event (only 0.5% in Asian populations). There is
currently a lack of consensus as to the appropriate patient selection for this procedure
and to whether it should be performed at all given the poor prognosis.114–116 Similarly,
594 Solsky & In

there are little data to guide the performance of pulmonary metastasectomy, which
can potentially result in a benefit for patients, but it is a rare event.

Palliative Interventions
When decision between provider and patient is no longer to pursue cure or life-
prolonging treatments, surgery still may have a role in a palliative sense and can include
options, such as stenting, palliative gastrectomy, and gastrojejunostomy. Although
chemotherapy is the cornerstone of effective treatment for metastatic disease, it often
is insufficient to address local symptoms secondary to obstruction, perforation, or
bleeding. Patients who present with bleeding may require endoscopy, angiography,
or radiotherapy.117 Patients who present with an obstruction may be managed with
endoscopic stent placement, a venting gastrostomy, and in some select patients, a
gastrojejunostomy or palliative gastrectomy can be considered.118 Studies have
compared endoscopic stenting with palliative gastrojejunostomy and have found that
although there was no difference in efficacy or complications, stenting was associated
with shorter hospital stays and faster relief of symptoms, which could be of critical
importance to patients with limited remaining time; however, there was a need for
more frequent reintervention in those who received stents.119 Therefore, palliative gas-
trojejunostomy is generally used in cases where stenting is not deemed to be feasible. It
is also considered when longer survival is anticipated. An even more aggressive pro-
cedure, a palliative gastrectomy, in general cannot be recommended given its high
morbidity, and it is reserved for extremely symptomatic cases where there are no other
options. The REGATTA randomized controlled trial examined whether the addition of
gastrectomy to chemotherapy improved survival for patients with advanced gastric
cancer with a single noncurable factor; however, the study was closed on the basis
of futility and found that gastrectomy followed by chemotherapy did not show any sur-
vival benefit compared with chemotherapy alone (overall survival at 2 years was 25.1%
vs 31.7%, respectively).120 The decision to pursue any of these interventions must take
into account the patient’s prognosis and goals in order to limit aggressive therapy at the
end of life that is not aligned with the patient’s wishes.

POSTOPERATIVE MANAGEMENT, SURVEILLANCE, AND RECURRENT DISEASE

Postoperatively, patients with gastric cancer will be admitted to the surgical floor or a
monitored setting based on what is necessary. When possible, enhanced recovery after
surgery, and fast-track protocols may be able to be followed,121,122 particularly for mini-
mally invasive procedures, which emphasize early mobilization and nonnarcotic anal-
gesia. These protocols may improve time to ambulation and oral intake while
decreasing length of hospital stay.123 Although there are no true gold-standard guidelines
for postoperative care, patients are started on enteral nutrition as soon as possible, and
the involvement of a dietician can be helpful to assist patients in adjusting to their new di-
etary regimen. Patients are advised to eat small frequent meals high in protein, inclusive of
fat, and supplemented by vitamins while avoiding carbohydrates to try to avoid weight
loss and nutritional deficiencies.124 There is some controversy in the literature as to
whether routine nasogastric decompression should be performed postoperatively122,125
and as to whether patients need a postoperative upper GI swallow study.36
After patients make it out of the acute postoperative period, they will need to continue
to be followed to monitor for recurrent disease. Although NCCN guidelines acknowl-
edge that there are sparse data to guide surveillance strategies, they in general recom-
mend the following: (1) a complete history and physical examination every 3 to 6 months
for the first 2 years, every 6 to 12 months for years 3 to 5, and annually thereafter; (2)
 Surgical Treatment for Gastric Cancer 595

complete blood count and chemistry laboratory tests when clinically indicated; (3)
Esophagogastroduodenoscopy (EGD) for patients with early-stage disease (TiS or
T1a) who underwent endoscopic resection every 6 months for the first year and then
annually for either 3 years (Tis) or 5 years (T1a); (4) EGD for patients who underwent sur-
gery as clinically indicated; (5) CT scan with oral and intravenous (IV) contrast based on
stage of disease (stage I: as clinically indicated; stage II–III: every 6–12 months for the
first 2 years, then annually for up to 5 years).4 Guidelines from the European Society
for Medical Oncology are also somewhat limited in their guidance, suggesting regular
posttreatment follow-up with dietary support without providing specifics as to other
testing or the frequency of follow-up.126 When gastric cancer does recur, it can be clas-
sified as local or distant recurrence. In general, curative resection is not attempted in pa-
tients with locally recurrent disease, although it has been described.127 Instead, most
patients with recurrent disease are offered systemic chemotherapy.

COMPLICATIONS

Despite surgery offering the best chance of cure for patients with gastric cancer, it is
not without its risks, and several patients will have complications. Complications can
include surgical site infections, intra-abdominal bleeding, anastomotic complications,
duodenal/pancreatic/lymphatic fistulas, cardiopulmonary complications, delayed
gastric emptying, and postgastrectomy syndromes.21 The perioperative surgical com-
plications after total gastrectomy are primarily due to anastomotic leak, and long-term
complications can include esophageal stricture and the postgastrectomy syndromes.
The most worrisome complication in the early postoperative period after total gastrec-
tomy is a breakdown of the esophagojejunal anastomosis, which has been reported to
occur in 5% to 7% of patients.128,129 Although minor leaks without sepsis can be
controlled nonoperatively with antibiotics, intestinal decompression, and percuta-
neous drainage, interventions may be needed for more significant disruptions.
Covered stents have been reported to have some success, but major disruptions
will need reoperation, and this is associated with increased mortality, which has
been reported to be about 30%.129,130 Anastomotic leak can also result in esophageal
stricture, reported in approximately 4% of patients, which usually can be managed
with serial endoscopic dilations.131 The jejunojejunal anastomosis rarely leaks.
Less worrisome but still problematic are the postgastrectomy syndromes.132,133
Following gastric resection, the motility of the stomach can be affected, resulting in
rapid or delayed transit. Rapid transit can be seen with dumping syndrome, which
is a phenomenon caused by destruction or bypass of the pyloric sphincter. It can pre-
sent with symptoms of diarrhea, nausea, vomiting, diaphoresis, sweating, and palpi-
tations. When these symptoms develop early after a meal, it is attributed to the rapid
emptying of hyperosmolar chyme into the small bowel; when it occurs late, it is
thought to be owing to hypoglycemia that occurs following an insulin peak after eating.
Most patients’ symptoms will improve with dietary changes.134 After gastrectomy,
some patients may also have delayed gastric emptying, which can be associated
with epigastric fullness and emesis. The degree of postsurgical gastroparesis de-
pends on several factors, including whether vagotomy was performed, the extent of
stomach and intestinal resection, the extent of lymphatic dissection, and the type of
reconstruction performed.135 Longstanding untreated gastroparesis has significant
nutritional and metabolic consequences, which can generally be managed with dietary
and behavioral modification in addition to the use of oral prokinetic and antiemetic
medications but could potentially require hospitalization in the setting of severe fluid
and electrolyte imbalances.136
596 Solsky & In

PERIOPERATIVE OUTCOMES

Over the past 2 decades, prognosis for gastric cancer has only improved modestly in
the United States, which is indicative of the fact that US gastric cancers are diagnosed
at later stages.137 Regarding perioperative mortality following partial gastric resection,
it is low and ranges from 1% to greater than 10% depending on patient age and med-
ical comorbidities.138–140 For total gastrectomy, perioperative death is reported in tri-
als as ranging from 2% to 13%.50,141 Regarding longer-term prognosis, it is
dependent on patient, tumor, and treatment factors, including histologic type, status
of resection margins, age and sex, the stage of disease, its location, the treatment
received, and the population studied. In general, Asian populations have been found
to have better outcomes than Western populations even when stratified by
stage.142–146 Hypotheses to explain these differences have included differences in
treatment (particularly surgical techniques), patient characteristics and behavior,
and race-related differences in tumor biology. Although long-term data on quality of
life after gastrectomy are limited, studies suggest that these procedures can be per-
formed while maintaining a satisfactory quality of life, which generally improves after
the short-term perioperative period.147–152

SUMMARY

The management of gastric cancer has evolved over the last several decades and will
continue to do so as new therapeutics are developed. At the heart of all gastric cancer
treatment has been surgery, and it is likely to stay this way for the time-being. All pro-
viders must continue to work together clinically and in research to continue to deter-
mine the best types of treatment, their sequence, and timing to achieve the best
outcomes for our patients.

CLINICS CARE POINTS

 Staging laparoscopy with peritoneal washings should be performed for gastric cancer clinical
stages T1b to evaluate for peritoneal spread when chemoradiation or surgery is considered.
 The decision to pursue gastric cancer resection should occur with consultation of a
multidisciplinary tumor board to ensure that an appropriate multimodality treatment
strategy is planned.
 The goal of gastric resection for adenocarcinoma is to obtain a tumor-free resection margin
(R0) on pathologic examination.
 A D2 lymphadenectomy is recognized as the optimal approach to lymph node dissection and
should accompany gastric resection when it can be safely performed.
 After gastric resection, Roux-en-Y reconstruction is better tolerated overall and associated
with an improved quality of life compared with the Billroth reconstructions.

DISCLOSURE

The authors have no disclosures.

SUPPLEMENTARY DATA

Supplementary data related to this article can be found online at https://doi.org/10.

1016/j.giec.2021.04.001.
 Surgical Treatment for Gastric Cancer 597

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Advances in Systemic
T h e r a p y fo r G a s t r i c C a n c e r
Andrew Hsu, MD, Alexander G. Raufi, MD*

KEYWORDS
 Gastric cancer  Targeted therapy  Immunotherapy  Cytotoxic chemotherapy

KEY POINTS
 Multiple randomized controlled trials have shown benefit with adjuvant and perioperative
chemotherapy with or without radiation therapy in resected stage I to III gastric
adenocarcinoma.
 Several standard-of-care options exist for resectable disease, and practices vary depend-
ing on region.
 Standard-of-care treatment options for metastatic gastric cancer is guided by perfor-
mance status, and multiple 2- and 3-drug regimens, with or without immunotherapy,
have shown efficacy.
 In human epidermal growth factor 2–overexpressing metastatic gastric cancer, trastuzu-
mab combined with chemotherapy is considered the standard of care.
 Several second- and third-line treatment options have recently been approved, including
the vascular endothelial growth factor antibody, ramucirumab, with or without paclitaxel,
as well TAS-102.
 Immunotherapy has been approved in the second- and third-line settings for select
patients.

INTRODUCTION

Although the global incidence of gastric cancer is declining, it continues to represent a

major health problem and leading cause of cancer-related mortality. Many cases are
diagnosed late, with unresectable or metastatic disease. For the approximately 50%
of patients diagnosed with early stage disease, characterized by disease localized to
the stomach or surrounding lymph nodes, systemic chemotherapy, with or without
radiotherapy, has proved to improve outcomes in select patients undergoing surgery.1
The prognosis remains poor for those patients diagnosed with metastatic or unre-
sectable gastric cancer, with standard-of-care therapies having a modest impact on

The Warren Alpert Medical School of Brown University, Lifespan Cancer Institute, Rhode Island
Hospital/The Miriam Hospital, 164 Summit Avenue, Fain Building, Third Floor, Providence, RI
02906, USA
* Corresponding author.
E-mail address: alex.raufi@gmail.com

Gastrointest Endoscopy Clin N Am 31 (2021) 607–623

https://doi.org/10.1016/j.giec.2021.03.009 giendo.theclinics.com
1052-5157/21/ª 2021 Elsevier Inc. All rights reserved.
608 Hsu & Raufi

patient survival and quality of life. Currently, the median survival ranges from 4 months
with best supportive care (BSC), to 12 months with traditional cytotoxic chemo-
therapy.2,3 Over the past few decades, improved understanding of the molecular path-
ogenesis and biology of cancer has led to the development of novel targeted
therapeutic strategies that have led to improvements in survival in select settings.
These targeted therapies are currently available as monoclonal antibodies (mAbs)
and small molecule inhibitors, most of which are tyrosine kinase inhibitors (TKIs). As
a result, current systemic treatments for metastatic gastric cancer consists of combi-
nation cytotoxic chemotherapy, with targeted therapies such as trastuzumab and
ramucirumab being incorporated in combination with cytotoxic chemotherapy in first-
and second-line treatment, respectively, in select settings.4,5 Furthermore, the discov-
ery of immune checkpoint inhibition in the past decade has been considered a major
medical and scientific breakthrough in the treatment of cancer; however, trials
examining the use of immunotherapy either as a monotherapy or in combination
with cytotoxic chemotherapy in gastric cancers have only led to limited approval in
the second-line setting, after failure of initial therapy, with relatively low response rates
ranging between 5% and 30%.6,7 The aim of this chapter is to summarize the currently
studied and approved treatments for gastric cancer and to briefly highlight some of the
most promising future treatments currently under investigation.

RESECTABLE DISEASE

Patients with early disease (ie, those with in situ or T1a tumors) can often be cured with
either endoscopic or surgical resection alone. However, in patients with more
advanced disease, those with invasion into or beyond the muscularis propria (T2 le-
sions) or those with regional lymph node involvement, recurrence rates are signifi-
cantly higher. For these patients, chemotherapy with or without radiotherapy plays
an important role in reducing recurrence and has been integrated into standard of
care treatment approaches. Table 1 summarizes several landmark trials that investi-
gated systemic and radiotherapies for the treatment of resectable gastric cancer.
The first study to demonstrate benefit with adjuvant therapy was the US Southwest
Oncology Group/Intergroup study (SWOG 9008/INT-0116) reported in 2001. This
phase III trial randomized 556 patients with adenocarcinoma of the stomach or gastro-
esophageal junction (GEJ) to receive surgery followed by adjuvant chemoradiotherapy
or surgery alone. Patients who received chemoradiotherapy were administered adju-
vant fluorouracil with leucovorin, followed by chemoradiotherapy with 45 Gy of radia-
tion with fluorouracil with leucovorin as a radiosensitizer, and radiation, followed by
fluorouracil with leucovorin. The addition of adjuvant chemoradiotherapy led to an
improvement in median overall survival (mOS) (36 vs 27 months; hazard ratio [HR]
1.35; CI 95% 1.09 to 1.66; P 5 .005).1 Although this was a practice changing trial, a
major criticism of this study was the low rate of D2 lymph node dissections performed
during surgery. Approximately 90% of patients underwent either a D0 or D1 lymph
node dissection, suggesting that adjuvant treatment primarily benefits those patients
receiving a less extensive lymph node dissection.16 A retrospective analysis of the
Dutch Gastric Cancer Group Trial (DGCT) in which patients were randomly assigned
to undergo either a D1 or D2 dissection followed by chemoradiotherapy have led
further support to this notion. The investigators found that adjuvant chemoradiother-
apy significantly benefited those patients who received a D1 dissection but had a more
limited impact on those who received a D2 dissection.17
The phase III CLASSIC trial sought to investigate the potential role for postoperative
chemotherapy in patients who underwent a curative D2 gastrectomy. In this study,
 Table 1
Landmark trials in the treatment of resectable gastric cancer

Total
Author (Date), Study Name Treatment Regimen Patients DFS, HR, P-value mOS, HR, P-value
MacDonald et al,1 2001, SWOG Adjuvant chemoradiotherapy 556 48% vs 31%, HR 1.52, P < .001 36 vs 27 mo, HR 1.35, P 5 .005
9008/INT-0116 (fluorouracil) vs surgery alone
Noh et al,8 2014, CLASSIC Adjuvant chemotherapy 1035 74% vs 59%, HR 0.58, P < .0001 78% vs 69%, HR 0.66
(capecitabine 1 oxaliplatin) vs
surgery alone
Lee et al,9 2012, ARTIST Adjuvant chemotherapy (XP) vs 458 78.2% vs 74.2%, P 5 .862 NR
chemoradiotherapy

Advances in Systemic Therapy for Gastric Cancer

Park et al,10 2019, ARTIST II Adjuvant chemotherapy vs 538 78% vs 73%, P 5 .667 NR
chemoradiotherapy in D2 node
positive disease
Cunningham et al, 11 2006, MAGIC Perioperative chemotherapy (ECF) 506 NR 36% vs 23%, HR 0.75, P 5 .009
vs surgery alone HR 0.66, P < .001
Ychou et al,12 2011, FNCLCC/FFCD Perioperative chemotherapy (CF) 224 34% vs 19%, HR 0.65, 0 5 0.003 38% vs 24%, HR 0.69, P 5 .02
vs surgery alone
Alderson et al,13 2017, UK Neoadjuvant chemotherapy ECX 897 14.4 vs 11.6, HR 0.86, P 5 .051 26.1 vs 23.4, P 5 .19
MRCOE05 vs CF
Cats et al,14 2018, CRITICS Perioperative chemotherapy (ECX) 788 NR 43 vs 37 mo, HR 1.01, P 5 .90
vs neoadjuvant
chemotherapy 1 adjuvant
chemoradiotherapy
Al-Batran et al,15 2019, FLOT4-AIO Perioperative ECX/ECF vs FLOT 716 30 vs 18 mo, HR 0.75, P < .001 50 vs 35 mo, HR 0.77, P 5 .012

Abbreviation: NR, not reported.

609
610 Hsu & Raufi

1035 patients were randomized to receive adjuvant capecitabine and oxaliplatin for
6 months versus observation following surgery. The addition of adjuvant chemo-
therapy led to a significant improvement in 3-year disease-free survival (DFS; 74%
vs 59%; HR 0.58; 95% CI 0.47–0.72; P < .0001) and 5-year overall survival (OS;
78% vs 69%; HR 0.66; 95% CI 0.51–0.85). Notably, 56% of patients in the adjuvant
chemotherapy arm experienced grade 3 or 4 toxicities primarily in the form of nausea,
neutropenia, and decreased appetite.8
Multiple studies have also attempted to determine the benefits of radiation therapy
when added to adjuvant chemotherapy in patients who achieve a D2 resection. The
ARTIST trial randomized 458 patients who had undergone a curative D2 gastrectomy
to receive either adjuvant chemotherapy or adjuvant chemoradiotherapy. Patients
received 6 cycles of adjuvant capecitabine and cisplatin (XP) versus 2 cycles of XP fol-
lowed by radiation therapy, then an additional 2 cycles of XP. Interestingly, the addi-
tion of radiation therapy did not lead to improvement in 3-year DFS (78.2% vs 74.2%;
P 5 .862) or OS. However, a subgroup analysis revealed that in those patients with
lymph node positive who received adjuvant chemoradiotherapy there was a 3-year
DFS benefit (77.5% vs 72.3%; P 5 .0365).9 This prompted the subsequent ARTIST
II trial, which further examined the role of adjuvant chemoradiotherapy in 538 patients
who had undergone curative D2 gastrectomy and were found to have lymph node
positive disease. Ultimately, there was no difference in 3-year DFS between adjuvant
chemotherapy versus adjuvant chemoradiotherapy (78% vs 73%, respectively;
P 5 .667) in this population.10
The MAGIC trial investigated the role of perioperative chemotherapy versus surgery
alone in 503 patients with potentially resectable gastric adenocarcinoma. Periopera-
tive chemotherapy consisted of 3 cycles of epirubicin, cisplatin, and fluorouracil
(ECF) given both before and after resection. The addition of perioperative ECF led
to an improvement in 5-year mOS (36% vs 23%; HR 0.75; CI 95% 0.60–0.93;
P 5 .009) but was associated with significant toxicities, with 58% of patients being un-
able to complete all 6 treatments. Of the patients who completed preoperative treat-
ments, 34% were unable to complete postoperative treatments due to disease
progression, patient choice, toxicity, or operative complications.11 In light of these
findings, much of the benefit observed on this trial has been attributed to the neoad-
juvant treatment received. Given the high rate of toxicity with perioperative chemo-
therapy in the MAGIC trial, the French FNCLCC/FFCD trial examined the use of
perioperative chemotherapy with cisplatin and fluorouracil (CF) versus surgery alone.
This study also demonstrated a statistically significant improvement in 5-year mOS
(38% vs 24%; HR 0.69; CI 95% 0.50–0.95; P 5 .02), similar to that noted in the MAGIC
trial with ECF. Furthermore, the incidence of grade 3 and 4 toxicity was lower, occur-
ring in 38% of patients.12 Given the improved toxicity profile with a similar survival
benefit, the UK Medical Research Council OE05 trial compared the neoadjuvant use
of epirubicin, cisplatin, and capecitabine (ECX) with CF. This phase III trial demon-
strated a similar mOS (26.1 vs 23.4 months, respectively; P 5 .19) with a lower rate
of treatment completion in the ECX arm (81% vs 96%).13 The CRITICS trial sought
to investigate the addition of radiotherapy to perioperative epirubicin, capecitabine,
and cisplatin or oxaliplatin (ECX or EOX) in patients with resectable gastric or GEJ
adenocarcinoma. In this phase III trial, 788 patients received 3 cycles of preoperative
and postoperative ECX/EOX. In the chemoradiotherapy arm, patients also received 3
cycles of preoperative and postoperative ECX/EOX with the addition of postoperative
radiotherapy. Ultimately, there was no difference in mOS with perioperative chemora-
diotherapy compared with chemotherapy alone (37 vs 43 months, respectively; HR
1.01; 95% CI 0.84–1.22; P 5 .90).14 This has become widely adopted as the
 Advances in Systemic Therapy for Gastric Cancer 611

perioperative treatment regimen of choice and has been adopted into major guidelines
throughout the United States.
Recently, the phase II/III FLOT4-AIO trial examined an alternative regimen, a com-
bination of fluorouracil with leucovorin plus oxaliplatin and docetaxel (FLOT), as peri-
operative therapy. In this trial, 716 patients with locally advanced, resectable gastric or
GEJ adenocarcinoma were randomized to receive 3 cycles of preoperative and post-
operative ECF/ECX or 4 cycles of preoperative and postoperative FLOT. This regimen
demonstrated an improved mOS (50 vs 35 months; HR 0.77; 95% CI 0.63–0.94;
P 5 .012) and progression-free survival (PFS) (30 vs 18 months; HR 0.75; 95% CI
0.62–0.91; P < .001) with a 27% toxicity rate in both arms.15
The role of chemotherapy with or without radiation in patients with resectable dis-
ease continues to evolve, and this is reflected in differing global treatment practices.
Perioperative chemotherapy is becoming widely adopted in the United States and
Europe, adjuvant chemoradiotherapy is still used in much of the United states, and
adjuvant chemotherapy alone is often favored in Asia.

ADVANCED DISEASE
First-Line Treatment
Cytotoxic chemotherapy has demonstrated modest activity against gastric cancer:
anthracyclines (eg, doxorubicin, epirubicin), fluoropyrimidines (eg, fluorouracil, cape-
citabine, S-1), platinums (eg, cisplatin, oxaliplatin), taxanes (eg, paclitaxel, docetaxel),
and topoisomerase inhibitors (eg, irinotecan). These agents have all shown activity
when used as a monotherapy. For example, the objective response rates (ORR)
with fluoropyrimidines lies between 20% and 40%,3,18 compared with an ORR of
approximately 20% with either taxanes ORR 20% or irinotecan use.19,20 Furthermore,
a Cochrane review showed an improved mOS with combination chemotherapy when
compared with single-agent fluorouracil (8.3 vs 6.7 months).3
In patients with human epidermal growth factor 2 (HER2)-negative, metastatic
gastric adenocarcinoma, deemed fit for multiagent chemotherapy, the current stan-
dard of care consists of either 2- or 3-drug regimens. Table 2 summarizes the land-
mark trials for first-line treatment of metastatic gastric cancer. The first multiagent
chemotherapy was established in 1980, based on the findings of a randomized trial
in which 62 patients with advanced gastric cancer were treated with fluorouracil,
doxorubicin, and mitomycin (FAM) and resulted in a partial response rate of 42%
and an mOS of 5.5 months.26 In 1991, a randomized phase III trial compared FAM
with fluorouracil, doxorubicin, and methotrexate (FAMTX) and demonstrated an
improvement in both mOS (9.7 vs 6.7 months; P < .004) and an ORR of (41% versus
9%; P < .001). Impressively, 6% of patients in the FAMTX arm demonstrated a com-
plete response (CR) compared with 0% in the FAM arm.21 FAMTX remained the stan-
dard front-line regimen until the late 1990s when the ECF demonstrated superiority in
the phase III randomized controlled trial. In this trial 274 patients with advanced
gastroesophageal cancer were randomized to ECF or FAMTX. ECF demonstrated
both an improved ORR (45% vs 21%; P 5 .0002) and mOS (8.9 vs 5.7 months;
P 5 .0009).22 Surprisingly, mOS of FAMTX in this trial was substantially lower as
compared with prior studies, and these results remain controversial to this day.
Furthermore, the added benefit of epirubicin, which adds substantial toxicity, has
been questions, similar to its use in resectable disease.
In 2006, the V325 study group compared the efficacy of a 2- versus 3-drug combi-
nation in a multinational phase II/III trial. In total, 445 patients with metastatic or locally
recurrent gastric or GEJ adenocarcinoma were randomized to receive either
 612
Hsu & Raufi
Table 2
Landmark trials in first-line treatment of metastatic gastric cancer

Total
Author (Date), Study Name Treatment Regimen Patients ORR/CR mPFS (mo) HR, P-value mOS (mo), HR, P-value
MacDonald, et al,26 1980 Fluorouracil, doxorubicin, & 62 42%/NR NR 5.5
mitomycin (FAM)
Wils, et al,21 1991 Fluorouracil, doxorubicin, & 160 41%/6% NR 9.7 vs 6.7
methotrexate (FAMTX) vs FAM 9%/0%
Webb, et al,22 1997 Epirubicin, cisplatin, & fluorouracil 219 45%/6% FFS: 7.4 vs 3.4 P 5 .00006 8.9 vs 5.7, P 5 .0009
(ECF) vs FAMTX 21%/2%
Van Cutsem, et al,23 2006, V325 Cisplatin & fluorouracil (CF) vs 270 37%/2% TTP: 5.6 vs 3.7 8.2 vs 9.6, HR 1.29, P 5 .02
docetaxel, cisplatin, & 25%/1% HR 1.47, P < .001
fluorouracil (DCF)
Shah et al,24 2015 DCF 1 granulocyte stimulating 85 33%/NR 6.5 vs 9.7 P 5 .2 12.6 vs 18.8, P 5 .007
factor (G-CSF) vs modified DCF 49%/NR
(mDCF)
Cunningham, et al,25 2008, REAL2 Epirubicin, cisplatin, & fluorouracil 1002 41%/4% 6.2 vs 6.7 vs 6.5 vs 7.0a 9.9 vs 9.9 vs 9.3 vs 11.2a
(ECF) vs Epirubicin, cisplatin, & 46%/4%
capecitabine (ECX) 42%/3%
Epirubicin, oxaliplatin, & 48%/4%
fluorouracil (EOF) Epirubicin,
oxaliplatin, & capecitabine
(EOX)
Bang, et al,5 2010, ToGAb Fluoropyrimidine, cisplatin, & 594 47%/5% 6.7 vs 5.5 13.8 vs 11.1
trastuzumab vs 35%/2% HR 0.71, P 5 .0002 HR 0.74, P 5 .0046
fluoropyrimidine, cisplatin, &
placebo

Abbreviation: NR, not reported.

a
Noninferior
b
HER2-positive only.
 Advances in Systemic Therapy for Gastric Cancer 613

docetaxel, cisplatin, and fluorouracil (DCF) or CF. In this trial, DCF demonstrated an
improved mOS (9.2 vs 8.6 months; P 5 .02), ORR (37% vs 25%; P 5 .01), and time
to progression (TTP) (5.6 vs 3.7 months; P < .001). Furthermore, the addition of doce-
taxel led to an increased rate of grade 3 and 4 toxicities, particularly neutropenia (29%
vs 12%) when compared with CF.23 Given the increased rate of neutropenia, a subse-
quent phase III study examined the use of granulocyte colony-stimulating factor (G-
CSF) with DCF support versus modified DCF (mDCF), which consisted of a shorter
continuous infusion of fluorouracil along with dose-reduced docetaxel and cisplatin.
Modified DCF demonstrated an improved toxicity profile when compared with DCF
plus G-CSF (22% vs 52% hospitalized) and a markedly improved mOS (18.8 vs
12.6 months; P 5 .007).24
In 2008, the results of the randomized phase III REAL2 trial was published. This
study evaluated the interchangeability of 2 fluoropyrimidines, fluorouracil and capeci-
tabine, and 2 platinums, cisplatin and oxaliplatin, in the treatment of advanced gastro-
esophageal cancer. Using a two-by-two design, the investigators evaluated 4
regimens: ECF; ECX; epirubicin, oxaliplatin, fluorouracil; and EOX. The 4 regimens
were ultimately found to have noninferior ORR (41% vs 47% vs 42% vs 48%, respec-
tively), PFS (6.2 vs 6.7 vs 6.5 vs 7.0 months, respectively), and mOS (9.9 vs 9.9 vs 9.3
vs 11.2 months, respectively).25 The investigators concluded that capecitabine and
oxaliplatin was as effective as fluorouracil and cisplatin. Notably, in current clinical
practice the toxicity profile of epirubicin has limited its use to younger patients with
excellent performance status.
S-1 is an oral fluoropyrimidine composed of tegafur (a prodrug of fluorouracil),
gimercil (a dihydropyrimidine dehydrogenase inhibitor, which prolongs the half-life
of fluorouracil), and oteracil potassium (an inhibitor of phosphorylation of intestinal
fluorouracil, which increases gastrointestinal tolerability). It is approved for use in
several Asian counties but has yet to be granted approval in the United States. This
approval was based on the SPIRITS trial in which cisplatin plus S-1 (CS) was
compared with S-1 monotherapy. CS demonstrated an improved mOS (13.0 vs
11 months; P 5 .04) and median PFS (mPFS) (6.0 vs 4.0 months; P < .0001).27
HER2 is a transmembrane protein of the ErbB family. Dimerization leads to the acti-
vation of downstream signaling pathways that ultimately drives cell-cycle progression,
cell proliferation, and resistance to apoptosis.28 As in breast cancer, HER2 gene
amplification is common and estimated to be present in up to 30% of gastric cancer
cases.29 Trastuzumab is an anti-HER2 mAb that represents one of the few successful
targeted therapies for metastatic gastric cancer. The ToGA trial was the first random-
ized controlled trial to show benefit of trastuzumab and led to its approval in combina-
tion with chemotherapy for front-line use in the HER2-positive, metastatic gastric and
GEJ adenocarcinoma.5 HER2-positive disease in this trial was defined as 31 positivity
on immunohistochemistry or a HER2:CEP17 ratio of 2 or greater by fluorescence
in situ hybridization. This landmark study randomized 584 patients to receive trastuzu-
mab with a fluoropyrimidine and cisplatin versus placebo plus fluoropyrimidine with
cisplatin and demonstrated an improved mPFS (6.7 vs 5.5 months; HR 0.71; 95%
CI 0.59–0.85; P 5 .0002) and mOS (13.8 vs 11.1 months; HR 0.74; 95% CI 0.60–
0.91; P 5 .0046). The addition of trastuzumab also demonstrated an improved dura-
tion of response (6.9 vs 4.8 months; HR 0.53; 95% CI 0.40–0.73; P < .0001), ORR (47%
vs 35%; P 5 .0017), and TTP (7.1 vs 5.6 months; HR 0.70; 95% CI 0.58–0.85;
P 5 .0003). The overall rates of all grades or only grade 3 to 4 toxicities were not signif-
icantly different between the 2 arms.5
In April 2021, nivolumab was approved for use in combination with chemotherapy
for metastatic gastric cancer and esophageal adenocarcinoma. As is described later
614 Hsu & Raufi

in this chapter, the CHECKMATE-649 trial demonstrated a statistically significant

improvement in PFS and OS with the combination of chemotherapy and immuno-
therapy over chemotherapy alone and is now redefining the standard of care.

Subsequent Lines of Treatment

In the second-line setting and beyond, cytotoxic chemotherapy has had a modest
impact on mOS. Ramucirumab, an mAb targeting vascular endothelial growth factors
(VEGF), has been examined in the front- and second-line setting. In the phase III RAIN-
FALL trial, 645 patients with HER2-negative, metastatic gastric or GEJ adenocarci-
noma were randomized to receive ramucirumab plus a fluoropyrimidine and
cisplatin or placebo plus a fluoropyrimidine and cisplatin. When added to chemo-
therapy in the front-line setting, ramucirumab did not significantly improve mOS
(11.7 vs 10.7 months, respectively; P 5 .6757), and only marginally improved mPFS
(5.7 vs 5.4 months; P 5 .0106).30 However, in the second-line setting, ramucirumab
has demonstrated benefit both as a single agent and in combination with chemo-
therapy. The phase III REGARD trial compared the use of ramucirumab monotherapy
versus BSC in the second-line setting for patients with metastatic gastric or GEJ
adenocarcinoma. Ramucirumab monotherapy led to an improvement in mOS (5.2
vs 3.8 months; HR 0.78; 95% CI 0.60–0.99; P 5 .047) and mPFS (6.7 vs 5.3 months;
HR 0.80; 95% CI 0.68–0.93; P 5 .037).31 More recently, the landmark RAINBOW trial
randomized patients who had progressed on or within 4 months of first-line chemo-
therapy (fluoropyrimidine-platinum with or without an anthracycline) to receive either
ramucirumab plus paclitaxel or placebo plus paclitaxel. Ramucirumab plus paclitaxel
demonstrated an improvement in mOS (9.6 vs 7.4 months; HR 0.81, 95% CI 0.68–
0.96; P 5 .0169), leading to the approval of ramucirumab plus paclitaxel in the
second-line setting, and this is currently a preferred second-line regimen for patients
with metastatic gastric cancer.4
Multiple trials have also investigated single-agent chemotherapy in the second-line
setting, demonstrating improvements in both quality of life and survival. In 2011, a ran-
domized study compared irinotecan with BSC in the second-line setting and demon-
strated a modest improvement in mOS (4.0 vs 2.4 months; HR 0.48, 95% CI 0.25–0.92;
P 5 .012).32 Another phase III study comparing salvage chemotherapy with either
docetaxel or irinotecan with BSC in the second-line setting also demonstrated a
modest improvement in mOS (5.3 vs 3.8 months, respectively; HR 0.657, 95% CI
0.485–0.891; P 5 .007) with salvage chemotherapy.33 COUGAR-02, an open-
labeled phase III study, compared docetaxel with BSC in the second-line setting in pa-
tients with esophageal, gastric, or GEJ adenocarcinoma that had progressed on or
within 6 months of treatment with a fluoropyrimidine-platinum regimen. This open-
labeled phase III study demonstrated that docetaxel led to an improved mOS (5.2
vs 3.6 months; HR 0.67, 95% CI 0.49–0.92; P 5 .01).34 Nanoparticle albumin-bound
paclitaxel (nab-paclitaxel) was compared with solvent-bound paclitaxel in the phase
III ABSOLUTE trial. In this study, nab-paclitaxel was administered either weekly or
every 3 weeks compared with solvent-bound paclitaxel, which was administered
weekly. This trial demonstrated noninferiority between the weekly nab-paclitaxel
and solvent-bound paclitaxel in terms of mOS (11.1 vs 10.9 months; HR 0.97,
97.5% CI 0.76–1.23; noninferiority margin 1.25; one-sided P 5 .0085). However,
when nab-paclitaxel was administered every 3 weeks and compared with the weekly
solvent-bound paclitaxel, nab-paclitaxel failed to meet the noninferiority threshold
(10.3 vs 10.9 months; HR 1.06, 97.5% CI 0.87–1.31; one-sided P 5 .062).35 Together,
these trials demonstrate benefit with single-agent chemotherapy in the second-line
setting providing clinicians with several options.
 Advances in Systemic Therapy for Gastric Cancer 615

Recently, TAS-102, a combination of trifluridine (FTD), a thymidine analogue, and

tipiracil (TPI), thymidine phosphorylase inhibitor, has been examined in patients with
metastatic gastric and GEJ cancer. The TAGS trial evaluated this agent in patients
with or without prior gastrectomy, who had progressed on at least 2 previous lines
of chemotherapy. A total of 507 patients were randomized 2:1 to receive TAS-102
or BSC. FTD/TPI demonstrated an improved mOS (6.0 vs 3.4 months; HR 0.57, CI
95% 0.41–0.79) and mPFS (2.2 vs 1.8 months; HR 0.48, 95% CI 0.35–0.65) in the pop-
ulation who had undergone prior gastrectomy and an improved mOS (5.6 vs
3.8 months; HR 0.80, CI 95% 0.60–1.06) and mPFS (1.9 vs 1.8 months; HR 0.65,
95% CI 0.49–0.85) in patients without a prior gastrectomy.36 These data led to the
approval of TAS-102 as a third-line therapy for patients with metastatic gastroesoph-
ageal cancer.

Immunotherapy for Gastric Cancer

Several novel classes of agents have also shown promise in advanced gastric cancer.
Immune checkpoint inhibitors (ICIs) are among those that have been most developed
and have recently been approved in the second- and third-line settings. Response
rates are variable and select patient populations derive more benefit, for example,
those with microsatellite instability (MSI-H) or deficient mismatch repair (dMMR),
and therefore careful selection is necessary.37
Pembrolizumab is the most extensively studied ICI in gastric cancer and is the only
agent approved for use in the second-line setting, in MSI-H or dMMR disease, and in
the third-line setting, for programmed death ligand 1 (PD-L1)-positive disease. In
2017, pembrolizumab gained approval for use in the third-line setting based on the
findings of KEYNOTE-059. This phase II trial enrolled 259 patients and administered
pembrolizumab every 3 weeks until disease progression and demonstrated an ORR
of 11.6% with 2.3% achieving a CR. Furthermore, inpatients whose tumors that
were PD-L1 positive had an ORR of 15.5% compared with 6.4% in those with PD-
L1–negative tumors. In tumors that were MSI, the ORR was 57% compared with
9% in MSS tumors.6
Subsequently, KEYNOTE-062 sought to examine the use of pembrolizumab mono-
therapy versus cisplatin plus a fluoropyrimidine with or without pembrolizumab in 763
patients with HER-2–negative, advanced or metastatic gastric or GEJ cancer whose
tumors expressed PD-L1 (defined as Combined Positive Score [CPS]  1). When
chemotherapy alone was compared with pembrolizumab monotherapy, there was
noninferior mOS (10.6 vs 11.1 months; HR 0.91, 95% CI 0.69–1.18; noninferiority
margin 1.2) although there was a lower ORR (14.5% vs 36.8%). When examining
the use of pembrolizumab monotherapy in patients whose tumors strongly expressed
PD-L1 (CPS  10), there was significant improvement in mOS (17.4 vs 10.8 months;
HR 0.69, 95% CI 0.49–0.97). Unfortunately, the addition of pembrolizumab to chemo-
therapy did not lead to an improved mOS (12.5 vs 11.1 months; HR 0.85, 95% CI 0.70–
1.03) or mPFS (6.9 vs 6.4 months; HR 0.84, 95% CI 0.70–1.02).38
Additional cohorts from KEYNOTE-059 have examined the use of pembrolizumab
monotherapy or in combination with chemotherapy (fluoropyrimidine and cisplatin)
in the front-line setting for advanced gastric and GEJ cancers. Patients who received
pembrolizumab monotherapy were required to have PD-L1–positive disease
(CPS  1) and demonstrated an ORR of 25.8% with 6.5% achieving a CR and
mPFS of 3.3 month. In the patients who received pembrolizumab in combination
with chemotherapy, PD-L1 expression was not a requirement, although 64% of pa-
tients had PD-L1 expression. In this arm, ORR was 60%, with 4% demonstrating a
CR and mPFS of 6.6 months.39–41
616 Hsu & Raufi

More recently, based on the results of the CHECKMATE-649 trial, the combination
of nivolumab and chemotherapy has been approved for use in patients with unresect-
able advanced metastatic gastric or gastroesophageal cancer. In this global phase III
study, a total of 1,581 patients with untreated, unresectable advanced or metastatic
gastric, GEJ or esophageal cancer were randomized to receive nivolumab with
chemotherapy versus nivolumab plus ipilimumab versus chemotherapy alone. In pa-
tients with a CPS > 5, the addition of nivolumab to chemotherapy led to improvement
in mOS (14.4 vs 11.1 months; HR 0.71; 98.4% CI 0.59-0.86; p<0.0001) and mPFS (7.7
vs 6.0 months; HR 0.68; 98% CI 0.56-0.81; p<0.0001). Notably, benefits with combi-
nation therapy were also statistically significant for the PD-L1 CPS  1 population (HR
5 0.77; P 5 .0001) and for all randomly assigned patients (HR 5 0.80; P 5 .0002).
Fewer than 5% of patients experienced grade 3 or 4 toxicities, and there were no
grade 5 events.42
In Asia, nivolumab is approved for monotherapy use based on the results of
ATTRACTION-2, which examined 493 patients with unresectable advanced or recur-
rent gastric or GEJ cancer who progressed after 2 or more previous chemotherapy
regimens. Patients from Japan, South Korea, and Taiwan were randomized to nivolu-
mab monotherapy or BSC and demonstrated an improved mOS (5.26 vs 4.14 months;
HR 0.63, 95% CI 0.51–0.78; P < .0001) and mPFS (1.61 vs 1.45 months; HR 0.60,
P < .0001).7 CheckMate-032 examined the use of nivolumab combined with ipilimu-
mab, an anticytotoxic T-lymphocyte–associated protein 4 antibody, in the second-
line setting any beyond in patients with locally advanced or metastatic esophageal,
gastric, or GEJ cancers regardless of PD-L1 or MSI status. In this phase I/II study,
160 patients were randomized to nivolumab, 3 mg/kg, monotherapy (NIVO3); nivolu-
mab, 1 mg/kg, plus ipilimumab, 3 mg/kg, (NIVO1 1 IPI3); and nivolumab, 3 mg/kg,
plus ipilimumab, 1 mg/kg, (NIVO3 1 IPI1). This trial demonstrated an ORR of 12%
versus 24% versus 8%, respectively; mPFS of 1.4 versus 1.4 versus 1.6 months,
respectively; and mOS of 6.2 versus 6.9 versus 4.8 months, respectively.
Treatment-related grade 3 and 4 toxicities were 17% versus 47% versus 27%,
respectively. As would be expected, there were higher rates of toxicity in the arms
with combination immunotherapy and particularly higher in the NIVO1 1 IPI3 arm.43
The results of this phase I/II study has led to subsequent larger phase II and III studies
investigating nivolumab’s role in front-line use either as a monotherapy or in combina-
tion with cytotoxic chemotherapy, other immunotherapies, or targeted therapies.
In Europe, avelumab, an mAb targeting PD-L1, is approved as a monotherapy for
unresectable or metastatic gastric cancer based on the phase Ib JAVELIN study,
which examined its use in patients who had progressed after one or more lines of
fluoropyrimidine-platinum chemotherapy. Overall, avelumab demonstrated an ORR
of 10%; however, in patient tumors with PD-L1 expression (defined as CPS  1),
ORR was improved to 27.3% with an mOS of 9.1 months and 7.5% grade 3 or 4 tox-
icities.44 JAVELIN Gastric 100 evaluated avelumab’s role in maintenance therapy after
first-line chemotherapy versus continued first-line chemotherapy. This phase III trial
failed to demonstrate any improvement of mOS (10.4 vs 10.9 months; HR 0.91,
95% CI 0.74–1.11; P 5 .1779).45 JAVELIN Gastric 300 is currently evaluating avelu-
mab’s role in the third-line setting, comparing it with either paclitaxel or irinotecan
monotherapy. Preliminary results suggest no improvement in mOS (4.6 vs 5.0 months;
HR 1.1, 95% CI 0.9–1.4; P 5 .81) or mPFS (1.4 vs 2.7 months; HR 1.73, 95% CI 1.4–
2.2; P > .99) with avelumab.46
Response rates to immunotherapy in the treatment of gastric cancer have been
modest; however, higher responses are observed in patients whose tumors express
PD-L1, are MSI-H, or dMMR. As a result, there has been limited approval of ICIs in the
 Table 3
Landmark trials in subsequent lines of treatment for metastatic gastric cancer

Author (Date), Study Name Treatment Regimen Total Patients ORR/CR mPFS (mo) HR, P-value mOS (mo) HR, P-value
Fuchs, et al,31 2014, REGARD Ramucirumab & best supportive 355 3%/<1% 2.1 vs 1.3 5.2 vs 3.8
care vs placebo & best 3%/0% HR 0.483, P < .0001 HR 0.776, P 5 .47

Advances in Systemic Therapy for Gastric Cancer

supportive care
Wilke, et al,4 2019, RAINBOW Ramucirumab & paclitaxel vs 665 28%/<1% 4.4 vs 2.9 9.6 vs 7.4
placebo & paclitaxel 16%/<1% HR 0.635, P < .0001 HR 0.807, P 5 .017
Fuchs et al,6 2018, KEYNOTE-059 Pembrolizumab 259 11.6%/2.3% 2.0 5.6
Kang et al,7 2017, ATTRACTION-2 Nivolumab vs placebo 493 11.2%/0% 1.61 v 1.45 5.26 vs 4.14
0%/0% HR 0.60, P < .0001 HR 0.63, P < .0001
Doi et al,44 2019, JAVELIN Avelumab 40 10%/2.5% 2.4 9.1

Abbreviation: NR, not reported.

617
618 Hsu & Raufi

second-line setting or beyond: pembrolizumab (United States),6 nivolumab (Asia),7 and

avelumab (Europe).44 Furthermore, these modest results have resulted in studies
combining immunotherapy with other modalities to improve outcomes. Table 3 summa-
rizes the landmark trials for subsequent lines of treatment of metastatic gastric cancer.

Ongoing Studies for Advanced Gastric Cancer

Currently, there are multiple ongoing trials testing novel agents as well as various com-
bination therapies. Success with trastuzumab in HER2-positive disease has prompted
further study with trastuzumab deruxtecan, an antibody-drug conjugate combining
trastuzumab with deruxtecan, a topoisomerase I inhibitor. The phase II DESTINY-
Gastric01 trial randomized patients with previously treated, advanced gastric cancer
to trastuzumab deruxtecan or the physician’s choice of cytotoxic chemotherapy and
demonstrated an improved ORR (51% vs 14%, P < .001) and mOS (12.5 vs
8.4 months; HR 0.59; 95% CI 0.39–0.88; P 5 .01).47 Given these promising results,
DESTINY-Gastric02 is evaluating its use in the second-line setting in patients who
have received front-line trastuzumab.48
With the introduction of immunotherapy onto the treatment landscape, there has
been interest in combining immunotherapy with a trastuzumab-chemotherapy back-
bone. A recent phase II trial examined the addition of pembrolizumab to trastuzumab
and fluoropyrimidine/platinum-based chemotherapy in 37 patients with metastatic
esophageal, gastric, or GEJ cancer regardless of PD-L1 expression. Notably, 26 of
37 patients (70%) were progression free at 6 months.49 These promising data have
prompted the ongoing, phase III trial, KEYNOTE-811.50
Regorafenib is a small molecular TKI with several targets including VEGF. It has
been evaluated in the INTEGRATE trial for use in patients with metastatic gastric or
GEJ adenocarcinoma who progressed on one or more lines of chemotherapy. In
this phase II trial, regorafenib led to an improvement in mPFS (2.6 vs 0.9 months;
HR 0.40; 95% CI 0.28–0.59; P < .001) with a trend toward improved mOS (5.8 vs
4.5 months; HR 0.74; P 5 .147).51 INTEGRATE II is the follow-up phase III trial that
is currently examining regorafenib in the refractory setting.52 Regorafenib has been
examined in combination with immunotherapy. The phase Ib REGONIVO trial com-
bined regorafenib with nivolumab in 50 patients with metastatic gastric or colorectal
cancer who had received at least 2 lines of prior therapy. In the gastric cancer cohort,
the mPFS was 5.6 months (95% CI 2.7–10.4 months) and mOS was 12.3 months (95%
CI 5.3-not reached) with few treatment-related adverse effects such as rash (12%),
proteinuria, (12%) and palmar-plantar erythrodysesthesia (10%).53 Similar to the
RAINBOW trial, regorafenib is currently being examined in the second-line setting in
combination with paclitaxel in the phase Ib REPEAT trial.54
Claudins are a family of proteins found in gastric mucosa that are involved with tight
cell junctions, controlling the movement of molecules between cells. Isoform 2 of
claudin-18 (CLDN18.2) is expressed in 50% to 70% of gastric tumors and is thought
to be critical for tumor growth and development.55 Zolbetuximab is a promising anti-
CLDN18.2 mAb that is currently being evaluated for use in metastatic gastric cancer.
In the phase II FAST trial, patients with advanced or recurrent, HER2-negative
CLDN18.2 expressing tumors (defined as >21 staining with anti-CLDN18 antibodies)
were randomized to receive EOX with or without zolbetuximab. The addition of the
anti-CLDN18.2 mAb led to an improved mOS (13.0 vs 8.4 months; HR 0.56, 95% CI
0.40–0.67; P 5 .0008) and mPFS (7.5 vs 5.3 months; HR 0.44, 95% CI 0.29–0.67;
P < .0005).56 These results prompted the ongoing phase III SPOTLIGHT trial, which
randomizes patients with HER2-negative, advanced or metastatic, CLDN18.2-
expressing gastroesophageal cancer to FOLFOX with or without zolbetuximab.57
 Advances in Systemic Therapy for Gastric Cancer 619

SUMMARY

In resectable, localized gastric cancer, randomized trials have demonstrated that

adjuvant and perioperative systemic chemotherapy, with or without radiotherapy, im-
proves patient outcomes. Although controversies regarding choice of regimen, timing
of therapy, perioperatively versus adjuvant, and whether or not to incorporate radio-
therapy remain, there is strong evidence that surgery alone is insufficient, especially
in those cases of locally advanced disease. Currently, there are multiple standard-
of-care treatment options including fluoropyrimidine/platinum doublet therapies
and, for those with strong performance status, a triplicate therapy with FLOT should
be considered.15
In metastatic disease, traditional cytotoxic chemotherapy has led to modest im-
provements in patient outcomes. In the front-line setting for HER2-negative, metasta-
tic gastric cancer, standard chemotherapy regimens consist of a combination of a
fluoropyrimidine/platinum doublet with the addition of a third chemotherapeutic agent
for patients who are medically eligible with good performance status. In HER2-positive
disease, trastuzumab is added to a fluoropyrimidine-platinum doublet, which is the
standard first-line treatment.5 In PD-L1 positive disease, nivolumab is added to a flu-
oropyrimidine-platinum doublet. In the second-line setting, ramucirumab with pacli-
taxel is a recommended regimen; however, in patients with PD-L1 expressing
tumors, pembrolizumab is a reasonable alternative for select patients.4,6 Currently,
several promising targeted therapies and immunotherapies are being investigated
and will likely further improve outcomes for patients in the near future.

DISCLOSURE

The authors have nothing to disclose.

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