Progress

Review

Groups

Report of the

Stomach/Esophageal Cancers

Progress Review Group

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES

National Institutes of Health

National Cancer Institute December 2002
Population Studies Establish collaborations for conducting interdisciplinary, population-based, 

endoscopic, multi-institutional studies to identify populations at greatest risk 

for gastric cancer, esophageal adenocarcinoma, and esophageal squamous 

cancer, and to determine the prevalence and natural history of premalignant 

lesions.

Prevention Develop prevention strategies based on the mechanisms of host/environment 

interactions that lead to metaplasia and neoplasia of the stomach and 

esophagus. Evaluate their effectiveness in at-risk populations. 

Patient/Provider 

Education 

Educate patients and their families, health care professionals, and the public 

regarding risk factors, risk reduction, and treatment options and outcomes for 

gastroesophageal cancers and their precursor states. 

Therapy Develop and test novel therapeutics, and optimize existing treatments for 

gastroesophageal cancers and their precursors, based on the identification 

and understanding of molecular pathways involved in oncogenesis, tumor 

response and resistance.

Therapeutic Targets Define host and molecular/biologic tumor characteristics that will help 

customize treatment and best predict recurrence and/or survival.

Markers and Molecular 

Profiling 

Profile the molecular, cellular, and epidemiological features of 

gastroesophageal tumors and their precursor lesions to identify diagnostic, 

prognostic, predictive, preventive, and therapeutic targets.

Outcomes Develop and refine disease-specific, patient-oriented methods to assess 

quality of life, quality of care, and cost effectiveness of treatment in patients 

with gastroesophageal cancers and their precursors through all stages of 

disease and treatment, and include these instruments in clinical trials and 

observational studies.

Host/Environmental 

Interactions 

Identify, develop, and validate genetic, biochemical, and biological markers 

that will help uncover host-environment interactions in esophageal and 

gastric carcinogenesis.

Technologies for 

Screening/Surveillance 

Develop noninvasive and minimally invasive technologies (e.g. serum 

markers and imaging techniques) for screening and surveillance of 

premalignant and malignant gastroesophageal lesions.

Preclinical Models Establish models to understand the biology of gastroesophageal cancers and 

their precursor lesions, and to stimulate prevention, diagnostic and treatment 

strategies.

Stomach/Esophageal Cancers Progress Review Group 

Priority Recommendations
REPORT OF THE 

STOMACH/ESOPHAGEAL CANCERS 

PROGRESS REVIEW GROUP 

National Cancer Institute 

Co-Chairs: 

Timothy J. Eberlein, M.D., Washington University School of Medicine 

Brian J. Reid, M.D., Ph.D., Fred Hutchinson Cancer Research Center 

Executive Director: 

Ernest T. Hawk, M.D., M.P.H., National Cancer Institute 

December 2002 

From the Leadership 

It is a great pleasure to submit this Report of the Stomach/Esophageal Cancers Progress Review 

Group (S/E PRG) to the Director and Advisory Committee to the Director of the National Cancer 

Institute (NCI). The S/E PRG accepted the charge of former NCI Director Dr. Richard Klausner 

to develop a national plan for stomach and esophageal cancer research over the next 5 years. The 

charge was advanced with the support of the current NCI Director, Dr. Andrew von Eschenbach. 

This report represents the collaborative efforts of the scientists, clinicians, industry 

representatives, and patient advocates who participated in the S/E PRG Roundtable Meeting. 

The priorities outlined in this report are a blueprint for progress toward preventing, diagnosing, 

and treating stomach and esophageal cancers. We look forward to discussing these priorities and 

the plan for their implementation with the leadership of the NCI. 

Timothy J. Eberlein, M.D. 

Washington University School 

 of Medicine 

Cancer Research Center 

PRG Co-Chair 

Brian J. Reid, M.D., Ph.D. 

Fred Hutchinson 

 Cancer Research Center 

PRG Co-Chair 

Ernest T. Hawk, M.D., M.P.H. 

National Cancer Institute 

PRG Executive Director
We the undersigned members of the Stomach/Esophageal Cancers Progress Review Group 

concur with the enclosed report.

Timothy J. Eberlein, M.D. 

PRG Co-Chair 

Alvin J. Siteman Cancer Center 

Washington University School of Medicine 

Brian J. Reid, M.D., Ph.D. 

PRG Co-Chair 

Public Health Sciences Division 

Fred Hutchinson Cancer Research Center 

Ernest T. Hawk, M.D., M.P.H. 

PRG Executive Director 

Division of Cancer Prevention 

National Cancer Institute

Jaffer Ajani, M.D. 

University of Texas 

M.D. Anderson Cancer Center 

Martin Blaser, M.D. 

New York University 

School of Medicine 

Jo Ann Brooks, Ph.D. 

Indiana University Medical Center 

Donald Castell, Ph.D. 

Medical University of South Carolina 

Daniel Coit, M.D., F.A.C.S. 

Memorial Sloan-Kettering Cancer Center 

Pelayo Correa, M.D. 

Louisiana State University 

Health Sciences Center 

Thomas R. DeMeester, M.D. 

University of Southern California 

Keck School of Medicine 

M. Brian Fennerty, M.D. 

Oregon Health and Sciences University 

Division of Gastroenterology 
We the undersigned members of the Stomach/Esophageal Cancers Progress Review Group 

concur with the enclosed report.

Arlene A. Forastiere, M.D., Ph.D. 

Johns Hopkins University 

Sidney Kimmel Comprehensive Cancer Center 

Karen J. Goodman, Ph.D. 

University of Texas Health Science Center 

 at Houston School of Public Health 

Stanley R. Hamilton, M.D. 

University of Texas 

M.D. Anderson Cancer Center 

Jimmie Holland, M.D. 

Memorial Sloan-Kettering Cancer Center 

Theodore Lawrence, M.D., Ph.D. 

University of Michigan 

Department of Radiation Oncology 

Douglas S. Levine, M.D. 

AstraZeneca 

Stephen Meltzer, M.D. 

University of Maryland Hospital 

Cherie Nichols, M.B.A. 

National Cancer Institute 

Roy C. Orlando, M.D. 

Tulane University 

Health Sciences Center 

Dawn Provenzale, M.D. 

Duke University Medical Center 

Anil K. Rustgi, M.D. 

University of Pennsylvania 

Richard Sampliner, M.D. 

University of Arizona 

Arizona Health Sciences Center 
We the undersigned members of the Stomach/Esophageal Cancers Progress Review Group 

concur with the enclosed report.

Robert Tell, M.S.H.A. 

Patient Advocate Joel E. Tepper, M.D. 

University of North Carolina at Chapel Hill 

School of Medicine 

Jacques Van Dam 

Stanford University Medical Center 

Thomas Vaughan, M.D. 

Fred Hutchinson Cancer Research Center 

Kenneth K. Wang, M.D. 

Mayo Clinic 

Michael Welch, Ph.D. 

Washington University Medical School 

 
Acknowledgments 

This report is the product of months of intense work that drew on the combined expertise and 

efforts of many individuals. The Stomach/Esophageal Cancers Progress Review Group (S/E 

PRG) particularly acknowledges the contributions of: 

• The many scientists, clinicians, and advocates from across the country who generously gave 

of their time and knowledge and without whose participation this report would not have been 

possible. 

• The staff of the NCI Office of Science Planning and Assessment (OSPA), under the 

leadership of Cherie Nichols, who provided ongoing guidance and technical support to the 

S/E PRG throughout the process of preparing this report. In particular, Deborah Duran, who 

coordinated the S/E PRG, as well as James Corrigan and Annabelle Uy.

• A group of experienced science writers, who provided excellent writing support during the 

Roundtable Meeting as well as during the subsequent development of this report: Laura 

Janusik, Lisa Chiu, Deborah Barnes, Jackie Beals, Deborah Berlyne, Laura Drake, Randi 

Henderson, Kit Johnston, Ramie Liebnitz, Cheryl Pellerin and Nancy Volkers. 

• The staff of Palladian Partners, Inc., who provided excellent logistical support to the S/E 

PRG: Syreeta Tate, Ellie Dorsey, Jean Kazares, Bridgette Saunders, and Asia Walton. 
TABLE OF CONTENTS

Overview ......................................................................................................................................... 1 

Introduction ..................................................................................................................................... 4 

SCOPE OF THE PROBLEM ...........................................................................................................................................4 

State of the Science ......................................................................................................................... 6

OPPORTUNITIES FOR SCIENTIFIC ADVANCEMENT .....................................................................................................6

CHALLENGES TO BE ADDRESSED ..............................................................................................................................9

Recommendations ........................................................................................................................... 9

Infrastructure: Resources and Partnerships................................................................................... 15 

STOMACH/ESOPHAGEAL NEOPLASIA TRANSLATIONAL RESEARCH NETWORK .......................................................15 

Overview............................................................................................................................................................15

SENTRNet’s Conceptual Foundation................................................................................................................15

Key Elements of SENTRNet’s Infrastructure/Components................................................................................18

Unique Management Strategy Concepts ...........................................................................................................20 

 How SENTRNet Will Facilitate Progress Toward Achieving the PRG Recommendations ...............................22

Conclusion..................................................................................................................................... 27

References ..................................................................................................................................... 28

Appendix A: About the National Cancer Institute=s Progress Review Groups..................... 29

CHARGE TO THE PRGS...........................................................................................................................................29

THE PRG PROCESS .................................................................................................................................................29

 THE PRG REPORT...................................................................................................................................................30

Appendix B: Breakout Reports.................................................................................................. 31

GUIDING PRINCIPLES ..............................................................................................................................................31

Biology ..............................................................................................................................................................31

Etiology .............................................................................................................................................................35

Genetics.............................................................................................................................................................39 

Imaging/Technologies .......................................................................................................................................43

Outcomes/Education/Communication/Quality of Life.......................................................................................47

Predictive and Prognostic Markers...................................................................................................................50

Prevention .........................................................................................................................................................52

Surveillance/Databases .....................................................................................................................................56

Therapeutics ......................................................................................................................................................59

Tumor Models....................................................................................................................................................62

DISEASE SITES ........................................................................................................................................................64

Adenocarcinomas ..............................................................................................................................................64

Gastric...............................................................................................................................................................67

Squamous...........................................................................................................................................................70

POPULATION MANAGEMENT...................................................................................................................................73

At Risk ...............................................................................................................................................................73

Premalignant.....................................................................................................................................................76

Localized Malignant..........................................................................................................................................79

Late Malignant ..................................................................................................................................................82

Appendix C: Stomach/Esophageal Cancers PRG Members................................................... 85

Appendix D: Stomach/Esophageal Cancers PRG Roundtable Participants......................... 87 
Priorities of the Stomach/Esophageal Cancers 

Progress Review Group 

Priorities of the Stomach/Esophageal Cancers Progress Review Group 1 

Overview 

Gastroesophageal cancers are an enormous 

cause of morbidity and mortality worldwide. 

In the year 2000, it was estimated that more 

than 1,288,000 new cases of 

gastroesophageal cancers were identified, 

and more than 984,000 people died from 

them, making this combination of cancers 

the most common form of incident cancer 

and the second most common cause of 

cancer death in the world.1

 

In the United States, gastroesophageal 

cancers are relatively uncommon; however, 

esophageal cancer appears to be on the rise. 

This suggests that there are many more 

individuals at risk for the disease, although 

their risk status may be unrecognized. Three 

issues particularly relevant to gastroesophageal cancers and their impact on the 

U.S. population include: 1) the significant 

morbidities associated with the diseases and 

their treatments, 2) their almost uniformly 

poor prognoses, and 3) their burden among 

minorities. 

Several aspects of gastroesophageal cancers 

provide opportunities for rapid scientific and 

clinical advancements. The stomach and 

esophagus are relatively easy and safe to 

access, which can provide ample specimens 

for research. Additionally, the technologic 

advances in molecular profiling, imaging, 

and molecular targeting of preventive/ 

therapeutic agents provide a foundation for 

further developments to reduce the burden 

of these cancers and perhaps others. At a 

minimum, advancing these important 

research opportunities will improve the 

identification, care, and management of 

persons at risk for and living with 

gastroesophageal cancers. 

There are several challenges to advancing 

these research opportunities. At a molecular 

level, the development of tumor models and 

a further understanding of the molecular 

basis for these cancers and the 

host/environment interactions underlying 

them are needed. Practical challenges 

include gaining access to adequate numbers 

of at-risk persons or cancer patients, 

recruiting physicians with the expertise to 

manage the many at-risk patients, and 

dealing with a disparate collection of 

cancers (i.e., gastric adenocarcinoma, 

esophageal squamous cell carcinoma, and 

esophageal adenocarcinoma). 

To capitalize on the current state of the 

science and to overcome these challenges, 

collaboration across borders is needed. Only 

through collaborative efforts can enough 

patient data be collected to enhance the 

understanding of the biology, etiology, 

pathology, and treatment of the diseases. To 

gain access to large numbers of at-risk 

patients for these cancers, there is a critical 

need to involve gastroenterologists and other 

specialists who perform esophagogastroduodenoscopy in NCI-sponsored research 

efforts. Pathologists, molecular biologists, 

epidemiologists, and clinical trial 

researchers can then use these data to 

identify important new markers and targets. 

There is a great opportunity-to-investment 

ratio related to research in these cancers. For 

instance, risk markers may be applied in 

screening, diagnosis, and prognostication; 

interventive response markers may identify 

new approaches to modulate risk. Therapeutic targets can inform agent identification 

and development. Additionally, many 

aspects of the molecular etiology of 

gastroesophageal carcinogenesis may be 

shared with other cancers that are less 

accessible or amenable to serial investigations; therefore, research findings may 

have broader implications. 

To develop these opportunities, the 

Stomach/Esophageal Cancers Progress 
2 Report of the Stomach/Esophageal Cancers Progress Review Group 

Review Group identified and prioritized 

research recommendations that will advance 

the understanding of these cancers over the 

next 5 years. 

Stomach and Esophageal Progress 

Review Group Process 

Premise for Planning. The 

Stomach/Esophageal Cancers Progress 

Review Group (S/E PRG) held a planning 

meeting January 24 and 25, 2002, to 

organize the Roundtable Meeting that would 

classify progress, identify gaps, and 

highlight research opportunities across the 

continuum of stomach and esophageal 

cancers research. A primary challenge was 

identifying an approach that would include 

the various stomach and esophageal cancers. 

It was agreed to focus on gastric 

adenocarcinoma, esophageal adenocarcinoma, and esophageal squamous cell 

carcinoma. A secondary challenge was to 

make certain that the full spectrum of the 

disease and the foundational scientific 

principles that underlie scientific advances 

in disease management were addressed. A 

three-dimensional, overlapping approach 

was developed to ensure that ideas had 

multiple audiences. The attendees would 

consider the cancers through the lenses of 

Scientific Guiding Principles, Population 

Management, and Disease Sites. Figure 1 

represents the conceptual foundation that 

organized the roundtable subgroup 

discussion format. This organization ensured 

that each topic would be discussed in 

adequate detail, with attention to the full 

spectrum of important issues. To guarantee 

expert facilitation of each discussion topic, 

S/E PRG members were assigned to serve as 

co-chairs, and roundtable participants were 

identified for each of the breakout 

subgroups.

Figure 1. PRG Organization 

Scientific Guiding Principles

Roundtable Meeting. The S/E PRG 

Roundtable Meeting, which included 

approximately 112 participants, convened 

May 5–7, 2002, at Westfield’s Conference 

Center in Chantilly, Virginia. Participants 

attended one session each on Scientific 

Guiding Principles, Population 

Management, and Disease Sites. Each 

session created three priorities and rationales 

addressing specific gastroesophageal

cancers. Afternoon sessions incorporated the 

morning sessions’ priorities and rationales 

into their discussions to ensure that 

comprehensive views were represented in 

each session. Each subgroup’s report and 

priorities can be found in Appendix B. The 
Priorities of the Stomach/Esophageal Cancers Progress Review Group 3 

Population Management and Disease Sites 

subgroups developed 21 priorities; each 

priority had its own rationale, partnership 

platforms, and resources needed to capitalize 

on existing opportunities and to overcome 

current challenges. On the final day, the S/E 

PRG Leadership clustered the 21 priorities 

to elucidate similar recommendations. These 

21 priorities were presented to the 

roundtable participants at the final 

consensus session. The roundtable 

participants reached consensus on 10 highpriority research recommendations (Table 1) 

and a single partnership platform aimed at 

improving prevention, diagnosis, and 

treatment of stomach and esophageal 

cancers. Recommendations and 

corresponding rationales are detailed in the 

Recommendations section that follows. 

Table 1. 

Population Studies Establish collaborations for conducting interdisciplinary, populationbased, endoscopic, multi-institutional studies to identify populations at 

greatest risk for gastric cancer, esophageal adenocarcinoma, and 

esophageal squamous cancer, and to determine the prevalence and 

natural history of premalignant lesions.

Prevention Develop prevention strategies based on the mechanisms of 

host/environment interactions that lead to metaplasia and neoplasia of 

the stomach and esophagus. Evaluate their effectiveness in at-risk 

populations. 

Patient/Provider 

Education 

Educate patients and their families, health care professionals, and the 

public regarding risk factors, risk reduction, and treatment options and 

outcomes for gastroesophageal cancers and their precursor states. 

Therapy Develop and test novel therapeutics, and optimize existing treatments 

for gastroesophageal cancers and their precursors, based on the 

identification and understanding of molecular pathways involved in 

oncogenesis, tumor response and resistance.

Therapeutic Targets Define host and molecular/biologic tumor characteristics that will help 

customize treatment and best predict recurrence and/or survival.

Markers and 

Molecular Profiling 

Profile the molecular, cellular, and epidemiological features of 

gastroesophageal tumors and their precursor lesions to identify 

diagnostic, prognostic, predictive, preventive, and therapeutic targets.

Outcomes Develop and refine disease-specific, patient-oriented methods to 

assess quality of life, quality of care, and cost effectiveness of 

treatment in patients with gastroesophageal cancers and their 

precursors through all stages of disease and treatment, and include 

these instruments in clinical trials and observational studies.

Host/Environmental 

Interactions 

Identify, develop, and validate genetic, biochemical, and biological 

markers that will help uncover host-environment interactions in 

esophageal and gastric carcinogenesis.

Technologies for 

Screening/Surveillance 

Develop noninvasive and minimally invasive technologies (e.g., serum 

markers and imaging techniques) for screening and surveillance of 

premalignant and malignant gastroesophageal lesions.

Preclinical Models Establish models to understand the biology of gastroesophageal 

cancers and their precursor lesions, and to stimulate prevention, 

diagnostic, and treatment strategies.

Stomach/Esophageal Cancers Progress Review Group 

Priority Recommendations
4 Report of the Stomach/Esophageal Cancers Progress Review Group 

The top research priority is the creation of a 

multi-institutional, multidisciplinary partnership of researchers focused on rapid 

translational biomedical advances in these 

cancers (detailed in the last section of the 

main report). This solution best addresses 

the S/E PRG recommendations within the 

context of the current state of the science 

and the incidence in the United States. The 

infrastructure is similar to cancer cooperative groups and other clinically oriented 

research consortia; however, two critical 

features distinguish this initiative from 

others. First, innovative and progressive 

management strategies will facilitate 

effective and efficient components that will 

foster group-wide priorities. These will 

include multi-institutional, inter-disciplinary 

collaborations and shared resources to 

enhance knowledge and reduce the burden 

of stomach and esophageal cancers. Second, 

involvement of gastro-enterologists and 

other funding partners will provide access to 

patients at risk for gastroesophageal cancers 

(a group not commonly cared for by 

specialists within traditional cancer 

cooperative groups) and diversify funding 

sources. Gastroesophageal tissues 

representative of the full spectrum of 

pathogenesis will be secured. The shared 

resources and the multidisciplinary experts 

will facilitate a true translational focus. 

This kind of comprehensive partnership, 

which will help to overcome the scattering 

of patients across the country and the limited 

resources of any one institution, is crucial to 

the NCI’s ability to make advances in 

combating stomach and esophageal cancers 

and addressing the S/E PRG recommendations. This model is explained in detail in 

the Infrastructure section that follows. 

Introduction 

Scope of the Problem 

Each year, gastroesophageal cancers account 

for an estimated 34,700 new cancer cases 

and 25,000 deaths in the United States.2

Gastroesophageal cancers are heterogeneous 

with regard to their molecular and cellular 

genesis, specific risk factors, and histopathologic character. For this report, the 

term “gastroesophageal cancers” encompasses three distinct cancers: esophageal 

squamous cell carcinoma, esophageal (or 

Barrett’s-related) adenocarcinoma, and 

gastric adenocarcinoma. Although they are 

distinct entities that originate in the same 

general anatomic region of the digestive 

system, these three cancers share some 

characteristics. Most importantly, they tend 

to remain clinically silent until late in the 

disease process; thus, they are often 

associated with later diagnoses, poorer 

prognoses, significant morbidities, and high 

mortality rates. 

Stomach Cancer. Worldwide, the incidence 

of stomach cancer is declining, pointing to a 

critical environmental component in its 

etiology. Although the specific reason for 

this decline is unknown, the increased 

consumption of fruits and vegetables and the 

decreased intake of salty foods, both at least 

partially resulting from improved methods 

in food preservation and storage, are often 

credited. Despite this encouraging trend, 

stomach cancer is the fourth most common 

new cancer diagnosis and the second leading 

cause of cancer mortality in the world, 

accounting for an estimated 876,341 new 

cancer cases and 646,567 deaths worldwide 

in 2000.1

 The highest incidence of stomach 

cancer occurs in Japan and Eastern Asia; by 

contrast, its incidence is relatively low in 

Western Europe. 

Stomach cancer was the most common 

cancer in the United States during much of 

the early 20th century; however, its incidence 

has declined significantly since the 1950s. 

U.S. incidence rates for stomach cancer are 

higher for Asian/Pacific Islanders, blacks, 

and Hispanics than for whites or American 

Indians/Alaska Natives. Men are 1.5 to 2 

times as likely to develop stomach cancer as 

women are. 
Priorities of the Stomach/Esophageal Cancers Progress Review Group 5 

Table 2. SEER Incidence Age-Adjusted Rates, 11 Registries, 1992–19993 

 ESOPHAGUS STOMACH

Race/Ethnicity All Males Females All Males Females 

All 4.5 7.5 2.1 9.3 13.5 6.3 

White 4.2 7.1 1.9 7.9 11.7 5.2 

Black 8.0 12.9 4.4 13.9 19.6 9.9 

American Indian/ 

Alaska Native 1.5 2.8 0.5

 

7.6 9.8 5.9 

Asian or Pacific 

Islander 3.0 5.6 1.0

 

18.5 24.9 13.6 

Hispanic 2.9 5.4 1.0 12.5 17.1 9.2 

Age-adjusted rates, 2000. Rates are expressed as cases per 100,000. 

Esophageal Cancer. Esophageal cancer has 

been relatively uncommon in the United 

States, but recent trends are of concern. 

Incidence rates for adenocarcinomas 

involving the gastric cardia and lower 

esophagus (Barrett’s esophageal 

adenocarcinoma) have increased markedly 

since the mid-1970s. Among white males, 

the rate of esophageal adenocarcinoma has 

increased more than 350 percent between 

1974 and 1994, making this one of the most 

rapidly rising cancers in the U.S. population 

and suggesting that environmental factors 

play important roles in its etiology. In the 

United States, Blacks have the highest rate 

of esophageal cancer, primarily squamous 

cell, almost double the incidence of all other 

groups. Incidence is higher among men than 

among women: men are 3 to 5 times as 

likely to develop esophageal cancer as 

women are. 

Esophageal cancer is the eighth most 

common new cancer diagnosis and the sixth 

leading cause of cancer death in the world, 

accounting for an estimated 412,327 new 

cancer cases and 337,501 deaths in 2000.1

Epidemiologists have identified some 

unexplained and remarkable differences in 

its distribution across the world. For 

example, esophageal cancer is more 

common in developing countries than in the 

United States. In addition, histopathologic 

types vary between these regions, with 

squamous cell carcinoma dominating in 

developing countries and adenocarcinomas 

becoming an increasing problem in the 

United States. 

Mortality. Stomach and esophageal cancers, 

while relatively uncommon in the United 

States, are highly lethal. The estimated 

overall 5-year survival rate is 22 percent for 

stomach cancer and 14 percent for 

esophageal cancer. In fact, mortality rates 

for these cancers approach their incidence 

rates, suggesting that current treatment 

options for these patients are limited and 

often ineffective. Notably, minorities tend to 

have disproportionately high mortality rates 

from these cancers. For stomach cancer, the 

rates are more than twice as high in blacks 

and Asian/Pacific Islanders, compared with 

whites. 
6 Report of the Stomach/Esophageal Cancers Progress Review Group 

Table 3. SEER Mortality Age-Adjusted Rates, Total U.S., 1990–19993

 ESOPHAGUS STOMACH

Race/Ethnicity All Males Females All Males Females 

All 4.3 7.5 1.8 5.4 7.7 3.7 

White 3.9 6.9 1.6 4.8 6.9 3.3 

Black 8.1 14.3 3.8 10.3 15.2 7.1 

American Indian/ 

Alaska Native 2.4 4.0 1.0 5.3 7.1 3.9 

Asian or Pacific 

Islander 2.4 4.1 .96 10.4 13.6 8.0 

Hispanic 2.4 4.4 .91 7.2 9.7 5.3 

Age-adjusted rates, 2000. Rates are expressed as cases per 100,000.

Three factors are associated with the poor 

survival rates associated with 

gastroesophageal cancers. First, symptoms 

are rare in the early stages of cancer 

development, often only occurring with 

advanced cancer; even then, they can be 

nonspecific. Second, although screening and 

diagnostic techniques exist for these cancers, 

the risks, benefits, and feasibility of 

screening have not been adequately tested 

and consequently are not routinely 

recommended by physicians. Finally, 

patients often fail to seek appropriate 

medical attention due to lack of knowledge 

of important risk factors and symptoms 

and/or reluctance to undergo invasive and 

relatively costly endoscopic procedures. 

Therefore, many patients present at late 

stages. 

Morbidity. Patients diagnosed with stomach 

and esophageal cancers often have 

significant morbidities (e.g., difficulty 

swallowing, painful swallowing, weight 

loss) as a result of their cancer or the 

treatments intended to help them. Necessary 

treatments often involve the removal of 

portions of the esophagus and/or stomach or 

the placement of a stent to maintain the 

patency of the GI tract. After surgery, some 

esophageal cancer patients may need to 

receive nutrients directly into a vein or 

through a feeding tube. If only a part of the 

stomach is removed, a patient should still be 

able to eat fairly normally. However, if the 

entire stomach is removed, a new eating 

pattern must be adopted, including frequent, 

small meals low in sugar and high in fat and 

protein. For many patients, chemotherapy 

and radiation also are necessary, so 

additional side effects are common. 

The incidence, morbidity, and mortality of 

stomach and esophageal cancers make them 

an important health concern, particularly 

within minority sectors of the population. 

The rapid rise of adenocarcinomas of the 

distal esophagus and proximal stomach 

among whites, as well as the high rates of 

esophageal cancer in blacks, suggests that 

these cancers are an important health issue 

today. With the increasing rates of 

Asian/Pacific Islander and Hispanic 

immigration, these cancers will be an 

important medical and public health issue in 

the future as well. 

State of the Science 

Opportunities for Scientific 

Advancement 

Gastroesophageal cancers are significant 

causes of morbidity and mortality in the 

United States; most individuals with these 
Priorities of the Stomach/Esophageal Cancers Progress Review Group 7 

cancers are not identified until the cancer is 

advanced and symptomatic. In these cases, 

even the best therapies are associated with 

significant morbidities and poor outcomes. 

Only a small fraction of patients is found to 

harbor preinvasive neoplastic lesions (e.g., 

Barrett’s dysplasia) while undergoing an 

endoscopic evaluation for nonspecific 

symptoms. Typically, such patients would 

have periodic endoscopic surveillance, and a 

small number of them would develop early 

stage cancer. Identified in this way, a patient 

would undergo an esophagectomy with the 

potential for significant post-operative 

morbidities, and in most instances, would 

have an excellent prognosis for long-term 

survival. 

There are tremendous opportunities to 

improve the management and care of people 

who have gastroesophageal cancers, as well 

as those at risk. Three factors specific to 

gastroesophageal cancers make scientific 

and clinical progress imminently attainable. 

First, the marked distributional 

heterogeneity of gastroesophageal cancers 

within the population suggests the presence 

of effective risk and preventive factors. 

Second, relatively easy and safe access to 

the stomach and esophagus is available 

through established technologies for serial 

endoscopic assessments with mucosal 

biopsies. Finally, technologic advances in 

genomics, proteomics, invasive and 

noninvasive imaging, as well as in the 

molecular targeting of preventive/ 

therapeutic agents, can be applied for rapid 

advances in a highly translational 

environment in which patients harboring 

preinvasive neoplasia undergo serial 

surveillance of their gastroesophageal 

mucosa as a matter of standard care. 

Several common conditions—for example, 

gastroesophageal reflux disease (GERD) and 

Helicobacter pylori infection—place 

affected individuals at increased risk for one 

or more of these cancers. Recent cohort 

studies suggest that symptoms of GERD 

occur weekly in approximately 20 percent of 

Americans, implying that the number of 

persons at risk for these cancers may be 

substantial. Of course, both of these diseases 

are much more common in other parts of the 

world, so attention to the problem within 

immigrants to the United States from Asian 

or Central/South American countries is 

important. Indeed, the marked heterogeneity 

in the worldwide distribution of these 

cancers, as well as their rapidly changing 

incidence patterns within the United States, 

suggest that there are important environmental risk or preventive factors acting at 

the molecular level, which, once identified, 

may be employed to reduce the burden of 

these diseases. 

Disease Pathogenesis. A detailed 

understanding of a disease’s pathogenesis 

and natural history is necessary to advance 

the care of affected individuals. 

Gastroesophageal cancers are believed to 

develop over decades with few or no 

presenting symptoms during most years. 

Fortunately, the availability of 

esophagogastroduodenoscopy (EGD) allows 

gastroenterologists to directly visualize the 

lining of these organs and easily obtain 

biopsies for molecular, cellular, and 

histopathologic assessments over time. 

Thus, gastroenterologists can use EGD to 

gain access to tissues at risk for these 

cancers, thus allowing improvements in the 

understanding of the disease process. 

Technologies. Recent technologic advances 

are providing opportunities to reduce the 

burden of gastroesophageal cancers. As 

evidenced from the study of other organs, 

knowledge of the molecular basis may lead 

to further understanding and identification 

of targets. Research may elucidate the 

identification of reliable indicators of cancer 

risk and patient response to interventions, as 

well as targets for preventive or therapeutic 

interventions. For example, with the advent 
8 Report of the Stomach/Esophageal Cancers Progress Review Group 

of genomic and proteomic technologies, it is 

now possible to examine the genesis of 

gastroesophageal neoplasia from the earliest 

molecular alterations through precursor 

lesions (cellular and tissue abnormalities) to 

invasive and metastatic cancers. Charting 

the molecular changes underlying the 

natural history of gastroesophageal cancers 

during every step of this process may allow 

the identification of environmental risk 

factors, genetic risk factors, and/or 

biomarkers that can be used for non-invasive 

screening and diagnostic tests. 

Bioinformatics. The advent of novel 

analytic approaches has facilitated deriving 

meaning from novel genomics and 

proteomics data. These approaches include, 

but are not limited to, hierarchical 

agglomerative clustering, significance 

analysis of microarrays, GeneFinder 

comparisons, artificial neural networks, and 

principal components analysis. Widespread 

use of such strategies will identify global 

patterns of gene and protein expression 

potentially useful a priori as early detection, 

diagnostic, prognostic, or risk assessment 

tools. Moreover, these techniques will 

identify individual genes or groups of genes 

worthy of further study and useful in 

hypothesis generation, such as in the 

implication of novel molecular pathways, 

environmental and socioeconomic factors, 

dietary influences, genetic makeup, and the 

host response in the genesis or progression 

of these important cancers.

Molecular Profiling. Understanding the 

molecular basis of these cancers also affords 

the opportunity for more careful study of 

host-environment interactions. For example, 

epidemiological evidence indicates a 

relationship between infection by the 

bacterium H. pylori and the development of 

gastric ulcers and adenocarcinoma. Genomic 

and proteomic technologies will facilitate 

the identification of genetic differences that 

may predispose one person to a gastric ulcer 

and another to gastric adenocarcinoma. 

Likewise, the molecular basis for the 

relationship between other agents, such as 

bile or nitrosamines, and gastroesophageal 

cancers also may become evident. 

Investigators will be able to develop 

prevention strategies based on the 

mechanism of protective host/environment 

interactions. 

Genes. Genomics-based methodologies may 

facilitate drug discovery and the translation 

of drugs from “bench to bedside”; they also 

may provide a means to monitor patient 

responses or resistance to new interventions 

applied with preventive or therapeutic intent. 

In addition, the examination of molecular 

genetic and host factors during clinical trials 

involving an intervention will provide 

another level of understanding of patient 

response and resistance. 

Models. Scientific advances require the use 

of appropriate in vitro and in vivo models, 

few of which exist for stomach and 

esophageal carcinogenesis. The development of improved tumor models—including 

cell lines, xenografts, and animal models— 

therefore represents an opportunity for 

scientific advancement. Once standardized 

and validated, tumor models specific to 

gastroesophageal cancers will aid 

investigators in the identification of 

molecular and cellular changes that mark 

disease progression and improve 

understanding of host/environment 

interactions. These models will provide a 

means for investigators to develop new 

molecularly targeted approaches to 

prevention and therapies. 

Patient Care and Outcomes. In addition to 

molecular and technologic efforts, the 

scientific community has the opportunity to 

make significant advances in patient care 

and morbidity reduction. Clinical 

researchers can develop disease-specific, 

patient-oriented methods to assess the 
Priorities of the Stomach/Esophageal Cancers Progress Review Group 9 

quality of life, quality of care, and cost 

effectiveness of preventive and therapeutic 

approaches. In addition, education and 

outreach measures addressing risk factors 

and screening that target the public and 

community physicians are likely to reduce 

morbidity and mortality from these diseases. 

Integration/Translation. Preliminary data 

from interdisciplinary translational research 

in stomach and esophageal cancer are 

promising. When interdisciplinary teams 

involve combinations of molecular 

biologists, gastroenterologists, pathologists, 

epidemiologists, medical/surgical oncologists, and other members, knowledge grows 

quickly and exponentially. For example, 

a recent study of familial gastric cancer 

identified a tightly linked mutation in 

E-cadherin that may provide insights into 

the pathogenesis of the syndrome. In 

addition, two studies of patients with 

Barrett’s metaplasia recently noted a 

significant correlation between cytometric 

aneuploidy and the future development of 

dysplasia or cancer. 

Challenges To Be Addressed 

Low Incidence. The relative rarity of these 

cancers in the United States presents a 

significant research challenge. Individual 

centers do not treat enough patients to 

conduct adequately powered clinical studies 

intended to evaluate the natural history of 

these diseases, develop new methods for 

screening and surveillance, or test new 

preventive and therapeutic interventions. As 

a result, few adequately powered studies 

addressing these issues have been 

completed, and most current care is based on 

observational data and expert opinion. To 

transcend this challenge, NCI must evaluate 

the current research infrastructure and 

develop a means to coordinate research and 

management of these relatively rare cancers 

in order to secure the critical mass of cases 

needed for scientific advancement. 

Incomplete Network Systems. There 

is a clear need for a coordinated, multiinstitutional partnership that involves a wide 

range of research professionals, some of 

whom—particularly gastroenterologists—

are not adequately represented in existing 

NCI consortia. In addition to providing a 

means for rigorous study of current and new 

treatments, a network will provide 

investigators with access to patients at 

different stages of carcinogenesis, and to the 

critical tissue samples needed for studies of 

the biology and etiology of these cancers. 

Lack of Awareness. Another challenge is 

the underestimation and limited awareness 

of these cancers by the public and some 

physicians. Unlike many other cancer 

cohorts, people with gastroesophageal 

cancers have not had a specific advocacy 

group or an important public figure to draw 

attention to the disease and advocate for 

resources. Public education in gastroesophageal cancers might encourage at-risk 

persons to seek earlier screening and 

diagnosis, thereby potentially reducing 

morbidity and mortality. 

To capitalize on the scientific opportunities 

and to overcome the challenges, the S/E 

PRG was convened by NCI and charged to 

provide recommendations to reduce the 

burden of these cancers. 

Recommendations 

The S/E PRG recognizes that these highmortality cancers present a unique set of 

challenges and opportunities. Gastroesophageal cancers represent diverse 

malignancies that have rapidly changing 

incidences, and their ethnic and gender 

disparities are not well understood. These 

cancers also have long premalignant phases 

that are uniquely accessible for endoscopic 

visualization and biopsy; this, combined 

with the rapidly advancing field of cancer 

genetics, offers unparalleled opportunities 
10 Report of the Stomach/Esophageal Cancers Progress Review Group 

for mechanism-based approaches to 

screening, surveillance, prevention, early 

detection, and treatment. 

It is difficult for any one center in the United 

States to generate enough cases to make an 

impact on gastroesophageal cancer 

morbidity and mortality. However, U.S. 

cases could, if combined, provide data for 

appropriately powered clinical and 

epidemiological studies. Through 

collaboration of clinical, population, 

laboratory, and computational scientists, 

private industry, and the NCI, the burden 

of these malignancies on society can be 

reduced. 

Therefore, the S/E PRG offers the following 

10 prioritized research recommendations 

and a high-priority infrastructure resource: 

Population Studies: Establish 

collaborations for conducting 

interdisciplinary, population-based, 

endoscopic, multi-institutional studies to 

identify populations at greatest risk for 

gastric cancer, esophageal adenocarcinoma, and esophageal squamous cancer, 

and to determine the prevalence and natural 

history of preneoplastic lesions.

Rationale 

Patients with gastroesophageal cancers 

usually present at late stages and have poor 

prognoses. To reverse this trend, patients at 

highest risk must be identified earlier. 

Recent epidemiologic studies suggest 

protective and risk factors for each of the 

gastroesophageal cancers. Non-steroidal 

anti-inflammatory drugs (NSAIDs) appear 

to be protective against esophageal 

squamous cell carcinoma, esophageal 

adenocarcinoma, and gastric adenocarcinoma. A diet high in fruits and vegetables 

may protect against all gastroesophageal 

cancers. H. pylori is a risk factor for gastric 

adenocarcinoma but is protective against 

esophageal adenocarcinoma, and gastroesophageal reflux and obesity are risk 

factors for esophageal adenocarcinoma. 

Although these associations are clear, 

critical gaps exist in our knowledge of the 

underlying mechanisms. Multidisciplinary, 

tissue-based studies across the spectrum of 

progression are needed to identify the 

linkages between molecular, cellular, and 

clinical pathogenesis. This knowledge then 

can be applied to better define the risk status 

of individuals and groups. 

Although gastroesophageal cancers are 

relatively uncommon in the United States, 

their predisposing conditions are relatively 

common: Barrett’s esophagus may be seen 

in as many as 10 percent of asymptomatic 

adults, and H. pylori infection rates may be 

as high as 40 percent. Despite the frequency 

of these conditions, the true population 

prevalence and natural history of 

preinvasive neoplastic lesions in the 

stomach and esophagus are poorly 

established because studies have come 

mainly from single institutions. Endoscopy 

can safely and systematically visualize and 

biopsy stomach and esophageal premalignant conditions prospectively, providing 

an unprecedented opportunity to define the 

prevalence and natural history of these 

conditions, establish risk stratification, and 

characterize the genetic and biological 

mechanisms of carcinogenic progression. 

Data from these multi-institutional, multidisciplinary studies must be aggregated to 

define statistically significant at-risk 

populations, risk and protective factors, and 

the natural history of gastroesophageal 

neoplasia. 

Prevention: Develop prevention strategies 

based on the mechanisms of 

host/environment interaction that lead to 

metaplasia and neoplasia of the stomach 

and esophagus. Evaluate their effectiveness 

in at-risk populations.
Priorities of the Stomach/Esophageal Cancers Progress Review Group 11 

Rationale 

Neoplastic progression in the stomach and 

esophagus is a multi-decade process 

characterized by genomic instability and the 

evolution of neoplastic clones, providing 

time and targets for intervention long before 

the development of cancer. Premalignant 

conditions can be prospectively monitored 

by endoscopic biopsy surveillance, 

providing an unparalleled opportunity to 

understand the evolution and impact of risk 

and protective factors in humans. 

Preliminary studies implicate gastric acid, 

bile, H. pylori, diet, tobacco, NSAIDs, 

obesity, and other exposures as risk and/or 

protective factors for these cancers, but little 

knowledge exists as to the molecular and 

cellular mechanisms involved. Knowledge 

of the mechanisms that predispose people to 

gastroesophageal cancers, especially at the 

genomic, transcription (expression) and 

proteomic levels, could identify novel 

interventions to prevent these cancers. 

Additionally, insight could be gained that 

may be useful in preventing or controlling 

the evolution of intervention-resistant 

clones. Finally, after promising interventions have been identified, they must 

be tested in adequately powered, wellcontrolled clinical prevention trials that 

allow prospective, tissue-based molecular 

and cellular characterizations of response. 

Patient/Provider Education: Educate 

patients and their families, health care 

professionals, and the public regarding risk 

factors, risk reduction, and treatment 

options and outcomes for gastroesophageal 

cancers and their precursor states.

Rationale 

Gastroesophageal cancers represent a 

diverse group of malignancies, and each 

subtype has a different risk profile. Some 

subtypes show recent rapid changes in 

incidence as well as striking variations by 

ethnicity, gender, and socioeconomic status. 

For example, esophageal adenocarcinoma, 

which was rare two decades ago, now 

accounts for 60 percent of all esophageal 

cancers. As many as 25 percent of gastric 

cancer patients receive no surgical 

treatment, even though they present at a 

treatable stage. These issues suggest that a 

critical lack of knowledge about risk factors, 

risk reduction, treatment options and 

outcomes among health care providers, 

patients, and the public. There is a lack of 

public awareness of the scope, magnitude, 

and premalignant stages of gastroesophageal cancers. Specifically, there has 

been a lack of focus on educating high-risk 

groups, including people with Barrett’s 

esophagus, GERD, and H. pylori infection. 

In addition, the possible roles of alcohol, 

tobacco, and diet in the etiology of these 

cancers have not been emphasized. 

Furthermore, public education on risk 

factors, common presenting symptoms, and 

interventions has been inadequate to 

motivate the public to seek early diagnosis. 

Presumably, more at-risk patients would 

self-identify and seek treatment earlier if 

risk profiles were more widely understood 

by the public, advocacy groups, and health 

care professionals. In addition, morbidity 

and mortality could decrease with welldeveloped tools, such as videos available in 

physicians’ offices and user-friendly Web 

sites, to assist the educational process. 

From primary prevention to survivorship 

and end-of-life issues, communication 

empowers people to make informed cancerrelated decisions and to engage in behaviors 

that will improve their health. To build on 

our progress in refining health 

communication theories and interventions, 

we must close major gaps in our 

understanding of how people access and use 

health information, as well as the 

discrepancies between what is known and 

what is practiced. 
12 Report of the Stomach/Esophageal Cancers Progress Review Group 

The quality of cancer communication can be 

enhanced by gaining a better understanding 

of the information needs of patients, 

families, and other decision makers involved 

in the choice of stomach and esophageal 

cancer interventions. These findings can 

lead to accurate and balanced information 

about areas such as cancer prevention, 

diagnosis, treatment, and care. In addition to 

these findings, current dissemination 

systems for quality, evidence-based cancer 

education materials and the use of multimedia technologies must be evaluated and 

improved. This information eventually will 

be applied to help people understand 

important health risks and to assist them in 

making informed choices despite exposure 

to contradictory or inaccurate health 

messages. 

Therapy: Develop and test novel 

therapeutics, and optimize existing 

treatments for gastroesophageal cancers 

and their precursors, based on the 

identification and understanding of 

molecular pathways involved in 

oncogenesis, tumor response and resistance. 

Rationale 

Gastroesophageal malignancies continue to 

be highly lethal, despite therapeutic 

advances over the past 30 years. Although 

treatment has become more complex—often 

involving combinations of surgery, 

chemotherapy, and radiation—physicians 

still do not know which patients benefit 

most from which approaches. The overall 

similarity of outcomes belies the biologic 

and genetic heterogeneity of these 

malignancies and the potential for 

differential sensitivities to existing and 

novel therapeutics. Identifying and understanding molecular pathways involved in 

oncogenesis and tumor sensitivity, as well as 

the evolution of therapeutic resistance, are 

facilitated by repeated endoscopic 

assessments with biopsies. Indeed, as 

oncologic drug development orients itself 

toward more molecularly targeted, 

“cytostatic” agents, serial assessment of 

tissue-based response markers becomes 

critical, particularly in early-phase clinical 

trials intended to prioritize agents before 

entry into more costly phase III trials. 

Knowledge from molecular inquiries during 

therapy also may be useful to improve the 

accuracy and reliability of predictions 

regarding response, survival, and long-term 

outcomes. 

Therapeutic Targets: Define host and 

molecular/biologic tumor characteristics 

that will help customize treatment and best 

predict recurrence and/or survival.

Rationale 

Therapies for gastroesophageal cancers are 

largely empirical. Despite surgery and 

adjuvant therapy, the majority of patients 

with gastroesophageal cancers run a 

substantial risk for both local and distant 

recurrences. There is an urgent need to 

identify molecular markers and pathways 

that confer sensitivity and resistance to 

existing and novel therapies. Advances in 

genomic, transcription (expression) and 

proteomic technologies, combined with 

endoscopic access for biopsy of the stomach 

and esophagus, make it possible to safely 

evaluate neoplastic tissue before and after 

therapy in a unique and unparalleled 

fashion. Insights gained from pre- and posttreatment tissue evaluation by a committed 

multidisciplinary team would guide 

development of customized therapy by 

identifying markers of sensitivity or 

resistance to existing and novel therapies. 

Using these markers, clinical researchers 

could better determine which patients were 

most suitable for which therapies, as well as 

develop therapies targeted specifically to 

gastroesophageal cancers. 
Priorities of the Stomach/Esophageal Cancers Progress Review Group 13 

Markers and Molecular Profiling: Profile 

the molecular, cellular, and epidemiologic 

features of gastroesophageal tumors and 

their precursor lesions to identify 

diagnostic, prognostic, predictive, 

preventive, and therapeutic targets.

Rationale 

Rapid technologic advances in genomics, 

expression arrays, proteomics, and 

bioinformatics, combined with the unique 

access of gastroesophageal cancers and their 

precursors to endoscopic biopsy, offer 

innovative and exciting opportunities to 

understand, prevent, and treat these 

malignancies. Endoscopic biopsies can be 

processed within seconds of being obtained, 

providing optimal material for genomic 

expression and proteomic analyses. In 

addition, premalignant gastroesophageal 

tissues are not typically removed according 

to current standards of care, so molecular 

findings may be evaluated with regard to 

prospective outcomes. These comprehensive methodologies can give insight into 

the molecular genesis and signatures of 

gastroesophageal cancers and their 

precursors. This knowledge provides 

unprecedented opportunities to develop 

molecular diagnostics for risk stratification 

and to predict therapeutic response. 

Such comprehensive methodologies also can 

identify molecular targets to prevent or treat 

cancer, as well as molecular endpoints to 

evaluate the success of interventions. New 

molecular markers and targets can aid in 

developing novel, customized treatment 

strategies that are more effective and less 

toxic than existing regimens. 

Outcomes: Develop and refine diseasespecific, patient-oriented methods to assess 

quality of life, quality of care, and cost 

effectiveness of treatment in patients with 

gastroesophageal cancers and their 

precursors through all stages of disease and 

treatment, and include these instruments in 

clinical trials and observational studies.

Rationale 

Solid data exist that describe patterns of 

recurrences and survival in patients treated 

for gastroesophageal cancers, but 

information is limited on patients’ long-term 

functional outcome and quality of life. 

Patients with gastroesophageal cancers have 

unique functional problems relating to both 

disease and treatment morbidity. Specific 

quality-of-life scales exist for stomach and 

esophageal cancers, but without longitudinal 

studies across large populations, generalizations cannot be made. Challenges to the 

study of patient-centered outcomes include 

the small number of cases and high mortality rates. In addition, patient-centered 

issues vary across the premalignant to 

late malignant disease spectrum. Thus, 

additional organ-specific instruments need 

to be created and utilized in large-scale 

clinical trials. Findings will inform 

assessments of quality-of-life and quality-ofcare issues, cost of care, patient preferences, 

and quality of symptom management. 

Host/Environment Interactions: Identify, 

develop, and validate genetic, biochemical, 

and biological markers that will help 

uncover host/environment interactions in 

esophageal and gastric carcinogenesis.

Rationale 

Gastroesophageal cancers encompass a 

diverse group of malignancies, each with 

identified protective and risk factors. Some 

environmental exposures appear to be risk 

(e.g., tobacco) or protective (e.g., a diet high 

in fruits and vegetables, NSAIDs) factors for 

most gastroesophageal cancers, whereas 

others appear to be specific for certain sites 

or histologic subtypes. For example, 

gastroesophageal reflux and obesity 

correlate with esophageal adenocarcinoma, 
14 Report of the Stomach/Esophageal Cancers Progress Review Group 

and H. pylori infection may even be a risk 

factor for gastric adenocarcinoma but a 

protective factor against esophageal 

adenocarcinoma. The mechanisms by which 

these factors modulate cancer progression 

are not well understood. The stomach and 

esophagus are accessible to endoscopic 

biopsy and prospective evaluation and thus 

are uniquely suited to research on 

environmental exposures and host-response 

relationships, which can be assessed 

comprehensively using genomic expression 

and proteomic technologies. Additionally, a 

new generation of molecular markers to 

identify at-risk patients for premalignant and 

malignant lesions will assist in both 

developing new prevention strategies and 

stratifying patients for surveillance. 

Technologies for Screening/Surveillance: 

Develop noninvasive and minimally invasive 

technologies (e.g., serum markers and 

imaging techniques) for screening and 

surveillance of premalignant and malignant 

gastroesophageal lesions.

Rationale 

Gastroesophageal carcinogenesis occurs 

over decades, and the long premalignant 

phases for these cancers provide great 

opportunities for screening, surveillance, 

early detection, and prevention. Unlike 

people with many other premalignant 

conditions, high-risk populations are 

identifiable, but many people do not seek 

evaluation because of the invasive 

procedures involved. Serologic markers to 

identify persons at increased risk would 

permit cost-effective screening of the 

population. Novel imaging technologies for 

screening (e.g., ultrathin endoscopes, 

colorimetric devices, capsule endoscopy) 

and surveillance (e.g., laser-induced 

fluorescence spectroscopy, reflectance 

spectroscopy, light-scattering spectroscopy, 

trimodal spectroscopy, Raman spectroscopy, 

optical coherence tomography, confocal 

microendoscopy) show promise, but multicenter clinical trials and comparisons among 

technologies are lacking. Such novel 

noninvasive and minimally invasive 

techniques could facilitate screening and 

surveillance by making the procedures more 

cost effective, acceptable, and available. 

Preclinical Models: Establish models to 

understand the biology of gastroesophageal 

cancers and their precursor lesions and to 

stimulate novel prevention, diagnostic, and 

treatment strategies. 

Rationale 

Few clinically relevant tumor models of 

stomach and esophageal cancers exist. 

Preclinical studies need well-characterized 

epithelial cell cultures, cell lines, xenografts, 

and animal models that accurately represent 

physiologically and genetically defined 

stages in human gastroesophageal 

carcinogenesis, including gastroesophageal 

reflux, intestinal metaplasia, H. pylorimediated progression, and gastroesophageal 

clonal evolution. Such preclinical tumor 

models could provide crucial mechanistic 

evidence for translation of advances in 

laboratory research and host-environmental 

interactions into clinical prevention and 

therapeutic trials. Preclinical tumor models 

also provide an efficient use of resources to 

investigate the efficacy and safety of 

therapeutic agents prior to human trials. 

Finally, gastroesophageal tumor models 

would be valuable assets for genomic 

expression and proteomic exploration to 

identify new targets for intervention.

These recommendations constitute a 

scientific framework to translate bench, 

bedside, and population advances into 

improved care for patients with and at risk 

for gastroesophageal cancers. The S/E PRG 

offers a high-priority infrastructure resource, 

the Stomach/Esophageal Neoplasia 

Translational Research Network 

(SENTRNet) to overcome challenges to 
Priorities of the Stomach/Esophageal Cancers Progress Review Group 15 

efficient translation of these research 

recommendations, as described below. 

Infrastructure: Resources 

and Partnerships 

The primary challenge in achieving the S/E 

PRG’s recommendations is that no single 

institution or organizational structure 

currently possesses the resources necessary 

to address the opportunities and challenges 

specific to gastroesophageal cancers 

outlined above. The rarity of these cancers 

means that no one center sees enough 

patients to conduct necessary clinical trials. 

Additionally, a single center may not have 

access to the tools, such as bioinformatics, 

that may be critical to the success of trials. 

Likewise, the dearth of patients at any single 

center prevents the development of qualityof-life interventions and assessment of 

prevention strategies. Thus, it is imperative 

that NCI supports the multidisciplinary, 

multi-institutional efforts of gastroesophageal cancer research. 

Accomplishing the priorities set forth by the 

S/E PRG will require resources specifically 

designed to capitalize on translational 

research opportunities and meet the 

challenges uniquely presented by gastroesophageal cancers. The progression of the 

disease, the late stage at diagnosis, the rarity 

of each of these cancers, and the coordination of translationally oriented biomedical 

investigators capable of thorough evaluation 

of these diseases are best addressed through 

the creation of a Stomach/Esophageal 

Neoplasia Translational Research Network 

(SENTRNet). 

The Stomach/Esophageal Neoplasia 

Translational Research Network 

Overview

SENTRNet (Figure 2) will be charged with 

prioritizing translational research 

opportunities with regard to their efficient 

and effective contributions to key 

foundational elements of trial design. These 

include 1) better risk characterization for 

cohort identification/stratification; 2) 

agents/interventions with greater efficacy 

and/or safety; and 3) markers/endpoints with 

greater accuracy and reliability. Once 

priorities are agreed upon, SENTRNet will 

conduct laboratory, clinical, and populationbased studies to achieve the goals. 

Population feedback will be used to refine 

interventions and improve patient care. 

The components of the model will include 

experts from various disciplines and 

institutions, a tissue repository, 

epidemiological data, surveillance, and the 

technologies necessary to develop basic 

science discoveries that will translate into 

high-quality prevention and treatment 

practices. SENTRNet will share scientific 

leadership with a coordinating center that 

will utilize a business model approach and 

foster linkages with academia, industry 

(both pharmaceutical and device-oriented), 

consumers, and federal agencies. A mutual 

dependence prototype for funding and 

collaborations will be employed to provide 

incentives for productivity and rewards for 

effective partnerships and resource sharing. 

The conceptual foundation, infrastructure, 

management strategies, and research 

priorities are further described below. 

SENTRNet’s Conceptual Foundation

SENTRNet will have multi-agency, 

multiinstitutional, and multidisciplinary 

collaborations with shared leadership. The 

innovative infrastructure and unique 

management style are likely to enhance 

collaborations as well as to facilitate 

achievement of the S/E PRG 

recommendations. 

In developing the idea for SENTRNet, 

existing institutions, consortia, and networks 
16 Report of the Stomach/Esophageal Cancers Progress Review Group 

devoted to clinical research (such as Cancer 

Cooperative Groups, Cancer Centers, the 

Cancer Genetics Network [CGN], the Early 

Detection Research Network [EDRN], the 

Specialized Programs of Research 

Excellence [SPORES], the Nonalcoholic 

Steatohepatitis consortium, and others) were 

considered and reviewed. Although each of 

these entities has strengths, none was ideally 

suited to meet the unique translational 

research challenges and opportunities 

available in stomach and esophageal 

cancers. Success is dependent upon the 

participation of gastroenterologists, as well 

as translationally focused interactions 

between diverse scientists working at the 

laboratory, clinical, and population levels. In 

addition, the proposed management system 

for SENTRNet is unique. For all of these 

reasons, we felt that the research agenda 

regarding stomach and esophageal cancers 

would be best advanced by the creation of 

SENTRNet.

Multi-Agency Partnerships and Linkages. 

A wide range of federal research agencies 

should be invited to partner scientifically 

and financially with NCI in this initiative as 

a means of drawing on needed expertise and 

resources, and providing coordination and 

information dissemination across relevant 

research and practice enterprises. NCI is not 

in a position to bring the full scope of the 

S/E PRG recommendations to fruition alone. 

Other potential support agencies include the 

National Institute of Allergy and Infectious 

Diseases (NIAID), the National Institute of 

Diabetes and Digestive and Kidney Diseases 

(NIDDK), the National Institute of Nursing 

Research (NINR), the National Institute on 

Aging (NIA), the Department of Veterans 

Affairs (VA), the Department of Defense 

(DOD), the Centers for Disease Control and 

Prevention (CDC), the Centers for Medicare 

and Medicaid Services (CMS), and the 

Agency for Healthcare Research and Quality 

(AHRQ). The John E. Fogarty International 

Center can be utilized to develop a better 

understanding of the international implications of these cancers and seek international research partners wherever 

possible. In addition, SENTRNet will seek 

biotechnology, pharmaceutical, and medical 

device industry partners as well as solicit the 

advice of the Food and Drug Administration 

(FDA) to steer new devices and therapies 

through the clinical trials process more 

effectively and efficiently. 
Priorities of the Stomach/Esophageal Cancers Progress Review Group 17 

Figure 2. Schematic Diagram of the Structure and Function of SENTRNet. 

Stomach/Esophageal Neoplasia Translational Research Network 

(SENTRNet)

Clinical 

Research

Centers

Translational

Labs

Analytic

Center

Administrative

Center

Informatics

Center

Pathology

Center

Foundation & Management Principles

• Multi-institutional/agency/disciplinary 

• Synergy with existing institutions

• Shared leadership

• Translational-focused

• Business model

• Mutual dependence

• Managed progressive growth

• Knowledge management

Research Priorities

• Population studies

• Prevention

• Patient/provider 

education

• Therapy

• Therapeutic targets

• Markers & molecular 

profiling

• Outcomes

• Host/environment 

interactions

• Technologies for 

screening/surveillance

• Preclinical models

Research Products 

To Improve Patient 

Care & Public 

Health

• Mechanistic insights

• Molecular targets

• Risk measures

• New devices

• New interventions

• New outcome measures

• Patient & provider 

education

Patients with cancer 

Persons at risk 

General population

Modeloriented

Humanoriented

SENTRNet will seek scientific 

collaborations with other established NCI 

programs, cooperative groups, and 

consortia. For example, the SENTRNet 

Virtual Tissue Resource might partner with 

already established programs, such as the 

EDRN, Cooperative Human Tissue 

Network, Tissue Array Research Program, 

Tissue Expeditor, Tissue Locator, and 

others. 

Finally, SENTRNet also will seek to include 

community physicians, consumer advocacy 

groups, relevant professional associations 

(e.g., the American Gastroenterology 

Association, American College of 

Gastroenterology, American Society for 

Gastrointestinal Endoscopy, American 

College of Surgeons, Oncology Nursing 

Society, American Society of Clinical 

Oncology, and others) and private cancer 

research foundations (e.g., the American 

Cancer Society, Cancer Research 

Foundation of America) to promote 

adequate representation of all interested 

parties. In addition, these affiliations will 

ensure that as many health care 

professionals and patients as possible will 

have access to the new information and 

advances this partnership will provide. 

Multidisciplinary and Multi-institutional. 

Representatives from many disciplines and 

institutions will be necessary to implement 

this comprehensive gastroesophageal 

cancers research plan, which will focus on 

the discovery and application of effective 

educational, prevention, and treatment 

strategies to improve patient care and the 

public’s health. Disciplines and 
18 Report of the Stomach/Esophageal Cancers Progress Review Group 

representatives will include basic scientists, 

especially geneticists and cell biologists, 

biostatisticians, epidemiologists, 

pathologists, gastroenterologists, informatics 

specialists, nurses, psychologists, prevention 

strategists, surgeons, radiation oncologists, 

medical oncologists, and consumers. These 

cross-disciplinary, multi-institutional 

collaborations will be essential to facilitate 

timely discoveries that can improve 

prevention, early detection, treatment, and 

comprehensive cancer care. The outcome of 

this collaboration could potentially reduce 

the burden of disease and increase the 

quality of life for those with or at risk for 

gastroesophageal cancers. 

Shared Scientific Leadership. A steering 

committee coordinated through the 

administrative center will provide scientific 

direction to SENTRNet to assure its efficient 

and productive translational focus. The 

SENTRNet steering committee will consist 

of one representative from each member 

institution and/or discipline, chosen to 

reflect the diversity of research professionals 

and advocates. 

Research Products. Clinical care is 

improved by the generation of high-quality 

reproducible data from unambiguously 

defined risks and benefits of tested devices, 

drugs, and behaviors. Once these data are 

generated, they may be assimilated into 

evidence-based recommendations and 

clinical/public health practices. 

SENTRNet’s first priority is the generation 

of products that will expedite clinical trials 

to improve the clinical care of patients with, 

or at risk of, gastroesophageal cancers, 

thereby improving the public’s health. 

Specific research products will exploit new 

mechanistic insights gained in the course of 

this research that will iteratively improve 

recognition of molecular targets and 

development of new interventions. It is 

expected that this research will suggest new 

risk and outcome measures that can be used 

to evaluate devices and interventions more 

efficiently and effectively. Finally, improved 

patient and provider education will apply 

these advances in a more equitable and 

productive manner. 

Key Elements of SENTRNet’s 

Infrastructure/Components

Administrative Center. The administrative 

center, under the scientific leadership of the 

steering committee, will attend to all 

administrative details and coordinating 

functions. These functions will include the 

development and adoption of standard 

common data elements, protocols, and 

informed consents; development and 

monitoring of budgetary expenditures and 

product timelines; development and 

promulgation of incentives; facilitation of 

communication within and across the 

network; promotion of industry relations; 

and dissemination of information beyond 

SENTRNet. A business administrator will 

lead the center, which will follow a business 

model of management (described later). 

Scientific priorities will be generated by the 

SENTRNet Steering Committee and 

implemented by the other components. 

Informatics Center. Knowledge 

management is key to the usefulness of the 

data generated. The network will assess the 

market pulls and demands to determine what 

data is needed and to assess how, when, and 

why this information is best translated into 

improved practice. Internally, the data will 

be used to identify needs, track progress, 

motivate future directions, and improve 

delivery capacity. In addition, 

bioinformatics tools will be developed for 

promoting, accessing, and adopting 

evidence-based interventions. 

Pathology Center. The histopathologic 

designation of premalignant conditions of 

the stomach and esophagus is hampered by 

tremendous inter- and intra-individual 
Priorities of the Stomach/Esophageal Cancers Progress Review Group 19 

heterogeneity. Unfortunately, current 

standards of care depend upon pathologic 

interpretations (e.g., low- versus high-grade 

dysplasia). For this reason, a pathology 

center devoted to histopathologic 

standardization is essential. Tissues 

subjected to molecular and cellular inquiries 

will first be characterized with regard to 

histopathology so that accurate and reliable 

interpretations of molecular and cellular data 

can be offered. 

Clinical Research Centers. These centers, 

positioned throughout the United States, will 

serve as the essential links to persons at risk 

for and living with gastroesophageal 

cancers, as well as their families. A team of 

clinicians (e.g., gastroenterologists, GI 

surgeons, medical oncologists, psychologists, nurses or clinical research associates, 

data or protocol managers) will staff the 

centers. These sites will develop clinical 

protocols; recruit, enroll, and manage the 

cohorts involved; assure the development of 

institutional tissue repositories; and monitor 

the epidemiologic data collection to identify 

risk and protective factors for gastroesophageal cancers and define the stages at 

which they act during carcinogenesis. 

Analytic Center. The analytic center will 

assume responsibility for the development 

of management tools, such as electronic 

databases and on-line study forms. 

Additionally, they will interact with the 

clinical research centers to develop clinical 

and population studies/protocols, emphasizing standardization of methods and tools. 

In addition, the analytic center will serve as 

SENTRNet’s biostatistical unit, closely 

linked to bioinformatics, providing support 

in the development of studies and analyzing 

data as they emerge. 

Translational Laboratories. A primary 

focus of SENTRNet is to move science into 

practice, and this can best be achieved 

through human-oriented and model-oriented 

translational laboratories.

Human-oriented Translational Labs. These 

laboratories will focus on high-priority 

research involving human specimens, 

including both resected and pinch biopsy 

specimens. These units will develop 

standard protocols for the handling and 

transportation of human materials from the 

moment they are obtained until they are 

received by the laboratories or virtual tissue 

repositories. Specimens delivered to these 

laboratories will be subjected to a variety of 

technologic inquiries, including expression 

arrays, genetic and epigenetic assays, 

assessments of cellular apoptosis and 

proliferation, and proteomics. There are two 

goals: first, to identify key aspects of human 

neoplastic progression for development as 

markers of risk, response, and therapeutic 

targets; second, to evaluate these markers as 

surrogate endpoints in epidemiological 

studies of risk and protective factors as well 

as in clinical treatment-response investigations. The human-oriented translational 

labs will interact closely with established 

NCI programs, such as the EDRN, to 

identify synergies and avoid overlap. 

Model-oriented Translational Labs. These 

labs will improve gastroesophageal stem cell 

models; identify stem cell-specific 

promoters for use in animal models; and 

develop, appropriate, and maintain cell lines. 

In addition, they will develop and maintain 

optimal animal models of these diverse 

diseases, use available models to evaluate 

preventive and therapeutic agents, and 

standardize criteria in mouse histopathology 

related to premalignant and malignant 

lesions. Previously established effective and 

ineffective agents in humans will be backvalidated by the models to definitively 

define them as reasonable positive or 

negative predictors of human efficacy. 

Additionally, molecular and cellular 
20 Report of the Stomach/Esophageal Cancers Progress Review Group 

investigations will be carried out in these 

models to identify risk markers, therapeutic 

targets, and response markers that may be 

rapidly translated into similar aspects with 

humans. The model-oriented translational 

labs will interact closely with established 

NCI programs, such as the Mouse Models of 

Human Cancers, to identify synergies and 

avoid overlap. 

Virtual Tissue Repository. A number of 

the S/E PRG’s priorities rely on the 

collection of tissues and/or blood of serially 

acquired samples that can be linked to 

patient demographic and medical information. The data can be used to exploit 

genomics, proteomics, and translation of 

basic science findings into everyday patient 

care. Therefore, SENTRNet will employ a 

virtual tissue bank with centralized reading 

as opposed to a centralized storage facility. 

The bank will be an electronic virtual tissue 

repository where specimens are handled in a 

standardized fashion and cataloged in a 

centralized location, but specimens will be 

housed at the individual institutions under 

uniform storage conditions. Researchers 

participating in SENTRNet will have 

incentives to share these tissue resources. 

Tissue samples will be prioritized for use 

centrally for collaborative studies of highest 

impact. This component will establish 

linkages with other established tissue 

resources. The multi-institutional collection 

and access to tissues will facilitate new 

discovery and rapid translation into daily 

clinical care of these rare cancers. 

The management of SENTRNet is as 

important as its multidisciplinary, multiinstitutional structure in assuring its 

translational function. SENTRNet will 

utilize unique management strategies that 

build upon the current research consortia 

and cooperative groups, and SENTRNet will 

adopt advances from other disciplines to 

resolve many issues specific to 

gastroesophageal cancers and contemporary 

models of translational research. Research 

conducted will be along the continuum from 

basic to practice to population. 

Unique Management Strategy 

Concepts 

SENTRNet’s concept is different from 

current cooperative efforts in a number of 

ways. SENTRNet’s unique management 

strategy will help achieve the recommen0tions of the S/E PRG and overcome the 

challenges of current models. SENTRNet 

will be managed with a business model 

approach and a spirit of mutual dependence. 

A strategy for progressive growth and the 

utilization of technology will be integrated 

throughout the components. 

Business Model Approach Strategy. Since 

1955, NCI has established a number of 

multi-institutional collaborative cancer 

groups to conduct coordinated therapeutic 

trials. However, gaining institutional 

cooperation was challenging, even when 

governing boards had been established. In 

addition, although cooperative groups 

require detailed attention to complex 

budgets, complicated issues in personnel 

management, and multifarious structures of 

tasks and authority, the groups’ scientists, 

clinicians, and government project officers 

typically were not trained in business 

management strategies. A well-managed 

matrix organization simplifies and organizes 

the uses of information processing, highly 

specialized resources, staff, and equipment. 

The predicted future of limited budgets and 

high performance demands sets the stage for 

shared resources and better management of 

participating individuals, organizations, and 

assets. Cooperation can enhance the cost to 

benefit ratio; thus, partners will be required 

to cooperate with SENTRNet’s concept of 

the matrix organizational governing 

structure for shared resources and better 
Priorities of the Stomach/Esophageal Cancers Progress Review Group 21 

business management. Those electing to 

participate in SENTRNet will receive 

training in general managerial skills, data 

management, systems evaluation, resource 

allocation and utilization, strategic planning, 

assessment, and monitoring. Those trained 

will evidence an overall awareness of the 

interrelationship and interdependency of 

various financial, economic, and 

administrative considerations within a 

business environment. This training will be 

required of participating investigators. 

Mutual Dependence Strategy. SENTRNet 

will address operational challenges by 

encouraging a spirit of mutual dependence 

between partners. In the spirit of mutual 

dependence, collaborations and partnerships 

will be stressed, but each of the components 

will be funded and peer-reviewed separately. 

The concept of mutual dependence 

capitalizes on the strengths and needs of 

SENTRNet’s partners and creates incentives 

for collaboration. For example, by creating 

an interface through which laboratory 

specialists gain access to patients and human 

tissues, clinical researchers have direct 

access to laboratory expertise. Mutual 

dependence, as opposed to individual 

accomplishments, rewards those who share 

resources, encourages productivity, 

promotes resourcefulness, strengthens 

collaborations, and provides latitude for 

creative endeavors, especially for 

translational progress. 

Those who participate in SENTRNet’s 

matrix organizational structure must 

demonstrate effective business management 

of their site, sharing of resources, 

collaborative discoveries (according to 

foundational review criteria that will be 

developed and employed), and translational 

productivity. Decisions related to continued 

support will be based on these accomplishments and not mere membership. 

Performance matters and is more important 

than participation. Using this philosophy as 

a framework, SENTRNet might reward 

productive collaborative research with 

additional funding and easier access to 

needed resources. 

Mutual dependence strategy applied to the 

virtual tissue resource will prevent any 

single institution or individual from 

wielding undue influence over the use of 

tissue. By applying the mutual dependence 

strategy, the Steering Committee or its 

designee (i.e., the Repository Subcommittee) will be able to prioritize utilization 

of the tissue and types of studies, while the 

investigators develop and maintain the tissue 

resource. The group will place the highest 

priority on collaborative studies of the 

greatest potential impact; however, an 

individual also may utilize the tissue for 

scientific discoveries based on his/her own 

initiative. 

Managed Progressive Growth Strategy. 

The intended scope of SENTRNet’s 

operation is quite large; however, the group 

will start on a smaller scale and move to a 

larger effort to ensure that all participants 

are trained and ready to participate in the 

group’s organizational structure and 

knowledge management systems. Training 

will be continuous as management, 

technology, and scientific advances 

progress. Standardized protocols and 

procedures will be established across 

partnering sites to protect data quality; to 

produce quality analyses; and to facilitate 

the development, translation, application, 

and dissemination of scientific advances into 

quality care. Standardized protocols will aid 

in ensuring aggregation of data and 

maintaining a focus on SENTRNet’s 

collaborative intent during the managed 

growth process. 

Knowledge Management and Technology 

Advances Strategy. The goals of 

knowledge management are twofold: it 

provides a means to share information and it 
22 Report of the Stomach/Esophageal Cancers Progress Review Group 

establishes user-friendly resources to obtain 

essential information to enhance individual 

and collective productivity. Knowledge 

management entails the storing of electronic 

files that have been created, edited, and 

tailored to a particular need. Information 

technology infrastructures facilitate the 

distribution of knowledge specific to the 

organizational needs for which it was 

developed. The electronic management of 

information facilitates knowledge-based 

categorization of new and archived data. 

SENTRNet will develop and capitalize on 

the daily use of a tailored knowledge 

management system that will enhance 

communication capabilities of partners; 

facilitate information sharing; provide a 

mechanism for information transfer; and 

foster standardized data collection within the 

partnership. In addition, the SENTRNet 

system will develop and establish 

technology capable of linking databases 

from various sources in an effort to speed 

research and to aid in accomplishing the S/E 

PRG’s priorities. 

Therefore, an integrated organizational 

matrix infrastructure, combined with sound 

management, will support multi-institutional 

and multidisciplinary research. SENTRNet 

will facilitate progress toward achieving all 

10 of the S/E PRG recommendations. 

How SENTRNet Will Facilitate 

Progress Toward Achieving the PRG 

Recommendations 

Population Studies. The unique 

accessibility of stomach and esophageal 

premalignant conditions to endoscopic 

biopsy is a driving force for translational 

research on neoplasms of these organs. 

Current knowledge concerning the natural 

history of stomach/esophageal premalignant 

conditions, risk and protective factors that 

modulate progression to cancer, and 

biomarkers for risk stratification have 

typically been accumulated at single centers 

or in large studies evaluating only patients 

who have progressed to cancer. Although 

these studies have made significant 

advances, existing approaches contain 

critical gaps in the accumulation of 

knowledge necessary to translate the 

research advances into improved patient 

care and public health. 

SENTRNet provides a vehicle to translate 

research results more rapidly than existing 

mechanisms. The patient/research 

participant is the foundation of SENTRNet’s 

research approach, and all clinical, 

epidemiological, and laboratory data are 

directly linked to a specific endoscopy for a 

specific patient. These results can be more 

rapidly generalized than those of single 

centers because of the multi-institutional 

nature of SENTRNet. For instance: 

• The clinical research centers will include 

gastroenterologists, who are presently 

not well represented in the NCI research 

and prevention community. These 

specialists are critical because they can 

provide access to tissue from their 

patients at risk for and with stomach and 

esophageal cancers. This access is 

essential to delineate the natural history 

of neoplastic lesions, validate biomarkers 

for risk stratification, and understand the 

effects of environmental risk and 

protective factors on the premalignant 

epithelium. 

• SENTRNet’s epidemiology section 

within the analytic center will develop 

standardized procedures and 

questionnaires that can be applied 

uniformly to patients in the clinical 

research centers at the time of 

endoscopy. 

• Tissue obtained by endoscopic biopsy 

can be evaluated by the Translational 

Laboratory to validate markers for 
Priorities of the Stomach/Esophageal Cancers Progress Review Group 23 

clinical risk stratification and provide 

surrogate endpoints to determine the 

mechanisms by which risk and protective 

factors modulate progression to cancer. 

• These data can be related to the 

pathology center, minimizing the 

confusion caused by significant intraand interobserver variations in dysplasia 

diagnosis and grading in single-center 

studies. 

• Database components of SENTRNet can 

be linked with existing databases, such as 

SEER, the gastrointestinal databases of 

existing cooperative cancer groups, the 

National Coalition of Cancer Survivorship, and the NIDDK database. The 

aggregated information may fill gaps in 

the information that any one database can 

provide. The technology developed for 

linking these databases also can be used 

for the network’s communication and 

bioinformatics efforts. 

Thus, SENTRNet can provide a clinical, 

epidemiologic, laboratory, pathology, and 

analytic research infrastructure. Those 

working within the infrastructure will be 

better able to estimate the prevalence of 

significant risk factors, to determine 

efficiently the natural history of 

premalignant disease states, and to 

determine the mechanisms by which risk 

and protective factors modulate progression 

as a prelude to prevention studies. In 

addition, they will validate markers that 

identify patients at high risk for progression 

to cancer, and establish or merge databases 

for hypothesis generation and disease 

modeling. SENTRNet’s contributions to 

population studies will facilitate the 

accomplishment of other S/E PRG priorities, 

including prevention, patient/provider 

education, markers and molecular profiling, 

outcomes, and host/environmental 

interactions. 

Prevention. SENTRNet’s research platform 

provides a vehicle for rapidly translating 

hypotheses on risk and preventive factors 

generated from preclinical and 

epidemiologic studies (such as those that 

will be done within the model-oriented 

translational labs and the analytic center) 

into efficient prevention trials in the clinical 

research centers. The development of those 

trials will be facilitated by other components 

of SENTRNet in several ways. Advances in 

the understanding of the prevalence and 

natural history of neoplasia (derived from 

epidemiologic research within SENTRNet) 

can provide solid data for power/sample size 

calculations of clinical trials, thereby 

improving their efficiency. For example: 

• Validated risk markers can improve risk 

estimates, thereby allowing intervention 

trials targeted more specifically toward 

persons most likely to benefit from them. 

• Tissue-based surrogate endpoints can be 

derived from an understanding of the 

mechanisms by which the risk and protective factors modulate carcinogenesis. 

• Translational Laboratories that have 

gained experience in population studies 

can provide high-throughput data for 

tissue-based inclusion/exclusion criteria 

and surrogate endpoints in prevention 

trials. 

• The pathology center can provide 

standardized interpretations to minimize 

the confounding influence of observer 

variation in dysplasia diagnosis. 

• The analytic center can provide data 

analysis. 

As new information is gained, prevention 

strategies can be refined to improve cost 

effectiveness. Thus, data obtained by 

SENTRNet population studies (such as 

information on the mechanisms by which 

NSAIDs and a diet high in fruits and 
24 Report of the Stomach/Esophageal Cancers Progress Review Group 

vegetables are protective against 

gastroesophageal cancers) can fuel 

randomized clinical trials to develop 

effective prevention strategies for these 

cancers. Similarly, SENTRNet population 

studies that lead to a better understanding of 

the mechanisms by which risk factors (such 

as gastroesophageal reflux, obesity, and H. 

pylori) promote esophageal and gastric 

adenocarcinomas can be translated 

efficiently into prevention trials. 

SENTRNet’s research platform provides a 

vehicle for prevention studies to synergize 

with other S/E PRG priorities, including 

patient provider education, therapy and 

therapeutic targets, markers and molecular 

profiling, outcomes, host/environmental 

interactions, and preclinical models. 

Patient/Provider Education. Previously, 

critical knowledge concerning at-risk 

symptoms, risk stratification, clinical trials, 

and outcomes has been scattered among a 

number of centers across the United States, 

with inadequate compilation and 

standardization of data and knowledge in a 

central resource. 

SENTRNet, through its centralized review, 

compilation, and updating of relevant 

information on at-risk subsets, risk 

stratification, clinical trials, and patientoriented measures, can provide a unique 

resource for research into the informational 

needs of patients with and at risk for cancer. 

Once those needs are better defined, 

SENTRNet can serve as a platform for the 

dissemination to the public of knowledge 

concerning gastroesophageal cancers. More 

specifically, SENTRNet can partner with 

NCI’s Physician Data Query, AHRQ, and 

the Centers for Disease Control and 

Prevention—in collaboration with 

representative professional organizations, 

advocacy groups, and private cancer 

foundations—to develop a central, standard 

resource of disease-specific knowledge and 

insights. That resource then can serve as a 

common information platform available for 

broad dissemination to health care providers, 

advocates, and patients via informatics links 

to each partner’s existing Web sites, as well 

as by other methods of communication. 

Therapy and Therapeutic Targets. 

SENTRNet can provide an integrated, 

comprehensive tissue-based approach to 

clinical trials that is beyond the capacity of 

any single cancer center. SENTRNet’s 

gastroenterologists can obtain endoscopic 

biopsies before and after treatment. This 

collection provides a valuable tissue 

repository to be used by SENTRNet 

molecular biologists and epidemiologists in 

an effort to investigate host and tumor 

characteristics predictive of positive and 

negative responses to existing and novel 

therapies. Furthermore, comprehensive 

genomic expression array and proteomic 

analyses of these tissues can identify novel 

therapeutic targets that can be investigated 

in SENTRNet tumor models and used to 

identify promising new interventions. The 

interventions then can be tested in clinical 

trials in an effort to improve the efficacy and 

safety of available therapeutic options. 

Ultimately, SENTRNet will evaluate 

contributions of different treatment 

modalities for esophageal and gastric 

cancers as well as the proper integration and 

sequencing for optimal treatment outcomes. 

Some therapeutic targets and treatment 

modalities are on the verge of breakthroughs, and they can be accelerated in 

clinical trials organized by SENTRNet. For 

example, exciting new agents that 

selectively modulate the behavior of cancer 

cells (i.e., cytostatic anti-cancer drugs) 

promise to be less toxic and more effective 

than current drugs. The effectiveness of 

these agents, particularly in early phases of 

drug development, can best be demonstrated 

by evaluating key biologic parameters 

before and after treatment in gastro-
Priorities of the Stomach/Esophageal Cancers Progress Review Group 25 

esophageal tissues. In addition, the 

effectiveness of traditional interventions is 

less than optimal, but additional research on 

patients and their tumors before and after 

intervention may better explain the 

mechanisms underlying response and 

resistance, thereby providing insights to 

guide the development of new, more 

effective combinations. 

Thus, SENTRNet provides a translational 

research model from the laboratory to 

standard practice. First, SENTRNet will 

determine which patients and tumors are 

most likely to respond to existing therapies. 

Second, SENTRNet will develop novel 

therapeutic approaches based on the 

molecular pathways of gastroesophageal 

carcinogenesis (interacting with established 

NCI programs such as the Chemoprevention 

Agent Development Program and the Drug 

Therapeutics Program). Finally, SENTRNet 

will evaluate the most effective therapies in 

clinical trials and move them efficiently into 

standard practice. 

Markers and Molecular Profiling. 

SENTRNet will have an unparalleled 

repository of normal, premalignant, 

pretreatment malignant, and posttreatment 

malignant tissues that can be used for 

molecular marker development ranging from 

exploratory preclinical investigations to 

marker validation to risk stratification and 

treatment response studies. Many of these 

activities may create synergy with existing 

NCI initiatives and services, including the 

Specimen Resource Locator, Tissue 

Expediter, and the EDRN. This partnership 

platform will allow laboratory experts on 

stomach and esophageal carcinogenesis in 

one institution to collaborate with other 

clinical and population-based research at 

other institutions. These collaborations can 

support other S/E PRG priorities, including 

population studies, prevention, therapy and 

therapeutic targets, host-environmental 

interactions, and preclinical models. By 

providing characterization of tissues at 

multiple stages of carcinogenesis, including 

its treatment, SENTRNet may create 

synergy with the Cancer Genome Anatomy 

Project. 

Outcomes. SENTRNet’s multi-institutional, 

multidisciplinary team can facilitate a rich 

understanding of how people use health 

information and access communication 

technologies of all kinds. SENTRNet can 

evaluate clinical and outcomes data related 

to symptoms, quality of life (QoL), and 

quality of care (QOC) in people with gastric 

and esophageal cancers and in those at risk 

for these conditions. Cross-sectional studies 

using existing databases can then provide a 

more formal assessment. SENTRNet can 

utilize and adapt current esophageal and 

gastric-specific QoL and QOC instruments 

to measure disease stage and treatmentrelated outcomes. SENTRNet’s 

infrastructure may best address the 

following: 

• Many patients with stomach and 

esophageal cancers present at a late stage 

that reduces their chance of survival, 

leaves little opportunity for non-surgical 

interventions, fosters surgical treatment 

that renders potential disabilities, and 

increases their likelihood of comorbidity. SENTRNet’s research 

initiatives can address important 

questions related to communication of 

health messages, treatment decisions, 

QOC, long-term follow-up, and QoL. 

• The number of cancer survivors is 

expected to increase as more people 

undergo cancer screening, as screening 

technologies improve, and as new 

therapies are introduced. While some of 

these cancer survivors are cured of their 

original malignancies, they may have 

health-limiting impacts and related side 

effects that remain poorly documented or 

understood. In addition, many of these 
26 Report of the Stomach/Esophageal Cancers Progress Review Group 

individuals may be at risk for the 

development of new tumors. The length 

of time projected for survival and the risk 

of co-morbid conditions often exert an 

impact on both cancer treatment and 

posttreatment follow-up care. Thus, there 

is a need for more research on the 

identification, prevention, treatment, 

post-therapeutic surveillance, and care of 

the broad spectrum of conditions 

experienced by survivors of stomach and 

esophageal cancers. 

• Evidence suggests that some patients 

with cancer do not receive newer, more 

effective treatments. Moreover, in some 

cases, there remains substantial 

disagreement or uncertainty about what 

constitutes optimal care, especially from 

the patient’s perspective. Clearly, too 

many patients face significant financial 

difficulties and other barriers to 

obtaining appropriate and timely care. As 

society wrestles with how to make health 

care more accessible to more people, it is 

critically important to advance a 

comprehensive research agenda that 

includes finding ways to improve 

outcomes and the quality of the cancer 

care. Additionally, a greater understanding of the factors that impede 

access, regardless of race/ethnicity, 

income and geographic location, is 

needed. Stomach and esophageal cancers 

provide an opportunity for such studies. 

Host/Environment Interactions. Early 

efforts to discover how genes and 

environmental factors interact to cause 

cancer are showing promise, but they also 

highlight the complexity of the puzzle. 

SENTRNet’s research in this area can 

uncover elements of gene-environment 

interactions that lead to improvements in 

preventing and controlling stomach and 

esophageal cancers. SENTRNet’s research 

platform will accelerate discovery and 

translation because all necessary elements 

are involved. For example, endoscopic 

biopsies with standardized pathology 

interpretations from patients with known 

environmental exposures can be evaluated 

by comprehensive genomic, expression 

array, and proteomic methods. These 

complex tissue-based data then can be 

analyzed in the analytic center, and the 

resulting hypotheses can be clinically tested. 

These studies might define strategies either 

to avoid or reduce adverse exposures, to 

identify genetic susceptibility far in advance 

of clinical disease, to identify appropriate 

treatment regimes, and to take special 

precautions for people at high risk. 

SENTRNet’s research infrastructure 

provides a means to create synergy between 

host/environmental interaction research 

advances and other S/E PRG priorities, 

including population studies, prevention, 

patient/provider education, therapy and 

therapeutic targets, markers and molecular 

profiling, and preclinical models. 

Technologies for Screening/Surveillance. 

Although endoscopic visualization and 

biopsy offer the potential for early detection, 

existing methods are not cost effective. 

Advances in imaging technology and 

molecular biopsy characterization have the 

potential to improve risk stratification, and 

the development of serum assays can make 

population-based screening possible. 

However, such advances have typically been 

suggested in single-center studies without 

rapid translation into more definitive, multicenter investigations that would be 

necessary to define the risks and benefits of 

these technologies. Current funding 

mechanisms through NCI or NIDDK do not 

match the developmental potential of these 

new technologies, nor do they provide for 

adequate comparisons between novel and 

existing approaches that have a direct impact 

on patient care and the public’s health. 

SENTRNet will dramatically improve the 

rapid translation of research observations 
Priorities of the Stomach/Esophageal Cancers Progress Review Group 27 

into clinical and public health interventions. 

Collaborations among SENTRNet’s clinical 

research centers, translation laboratories, 

pathology center, and analytic center can 

collectively offer what is not possible now. 

The collaborations can develop a menu of 

markers for stomach and esophageal cancers 

and their precursor states. They can conduct 

multicenter, multidisciplinary studies for 

validation of existing and novel biomarkers. 

Finally, they can provide specified standards 

of performance for tissue and blood 

collections, quality control, database 

tracking, prioritization, and specimen 

distribution. 

SENTRNet clinical research centers also can 

develop, compare, and validate novel 

imaging techniques, including ultrathin 

endoscopes, colorimetric devices, optical 

detection of dysplasia, autofluorescence, 

Raman spectroscopy, light-scattering 

spectroscopy, and synchronous 

luminescence. These devices can have a 

profound impact on identifying the true 

incidence of both esophageal and gastric 

cancers by identifying patients at risk for the 

disease and interrupting such conditions as 

the “dysplasia-carcinoma” sequence far in 

advance of cancer. As serum markers 

become available, SENTRNet’s virtual 

tissue and serum repository will provide the 

best means available to rapidly validate and 

compare them to imaging and tissue-based 

markers in phase III studies. SENTRNet’s 

components will allow for the rapid 

comparison of endoscopic, imaging, and 

molecular risk stratification for translation to 

improved patient care in phase IV studies. 

SENTRNet is the only potentially available 

vehicle by which imaging and molecular 

screening and surveillance can be evaluated 

in definitive biomarker studies to demonstrate reduction in mortality in patients who 

have stomach and esophageal cancers. 

Preclinical Models. Valid preclinical 

models of gastroesophageal carcinogenesis 

can facilitate the achievement of many S/E 

PRG priorities. However, esophageal and 

gastric tumor models face many challenges, 

which have been discussed previously. In 

spite of these challenges, there have been 

limited successes in animal models. These 

include transgenic and knockout mice with 

alterations in APC, SMAD-4, TFF-1, TGFbeta 1, RUNX3, CDX 2 cyclin D1 and 

EGFR, as well as animal models of H. pylori 

infection, Barrett’s esophagus, and 

esophageal adenocarcinoma, and primary 

cell cultures of Barrett’s esophagus. 

SENTRNet can work with NCI’s Mouse 

Models of Human Cancer Consortium to 

create robust mouse models, using hybrid 

techniques (genetic approaches, surgery, H. 

pylori infection) to define underlying 

molecular mechanisms of esophageal or 

gastric carcinogenesis, as well as to allow 

for preclinical evaluation of novel 

chemoprevention and therapeutic agents. 

Additionally, SENTRNet can develop and 

characterize primary cells, immortalized 

cells, transformed cells, organ cultures, and 

organotypic cultures for studying stem-cell 

biology, intestinal metaplasia, and cancer in 

esophagus and stomach, as well as develop 

immunocompetent rodent models of 

advanced disease. SENTRNet also can 

define the genetic factors that regulate 

epithelial cell responses to injury that lead to 

esophageal and gastric cancers, but which 

are difficult to study directly in humans. 

Conclusion 

The S/E PRG has identified 10 recommendations essential to making progress in 

understanding and treating stomach and 

esophageal cancers. The best approach to 

achieve those recommendations is through a 

multi-institutional and multidisciplinary 

group employing unique strategies to 

enhance effectiveness, collaboration, and 

quality in a translational research enterprise 
28 Report of the Stomach/Esophageal Cancers Progress Review Group 

that fluidly moves advances between the lab, 

the clinic, and the population. SENTRNet is 

necessary to advance the scientific priorities 

of the S/E PRG. 

References 

1

Ferlay J, Bray F, Pisani P, Parkin DM. 

GLOBOCAN 2000: Cancer incidence, 

mortality, and prevalence worldwide; ed 

Version 1.0, International Agency for 

Research on Cancer Press, 2001, vol 2002. 

2

Jemal A, Thomas A, Murray T, Thun M. 

Cancer statistics, 2002. CA Cancer J Clin 

2002; 52:23–47. 

3

Ries LAG, Eisner MP, Kosary CL, Hankey 

BF, Miller BA, Clegg L, Edwards BK. 

SEER Cancer Statistics Review, 1973–1999. 

Bethesda, MD: National Cancer Institute, 

2002. 
Appendix A 

About the National Cancer Institute’s 

Progress Review Groups 

Appendix A: About the National Cancer Institute’s Progress Review Groups 29

Appendix A: About the National Cancer Institute=s Progress Review 

Groups 

The National Cancer Institute (NCI) 

supports basic, clinical, and 

population-based research to elucidate the 

biology, etiology, early detection, 

prevention, and treatment of cancers of 

various organ sites. These research efforts 

have produced a substantial base of 

knowledge that, while providing a wealth of 

new scientific opportunities that can further 

advance our knowledge and progress against 

these diseases, also requires that the Institute 

determine the best uses for its resources. 

To help ensure the wise use of resources, 

NCI has established Progress Review 

Groups (PRGs) to assist in assessing the 

state of knowledge, reviewing the Institute=s 

research portfolio, and identifying scientific 

priorities and needs for its large, 

site-specific research programs. 

CHARGE TO THE PRGS

Each PRG is charged to:

• Identify and prioritize scientific research 

opportunities and needs to advance 

medical progress against the cancer(s) 

under review. 

• Define the scientific resources needed to 

address these opportunities and needs. 

• Compare and contrast these priorities 

with the current NCI research portfolio. 

• Prepare a written report that describes 

findings and recommendations. 

• Discuss a plan of action with NCI 

leaders to ensure that the priority areas 

are addressed. 

The following section details the process 

used to execute these charges. 

THE PRG PROCESS

PRG members are selected from among 

prominent members of the scientific, 

medical, and advocacy communities and 

from industry to represent the full spectrum 

of scientific expertise required to make 

comprehensive recommendations for the 

NCI’s cancer research agenda. The 

membership is also selected for its ability to 

take a broad view in identifying and 

prioritizing scientific needs and opportunities that are critical to advancing the 

field of cancer research. 

The leadership of each PRG finalizes an 

agenda and process for a PRG Planning 

Meeting. At the Planning Meeting, 

participants are identified to take part in a 

subsequent Roundtable meeting. Topics are 

identified for Roundtable breakout sessions 

to which participants will be assigned and 

for which the PRG members will serve as 

co-chairs. 

A PRG Roundtable brings together in an 

open forum approximately 100B180 leading 

members of the relevant cancer research, 

medical, industry, and advocacy 

communities to formulate key scientific 

questions and priorities for the next 5B10 

years of research on specific cancers. As 

part of the process, the NCI provides the 

PRG Roundtable with an analysis of its 

portfolio of cancer research in the relevant 

organ site. This analysis is intended to 

enable the Roundtable to compare and 

contrast identified scientific priorities with 

the research currently being done under the 

Institute=s auspices. Input from the Roundtable is used by the PRG in delineating and 

prioritizing recommendations for research, 

related scientific questions, and resource and 

infrastructure needs. At its discretion, the 
30 Report of the Stomach/Esophageal Cancers Progress Review Group

PRG may solicit additional input from the 

research and advocacy communities through 

workshops, ad hoc groups, or by other 

means. The PRG also may consider the 

deliberations of previously convened expert 

groups that have provided relevant cancer 

research information. 

THE PRG REPORT

After the Roundtable, the PRG=s 

recommendations are documented in a draft 

report, multiple iterations of which are 

reviewed by the PRG leadership and PRG 

members. The final draft report is then 

submitted for deliberation and acceptance by 

the NCI Advisory Committee to the 

Director. After the report is accepted, the 

PRG meets with the NCI Director to discuss 

the Institute=s response to the report, which 

is widely disseminated and integrated into 

the Institute=s planning activities. At this 

meeting, the PRG and NCI identify the 

research priorities that ongoing NCI 

initiatives and projects do not address. Then 

the PRG and NCI discuss a plan for 

implementing the highest research priorities 

of the PRG. This plan becomes a blueprint 

for tracking and hastening progress against 

the relevant cancer. 

PRG reports on breast cancer; prostate 

cancer; colorectal cancer; pancreatic cancer; 

lung cancer; brain tumors; leukemia, 

lymphoma, and myeloma; gynecologic 

cancers; and kidney/bladder cancers, in 

addition to this PRG report on stomach/ 

esophageal cancers are available online at 

http://planning.cancer.gov. 
Appendix B 

Breakout Reports 

Appendix B: Breakout Reports 31

Guiding Principles 

Biology 

Co-Chairs: Correa, Pelayo and Orlando, Roy C.; Peek, Richard

Participants: 

Coit, Daniel 

Dawsey, Sandy 

Karpeh, Martin 

Rothman, William 

Souza, Rhonda 

Stoner, Gary 

Wojcik, Brian 

Overview/Background 

Information/Barriers 

The biology of squamous and columnar 

epithelia is of critical importance in 

understanding their transition to stomach 

and esophageal cancers. The carcinogenic 

process is driven by three main influences: 

(1) an injurious chemical or infectious agent; 

(2) host factors that modulate the response 

to the injurious agent(s), such as immune 

responses (IL-1 beta), protective molecules 

(MUC-1), and adhesion molecules (Ecadherin); and (3) environmental factors that 

determine the host response to the 

carcinogenic agents. The carcinogenic 

process appears to be closely related to 

chronic active inflammation, which may 

lead to a neoplastic or a nonneoplastic 

outcome. 

Gastroesophageal carcinogenesis consists of 

a series of events that can be viewed as 

those that initiate and subsequently mediate 

genetic changes within epithelial cell DNA. 

These genetic changes then provide a 

survival advantage for affected cells, 

resulting in malignancy. An underlying 

theme that unifies stomach and esophageal 

cancers is that both develop in response to 

chronic inflammation or injury. Another 

common theme, exclusive of initiating 

factors that may not always be identifiable, 

is that the mediation of disease progression 

may be via inflammation-induced DNA 

damage, due to the production of superoxide 

radicals and other products of oxidation. 

Described below are some of the molecular 

and cellular changes triggered by infection 

with the bacterium H. pylori. These will be 

used as a model to explore other pathways 

of carcinogenesis in the esophagus and 

stomach that occur within the context of 

inflammatory states. The example of H. 

pylori infection provides a paradigm of a 

known initiator that, through induction of an 

inflammatory response, leads to neoplastic 

transformation. 

Gastric adenocarcinoma is the second 

leading cause of cancer mortality 

worldwide. Infection with H. pylori

significantly increases the risk of the two 

predominant histologic subtypes of gastric 

adenocarcinoma. The more common type is 

intestinal-type gastric cancer. The other 

form is diffuse gastric cancer, which 

originates within a background of superficial 

gastritis and may occur spontaneously 

without well-defined glandular structures. 

Intestinal-type gastric cancer progresses 

through well-defined histologic steps, 

including atrophic gastritis, intestinal 

metaplasia and dysplasia, which are 

followed by frank adenocarcinoma. The first 

stage is the transition from normal mucosa 

to chronic superficial gastritis. 

The relationship between H. pylori infection 

and gastric cancers stems from interactions 

between the bacterium and the host. Some of 

the genetic components of H. pylori that 

increase the risk of cancer include the cag

pathogenicity island and the vacuolating 
32 Report of the Stomach/Esophageal Cancers Progress Review Group

cytotoxinVacA, the effects of which are less 

well understood. Components of the cag

pathogenicity island induce (1) increased 

release of the proinflammatory cytokine IL8, and (2) profound morphologic 

derangements of gastric epithelial cells 

following bacterial attachment. The 

molecular pathways that underlie these 

events are (1) activation of NF kappa B and 

MAP kinase signaling; and (2) translocation 

of the CagA protein into the host cell, which 

induces the morphologic derangements of 

the cells themselves. The latter phenotype 

mirrors mitogenic stimulation with growth 

factors. More virulent strains of H. pylori

(e.g., cag-positive strains) may increase the 

risk of cancer by inducing a more intense 

inflammatory response and by mimicking 

the effects of growth factor stimulation. 

Host polymorphisms within immuneresponse genes, including IL-1-beta and 

TNF-alpha, also influence disease risk. 

Specifically, the IL-1 gene cluster contains 

several informative polymorphisms that can 

be correlated with either increased or 

decreased IL-1-beta production. Studies 

have shown that persons who possess 

polymorphisms associated with high levels 

of IL-1-beta production have an increased 

risk of atrophic gastritis and gastric cancer, 

but these relationships only hold sway in H. 

pylori-infected persons. Therefore, a 

synergism exists between H. pylori infection 

and host genotype. A consequence of longterm H. pylori infection is the development 

of hypochlorhydria, which allows the 

overgrowth of non-H. pylori pH-sensitive 

bacteria, conversion of ingested nitrites to 

N-nitrosamines, and an increased risk of 

gastric cancer. 

Chronic H. pylori infection also leads to 

hypergastrinemia, which can stimulate 

epithelial cell growth. Thus, multiple factors 

contribute to the survival of the mutagenic 

cell in an environment of genetic instability: 

hyperproliferation in the presence of 

inflammation, and production of oxygenfree radicals that induce DNA damage over 

time. Animal models may mimic aspects of 

the process that occur in humans. For 

example, after H. pylori-induced 

inflammation, intestinal metaplasia may 

result from overexpression of Cox-2 (in 

mice), which hastens the progression from 

atrophic gastritis to intestinal metaplasia. 

Other mediators of intestinal-type gastric 

cancer include exogenous causes of 

hypochlorhydria and hypergastrinemia, such 

as vagotomy and acid-suppression therapy. 

The paradigm for H. pylori-induced 

inflammation in the stomach can also be 

applied, in principle, to esophageal 

squamous cancer and adenocarcinoma, 

although the initiating factors are distinctly 

different. The initiators of squamous cancer 

include achalasia, which results in stasis of 

ingested food; infection with human 

papillomavirus (HPV); and environmental 

factors such as high alcohol intake, smoking, 

and lye ingestion. Genetic risk factors also 

play a role in squamous carcinoma, 

including the inherited disorder, tylosis, 

which results in squamous cell 

hyperproliferation. The initiation of 

esophageal adenocarcinoma is primarily 

through reflux esophagitis-induced Barrett’s 

metaplasia. 

Strategies for cancer protection include 

removal of the initiating events (where 

identified) and/or inhibition of one or more 

of the inflammatory mediators, such as Cox2, IL-1, and/or NF kappa B activation. 

However, these relationships are complex, 

because while infection with H. pylori

increases the risk of distal gastric cancer, it 

may protect against the development of 

esophageal adenocarcinoma. This 

complexity underscores the importance of 

precisely identifying the mechanisms 

through which inflammation can induce the 

carcinogenic cascade. 
Appendix B: Breakout Reports 33

Future Research Directions 

Future research in stomach and esophageal 

cancers should include the following: 

• Identification and appropriate eradication 

(where possible) of initiating factors. 

• Identification of novel means to suppress 

the inflammatory response. For example, 

inhibition of NF kappa B activation may 

be an important strategy for cancer 

prevention, either by disrupting the 

inflammatory process or normalizing 

imbalances in cell-cycle dynamics. 

• Suppression of the hyperproliferative 

response, irrespective of its initiating and 

mediating events. 

• Identification of additional strain-specific 

H. pylori virulence determinants, which 

may in turn identify persons at increased 

risk for gastric cancer. 

• Identification of specific bacterial 

strains in conjunction with a particular 

host background to allow focused 

therapeutic interventions, rather than 

indiscriminately treating all persons who 

are colonized with H. pylori, because in 

some persons the bacterium may protect 

against the development of esophageal 

adenocarcinoma. 

• Identification of biomarkers in Barrett’s 

metaplasia to serve as predictors of 

cancer risk. 

• Characterization of the biology of 

Barrett’s metaplasia as it relates to its 

origination and protection against refluxinduced esophageal injury. 

• Establishment of animal models to study 

the pathogenetic pathways for both 

squamous and adenocarcinoma of the 

esophagus. 

Three Scientific Priorities and 

Rationales 

Priority 1: Define the genetic bacterial and 

host factors that regulate epithelial cell 

responses to injury that lead to esophageal 

and gastric cancer. 

Rationale: It is essential to understand the 

underlying genetic factors and molecular 

mechanisms that regulate progression to 

cancer, because only a minority of patients 

with identifiable risk factors progress to 

develop esophageal or gastric cancers. For 

gastric carcinoma, H. pylori genotypes that 

may augment the risk of neoplastic 

transformation need to be identified. This 

will help identify specific patient cohorts for 

screening and treatment in the future. 

Priority 2: Define the environmental and 

host factors that regulate inflammatory 

responses to epithelial cell injury in 

esophageal and gastric mucosa that lead to 

cancer. 

Rationale: There is increasing recognition 

that inflammatory responses play a central 

role in progression to cancer. In addition, 

targeting inflammation may be an effective 

method of preventing the development of 

malignancy. 

Priority 3: Develop more relevant animal 

model systems for understanding upper GI 

carcinogenesis, including squamous and 

adenocarcinomas of the esophagus and 

stomach. 

Rationale: Animal models are essential to 

understanding the development of gastric 

and esophageal cancers and identifying hostfactor interactions that increase disease risk. 

Studies of these models are a key step in the 

process of translating basic research into 

more effective methods for screening and 

treatment. 
34 Report of the Stomach/Esophageal Cancers Progress Review Group

Infrastructure Needed To 

Accomplish Priorities 

Partnership Platforms 

Gastric and esophageal cancers are a global 

problem and account for a high proportion 

of cancer deaths worldwide. International 

collaborations in high-prevalence 

populations will facilitate a more efficient 

and more complete understanding of the 

disease and the development of more 

effective interventions and treatments. 

Partnership platforms for these studies 

include investigations of all age groups, 

including children (NICHD), immunologic 

studies (NIAID), and collaborative studies 

of basic biology, specimen collection, and 

development of screening and prevention 

(NIDDK). Specific recommended initiatives 

include: 

• Multi-institutional funding initiatives 

• Dual-investigator RO1’s 

• Development of SPORES—the 

establishment of tissue banks and cell 

lines that are available to all 

investigators. 

Expected Resources To Overcome 

Limitations of Previous Research and To 

Capitalize on Existing Opportunities 

• Development of gerbil and other animal 

models 

– Establish cell lines that represent 

normal cells as well as all stages of 

cancer progression 

– Develop specific reagents, such as 

antibodies, to be employed in gerbil 

studies 

– Establish H. pylori strain repositories 

– Establish tissue-specimen banks, 

including blood banks, to identify 

genetic factors, having as a goal the 

development of a nationwide tissue 

bank. 
Appendix B: Breakout Reports 35 

Etiology 

Co-Chairs: Blaser, Martin S. and Vaughan, Thomas; Nyren, Olof

Participants: 

Bernstein, Leslie 

Chow, Wong-Ho 

Daschner, Phillip 

Fox, James 

Gammon, Marilie D. 

Mayne, Susan 

Tell, Robert 

Ward, Mary H. 

Weston, Allan 

Overview/Background 

Information/Barriers 

Non-cardia gastric adenocarcinoma, 

esophageal adenocarcinoma, and esophageal 

squamous cell carcinoma are each a distinct 

entity with its own uniquely identified 

causes. Although they share a superficial 

anatomical relationship, each is distributed 

in different populations in differing 

amounts. 

 

Gastric cancer remains the second most 

common cancer worldwide, although a 

decline over the past 30–40 years has 

decreased the age-specific incidence of this 

cancer in most western countries by 50%. 

Due to the aging of the world’s population, 

and a steep gradient in occurrence among 

the elderly, the actual numbers of victims 

are increasing. Efforts to improve treatment 

have had only limited success, and the agespecific decrease is likely attributable to 

decreased exposure to causal factors. Most 

prominent among these is infection by H. 

pylori, now identified as the strongest and 

most important risk factor. 

Squamous cell carcinomas comprise the 

majority of esophageal cancers in the world, 

with the majority of cases occurring in 

developing countries. Areas of China, 

central Asia, and southern Africa have 

extremely high mortality, but with large 

variations in occurrence over short 

distances. In the U.S., the occurrence of 

squamous cell carcinoma is low by 

comparison and has changed little in recent 

years. Many studies, but not all, have shown 

a correlation between the prevalence of 

esophagitis and esophageal squamous cell 

carcinomas, but the importance of 

esophagitis remains poorly defined. 

The increased incidence of adenocarcinoma 

has been recognized since the mid-1980s. 

Gastroesophageal reflux is identified as a 

key risk factor: people with weekly reflux 

symptoms demonstrate a 5- to 8-fold higher 

risk of developing this cancer. Even more 

striking is that persons with Barrett’s 

esophagus, estimated to develop in 10–15% 

of people with chronic reflux, are recognized as having at least 30–40 times the 

incidence as in the general population. 

In considering major secular factors in 

cancer etiology and distribution, the 

following relationships are of interest: 

• Fruits and vegetables (anti-oxidants) are 

protective in all three types of cancers. In 

the stomach, nearly 85% of studies have 

revealed a decreased risk of gastric 

cancer with a high intake of raw 

vegetables, and the evidence is similarly 

strong for the beneficial effects of citrus 

fruit. The preventive effect of fruit and 

vegetable intake is also strong in 

esophageal cancer. A strongly reduced 

risk of squamous cell carcinoma has been 

reported along with intake of vegetables, 

fresh fruits, and vitamin C. Although the 

data are less plentiful, studies have also 
36 Report of the Stomach/Esophageal Cancers Progress Review Group

identified an inverse relationship 

between fruit and vegetable consumption 

and esophageal adenocarcinoma. 

• A review of literature through the early 

1990s revealed no substantial effect of 

alcohol consumption on the risk of 

stomach cancers. By contrast, alcohol 

consumption has been identified as a 

major cause of squamous cell carcinoma. 

That cancer is more frequent in people 

who drink alcoholic beverages, with the 

risk depending more on mean daily 

intake than on the length of the habit. 

The risk of esophageal cancer returns to 

the level for abstainers only after 10 

years without drinking alcohol. Alcohol 

consumption has no significant effect on 

the risk of adenocarcinoma. 

• Smoking tobacco contributes to the risk 

of these cancers, with a 1.5–2.5-fold 

increase in the risk of stomach cancer 

among current smokers. Several studies 

have shown increasing risk with longer 

and heavier tobacco use. For squamous 

cell carcinoma, tobacco use is one of the 

major causative factors. The life-time 

duration of cigarette smoking is a 

significant variable. For adenocarcinoma, smoking increases the risk 

that remains at its increased level until 

more than 20 years after smoking 

cessation. 

• All three cancers are more common in 

men than in women. 

• Low socioeconomic status correlates 

with increased frequency of all three 

cancers. The strength of this effect is 

strongest for squamous and weakest for 

adenocarcinoma. 

• All three cancers are rare before the age 

of 50. Their incidence then rises with age 

but never reaches a plateau. 

• In the U.S., gastric cancer is more 

common in non-whites than in whites. 

Squamous cell carcinoma occurs 6 times 

more frequently in blacks than in whites; 

adenocarcinoma occurs 5 times more 

frequently in whites than in blacks. 

• The incidence of gastric and squamous 

cell carcinoma co-vary, while adenocarcinoma is often reciprocal in its 

occurrence. 

A summary of many of these secular factors 

in cancer etiology appears in Table 1. 
Appendix B: Breakout Reports 37

Table: Etiology-1 

 Direction and Magnitude of the Association 

Risk/protective factor Gastric (a) Squamous Adeno (a) 

Fruits/vegetables ↓↓ ↓↓ ↓↓

Alcohol (b) -- ↑↑↑ -- 

Smoking ↑ ↑↑↑ ↑↑

Male sex (c) ↑ ↑↑ ↑↑↑

Low Socioeconomic Status ↑↑↑ ↑↑↑ ↑

Age (d) ↑↑↑ ↑↑↑ ↑↑↑

Ethnicity (e) 

 Black ↑↑ ↑↑↑ ↓↓↓

 Hispanic ↑↑ -- -- 

 Asian ↑↑↑ ↑↑ ↓↓↓

 Native American ↑↑ Unknown Unknown 

(a) Excludes cardia. 

(b) There may be an inverse association with wine. 

(c) Squamous and adeno may be closer.

(d) Over age 50, no plateau with age, typical of epithelial cancer. 

(e) Compared with whites. 

Three Scientific Priorities and 

Rationales 

Priority 1: Identify and explore the 

relationship of H. pylori to gastric cancer 

and esophageal adenocarcinoma in terms 

of physiology, premalignant lesions, and 

interaction with other factors (e.g., age of 

acquisition, strain differences, ethnicity, 

host susceptibility, and exogenous 

exposures). 

Rationale: There is a wide body of evidence 

that H. pylori is the single most important 

risk factor identified for gastric cancer; 

however, because of its high prevalence, it is 

clearly not sufficient to explain these 

cancers. Therefore, a deeper understanding 

of the steps from H. pylori acquisition to 

development of these cancers must be 

determined, including the relationship with 

modifying factors. 

Conversely, there is preliminary evidence 

that the presence of H. pylori is associated 

with protection against adenocarcinoma of 

the esophagus and precursor lesions. This 

point needs clarification because the 

implications are opposite to those for gastric 

cancer. 

Priority 2: Identify the causation, normal 

variation, and pathophysiologic consequences of reflux, and its interrelationship 

with BMI, fat distribution, and other 

factors in the development of esophageal 

and gastric cardia adenocarcinomas and 

their precursors. 

Rationale: There is a wide body of evidence 

that reflux and anthropometric measures are 

very important risk factors for adenocarcinoma of the esophagus. Despite this 

importance, our knowledge base is 

insufficient. There are important 
38 Report of the Stomach/Esophageal Cancers Progress Review Group

definitional questions and questions about 

natural history and mechanisms. 

Priority 3: While independent etiologic 

factors have been identified in the 

development of esophageal and gastric 

cancers and their precursors, the priority is 

to understand how these factors interact in 

affecting the disease continuum and 

explaining patterns of incidence in the 

population. 

Rationale: Existing evidence suggests that 

these cancers are multifactorial diseases, and 

reliance on approaches directed toward 

single risk factors are unlikely to be 

sufficient to provide a complete explanation 

of etiology. 

Infrastructure Needed To 

Accomplish Priorities 

Partnership Platforms

Large, collaborative cohort studies could be 

coordinated through such agencies as NCI 

and NIDDK. 

Expected Resources To Overcome 

Limitations of Previous Research and To 

Capitalize on Existing Opportunities 

• Investment in/improvement of databases 

with emphasis on enrollment of minority 

populations 

• Archival specimen and tissue banking 
Appendix B: Breakout Reports 39

Genetics 

Co-Chairs: Meltzer, Stephen and Fennerty, Brian M.; Powell, Steven

Participants: 

Chak, Amitabh 

Christie, Adrian 

Henley, Donald 

Mori, Yuriko 

Moss, Steven 

Romero, Yvonne 

Taylor, Philip 

Triadafilopoulos, George 

Overview/Background 

Information/Barriers 

Many molecular alterations have been 

described in gastric and esophageal 

carcinogenesis. The genetic features of these 

cancers can potentially be used to develop 

ways of assessing risk, improving detection, 

identifying prognostic markers, and stratifying therapies. However, such advances 

will require careful prioritization of 

strategies in order to discover and validate 

both inherited and acquired molecular 

alterations in these cancers and their 

precancerous states. Three research areas 

adequately describe approaches to 

advancement in this field: laboratory 

research, technology, and goal setting. Each 

area is described in detail below. 

Laboratory Research 

The first area—laboratory research into the 

genetics of gastric and esophageal cancers—

involves investigation into several categories 

of genetic alterations. For example, genetic 

instability is a hallmark of cancer. This 

category of abnormality includes two 

subcategories: chromosomal instability 

(aneuploidy) and deficient DNA mismatch 

repair (microsatellite instability). This latter 

mechanism involves targets that occur 

downstream in the pathway of disordered 

mismatch repair, such as TGF-beta1 RII, 

MSH-3, MSH–6, BAX, and ActRII. Genetic 

activation also involves several mechanisms, 

such as point mutation and DNA amplification. Examples of genes activated in 

gastric and/or esophageal cancers include cmyc, c-erbB-2, and those encoding cyclin D 

and EGF-R. DNA amplification occurs at 

the chromosomal loci 7q, 17q, and 20q. 

Inactivation, another category of genetic 

alteration, is exemplified by E-cadherin, 

p53, p16, APC, hMLH1, and by genetic loci 

showing allelic loss, such as 4q, 5q, 8p, 9p, 

17p, 18p, and18q. Mechanisms of gene 

inactivation include point mutation, allelic 

loss, and hyper-methylation. For example, 

hyper-methylation of the hMLH1, Ecadherin, and APC genes has been reported 

in gastric epithelia and tumors (Tamura et 

al., JNCI, 2000; Fleisher, A.S. et al., Cancer 

Research, 1999, Oncogene, 2000; Tamura et 

al., Oncogene, 2000). Finally, further 

research is needed on altered gene 

expression in order to establish the clinical 

or biological significance of global gene 

expression patterns as well as to advance 

understanding of the role of aberrant 

expression of individual genes. Genes 

already known to be important in these 

cancers include those encoding Cox-2, 

iNOS, growth factors and their receptors, 

and the proline-rich differentiation gene 

esophagin. 

Another important area of laboratory 

research is studying the molecular genetics 

of gastric and esophageal cancers to 

distinguish hereditary from somatic gene 

alterations. Although most abnormalities 

that have been described are somatic, some 

are altered in the germ line. One prime 
40 Report of the Stomach/Esophageal Cancers Progress Review Group

example of germ line alteration is Ecadherin in familial gastric cancer. Similar 

alterations in germ line abnormalities of 

esophageal cancer still need to be 

investigated. 

Finally, laboratory research is also needed to 

assess the role of infection on the advent of 

gastric, esophageal adenocarcinoma, and 

esophageal squamous cancers. For example, 

H. pylori infection is very common, yet less 

than 2% of those infected ultimately develop 

gastric cancer. El-Omar, et al. (Nature, 

2000) determined that common 

polymorphisms that exist in the population 

for the Interleukin I (IL-1) gene strongly 

influence, either positively or negatively, the 

gastric response to H. pylori. Other studies 

in Portugal and UK/Poland have confirmed 

and extended this concept for TNF-α, IL-10, 

and the IL-1 receptor. Thus, the pro/anticancer risk is related not only to the type of 

bacterium, but to the genetically determined 

response to the bacterium. 

Technology 

Technological advances, the second research 

area to advance gastric and esophageal 

cancers, have changed both basic research 

and clinical investigation. Some techniques 

have been perfected, while others have only 

recently been developed, but all deserve 

consideration as emerging approaches to the 

genetic understanding of gastric and 

esophageal cancers. These technologies 

include genomics, proteomics, bioinformatics, flow cytometry, immunohistochemistry, comparative genomic 

hybridization (CGH), single nucleotide 

polymorphisms (SNPs), fluorescent in situ

hybridization (FISH), microarray, DNA 

mutational screening, imaging technologies 

(e.g., endoscopic/whole body), methylation 

discovery platforms, and systems biology 

approaches (i.e., multidisciplinary 

integration). For example, bioinformatics 

studies based on cDNA microarray data 

suggest that esophageal cancers and their 

premalignant precursor lesions can be 

accurately diagnosed based on molecular 

phenotyping (Selaru et al., 2002; Xu et al., 

2002). 

A second technologic advance, 

instabilotyping, has been used to show that 

gastric and other cancers have a unique 

profile of mutations. This technique has also 

resulted in the discovery of several novel 

candidate tumor suppressor genes (Mori et 

al., 2001; 2002). 

One technology in particular, SNPs, can be 

used to assess risk of upper gastrointestinal 

cancers. Although studies of risk related to 

SNPs have been limited, SNPs hold promise 

as potential risk factors themselves and as 

factors that influence environmental 

exposures. SNPs under study include those 

for carcinogen activation (P450s) and 

metabolism (glutathione s-transferase), 

nutrient metabolism (folate, selenium, and 

proteins), and alcohol metabolism. 

Goal Setting 

Goal setting defines the third research area 

and qualifies as an approach to advance the 

understanding of gastric and esophageal 

cancers by focusing investigation and 

generating collaborations. In particular, the 

discovery of new genes and biomarkers 

should be emphasized and priorities set for 

their further study. The function of novel 

genes should be determined by using in vitro

and in vivo models. Noninvasive or 

minimally invasive “bedside” assays need to 

be developed in order to translate bench 

discoveries to the clinic. Importantly, 

putative or potential genetic markers must 

be validated, because the clinical utility and 

“generalizability” of these markers have not 

been definitively established. These markers 

need to be assessed for clinical utility, 

technical reliability, translation into high 

throughput assays, and recognition of their 

general importance in other cancers. 
Appendix B: Breakout Reports 41

Future Research Directions 

Gastric, esophageal Adenocarcinoma, and 

esophageal Squamous (GAS) cancers are 

relatively underresearched, are much more 

lethal than other cancers, have had relatively 

fewer candidate genes identified, and have 

had fewer opportunities for intellectual 

sharing than have other types of cancer. 

Only a small portion of the genome has been 

investigated, and the identified genes have 

not been translated to the clinic. Current 

funding for these cancers has not provided 

sufficient incentives for sharing resources 

across disciplines and institutions. 

Traditional funding mechanisms have 

encouraged single-center academic 

institutional studies, thereby limiting 

community patient enrollment and 

participation. Therefore, a novel guiding 

principle to address these needs is proposed: 

VIDA: Validate, Identify/Discover, and 

Adapt. 

To form a large, multi-institutional, transdisciplinary, patient-centered, academic and 

community-based consortium of basic, 

translational, and clinical investigators to 

achieve the following priorities in gastric, 

esophageal adenocarcinoma, and squamous 

esophageal (GAS) carcinogenesis. 

Three Scientific Priorities and 

Rationale for Each 

Priority 1: Validate genetic alterations in 

GAS neoplasia. 

Rationale: In GAS and their precursor 

conditions, no previously identified genetic 

alterations of early detection, prognostic, or 

diagnostic biomarkers have been reliably 

validated. Currently, validation strategies 

have been predominantly applied to small, 

geographically localized patient populations. 

Current technology permits following 

subjects endoscopically and longitudinally, 

so the clinical significance of genetic and 

epigenetic alterations in GAS malignant and 

premalignant lesions can be determined. 

Priority 2: Identify and discover novel 

genes and biomarkers in GAS neoplasia. 

Rationale: In GAS cancers and their 

precursor conditions, little is known of the 

genome for genetic and epigenetic 

abnormalities. The majority of alterations 

remains to be discovered. This situation 

stands in stark contrast to that in other 

cancers, where many more viable candidate 

genes have already been identified and 

characterized. Moreover, many of the 

candidate genes identified in other cancer 

types have been found to be uninvolved or 

clinically insignificant in GAS lesions. A 

broader palette of genetic alterations and 

candidate genes in GAS neoplasia would not 

only increase the basic understanding of 

these diseases but also yield potential 

biomarkers for validation and adaptation 

(priorities 1 and 3). 

Priority 3: Adapt current and future 

technologies and biomarkers to the clinical 

arena. 

Rationale: In GAS cancers and their 

precursor lesions, both current and future 

markers must be clinically measurable. One 

unique advantage of GAS premalignant 

tissues is that they remain in situ, in contrast 

to preneoplastic lesions arising in other 

organ systems. Thus, proposed technologies 

and biomarkers should utilize this unique 

advantage. 

Infrastructure Needed To 

Accomplish Priorities 

Partnership Platforms 

A SWOG-like structure needs to be formed 

as an incentive to cross-institutional and 

cross-disciplinary fertilization and 

collaboration in GAS studies. This structure, 

known as VIDA (Validation, Isolation, 
42 Report of the Stomach/Esophageal Cancers Progress Review Group

Discovery, and Adaptation), would be 

composed of a large network of 

gastroenterologists, epidemiologists, 

pathologists, bioinformaticists, and experts 

in other appropriate disciplines. VIDA’s 

purpose would be to promote large-scale 

cooperation, patient enrollment, and 

biomarker validation. 

Expected Resources To Overcome 

Limitations of Previous Research and To 

Capitalize on Existing Opportunities 

• A specified line item, Southwest 

Oncology Group-like, cooperative group 

mechanism for this consortium of 

gastroenterologists and other specialists 

studying GAS neoplasia. 

• Cooperative mechanisms that produce 

incentives for sharing of resources 

among community-based or academic 

investigators. GAS carcinogenesis is 

uniquely suited to make use of this 

mechanism because of the ability to 

serially access these lesions longitudinally, as well as with detailed spatial 

mapping, to improve the under-standing 

of neoplastic progression in these 

diseases. 

• Research strategies devolving from this 

GAS human model may be applicable to 

cancers arising in other organ sites. 

References 

1

Tamura G, Yin J, Wang S, Fleisher AS, 

Zou T, Abraham JM, Kong D, Smolinski 

KN, Wilson KT, James SP, Silverberg SG, 

Nishizuka S, Terashima M, Motoyama T, 

Meltzer SJ. E-Cadherin gene promoter 

hypermethylation in primary human gastric 

carcinomas. J Natl Cancer Inst. 2000; 

92(7):569–573. 

2

Fleisher AS, Esteller M, Wang S, Tamura 

G, Suzuki H, Yin J, Zou TT, Abraham JM, 

Kong D, Smolinski KN, Shi YQ, Rhyu MG, 

Powell SM, James SP, Wilson KT, Herman 

JG, Meltzer SJ. Hypermethylation of the 

hMLH1 gene promoter in human gastric 

cancers with microsatellite instability. 

Cancer Res. 1999; 59(5):1090–1095. 

3

Tsuchiya T, Tamura G, Sato K, Endoh Y, 

Sakata K, Jin Z, Motoyama T, Usuba O, 

Kimura W, Nishizuka S, Wilson KT, James 

SP, Yin J, Fleisher AS, Zou T, Silverberg 

SG, Kong D, Meltzer SJ. Distinct 

methylation patterns of two APC gene 

promoters in normal and cancerous gastric 

epithelia. Oncogene 2000; 19(32):3642-

3646. 

4

Selaru FM, Zou T, Xu Y, Shustova V, Yin 

J, Mori Y, Sato F, Wang S, Olaru A, Shibata 

D, Greenwald BD, Krasna MJ, Abraham 

JM, Meltzer SJ. Global gene expression 

profiling in Barrett’s esophagus and 

esophageal cancer: a comparative analysis 

using cDNA microarrays. Oncogene 2002; 

21(3):475–478. 

5

Xu Y, Selaru FM, Yin J, Zou TT, Shustova 

V, Mori Y, Sato F, Liu TC, Olaru A, Wang 

S, Kimos MC, Perry K, Desai K, Greenwald 

BD, Krasna MJ, Shibata D, Abraham JM, 

Meltzer SJ. Artificial neural networks and 

gene filtering distinguish between global 

gene expression profiles of Barrett’s 

esophagus and esophageal cancer. Cancer 

Res. 2002; 62(12):3493–3497. 

6

Mori Y, Yin J, Rashid A, Leggett BA, 

Young J, Sims L, Kuehl PM, Langenberg P, 

Meltzer SJ, Stine OC. Instabilotyping: 

comprehensive identification of novel 

cancer-related genes by large-scale probing 

for mutations in coding region microsatellites. Cancer Res. 2001; 61(16):6046–

6049. 

7

Mori Y, Sato F, Selaru FM, Olaru A, Perry 

K, Kimos MC, Tamura G, Matsubara N, 

Wang S, Xu Y, Yin J, Zou T-T, Leggett B, 

Young J, Nukiwa T, Stine OC, Abraham 

JM, Shibata D, Meltzer SJ. Instabilotyping 

reveals novel unique mutational spectra in 

microsatellite-unstable gastric cancers. 

Cancer Res. 2002; 62(13):3641–3645. 
Appendix B: Breakout Reports 43

Imaging/Technologies 

Co-Chairs: Welch, Michael and Van Dam, Jacques; Fischman, Alan

Participants: 

Balakrishnan, Krishna 

Burakoff, Peter 

Dehdashti, Farrokh 

Georgakoudi, Irene 

Knisley, Eric 

MacAulay, Calum 

Michaels, Margo 

Sivak, Jr., Michael V. 

Overview/Background 

Information/Barriers 

There is a dramatic, ongoing increase in 

the incidence of adenocarcinoma of the 

esophagus and gastric cardia. For both 

tumors, precursor lesions have been identified and are identifiable endoscopically. In 

the past 20 years, remarkable advances in 

imaging and technologies in esophageal and 

gastric cancers have occurred. Advances in 

endoscopic technology, non-endoscopic 

optical imaging techniques, radiological 

techniques, and other new technologies 

provide opportunities to affect the course 

of esophageal and gastric cancers. 

Advances in endoscopy include new 

ultrathin endoscopes capable of being used 

clinically without sedation. New highmagnification endoscopes with or without 

the use of exogenous dyes (chromoendoscopy) provide high-resolution images 

of gastrointestinal mucosa, which correlate, 

in many cases, with histopathological 

diagnosis. New endoscopic staging 

technologies have advanced in just the past 

10 years to become the state-of-the-art for 

esophageal and gastric cancers. Endoscopic 

ultra-sonography (EUS), which combines 

the benefits of medical ultrasound with the 

access of endoscopy, provides unparalleled 

imaging and staging accuracy. The advent of 

EUS-guided fine needle aspiration provides 

a tissue diagnosis in the case of metastatic 

regional lymph nodes in patients with 

esophageal and gastric cancer. Adjuncts to 

tissue cytopathology include immunocytochemistry and PCR amplification. 

A number of studies have demonstrated the 

feasibility and safety of endoscopy, without 

sedation, using a variety of instruments 

including narrow diameter endoscopes. 

Early instruments were relatively unsatisfactory in terms of the resolution and 

illumination. Newer technology has made 

these small diameter instruments equivalent 

or nearly equivalent to standard endoscopes. 

However, the sensitivity and specificity of 

these instruments for the detection of 

Barrett’s esophagus and cardia cancer is not 

fully established. At the same time, the 

technology has advanced more quickly than 

data can be accumulated from clinical trials, 

primarily because most published data from 

trials have been from single centers, both 

within and outside of the United States. 

Another difficulty with using endoscopy 

without sedation is that expert endoscopists 

have not acquired all of the available 

screening data. It is not known whether this 

imaging method can be used by primary 

care physicians as an office-based 

procedure. This would require the 

development of additional cost-effective 

technology largely related to the processing 

and disinfecting of the instruments. 

A number of high-resolution adjuncts to 

endoscopy are currently under development 

and are the focus of intense research. 

Referred to collectively as “optical biopsy,” 
44 Report of the Stomach/Esophageal Cancers Progress Review Group

these techniques include laser-induced 

fluorescence spectroscopy, reflectance 

spectroscopy, light-scattering spectroscopy, 

trimodal spectroscopy, Raman spectroscopy, 

optical coherence tomography, and confocal 

microendoscopy. The precursor for 

esophageal and cardia cancers is one 

proposed target for imaging by these highly 

advanced techniques. Preliminary reports 

suggest that one or more of these imaging 

techniques may be capable of detecting 

mucosal dysplasia. This could have a 

profound impact on the incidence of both 

esophageal and gastric cancers by 

identifying patients at risk for the disease 

and interrupting the “dysplasia-carcinoma” 

sequence. 

High-resolution spiral computed 

tomography scans, magnetic resonance 

imaging, and FDG-Positron Emission 

Tomography (PET) scanning represent 

nonendoscopic advances in imaging. The 

latter technology may rival the sensitivity 

and specificity of EUS as a staging tool for 

patients with advanced disease. With the use 

of neoadjuvant therapy, assessment of 

response has been very important. However, 

the conventional imaging modalities are 

quite limited in prediction of response to 

therapy or in monitoring therapy. PET with 

Flourine-18-fluoro-2 deoxy-D-Glucose 

(FDG), which localizes rapidly to many 

human cancers following intravenous 

injection, has been shown to have potential 

for use in this setting. 

Contrast agents have the potential to be a 

powerful adjunct to current radiological 

imaging techniques. Contrast agents under 

development for use in conjunction with 

nuclear and magnetic resonance imaging are 

capable of quantifying tissue metabolic 

processes, angiogenesis, apoptosis, hypoxia, 

receptors, enzymes, and the degree of 

cellular proliferation. Stomach and 

esophageal cancers offer a unique 

opportunity, because oral delivery of 

contrast agents is possible to target 

molecular markers expressed on 

precancerous and cancerous cells. Capsule 

“endoscopy” is the newest non-endoscopic, 

non-radiological imaging technique capable 

of imaging the stomach. Sometimes referred 

to as a “remote” or “wireless” endoscopy, 

the system is a pill-sized unit containing a 

camera, battery, and telemetry unit. Images 

from within the GI tract are transmitted to a 

receiver worn as a harness by the patient. 

Currently in development, advanced capsule 

devices are capable of real-time imaging and 

propulsion within the stomach so that a 

complete gastric examination may be 

performed. 

Three Scientific Priorities and 

Rationales 

Priority 1: Develop and implement 

improved screening modalities that do not 

require sedation for esophageal and gastric 

cancers. 

Rationale: Available data from studies 

indicate that a screening endoscopy without 

sedation is well-tolerated and acceptable to 

patients. However, these studies also 

indicate that as many as 40% of patients 

decline to undergo unsedated screening 

endoscopy. This problem needs to be 

addressed through the development of 

improved screening modalities and 

educational programs for physicians and 

patients. Ultimately, screening of large 

patient populations for esophageal and 

gastric cancers will enable improved 

identification of the risk factors associated 

with progression to cancer, and a better 

understanding of the molecular, biochemical, and morphological changes 

associated with the progression or regression 

of esophageal and gastric cancers. 

Priority 2: Develop improved imaging 

techniques and contrast agents specific to 

stomach/esophageal cancers. 

Rationale: Using imaging, it is possible to 

define a signature of cancerous and 
Appendix B: Breakout Reports 45

precancerous cells. Various optical imaging 

techniques are in development for imaging 

stomach and esophageal cancers; these 

include trimodal spectroscopy, optical 

coherence tomography, and confocal 

microendoscopy. In the future, clinical 

comparisons and evaluations will need to be 

conducted. Due to cost and the high level of 

technology required, it will be necessary to 

partner with industry to continue the 

development of suitable instruments and 

equipment. 

Priority 3: Develop and evaluate imaging 

techniques to define or predict responses to 

new therapies. 

Rationale: Using imaging, it is possible to 

predict therapeutic response soon after 

initiating therapy or to tailor dosimetry to 

the physiology of the individual patient to 

optimize its effectiveness. Early diagnosis 

will avoid the morbidity and expense 

associated with ineffective treatments. As 

new therapies evolve, innovative probes and 

techniques would be adopted for monitoring 

therapy. 

As examples: 

• In the case of esophageal cancer, 

persistent FDG uptake in a lesion after 

treatment with radiation could represent 

either residual tumor or inflammation 

induced by radiation. Development of an 

agent to distinguish between these states 

would be a major advance. 

• Local and systemic disease evaluation. 

Specifically, the use of PET with FDG 

(or new radiotracers) as a tool to evaluate 

the effectiveness of new therapeutic 

strategies. 

• Local disease evaluation. Optical 

techniques such as Optical Coherence 

Tomography (OCT), which provides 

cross-sectional images of tissues in situ, 

may have application in a specific group 

of patients in a similar way that PET is 

currently being used. 

• Imaging can be used to define doses of 

therapeutic agents. For example, optical 

techniques can be used to define therapeutic doses of agents for photodynamic 

therapy based upon the activity of the 

optical agent. Therapeutic drugs can be 

labeled with optical or nuclear probes, 

and the pharmacokinetics of uptake and 

biological effect can be quantified prior 

to determining the dosing of the 

therapeutic agent. 

Infrastructure Needed To 

Accomplish Priorities 

Partnership Platforms 

• Partnerships must be developed between 

the various groups developing imaging 

techniques and applying them. 

• Individuals developing optical probes 

and agents (in gastroenterologists and 

engineers) need to partner with 

radiologists and imaging scientists in 

developing CT, MRI, and PET 

techniques and probes. 

Expected Resources To Overcome 

Limitations of Previous Research and To 

Capitalize on Existing Opportunities 

• Current advances in imaging have been 

largely due to ad hoc collaborations 

between physician scientists and 

physicist/engineers. Such interdisciplinary collaborations should be 

encouraged. 

• Establish and fund imaging centers of 

excellence for laboratory and clinical 

research. 

• Foster interdisciplinary research by 

creating RFAs that support research 
46 Report of the Stomach/Esophageal Cancers Progress Review Group

conducted by collaborations between 

radiologist/molecular biologists, 

gastrointestinal endoscopists/engineers, 

and/or applied physicists and other 

scientists. 

• Support the training and education of 

patients and physicians regarding the 

benefits of screening for precursors of 

esophageal and gastric cancers in 

patients at risk for the disease. 

• Encourage increased collaboration 

between scientists in academia and 

industry in the development of imaging 

instrumentation and probes. One method 

to encourage such collaboration is 

through the SBIR/STTR grant 

mechanisms. 
Appendix B: Breakout Reports 47

Outcomes/Education/Communication/Quality of Life 

Co-Chairs: Brooks, Jo Ann; Holland, Jimmie and Provenzale, Dawn; Lipscomb, Joseph

Participants: 

Bloom, Bernard 

Donaldson, Molla 

Frazzitta, Bart 

Hayman, James 

Helft, Paul 

Hornbook, Mark 

Rabeneck, Linda 

Rowland, Julia 

Tepper, Joel 

Valentine, Janet 

Overview/Background 

Information/Barriers 

Each year in the United States, there are 

21,600 new cases of gastric cancer and 

12,400 deaths. Survival rates for esophageal 

cancer are worse, with 13,100 new cases 

annually and approximately 12,600 deaths. 

While studies of diagnosis and treatment 

have focused on the traditional outcomes of 

disease-free survival and tumor progression, 

there have been few studies focusing on 

patient-centered outcomes directed toward 

health-related quality of life (HRQoL), 

patient care experiences, symptom 

management, and total economic burden. 

Education for the public and professional 

sectors regarding both cancers in regard to 

their presenting symptoms, interventions, and 

treatment options has been inadequate. 

Furthermore, since many patients are 

diagnosed in late stages of stomach and 

esophageal cancers, there are virtually no 

outcome studies in patients identified in 

premalignant phases. 

There is an increased symptom burden 

resulting from both disease and treatment in 

advanced stages of stomach and esophageal 

cancers. Currently, only two well-validated 

disease-specific instruments exist for 

measuring HRQoL in stomach and 

esophageal cancers: the EORTC QLQ-C30 

instrument and the FACT-Gastric and FACTEsophageal instruments. The European 

Organization for Research and Treatment of 

Cancer (EORTC QLQ-C30) consists of a 

core module covering physical, emotional, 

and social aspects, accompanied by a 

disease-specific set of questions for 

esophageal (OES24 module) and gastric 

(STO 22 module) cancers. The Functional 

Assessment of Cancer Therapy – General 

(FACT-G), the U.S. counterpart to the 

EORTC, addresses both generic and diseasespecific issues. The disease-specific issues 

are investigated through the esophageal and 

gastric subscales. For both instruments, the 

general components are relevant to a broad 

range of patients with cancer. Both 

instruments have provided rich information 

in the general core areas through a large 

number of studies. However, few studies 

have used these instruments in patients with 

stomach and esophageal cancers, so diseasespecific information on HRQoL is severely 

lacking. Additionally, HRQoL issues, 

including the ability to perform activities of 

daily living, to work, and to attend school, as 

well as common symptoms resulting from 

disease and treatment have not been among 

outcome variables in large-scale clinical 

trials and observational studies. 

Currently, a range of validated symptom 

identification and management instruments 

exists for measuring pain, nausea, fatigue, 

anxiety, depression, and dysphagia, but none 

of these instruments has been studied 

specifically for stomach and esophageal 

cancers. Nor do these instruments address 

differences in terms of ethnicity, culture, 
48 Report of the Stomach/Esophageal Cancers Progress Review Group

race, gender, or health literacy, which would 

potentially influence responses to HRQoL 

questions. These instruments have generally 

been used in studies for palliative care as 

opposed to earlier stages of care, and they 

have been used for multiple cancer sites but 

not specifically for gastric and esophageal 

cancers. Additionally, these instruments have 

not been integrated into clinical trials and 

observational studies on a large-scale basis. 

Thus, little is known about symptom 

management for stomach and esophageal 

cancers. 

A number of evidence-based interventions 

have been tested for the management of 

symptoms (e.g., pain, dysphagia) associated 

with disease and treatment of gastric and 

esophageal cancers. However, few clinical 

trials have employed these interventions in 

patients with these specific cancers. 

Additionally, a body of science building on 

HRQoL issues is nonexistent. Thus, 

information on best practice interventions 

and management of symptoms is lacking. 

In terms of education, the evidence and 

consensus-based treatment guidelines for 

esophageal and gastric cancers have not been 

uniformly disseminated and implemented. 

Thus, the quality of care (QOC) varies 

widely by geographic region, socioeconomic 

level, and provider preferences. In addition, 

there has been a lack of an interdisciplinary 

approach that includes not only chemotherapy, radiation, and surgery, but also 

nutrition management, pain control, counseling, and concern for psychological, social, 

existential, and spiritual issues. For those 

patients who survive for longer periods, there 

has not been adequate attention to physical 

and psychosocial rehabilitation measures. 

For the general public, there is a lack of 

public awareness of the scope and magnitude 

of stomach and esophageal cancers, and their 

premalignant and preventive aspects. 

Specifically, there has been a lack of focus 

on educating high-risk groups including 

those with Barrett’s esophagus, GERD, and 

H. pylori infection. For others, the possible 

role of alcohol, tobacco, and diet in these 

cancers has not been emphasized. 

Furthermore, public education on risk 

factors, common presenting symptoms, and 

interventions has been inadequate to motivate 

the public to seek early diagnosis. Finally, 

the public has not received information about 

the possible treatment options available for 

premalignant disorders. 

Barriers to the study of patient-centered 

outcomes in stomach and esophageal cancers 

relate to the small number of cases, the high 

mortality rate, and the consequent need for 

multidisciplinary, multicenter studies to 

generate an adequate sample size. Studies are 

also constrained by changes in the incidence 

and demographic characteristics of patients 

who develop these cancers. In addition, 

patient-centered issues are very different 

across the spectrum of disease stages, from 

premalignant to late malignant. Finally, there 

is a lack of evidence-based information on 

the efficacy of early diagnosis and treatment 

of these cancers. These factors all serve as 

barriers to public education. 

TWO SCIENTIFIC PRIORITIES AND 

RATIONALES

Priority 1: Evaluate clinical and patient/ 

family data available for patient-centered 

outcomes related to symptoms, HRQoL, and 

QOC in gastric and esophageal cancer. This 

should include assessment of the aggregate 

economic burden of these cancers 

considering years of productive life lost, 

negative impacts on survival, cost of care 

and caregiving, and other factors. Then 

conduct a cross sectional study using existing databases to provide a more formal 

assessment. Importantly, all clinical trials 

and observational studies should include 

patient-centered outcomes for HRQoL and 

QOC. 
Appendix B: Breakout Reports 49

Rationale: There is a lack of data on patientcentered outcomes related to symptoms, 

HRQoL, and QOC. 

Priority 2: Utilize and adapt current 

esophageal and gastric-specific HRQoL and 

QOC instruments to measure disease stage 

and treatment-related outcomes. 

Tools for developing and testing care 

experiences—including pain control, 

treatment options, effects of therapy, and 

others—are critical for measuring patientcentered outcomes. Ensure that patient 

advocates are involved in all aspects of 

evaluation and development of measures of 

patient-focused issues and QOC. 

Rationale: Current instruments have not 

been widely used and tested in observational 

studies and clinical trials. Patients bring a 

unique perspective regarding their 

experiences and responses concerning these 

diseases. 

Infrastructure Needed To 

Accomplish Priorities 

Partnership Platforms 

• New health Web sites 

• Pharmaceutical firms 

• Academic and high-volume institutions 

• ASCO symptom management to add 

modules 

• Partnering among agencies 

• American Cancer Society 

• Quality of Cancer Care Committee 

• Professional organizations–thoracic 

surgeons, general 

• Recommend that patient advocates be 

involved across the spectrum 

• Foundations (e.g., The Robert Wood 

Johnson Foundation, Pew Memorial 

Trust, Kaiser Family Foundation, and 

others) 

• Veteran’s Health Administration 

Expected Resources To Overcome 

Limitations of Previous Research and To 

Capitalize on Existing Opportunities 

• Multimodality and multicenter clinical 

trials and observational studies 

• Well-defined cohorts 

• Availability of databases (e.g., SEER, 

Medicare, etc.)
50 Report of the Stomach/Esophageal Cancers Progress Review Group

Predictive and Prognostic Markers 

Co-Chairs: Ajani, Jaffer A. and Hamilton, Stanley R.

Participants: 

Conner, Jerry 

Kumar, Rakesh 

Lawrence, Theodore S. 

Lugo, Tracy 

Okunieff, Paul 

Selaru, Florin M.

Shibata, David 

Srivastava, Sudhir

Overview/Background 

Information/Barriers 

A predictive marker is an indicator of 

response to therapy, preferably defining a 

patient’s survival after treatment. A 

prognostic marker is an indicator of the 

natural history of the disease, and it is used 

to help define patients with high and low 

risks of death that result from the inherent 

heterogeneity of the disease process. 

These markers are applicable to screening 

patient populations with normal risk, 

surveillance of patient populations at 

increased risk, diagnosing symptomatic 

patients, determining disease stage, and 

prevention strategies. These principles are 

applicable to adenocarcinomas of the 

esophagus, the esophagogastric junction, 

and the stomach as well as to esophageal 

squamous cell carcinoma. These principles 

also are applicable to premalignant 

conditions, such as Barrett’s metaplasia. 

The era of molecular biology has yielded a 

plethora of potential predictive and 

prognostic markers, but none has achieved 

routine clinical use because methods for 

assessing response or prognosis are neither 

standardized nor correlative. Applying 

individual predictive markers is complicated 

by the use of multimodality therapies, which 

employ chemotherapeutic agents with 

differing mechanisms of action, biological 

effects, and radiotherapy. In addition, these 

therapies often cause substantial damage to 

normal tissue. Molecular markers may help 

alleviate the problem of widespread tissue 

damage by allowing physicians to test 

tumors for susceptibility to these toxins. In 

addition, biological modulators of toxicity 

are becoming clinically available by 

identifying prognostic markers and 

integrating them into clinical staging for 

better prediction of the natural history of 

carcinomas and premalignant conditions. 

There are currently no well-defined 

pathways for validating predictive and 

prognostic markers and incorporating them 

into routine clinical practice. Gene arrays of 

Barrett’s esophagus tissue indicate that the 

number of molecular pathways and targets 

are limited. Since esophageal tumors are 

similar to other cancer tumors, esophagus 

cancers could finally provide a window on 

these markers. Finally, a clear infrastructure 

does not exist that permits multicenter 

routine molecular correlative studies of 

predictive and prognostic markers in clinical 

trials of esophageal and gastric cancers. 

Gastric and esophageal cancers affect many; 

however, there is little information from 

multicenter trials. 

Three Scientific Priorities and 

Rationale for Each 

Priority 1: Develop rapid, flexible, and 

adequate funding mechanisms for 

cooperative groups and institutions 

conducting clinical trials. They will focus 

on engaging in real-time collaborative 
Appendix B: Breakout Reports 51

studies of existing markers for validation of 

laboratory methodologies, tissue and blood 

collection, quality control, database 

tracking, prioritization, and specimen 

distribution, with minimum standards of 

performance. 

Rationale: The NCI research portfolio 

heavily emphasizes clinical trials and 

biologic studies. Large numbers of patients 

with esophageal or stomach cancers are 

enrolled in therapeutic trials, but 

translational studies of correlative markers 

are not constant features of the protocols. 

Current funding mechanisms for such 

translational studies are out of phase with 

clinical trial development and 

implementation. There is an urgent need to 

support cooperative groups and institutions 

conducting clinical trials for marker studies. 

Priority 2: Development and validation of 

novel methods for both clinical and 

operative molecular staging, particularly by 

means of molecular markers and imaging 

techniques (molecular and/or functional). 

Rationale: Despite curative surgery and 

adjuvant therapy, the majority of patients 

with gastric and esophageal cancers suffer 

from both local and distant recurrence. 

Conventional staging techniques, 

particularly T and N, do not adequately 

predict heterogeneity of patient outcomes. 

An integrated molecular staging might 

predict patient outcomes more accurately. 

Novel molecular staging techniques may 

assist in guiding operative treatment, (e.g., 

extent of surgery/lymphadenectomy, use of 

intraperitoneal chemotherapy and/or 

biologic therapy) as well as the use of 

appropriate adjuvant chemotherapy, 

radiation therapy, and biologic therapy. This 

advance will establish a novel panel of 

prognostic markers that will supersede the 

current parameters. 

Priority 3: Identify specific and 

quantitatively valid molecular pathways 

involved in oncogenesis, tumor response, 

tumor progression, and normal tissue 

tolerance. 

Rationale: Premalignant and malignant 

progression can be identified for squamous 

and adenocarcinoma of the esophagus and of 

the stomach, and these organs allow for 

access to tissue both preoperatively and after 

therapy. Insights would be valid for much of 

adult cancer, amplifying the impact for 

understanding and treating cancer. In 

malignant tumors, targets for therapy (such 

as enzymes, receptors, genes, and proteins) 

have also been described; however, their 

clinical implementation and validation of 

methodology is lagging. Additionally, 

reducing toxicity should be a major goal, 

given the limited success of existing 

therapies. 

Infrastructure Needed To 

Accomplish Priorities 

Partnership Platforms 

• Multicenter trials 

• Partner with insurance companies to 

explore endoscopic screening as a 

preventative measure, similar to Japan 

Expected Resources To Overcome 

Limitations of Previous Research and To 

Capitalize on Existing Opportunities 

• Coordinator for multicenter trials 

• Tissue banks need to be reorganized to 

include untreated tissue 

• Expedited grant process 
52 Report of the Stomach/Esophageal Cancers Progress Review Group

Prevention 

Co-Chairs: DeMeester, Tom R. and Goodman, Karen J; Falk, Gary

Participants: 

Fontham, Elizabeth 

Forastiere, Arlene 

Lines, Stephen 

O’Toole, Liam 

Richmond, Ellen 

Tell, Robert 

Wu, Anna 

Overview/Background 

Information/Barriers 

The decline in gastric cancer has been 

viewed as a public health triumph in the 

United States, yet it is still an important 

cause of death for high-risk groups. 

Although the incidence of esophageal cancer 

in the United States is even lower than 

stomach cancer, it accounts for slightly more 

deaths each year due to dismal survival 

rates. Thus, consideration of prospects for 

prevention is warranted. Specifically, have 

the high-risk groups been appropriately and 

fully identified, and what are the most 

effective means for reducing their risk? 

Prevention research on stomach and 

esophageal cancers in the last decade has 

focused on four disease subtypes: non-cardia 

and cardia adenocarcinoma of the stomach; 

adenocarcinoma; and squamous cell 

carcinoma of the esophagus. Nearly all 

stomach cancers are adenocarcinomas; 

however, recent research has revealed 

potentially different etiologies according to 

whether the site is the cardia or more distal 

(“non-cardia”). Adenocarcinomas of the 

esophagus and gastric cardia have been 

increasing in some population groups at 

alarming rates. Some studies group 

esophageal adenocarcinomas with cardia 

adenocarcinomas, in part because the 

available number of cases is often small. 

Emerging epidemiologic evidence suggests 

that esophageal and cardia adenocarcinomas 

may have a common etiology; however, this 

is difficult to confirm when studies do not 

report results separately for these two types. 

Difficulties in determining whether a cancer 

in this region originated in the stomach or 

esophagus may contribute to this problem. 

Little research in the United States has 

focused on the two major subtypes of gastric 

carcinoma, intestinal and diffuse, perhaps 

because the distinction may not be recorded 

routinely and is therefore frequently 

unavailable. There has been minimal 

investigation of rare subtypes such as gastric 

lymphoma. 

The more common stomach and esophageal 

cancer subtypes (non-cardia gastric 

carcinoma and esophageal squamous cell 

carcinoma) occur most frequently in 

populations of low socioeconomic status. 

Esophageal, and perhaps cardia, 

adenocarcinomas appear to be increasing in 

more affluent populations. The major shared 

risk factors for non-cardia gastric carcinoma 

and esophageal squamous cell carcinoma are 

low intake of fruits and vegetables and 

tobacco smoking (although the effect of 

smoking appears stronger for esophageal 

cancer). 

Other major risk factors for esophageal 

squamous cell carcinoma are alcohol 

consumption and nutrient deficiencies. 

Suspected modifiable risk factors, for which 

current evidence is less convincing, include 

hot food and drink, pickled vegetables, 

moldy food (mycotoxins), nitrosamines, and 

human papillomavirus. Other major risk 
Appendix B: Breakout Reports 53

factors for non-cardia gastric carcinoma are 

H. pylori infection and a high intake of 

preserved (salted, pickled) foods. 

Risk factors for cancers of the 

gastroesophageal junction are beginning to 

emerge from recent research. These 

subtypes are associated with 

gastroesophageal reflux. Suspected 

modifiable risk factors for adenocarcinoma 

of the esophagus include obesity, high 

intake of fat and vitamin A, low intake of 

fiber, smoking, and perhaps alcohol intake. 

Suspected modifiable risk factors for cardia 

adenocarcinoma are similar. The evidence 

for risk factors specific to cancers of the 

gastroesophageal junction comes from a 

small body of studies; therefore, the risk 

patterns need to be confirmed in more 

extensive research. 

Squamous cell carcinoma of the esophagus 

is considered preventable through reductions 

in smoking and alcohol consumption, and 

improvements in basic nutrition. For noncardia gastric carcinoma, perhaps the 

greatest promise is in interventions aimed at 

eliminating H. pylori infection through 

treatment or immunization. However, 

research suggests that a vaccine will not be 

available in the near future. Meanwhile, 

studies have focused on evaluating the costeffectiveness of screening for H. pylori

infection and treating those who are 

positive. Given concerns about potential 

adverse consequences of H. pylori treatment 

of asymptomatic individuals, there have 

been calls for intervention trials to assess 

benefits relative to adverse effects. 

Chemoprevention trials also need to be 

evaluated for cost-effectiveness. Most are 

aimed at preventing progression of 

premalignant lesions through combinations 

of micronutrient supplementation and H. 

pylori eradication. Recent studies have 

shown that aspirin and garlic may have 

protective effects. 

Gastric carcinoma of the intestinal type is 

associated with identifiable premalignant 

lesions, such as atrophic gastritis, intestinal 

metaplasia, and dysplasia. Diffuse-type 

gastric carcinoma has not been linked to 

identifiable premalignant lesions. Population 

screening for detection of premalignant 

gastric lesions or early invasive cancers is 

not considered cost-effective for low-risk 

populations. This approach has not been 

advocated in the United States, where there 

has been little evaluation of its costeffectiveness in high-risk groups. Population 

screening has been used successfully in 

Japan, where gastric cancer rates are high. 

Squamous cell carcinoma of the esophagus 

is associated with identifiable premalignant 

lesions such as chronic esophagitis, atrophy, 

and dysplasia, but the predictive value of 

cytology has not been considered adequate 

for population screening. Screening trials in 

high-risk populations in China have had 

equivocal results. Esophageal 

adenocarcinomas are generally preceded by 

reflux esophagitis and Barrett’s esophagus. 

Currently, more than 26 NCI projects are 

related to the prevention of stomach and 

esophageal cancers. These include projects 

on dietary interventions for general cancer 

prevention (2 projects); cancer awareness 

for minority populations (5 projects); 

screening for early detection of esophageal 

cancer in China (1 project); dietary 

intervention for preventing disease 

progression in Barrett’s esophagus patients 

(1 project); laboratory research focused on 

mechanisms of carcinogenesis and potential 

chemotherapeutic agents (4 projects); human 

chemoprevention trials for the esophagus 

and stomach in China (1 project) and for the 

stomach alone in Colombia and Mexico (2 

projects); improving cost-effectiveness of 

strategies for early detection of esophageal 

adenocarcinoma (1 project); identification of 

biomarkers of risk of disease progression in 

Barrett’s esophagus (1 project); identifying 
54 Report of the Stomach/Esophageal Cancers Progress Review Group

prognostic markers and improving treatment 

outcomes in stomach and esophageal cancer 

patients (3 projects); and observational 

studies to identify modifiable risk factors or 

potential preventive agents (5+ projects). 

There are three major barriers. First, there 

are small numbers of cases of these cancers, 

which limits subgroup analysis. Second, 

there is a lack of uniformity in classifying 

neoplasms by subsite/subtype, particularly 

regarding the location of adenocarcinomas 

proximal to the gastroesophageal junction. 

Finally, sampling variability in ascertaining 

intermediate endpoints leads to classification 

errors. 

Three Scientific Priorities and 

Rationales 

Priority 1: Develop risk profile(s) for 

stomach and esophageal cancers that serve 

as a basis for subsequent intervention 

(similar to the GAIL model for breast 

cancer). 

Rationale: Some known risk factors can be 

used to develop preliminary risk profiles. 

However, more etiological and 

epidemiological information is needed. The 

goal is to define the populations at risk so 

prevention efforts can be targeted 

effectively. Due to the relatively low 

incidence of these cancers, accurate 

estimates of risk require research efforts that 

involve a broad collaborative network across 

institutions and geographic regions to 

develop and maintain a comprehensive 

exposure database, to increase the statistical 

power of studies, and to develop uniform 

questionnaires and diagnostic classifications. 

Priority 2: Develop a menu of biomarkers 

of risk for stomach and esophageal cancers 

and their precursor states. 

Rationale: Intermediate disease endpoints 

should be established that can (a) inform the 

appropriateness of plans for screening and 

treatment (within the context of risk-profile 

models), and (b) provide guidelines for 

assessing effectiveness of prevention 

measures in low-, middle-, and high-risk 

groups. 

Priority 3: Develop cost-effective 

prevention strategies for reducing mortality 

of stomach and esophageal cancers. 

Rationale: Prevention research needs to 

weigh the costs and benefits of intervention 

at three levels: preventing disease onset by 

modifying risk factors, early detection of 

asymptomatic disease, and minimizing 

potential adverse consequences of treatment. 

Again, without increasing the power of 

studies through broad collaborative networks, the cost-effectiveness of screening 

and treatment plans cannot be assessed 

accurately. In particular, controversy over 

the need for and effectiveness of H. pylori

screening and treatment cannot be resolved 

until research examines the costs, including 

adverse effects, and benefits of such an 

approach. 

Infrastructure Needed To 

Accomplish Priorities

Partnership Platforms 

• Partnership with NIDDK (National 

Institute of Diabetes and Digestive, and 

Kidney Diseases) 

• Pharmaceutical companies (these 

already share some structures for 

collaborative networks, but what is 

missing is uniting under a common 

agenda) 

• Academic centers 

• Patient advocacy groups 
Appendix B: Breakout Reports 55

Expected Resources To Overcome 

Limitations of Previous Research and 

To Capitalize on Existing Opportunities 

• Infrastructure: All of the priorities and 

collaborative efforts outlined above 

depend on establishing a broad 

collaborative network for increasing the 

power of research through large, 

multicenter studies. Given that numbers 

of cancer cases at any given institution 

are low, potentially useful information 

about risk factors, surveillance, and 

outcomes is dispersed and isolated rather 

than aggregated. Existing data about 

screening, early detection, intervention, 

and social, behavioral, dietary, 

microbiological, or genetic predictors 

must be aggregated for increased 

statistical power. 

• The validity of new prevention research 

efforts will be maximized through 

collaborations that allow the use of 

uniform methods in study design, 

conduct, and analysis. 

• The development and maintenance of 

shared databases will maximize the 

efficiency of the research. 

• Patient advocacy group stimulation can 

support research efforts. Such groups 

capitalize on patient involvement to 

provide information for databases. Many 

patients with Barrett’s esophagus are 

motivated and compliant. Creative 

approaches are needed to stimulate 

advocacy for stomach and esophageal 

cancer subtypes that occur primarily in 

hard-to-reach populations. 
56 Report of the Stomach/Esophageal Cancers Progress Review Group

Surveillance/Databases 

Co-Chairs: Levine, Douglas and Sampliner, Richard, Sharma, Prateek

Participants: 

Blount, Patricia 

Cameron, Alan J. 

Lieberman, David 

Queirolo, Lewis 

Sandler, Robert 

Sonnenberg, Amnon 

Spechler, Stuart 

Overview/Background 

Information/Barriers 

Intestinal metaplasia is the premalignant 

lesion for adenocarcinoma of the esophagus 

and stomach. In the United States, 

esophageal adenocarcinoma has the most 

rapidly rising incidence of all cancers in 

White males. Current screening and 

surveillance for esophageal adenocarcinoma 

is based on endoscopic biopsies and the 

histologic confirmation of Barrett’s 

metaplasia. If Barrett’s metaplasia is 

diagnosed, follow-up endoscopic biopsy 

surveillance for evidence of dysplasia and/or 

early adenocarcinoma is warranted. No 

prospective evidence exists that shows that 

screening and surveillance of Barrett’s 

esophagus reduces the mortality from 

adenocarcinoma of the esophagus. Most 

patients who develop esophageal 

adenocarcinoma are unaware that they have 

Barrett’s esophagus, and they are not in a 

surveillance program. 

Barriers to effective screening and 

surveillance of Barrett’s esophagus include 

the expense of screening the at-risk 

population for the presence of Barrett’s 

esophagus; the expense of endoscopy with 

biopsy in low-risk Barrett’s patients; the 

technical difficulties of performing intensive 

systematic biopsy protocols and targeting 

small areas of endoscopically invisible 

dysplasia or cancer; the inter-observer 

disagreement in the reading of dysplasia; 

and the large numbers of patients and long 

duration of follow-up necessary to document 

effective screening and surveillance. 

Compared to esophageal adenocarcinoma, 

the incidence of gastric adenocarcinoma is 

at least twofold higher. The incidence of 

proximal gastric cancer was rising rapidly 

before recently leveling off. Barrett’s 

esophagus is associated with and may be the 

premalignant lesion for this cancer. The 

incidence of distal gastric cancer has 

decreased dramatically as has the prevalence 

of H. pylori infection. H. pylori infection 

results in a sequence of mucosal changes, 

including intestinal metaplasia, which can 

lead to gastric adenocarcinoma. 

The overall incidence of esophageal 

squamous carcinoma is approximately the 

same as that of esophageal adenocarcinoma, 

but it is at least twice as high in Black males 

than in White males. A premalignant lesion 

for esophageal squamous cell carcinoma is 

not recognized in the United States; however, in China, dysplasia, diagnosed by nonendoscopic brush cytology, is commonly 

recognized prior to the development of 

squamous cell cancer as part of mass 

population screening. 

The major barrier to screening and surveillance of these cancers is the lack of a 

well-defined, precancerous condition that is 

endoscopically visible. An important need is 

to identify patients at risk for gastric 

adenocarcinoma and esophageal squamous 

cell carcinoma who might benefit from 
Appendix B: Breakout Reports 57

screening and surveillance procedures. 

There is the global issue of what magnitude 

of increased cancer risk warrants screening 

and surveillance. 

NCI funding addresses two areas that may 

improve the clinical effectiveness and costeffectiveness of screening and surveillance 

strategies for Barrett’s esophagus. These 

areas include the optical detection of 

dysplasia by such methods as 

autofluorescence, RAMAN spectroscopy, 

light-scattering spectroscopy, and 

synchronous luminescence. Development of 

biomarkers in tissue samples—including 

array analysis, peptides, DNAploidy, p53 

mutation, Cox-2 expression, angiogenesis 

factors, retinoic acid receptor, iNOS, and 

telomerase—are being evaluated. NCI is 

also supporting an epidemiologic study of 

Barrett’s esophagus. 

Three Scientific Priorities and 

Rationales 

Priority 1: Establish a clinical research 

infrastructure with multispecialty and 

multi-institutional centers to perform 

surveillance to determine the natural 

history of the premalignant disease states. 

Rationale: Current studies do not allow risk 

stratification of patients with premalignant 

disease (epidemiologic and biomarkers), 

given the lack of validated prognostic 

markers. They do not provide statistical 

power for hypothesis testing, given the lack 

of sufficiently large sample sizes with 

adequate clinical outcomes. Finally, current 

tissue repositories are not linked to the 

clinical databases and actively managed 

patient populations in an effort to translate 

basic research into clinically relevant 

information. An infrastructure of this 

magnitude and detail would correct for 

all of these. 

Priority 2: Conduct population-based 

screening to identify patients at high risk 

for premalignant disease states. 

Rationale: The prevalence of premalignant 

disease states in the general population is 

currently undefined. Therefore, risk 

stratification criteria to increase costeffectiveness of screening have not been 

developed. Endoscopy is currently the 

screening method of choice; however, newer 

technologies that are more effective, more 

cost-effective, better tolerated, and safer 

need to be developed and promoted. 

Priority 3: Establish or merge databases 

for hypothesis generation and disease 

modeling to understand the natural history 

of these diseases. 

Rationale: More detailed databases will 

improve the identification of at-risk 

populations as well as assist in assessing 

costs of disease management and impacts on 

the quality of life of patients with 

premalignant conditions and cancer. Access 

to greater information can help guide the 

development of methodologies for clinical 

trials and protocols. Finally, more 

information from more sites will increase 

the generalizability of the findings. 

Infrastructure Needed To 

Accomplish Priorities 

Partnership Platforms 

• Link independent research centers for 

expanding the databases 

• Take advantage of multidisciplinary 

expertise for research on natural history 

of disease, new technologies for 

screening, and surveillance 

• Validate prognostic markers 
58 Report of the Stomach/Esophageal Cancers Progress Review Group

Expected Resources To Overcome 

Limitations of Previous Research and To 

Capitalize on Existing Opportunities 

• Patient cohorts 

• Multidisciplinary expertise (intellectual 

synergies) 

• Centralized tissue banks, pathology 

readings, and biomarker assessment 

• Standardized disease classification, data, 

and tissue collection 
Appendix B: Breakout Reports 59

Therapeutics 

Co-Chairs: Castell, Donald O; Hundahl, Scott and Rothenberg, Mace

Participants: 

Bowersox, Jon 

Govindan, Ramaswamy 

Haller, Daniel G. 

Jatoi, Aminah 

Leichman, Lawrence 

Patterson, Reese 

Willett, Christopher 

Overview/Background 

Information/Barriers 

Even though the esophagus and stomach 

share close proximity, cancers of these 

organs are distinct diseases. They differ both 

in etiology and in their reaction to therapy. In 

addition, esophageal cancer comprises two 

different types: squamous and 

adenocarcinoma. Nevertheless, both 

esophageal and gastric cancers require a 

coordinated, interdisciplinary approach to 

therapy. 

Stomach cancer. Worldwide, stomach 

cancer accounts for 9.9% of all reportable 

cancers, ranks as the second most frequently 

reported neoplasm, and is responsible for 

12.1% of all cancer deaths (Parkin et al., 

19991

). In the United States, stomach cancer 

was the most common solid tumor in the 

early 1900s, but it is now relatively 

uncommon, accounting for less than 2% of 

reported cancers (Greenlee et al., 20012

). 

The median age of afflicted patients in the 

United States is 68 years, and the impact of 

co-morbid disease on treatment selection 

must be considered. As many as 25% of 

gastric cancer patients receive no surgical 

treatment despite presenting in a treatable 

stage (Hundahl et al., 20003). Surgery, the 

mainstay of current treatment, carries notable 

morbidity and mortality. For example, inhospital surgical mortality in New York State 

for gastrectomy for cancer is 6.2%, with a 

clear volume-to-mortality relationship. 

Further, sub-optimal surgical treatment 

appears common. Clearly, strategies are 

needed to enhance the safety and efficacy of 

surgical treatment. 

Recently, the use of adjuvant postoperative 

chemoradiation resulted in about 40% 

survival, double the survival rate of surgery 

alone (Macdonald et al., 20014

). A recent 

surgical analysis (Hundahl et al., 20025) 

revealed that most cases had a high likelyhood of residual regional disease that could 

have been addressed by the surgeon; an index 

of residual regional nodal disease proved a 

significant independent predictor 

of survival. Patients with a low residualdisease index displayed a 60% survival rate 

compared with 25% for the rest of the group. 

Importantly, adjuvant chemoradiation 

appeared to improve survival in all surgicalpathologic subgroups. Enhanced localregional treatment appears to enhance 

survival, and chemoradiation increases 

survival for all subgroups. Nonetheless, at 

least 40% of the cases with apparent localregional disease still recur. Also, the optimal 

sequence of systemic treatment (biological or 

chemotherapeutic) and local-regional 

(surgical or radiotherapeutic) treatments 

remains undefined. 

For patients with metastatic disease being 

treated with multi-agent chemotherapy 

regimens, relative response rates of 50–60% 

are common. However, the complete 

response rate remains less than 10%, and 

survival remains brief (8 to 10 months). 
60 Report of the Stomach/Esophageal Cancers Progress Review Group

There is no consensus regarding the optimal 

chemotherapeutic regimen for these patients. 

Esophageal cancer. One of the remarkable 

characteristics of esophageal cancer during 

the past 30 years has been the change in 

predominant histologic subtype from 

squamous cell carcinoma to adenocarcinoma. 

There has been a 10- to 20-fold increase in 

the incidence of esophageal adenocarcinoma 

over the past 20 years, which represents the 

largest increase of any solid tumor during 

this period. Currently, the incidence of 

adenocarcinoma exceeds that of squamous 

cell carcinoma. The site of the primary lesion 

has migrated down from mid-esophagus to 

the lower esophagus/GE junction. All of 

these changes have definite therapeutic 

implications. 

Historically, surgery has been the cornerstone 

of treatment for patients with local (stage I) 

or locally advanced (stages IIA to III) cancer. 

However, the high rate of unresectability, 

coupled with the high rate of extra-regional 

disease, has challenged the notion of singlemodality treatment of esophageal cancer. 

During the past 15 years, studies of combined 

chemoradiotherapy generated encouraging 

results in phase II and phase III trials. 

Combined chemoradiotherapy is a valid 

alternative to surgery for patients with stage 

II or III (T3) disease. Whether long-term 

survival is increased through the use of 

trimodality therapy is an area of active 

investigation. In addition, the preferred 

timing of chemoradiotherapy in relation to 

surgery remains unknown. 

Esophageal cancer is highly symptomatic: 

90% of patients have dysphagia and weight 

loss at presentation. Fifty percent have 

odynophagia (pain on swallowing). Because 

many patients are symptomatic, symptom 

palliation is an important goal of therapy. 

Given the ease of access to the esophagus, 

therapeutic trials should make every attempt 

to include pre- and post-tissue collection and 

analysis. This could provide important 

predictive and prognostic information to 

guide future research directions. 

Three Scientific Priorities and 

Rationale for Each 

Priority 1: Develop meaningful anatomic 

and biological subsets of esophageal and 

gastric cancers. 

Rationale: There are at least four major 

anatomic subsets of gastroesophageal 

neoplasms. Overall similarity of outcomes 

belies the biological heterogeneity of these 

malignancies and the potential for differential 

sensitivity to newer therapies. 

Priority 2: Evaluate contributions of 

different treatment modalities for 

esophageal and gastric cancers and their 

proper integration and sequencing for 

optimal treatment outcomes. 

Rationale: Existing predictive models for 

gastric cancers based on clinicopathologic 

features may help in selection of optimal 

surgical treatment. In addition, molecularly 

based models could be developed to predict 

response, survival, and long-term outcomes 

to specific therapeutic interventions. 

Different treatments have different outcomes 

in mortality and morbidity. For example, 

surgery avoids adverse events associated 

with chemoradiotherapy, whereas chemoradiation avoids surgical-associated 

mortality. 

Priority 3: Expand a clinical trials network 

for these diseases to include multispecialty 

representation. 

Rationale: Low accrual makes it difficult to 

test new therapies. Trials should be expanded 

to include participation from gastroenterologists, epidemiologists, surgeons, 

pathologists, basic scientists, diagnostic 
Appendix B: Breakout Reports 61

radiologists, nutritionists, statisticians, 

specialists in outcome measures, and 

representatives of industry. 

Infrastructure Needed To 

Accomplish Priorities 

Partnership Platforms 

• Practitioner-focused tissue-acquisition 

programs oriented toward outcomelinked integrated research. 

• Clinical trial network explicitly to bring 

in all the different types of specialists. 

Expected Resources To Overcome 

Limitations of Previous Research and To 

Capitalize on Existing Opportunities 

Central office to coordinate and facilitate 

attracting interested practitioners to 

contribute tissue and to collaborate in clinical 

trials 

References 

1

Parkin DM, Pisani P, Farlay J. Global cancer 

statistics. CA Cancer J Clin 1999; 49(1):33–

64. 

2

Greenlee RT, Hill-Harmon MB, Murray T, 

Thun M. Cancer statistics 2001. CA Cancer J 

Clin 2001; 51(1):15–36. 

3

Hundahl SA, Phillips JL, Menck HR. The 

National Cancer Data Base Report on poor 

survival of U.S. gastric carcinoma patients 

treated with gastrectomy: Fifth edition, 

American Joint Committee on Cancer 

staging, proximal disease, and the “different 

disease” hypothesis. Cancer 2000; 

88(4):921–932. 

4

Macdonald JS, Smalley SR, Benedetti J, 

Hundahl SA, Estes NC, Stemmermann GN, 

Haller DG, Ajani JA, Gundersun LL, Jessup 

JM, Martenson JA. Chemoradio-therapy after 

surgery compared with surgery alone for 

adenocarcinoma of the stomach or 

gastroesophageal junction. N Engl J Med 

2001; 345(10):725–730. 

5

Hundahl SA, Macdonald JS, Benedetti J, 

Fitzsimmons T, for the Southwest Oncology 

Group and the Gastric Intergroup. Surgical 

treatment variation in a prospective, 

randomized trial of chemoradiotherapy in 

gastric cancer: the effect of undertreatment. 

Ann Surg Oncol 2002; 9(3):278–286. 
62 Report of the Stomach/Esophageal Cancers Progress Review Group

Tumor Models 

Co-Chairs: Wang, Kenneth and Rustgi, Anil; Wang, Timothy

Participants: 

Beer, David 

Burgart, Lawrence 

Ilson, David 

MacDonald, John 

Navtej, Buttar 

Silberg, Debra 

Tobey, Nelia 

Overview/Background 

Information/Barriers 

Models of esophageal and gastric cancers 

are necessary for dissecting biological, 

biochemical, and genetic pathways and for 

applying innovative diagnostic and 

therapeutic strategies. 

Historically, the vast majority of models 

have been based on carcinogen application 

in rodents, especially rats. A number of 

carcinogen-based animal models for upperGI cancers have been described in the past 

with respect to stomach cancer. The 

carcinogen MNNG has been used in the rat; 

and in the mouse, NMU has been used with 

variable success. In recent years, greater 

attention has been paid to H. pylori species 

as the more relevant and physiologic 

carcinogen for inducing stomach cancer. H. 

pylori has been shown to induce gastric 

cancer in mouse, ferret, and Mongolian 

gerbil models. 

With respect to esophageal cancer, DMBA 

and NMBA have been used in the rat, and to 

a lesser extent in the mouse, for inducing 

squamous papillomas and squamous cell 

carcinoma. These lesions are accentuated in 

the setting of various mineral deficiencies. 

From a surgical viewpoint, rats have been 

subjected to esophageal jejunostomy with 

resulting Barrett’s esophagus and 

esophageal adenocarcinoma. These lesions 

are accelerated in a p53-deficient 

background in the mouse. 

The mouse offers multiple opportunities for 

genetic approaches to understanding 

molecular mechanisms underlying 

esophageal and gastric cancers. Mutations in 

a number of genes have led to the 

development of premalignant or malignant 

tumors of the stomach. These include 

mutations in APC, SMAD-4, TFF-1, TGFbeta 1, and RUNX3. The Cdx2 gene can 

induce intestinal metaplasia in the stomach. 

Perturbations in cyclin D1 or EGFR have 

been demonstrated to induce esophageal 

squamous dysplasia in transgenic mice. 

When cyclin D1 mice are bred into a p53-

deficient background, there is development 

of esophageal squamous cancer. However, 

genetic models that recapitulate Barrett’s 

esophagus are lacking. Apart from these 

considerations, in vitro or cell-culture based 

models are in a nascent stage. 

Currently, primary mouse and human 

esophageal squamous epithelial cells have 

been established in culture. Recently these 

cells were placed in organotypic culture to 

recapitulate the stratified squamous 

epithelium. However, the role of oncogenes 

and tumor-suppressor genes in these cellculture models requires elucidation. There 

has been limited success in maintaining 

primary cultures of Barrett’s esophageal 

specimens. These particular cultures 

maintain the genotypic profile of the original 

tissues. There has been a wealth of 

utilization of transformed esophageal cancer 

cell lines. 
Appendix B: Breakout Reports 63

With respect to stomach cancer, there has 

been considerable work with transformed 

and non-transformed cell lines in culture and 

in nude mice and some recent work with 

gastric cancer spheroids. There are no cell 

lines representative of intestinal metaplasia 

of the stomach. 

Barriers to esophageal and gastric tumor 

models include a lack of identification of 

stem cells and markers for esophagus and 

stomach, a lack of stem-cell-specific 

promoters for use in animal models, a lack 

of centralized core facilities for cell lines 

and animal models, a lack of uniform 

criteria in mouse histopathology, and a lack 

of physiologic tools and approaches to 

animal models.

Three Scientific Priorities and 

Rationale for Each 

Priority 1: Create robust mouse models 

using hybrid techniques (genetic 

approaches, surgery, H. pylori infection) to 

define underlying molecular mechanisms 

of esophageal and gastric carcinogenesis. 

Rationale: Defining underlying molecular 

mechanisms would assist in elucidating 

biological and genetic mechanisms as well 

as in developing surrogate biomarkers. 

There is a strong need to test the efficacy of 

chemoprevention and therapeutic agents. 

Priority 2: Develop and characterize 

primary cells, immortalized cells, 

transformed cells, organ cultures, and 

organotypic cultures for studying stem-cell 

biology, intestinal metaplasia, and cancer 

in esophagus and stomach. 

Rationale: There is strong need to test 

biological mechanisms, investigate stem-cell 

biology, investigate stepwise progression to 

cancer, and test chemoprevention and 

therapeutic agents. Cooperative groups that 

share resources in these investigations 

would decrease duplicate efforts. 

Priority 3: Develop an immunocompetent 

rodent model of advanced disease. 

Rationale: There is a need to develop 

biomarkers for diagnosis and treatment 

stratification as well as to test targeted 

therapeutic agents. 

Infrastructure Needed To 

Accomplish Priorities 

Partnership Platforms 

Core facilities for the following: 

• Mouse models: Surgery, H. pylori

infection, breeding 

• Morphology: Histology interpretation, 

microdissection 

• Technology (devices) and imaging 

• Genomics/proteomics 

• Drug prioritization for testing 

Expected Resources To Overcome 

Limitations of Previous Research and To 

Capitalize on Existing Opportunities 

• NCI (UO1, SPORE, PO1) 

• AACR, AGA, ASCO, ACS 

• Industry (biotechnology, pharmaceutical, 

animal labs) 

• Cooperative oncology groups 
64 Report of the Stomach/Esophageal Cancers Progress Review Group 

Disease Sites 

Adenocarcinomas 

Co-Chairs: Tepper, Joel; Forastiere, Arlene and Blaser, Martin J; Spechler, Stuart

Participants: 

Beer, David 

Bernstein, Leslie 

Buttar, Navtej 

Cameron, Alan J. 

Chak, Amitabh 

Christie, Adrian J. 

Conner, Jerry 

Dehdashti, Farrokh 

DeMeester, Tom R. 

Falk, Gary 

Frazzitta, Bart 

Gammon, Marilie D. 

Govindan, Ramaswamy 

Hayman, James 

Henley, Donald 

Hamilton, Frank 

Hamilton, Stan 

Ilson, David 

Kumar, Rakesh 

Levine, Douglas S. 

Lieberman, David 

Lines, Stephen 

MacAulay, Calum 

Mayne, Susan 

Nyren, Olof 

Powell, Steven 

Richmond, Ellen 

Rodriguez, Luz M. 

Romero, Yvonne 

Rothenberg, Mace 

Sampliner, Richard 

Silberg, Debra 

Sivak, Michael 

Souza, Rhonda 

Srivastava, Sudhir 

Stoner, Gary 

Tell, Robert 

Tobey, Nelia 

Triadafilopoulos, George 

Vaughan, Thomas 

Wang, Kenneth K. 

Weston, Allan 

Willett, Christopher 

Wu, Anna 

Overview/Background 

Information/Barriers 

Barrett’s esophagus, a metaplastic change in 

the esophageal lining from normal squamous 

epithelium to columnar intestinal-type 

epithelium, is recognized as a common 

sequela of gastroesophageal reflux disease 

(GERD), developing in approximately 10–

15% of persons with reflux disease. Because 

people with Barrett’s esophagus display 30–

40 times the incidence of esophageal 

adenocarcinoma found in the general 

population, GERD and Barrett’s esophagus 

have been identified as major risk factors 

predictive of esophageal adenocarcinoma. 

Each year, approximately 0.5% of patients 

with Barrett’s esophagus develop esophageal 

adenocarcinoma. The tumors occur 

predominantly among White males, and the 

incidence has quadrupled since the mid1970s. During the same period, the incidence 

of adenocarcinomas of the gastric cardia 

(upper stomach) has also increased 

dramatically. 

With the increased occurrence of both 

esophageal and gastric cardia adenocarcinomas, it is important to identify these 

tumors as either esophageal or gastric in 

origin for both diagnostic and therapeutic 

reasons. The distinction between tumors of 

the proximal stomach or the distal esophagus 

is frequently a difficult one, especially when 

a tumor straddles the gastroesophageal (GE) 

junction. For glandular cancers that cross the 

GE junction, this situation is even more 

complex, because glandular elements may 

arise from either side of the GE junction. 

To date, no test is able to determine 

unequivocally where the tumor arose. A 

major problem confounding investigations of 

tumors of the GE junction is the lack of 

standardized anatomic landmarks that could 

clearly delimit the extent of the gastric 

cardia. The gastric cardia has been variously 

described as comprising a rim as wide as 1-2 

cm to as little as 1-4 mm adjacent to the GE 

junction. Factors such as hiatal hernia or the 

distortion accompanying a lesion make 

anatomical localization even more difficult. 
Appendix B: Breakout Reports 65

The common precursor lesion to these three 

anatomic areas (distal esophagus, GE 

junction, and gastric cardia) is intestinal 

metaplasia. However, the pathways to 

intestinal metaplasia differ depending on its 

site of origin. In the esophagus, GERD 

appears to be a key in the development of 

intestinal metaplasia. In addition to GERD 

and Barrett’s esophagus, factors that increase 

the risk of developing intestinal metaplasia 

include obesity, diet, and perhaps smoking. 

The roles of other potential environmental 

exposures are yet to be evaluated. 

Despite the strong evidence of a relationship 

between GERD and adenocarcinomas, 40% 

of patients diagnosed with these tumors give 

no history of GERD or Barrett’s esophagus. 

Large gaps in current epidemiological data 

about GERD and Barrett’s esophagus have 

resulted from difficulties in defining, 

recognizing, and verifying both conditions. 

In addition, environmental risk factors 

remain ill defined. An effective screening 

protocol has yet to be developed, because it 

is difficult to identify those actually at risk. 

Most clinical trials fail to distinguish among 

adenocarcinomas from the esophagus, GE 

junction, cardia, or distal gastric cancers. In 

fact, even the most recent staging system 

does not distinguish between these cancers. 

As a result, very little data exist on either 

single or combined modality therapies 

focused on this entity. Incorporating 

chemotherapy and radiation into primary 

treatments has made some progress, but the 

benefits of platinum-based therapies have 

reached a plateau. Both screening and 

therapies present significant quality of life 

issues as they can cause patient morbidity. 

Further improvements in outcomes will 

require a major change in strategy, such as 

incorporating molecular characterization of 

the adenocarcinomas in order to optimize 

both diagnostic and therapeutic protocols. 

Three Scientific Priorities and 

Rationale for Each 

Priority 1: Elucidate the mechanisms by 

which host and environmental factors 

interact in the development of metaplasia in 

the stomach and esophagus and its 

progression to cancer, and apply this 

knowledge to develop prevention strategies, 

improve therapeutics, and diagnostics.

Rationale: These cancers represent a 

multidecade process, and they progress in an 

orderly fashion from intestinal metaplasia to 

dysplasia and invasive disease. Preliminary 

studies implicate disorders involving gastric 

acid, bile, exposure to nitrosamines, and 

possibly a protective effect of H. pylori

colonization in the development of these 

conditions. Ascertainment of mechanisms, 

especially at the molecular level, may allow 

preventive steps. 

Priority 2: Develop a molecular 

characterization of adenocarcinoma of the 

esophagus, GE junction, and cardia for 

classification and staging, and compare 

with other foregut malignancies to help 

define causation and to develop and apply 

novel and specific therapies. 

Rationale: The mortality rates for these 

adenocarcinomas remain unacceptably high 

compared to many other cancers for which 

major therapeutic advances have occurred. 

Currently, the clinical management of 

adenocarcinomas of the distal esophagus, 

GE junction, and cardia has not been 

distinguished from that of squamous cancers 

and distal gastric cancers. These tumors are 

arbitrarily classified as either gastric or 

esophageal cancers. This arbitrary 

categorization impairs knowledge of 

causation and true incidence, as well as 

making it difficult to define differences that 

could be important in the development of 
66 Report of the Stomach/Esophageal Cancers Progress Review Group 

novel therapeutics. There is an urgent need to 

identify potential markers of response or 

resistance to therapy and molecular pathways 

that could be targeted by specific therapies. 

Priority 3: Target screening to populations 

at greatest risk by first defining the 

prevalence of premalignant lesions and 

associated risk factors in populations of 

diverse ethnicity not seeking medical 

attention, and then defining the natural 

history of these lesions. 

Rationale: The vast majority (95%) of 

patients presenting with adenocarcinoma of 

the esophagus were not known to have any 

premalignant lesions. Thus, there is a need to 

detect more quickly individuals at increased 

risk. In particular, knowledge of the extent of 

these lesions in members of minority groups 

is limited, and there is good reason to suspect 

that important differences exist. Understanding the natural history of these lesions is 

important to develop strategies for 

appropriate interventions. Better knowledge 

of risk factors should lead to improved 

diagnostics for identification of at-risk 

individuals. 

Infrastructure Needed To 

Accomplish Priorities 

Partnership Platforms 

• Develop a multidisciplinary consortium 

to identify the epidemiological, 

molecular, and clinical/pathologic 

parameters of esophageal, GE junction/ 

cardia adenocarcinoma development and 

translate them into clinical trials 

• Partner with industry 

• Create interinstitutional cooperation with 

NIAID, NIDDK, NIA, Department of 

Veterans Affairs, DOD, and CDC 

Expected Resources To Overcome 

Limitations of Previous Research and To 

Capitalize on Existing Opportunities 

• Support for tissue acquisition, 

classification, and storage 

• Bioinformatics and biostatistical core 

• Imaging facilities 
Appendix B: Breakout Reports 67

Gastric 

Co-Chairs: Ajani, Jaffer; Coit, Daniel and Correa, Pelayo; Macdonald, John

Participants: 

Bloom, Bernard 

Burgart, Lawrence 

Chow, Wong-Ho 

Daschner, Phillip 

Fontham, Elizabeth 

Fox, James 

Goodman, Karen 

Helft, Paul 

Hundahl, Scott 

Lugo, Tracy 

Mayne, Susan 

Meltzer, Stephen 

Michaels, Margo 

Mori, Yuriko 

Moss, Steven 

Patterson, Reese 

Peek, Richard, 

Rabeneck, Linda 

Richmond, Ellen 

Rodriguez, Luz 

Rothman, William 

Selaru, Florin 

Shibata, David 

Wang, Timothy 

Ward, Mary 

Welch, Michael 

Weston, Allan 

Willett, Christopher 

Overview/Background 

Information/Barriers 

Gastric cancer will occur in 21,900 patients 

this year and cause 13,500 deaths in the 

United States. Worldwide, gastric cancer 

will occur in 798,000 patients. The most 

common known antecedent to the 

development of gastric cancer is prior 

infection with H. pylori with subsequent 

development of chronic gastritis. Host and 

environmental factors modulate the process 

of carcinogenesis. H. pylori infection is not 

inevitably associated with the development 

of gastric cancer, and it is unknown whether 

the eradication of H. pylori will decrease the 

risk of gastric cancer. 

The conventional therapy of primary gastric 

cancer is based upon enbloc surgical 

resection of the stomach tumor and the 

draining lymph nodes. In the United States, 

overall 5-year survival after gastric resection 

is approximately 20%. Because of the high 

relapse rate after gastric resection, extensive 

studies of adjuvant chemotherapy have been 

performed. There is no solid evidence that 

patients benefit from this approach. 

However, a recent NCI intergroup phase III 

trial of postresection chemoradiation versus 

surgery alone demonstrated significant 

improvement in disease-free and overall 

survival. In the United States, postoperative 

chemoradiation is now considered a standard 

of care for patients at risk for recurrence 

following resection. 

The use of preoperative chemotherapy or 

chemoradiation therapy (neoadjuvant 

therapy) produces objective responses in as 

many as 50% of patients with primary 

gastric cancer. This therapeutic approach has 

not been evaluated in phase III trials and, 

thus, must be considered investigational in 

the management of gastric cancer. 

Conventional staging techniques 

(particularly T and N) do not adequately 

predict the heterogeneity of patient 

outcomes. Novel molecular staging 

techniques may assist not only in more 

accurately predicting outcome but also in 

guiding treatment decisions, including extent 

of surgery, use of adjuvant chemotherapy, 

radiation therapy, and/or biologic therapy. 

Current measurements of outcome in 

patients treated for gastric cancer are 

inadequate. Assessment of tumor- and 

treatment-related morbidity is critical, and 
68 Report of the Stomach/Esophageal Cancers Progress Review Group 

data measuring quality of life (QoL) are 

scant. There is a need to disseminate 

guidelines for optimal treatment in this 

disease. 

Three Scientific Priorities and 

Rationale for Each 

Priority 1: Use multidisciplinary research 

approaches to understand the interactions 

of various strains of H. pylori, host factors, 

and other lifestyle/environmental factors in 

gastric carcinogenesis. 

Rationale: Chronic inflammatory states are 

commonly associated with carcinogenesis. 

H. pylori infection is recognized as a 

common precursor to gastric cancer. The 

availability of human, animal, and H. pylori

genomics offer a unique opportunity to study 

the mechanisms of gastric carcinogenesis. 

This type of approach may evolve into a 

template for the study of other cancers. 

Priority 2: Develop novel methods, using 

molecular profiling of gastric neoplasia, to 

stratify patients into risk groups to help 

direct therapeutic decision-making. This 

would include sequential and anatomic 

mapping of alterations in tumor compared 

to adjacent nonmalignant tissue. It would 

also include genomic and bioinformatic 

approaches to create comprehensive 

profiles of these lesions. 

Rationale: Conventional staging is 

inadequate for assessing prognosis and 

optimizing treatment decisions. The 

application of current therapies is largely 

empiric. The opportunity to understand 

molecular profiles may lead to the 

identification of new targets and new 

therapies. 

Priority 3: Measure outcomes of diagnostic 

and treatment strategies, including early 

detection, response to treatment, survival, 

QoL, and quality and cost of care in 

patients with gastric cancer. This would 

include the application and/or development 

of disease-specific QoL instruments. 

Rationale: While the clinical endpoints of 

relapse and death are often reported, there 

are very few tools to measure the functional 

outcome and QoL of patients treated for 

gastric cancer. Tumor and treatment-related 

morbidity is substantial and often affects not 

only relapse/survival rates, but also treatment 

decisions. QoL tools and functional 

measurements become imperative as 

increasing numbers of patients are cured of 

disease, as a result of early detection or 

multimodality therapy. Long-term functional 

sequelae in patients treated for gastric cancer 

are undefined. 

Infrastructure Needed To 

Accomplish Priorities 

Partnership Platforms 

• Establish close interactions with the NCI 

Office of Communications to use the 

resources of the Federal Government to 

distribute uniform information in a 

thoughtful and effective way. 

• Emphasize interactive relationships and 

incentives to encourage adherence to 

guidelines. 

• Establish partnerships with other NIH 

institutes, Department of Defense, and 

Veterans Administration, and industry. 

International collaborations in highprevalence populations will facilitate 

more efficient and complete understanding of disease and the development 

of more effective interventions. 

Expected Resources To Overcome 

Limitations of Previous Research and To 

Capitalize on Existing Opportunities

• Explore the development of an 

international, interactive, 
Appendix B: Breakout Reports 69 

interdisciplinary, multi-institutional 

consortium for gastric cancer, possibly 

joining with other gastrointestinal 

disease. 

• Establish an international H. pylori

species bank.
70 Report of the Stomach/Esophageal Cancers Progress Review Group 

Squamous 

Co-Chairs: Hamilton, Stanley R.; Castell, Donald O. and Orlando, Roy C; Leichman, Lawrence 

Participants: 

Brooks, Jo Ann 

Dawsey, Sandy 

DeMeester, Thomas 

Donaldson, Molla 

Fischman, Alan 

Georgakoudi, Irene 

Hamilton, Frank 

Holland, Jimmie 

Ilson, David 

Jatoi, Aminah 

Knisley, Eric 

Okunieff, Paul 

Queirolo, Lewis 

Rowland, Julia 

Sandler, Robert 

Silberg, Debra 

Sivak, Michael 

Sonnenberg, Amnon 

Stoner, Gary 

Taylor, Philip 

Tobey, Nelia 

Wojcik, Brian 

Overview/Background 

Information/Barriers 

Esophageal squamous cancer is uncommon 

in the U.S. population, accounting for 6,000 

cases each year, with the incidence 

decreasing. The histopathologic subtype of 

squamous cell carcinoma is now less 

common than esophageal adenocarcinoma. 

However, the occurrence of esophageal 

squamous cell carcinoma is known to relate 

to well-recognized socioeconomic, lifestyle, 

and demographic factors that identify highrisk groups. The vast majority of cases occur 

in males, and the incidence is about 15 per 

100,000 population in non-White males, as 

contrasted with about 2 per 100,000 in White 

males. 

Few cases occur in the absence of known 

predisposing conditions that include tobacco 

use (in common with other upperaerodigestive squamous cell carcinomas), 

alcohol consumption, a history of caustic 

injury to the esophagus, human papilloma 

virus infection, or tylosis and other rare 

genetic syndromes. Nonsteroidal antiinflammatory drugs and a diet rich in fruits 

and vegetables are reported to have 

protective benefit, giving additional clues to 

possible prevention strategies but without 

evidence for the phase of initiation and 

progression at which the effects may occur. 

Also, the incidence rate is nearly equaled by 

the mortality rate, and medical care for 

patients with advanced disease is complex 

and expensive, indicating that improvements 

in therapy and end-of-life care are needed. 

The NCI funding portfolio for esophageal 

squamous cell carcinoma is small and heavily 

weighted toward treatment research, 

especially clinical trials that also include 

patients with esophageal adenocarcinoma. In 

terms of absolute dollars and as a proportion 

of research funding, there is a much lower 

allocation of NCI funds dedicated to the 

biology of squamous esophageal cancers than 

other tumor types (7% versus 24%). The 

characteristics of esophageal squamous cell 

carcinoma and the current research 

environment suggest opportunities for 

initiatives to attempt to improve population 

incidence, morbidity, and mortality of 

individuals with the disease. 

Three Scientific Priorities and 

Rationale for Each 

Priority 1: Further define the molecular 

events involved in the multistage process of 

squamous cell carcinoma development in 
Appendix B: Breakout Reports 71 

the human esophagus with a focus on 

different ethnic groups and geographic 

locations. Clarify the similarities and 

differences in development of esophageal 

adenocarcinoma. 

Rationale: To elucidate the process of 

oncogenesis in squamous cell esophageal 

cancers, the molecular genetic events 

involved in this process must be defined. 

This opportunity is afforded by the 

esophageal mucosa because it can be targeted 

for serial biopsies over time. Consequently, 

this characteristic enables serial examination 

of the molecular processes in oncogenesis, 

tumor prevention (environmental risks and 

chemoprevention), and tumor progression 

before and after treatment. 

Priority 2: Characterize the molecular, 

cellular, and epidemiological features of 

squamous cell carcinoma of the esophagus, 

with the goal of using these findings to 

identify diagnostic, prognostic, predictive, 

and therapeutic targets. 

Rationale: Intratumoral markers and targets 

are essential to developing molecular and 

physiological imaging and diagnostic 

strategies that are less invasive, and treatment 

strategies that are more efficacious and less 

toxic than existing modalities. Therapeutic 

programs should be developed to enhance 

quality of life (QoL) considerations for the 

affected patient population. 

Priority 3: Develop clinically relevant 

human or genetically defined animal 

models of established squamous cell 

carcinoma and its premalignant phase. 

Rationale: Few clinically relevant animal 

models of esophageal squamous cell 

carcinomas exist. Animal models are 

essential to understanding the development 

of esophageal cancers and to identifying host 

interactions with various environmental 

agents that increase disease risk. Consequently, study of animal models is key in the 

process of translating basic research into 

effective clinical methods for prevention, 

screening, and treatment. Moreover, in this 

low-prevalence disease, cell line xenografts, 

and animal models provide an economic use 

of resources from which valuable material 

can be obtained to study diagnostic, 

therapeutic, and chemopreventive 

approaches. 

Infrastructure Needed To 

Accomplish Priorities 

Partnership Platforms 

Develop consortia of investigators who treat 

patients with squamous cell esophageal 

carcinoma to collaborate in studies of its 

epidemiology and natural history. 

Collaborative groups should collect cancer 

and premalignant tissue, and contribute to the 

conduct of the genetic and biology studies 

outlined in the above priorities. 

• Establish a clinical research infrastructure 

with multispecialty and multiinstitutional centers to perform surveillance in 

an effort to determine the natural history 

of the premalignant state. 

• Minorities and high-risk populations 

should be targeted for prevention efforts. 

The QoL issues in cancer survivors and 

predictors of survivorship in patients who 

have esophageal cancer should be 

studied. Public education programs 

should be developed to publicize the links 

between esophageal cancer, smoking, and 

alcohol. 

• Continue the clinical trials of esophageal 

squamous carcinoma as a feature of GI 

Committees of the existing Cooperative 

Oncology Groups. 
72 Report of the Stomach/Esophageal Cancers Progress Review Group 

Expected Resources To Overcome 

Limitations of Previous Research and To 

Capitalize on Existing Opportunities 

• Increased funding from a variety of 

sources to support human and animal 

tissue banks as well as databases. 

• Rapid, flexible, and adequate funding 

mechanisms for cooperative groups and 

institutions conducting clinical trials to 

enable them to engage in real time, 

collaborative studies to validate existing 

markers based on levels of evidence. 

These resources should be applied to 

validation of laboratory methodologies, 

tissue and blood collection, quality 

control/quality assurance of research 

materials, database tracking, 

prioritization, and specimen distribution 

with established minimum standard of 

performance in the clinical trials setting. 

• Development of consortia of 

investigators, NCI, and local agencies 

where these cancers are prevalent. 

• Sponsorship of nationwide workshops for 

investigators and public health personnel 

to highlight the relationship between 

smoking and squamous cell carcinomas 

of the esophagus and other organs. 
Appendix B: Breakout Reports 73 

Population Management 

At Risk 

Co-Chairs: Tell, Robert; Meltzer, Stephen and Rustgi, Anil; Christie, Adrian 

Participants: 

Balakrishnan, Krishna 

Blaser, Martin J. 

Daschner, Phillip 

Donaldson, Molla 

Goodman, Karen J. 

Hornbrook, Mark C. 

Kumar, Rakesh 

Lieberman, David 

Michaels, Margo 

Moss, Steven 

Nyren, Olof 

Orlando, Roy C. 

Peek, Richard 

Queirolo, Lewis 

Rabeneck, Linda 

Romero, Yvonne 

Sivak, Jr., Michael V. 

Souza, Rhonda 

Srivastava, Sudhir 

Tobey, Nelia A. 

Vaughan, Thomas 

Willett, Christopher 

Wu, Anna 

Overview/Background 

Information/Barriers 

Currently, there is no way to identify 

everyone who is at risk for gastric cancer, 

esophageal adenocarcinoma, and esophageal 

squamous cancer. The mortality rate of 

approximately 95% indicates that a majority 

of patients are not presenting with earlystage cancer. Moreover, adequate markers 

are not available to predict which patients 

will develop Barrett’s esophagus, gastric 

intestinal metaplasia, or squamous dysplasia. 

To the best of our knowledge, existing 

markers have only been tested in patients 

with Barrett’s esophagus or gastric cancer, 

esophageal adenocarcinoma, and esophageal 

squamous cancer, and have not been tested 

in the general population, which includes the 

at-risk population. For example, inactivation 

of the tumor-suppressor gene p53 is known 

to occur early in esophageal 

adenocarcinogenesis, but it has never been 

studied in asymptomatic patients without 

Barrett’s esophagus. Similarly, 

hypermethylation of the familial polyposis 

gene APC occurs in the tissues of 92% of 

tumors and 25% of sera from patients with 

esophageal adenocarcinoma. 

Little accurate information on gastric cancer, 

esophageal adenocarcinoma, and esophageal 

squamous cancer is readily available to the 

general public. With the advent of an 

enormous array of information on the 

Internet, many patients who are diagnosed 

with Barrett’s esophagus quickly obtain 

erroneous or misleading information, or none 

at all. They need tools to effectively evaluate 

this information, to learn about their options, 

and to make informed decisions. In addition, 

some general practitioners, other primary 

care physicians, and gastroenterologists have 

insufficient knowledge of gastric cancer, 

esophageal adenocarcinoma, and esophageal 

squamous cancer, or their precursors, due to 

the rarity of these diseases. Providing 

information to practitioners as well as to 

educational media that can best meet the 

needs of those at risk is important. 

Our understanding of host/environment 

interactions in gastric cancer, esophageal 

adenocarcinoma, and esophageal squamous 

cancer is limited. For example, we know that 

acid and H. Pylori induce cyclooxygenase 

(Cox)-2 expression in vitro. However, we 

know little about other pathways or genes 

involved in the host’s response to 

environmental risk factors. An improved 

understanding of these interactions would 
74 Report of the Stomach/Esophageal Cancers Progress Review Group 

generate new biomarkers to identify patients 

at risk for premalignant and malignant 

lesions. Moreover, insights into the biology 

of these interactions could have far-reaching 

ramifications for other human premalignant 

syndromes, particularly those related to 

chronic inflammatory states. 

Many millions of dollars currently are spent 

on treating both premalignant and malignant 

gastric and esophageal lesions. For example, 

proton pump inhibitors are used widely (and 

perhaps indiscriminately) to treat a broad 

array of symptoms. More precise diagnosis 

and disease classification could result in 

more discriminate use of these agents, 

yielding significant cost savings. 

Several barriers to identifying the at-risk 

population exist. First, no uniform 

classification system is available for the 

different cancer subtypes. Moreover, 

interventions affect the natural history of 

these diseases at both the testing (e.g., H. 

pylori) and treatment levels (e.g., proton 

pump inhibitors, antibiotics, nonsteroidal 

anti-inflammatory agents). In addition, with 

the decreasing prevalence of H. pylori and 

the relatively low prevalence of gastric 

cancers, esophageal adenocarcinomas, and 

esophageal squamous cancers, studies with 

large numbers of patients are difficult to 

conduct. International collaborations would 

be instrumental in addressing this need. 

Finally, the genomic diversity of populations 

within the United States and in other 

countries makes population studies 

challenging. 

Three Scientific Priorities and 

Rationale for Each 

Priority 1: Implement broad-based, 

integrated, population-based, endoscopic, 

multi-institutional studies to define 

environmental, clinical, and laboratory 

markers in an effort to identify groups at 

risk for gastric cancer, esophageal 

adenocarcinoma, and esophageal 

squamous cancer. 

Rationale: A study of this magnitude would 

assist in defining lifestyle, dietary, environmental, and genetic factors affecting risk, 

which is important because cancers of the 

esophagus and stomach often present at a 

late stage. With improved screening 

procedures to identify patients at risk, 

more patients could be treated earlier. 

Additionally, a large study could determine 

whether endoscopy reduces mortality, which, 

in turn, would help better define risk factors 

as a platform for stratifying who should and 

should not be screened. 

Priority 2: Educate health care 

professionals and the general public 

regarding risk for gastric cancer, 

esophageal adenocarcinoma, and 

esophageal squamous cancer and their 

precursor states. 

Rationale: Presumably, more at-risk patients 

would self-identify and seek treatment 

earlier if a risk profile were disseminated to 

the public and health care professionals. 

Mortality and morbidity could decrease with 

well-developed tools to establish an 

educational infrastructure and disseminate 

information. 

Priority 3: Identify, define, and validate 

biomarkers (genetic, biochemical, 

biological) that stem from interactions 

between host and environmental factors 

specific to esophageal and gastric 

carcinogenesis (e.g., H. pylori, acid, bile, 

nitrosamines), using appropriate in vivo 

and in vitro models. 

Rationale: Genomics and proteomics could 

assist in discovering novel genes and 

biomarkers, which, in turn, could assist in 

developing strategies for more effective risk 

stratification and prevention of cancer in the 

stomach and esophagus. 
Appendix B: Breakout Reports 75 

Infrastructure Needed To 

Accomplish Priorities 

Partnership Platforms 

• Form a national consortium of 

gastroenterologists, epidemiologists, 

pathologists, bioinformatics specialists, 

and other related specialists to conduct 

multicenter, interdisciplinary studies. A 

proposed name for this consortium is 

Validate, Identify, Discover, and Adapt 

(VIDA). 

• HMO Research Network. 

• Tap into existing professional societies 

and advocacy groups, and encourage the 

creation of new advocacy groups, where 

a need exists. 

• Industrial partnerships to move new 

technologies forward. 

• Enhance and expand large-scale studies 

by incorporating community hospitals as 

well as multiple academic centers. 

Expected Resources To Overcome 

Limitations of Previous Research and To 

Capitalize on Existing Opportunities 

• Attract more researchers to the field of 

gastric cancer, esophageal 

adenocarcinoma, and esophageal 

squamous cancer. 

• Use information technology to increase 

awareness. 

• Develop tissue banks (esophagus, 

stomach) for large, multicenter studies. 

• Develop blood banks (DNA, RNA, H. 

pylori genotyping) for large multicenter 

studies, as well as host/environment 

interactions. 

• Develop questionnaires for demographics, dietary factors, environmental 

factors. 

• Linkages to existing and new databases. 

• Develop common data elements. 

• Provide incentives for collaboration. 

• Bioinformatics and statistics core 

(medical and genomic) to support 

priority 1. 

• Identify the minority of patients with 

known risk factors who develop 

esophageal and gastric cancers. 
76 Report of the Stomach/Esophageal Cancers Progress Review Group 

Premalignant 

Co-Chairs: DeMeester, Tom R; Fennerty, Brian and Sampliner, Richard 

Participants: 

Beer, David 

Bernstein, Leslie 

Blount, Patricia 

Cameron, Alan J. 

Castell, Donald 

Correa, Pelayo 

Dawsey, Sandy 

Falk, Gary 

Georgakoudi, Irene

Goldblum, John R. 

Govindan, Ramaswamy 

Hamilton, Frank A. 

Hamilton, Stanley R. 

Hundahl, Scott 

Knisley, Eric 

Leichman, Lawrence 

Levine, Douglas S. 

MacAulay, Calum

Mayne, Susan 

Provenzale, Dawn 

Rodriguez, Luz 

Rothman, William 

Selaru, Florin M. 

Silberg, Debra 

Spechler, Stuart 

Triadafilopoulos, George 

Wang, Timothy C.

Overview/Background 

Information/Barriers 

There are well-described and identifiable 

premalignant lesions that precede esophageal 

squamous cell carcinoma, esophageal 

adenocarcinoma, and gastric 

adenocarcinoma: squamous dysplasia, 

Barrett’s esophagus, and gastric intestinal 

metaplasia. These premalignant lesions are 

well described in part because they remain in 

situ for long periods, which allows them to 

be identified and studied. Some groups, such 

as African American males, are at higher risk 

for developing esophageal squamous cell 

carcinoma, and other contributing exposures, 

such as alcohol consumption and smoking, 

have been linked to these diseases. Other 

groups, such as Caucasian males, are at 

higher risk for developing esophageal 

adenocarcinoma, a cancer that has been 

linked to gastro-esophageal reflux disease. 

Of particular interest, esophageal 

adenocarcinoma is the cancer with the most 

rapidly rising incidence in the United States. 

Helicobacter infection is strongly associated 

with gastric adenocarcinoma across ethnic 

groups. 

Barriers exist to the identification of 

premalignant lesions. Endoscopic biopsy 

histology is required for diagnosis of these 

lesions that cannot be detected by a routine 

history and physical examination. Another 

barrier to early identification of these 

diseases is that gastric and squamous 

precursor lesions cannot be seen in a routine 

endoscopic screening examination, and 

symptoms related to these lesions or their 

associated etiologic conditions can overlap 

broadly with other diseases. For example, 

many patients visit their physicians for 

reflux, and approximately 12% of these 

patients have Barrett’s esophagus; however, 

cancer is rarely identified at this early stage, 

and many of those with adenocarcinoma do 

not have reflux. Conversely, 95% of those 

with adenocarcinoma have not been 

diagnosed previously with Barrett’s 

esophagus. 

Little is known regarding the natural history 

of these lesions. As yet, it is unclear whether 

current screening or surveillance strategies 

are effective in preventing malignant 

transformation or reducing mortality from 

these cancers. Many other factors regarding 

these lesions also remain unknown, 

including who is and is not at risk for 

acquiring them, their biology, including the 

process of carcinogenesis, the optimal 

management of individuals at risk, and what 
Appendix B: Breakout Reports 77 

can be done to reduce their risk. What we 

know is limited because precancer is not 

always a reportable disease; existing cancer 

registries rarely include these premalignant 

lesions; and burdening physicians with 

recording more information is often viewed 

as an additional barrier. 

Clinical issues include whom, when, and 

how often, or even whether, we should 

screen and survey individuals at risk. 

• What technologies are applicable for 

improving screening and surveillance 

strategies? 

• What is the optimal treatment of early 

neoplastic and nonneoplastic 

premalignant upper gut lesions? 

• What is the natural history of these 

lesions? 

• What are the outcomes of untreated and 

treated lesions? 

• Are screening, surveillance, and 

treatment of these lesions cost-effective? 

Without answers to these questions, it is 

difficult for us to focus on preventing the 

disease. 

Currently, NIH funding for studies of the 

premalignant lesions that precede these 

cancers is very limited and includes one 

early detection project for squamous 

dysplasia in China; one risk stratification 

project for Barrett’s esophagus in the United 

States; and two funded gastric preneoplasia 

studies in Mexico. 

Three Scientific Priorities and 

Rationales 

Priority 1: Establish the prevalence of 

preneoplastic lesions (squamous dysplasia, 

Barrett’s esophagus, and gastric intestinal 

metaplasia) in the U.S. population for 

esophageal squamous cell, adenocarcinoma, and gastric cancer by performing a 

population-based endoscopic screening 

study. 

Rationale: Impact of cancer outcomes 

requires a better characterization of these 

cancers in their premalignant disease states. 

Additionally, there are large potential 

populations at risk for these cancers (GERD, 

H. pylori, alcoholism, smoking, obesity), 

thus lending credibility to population-based 

prevalence studies. Within these at-risk 

populations, high-risk and low-risk or norisk subjects can be identified through 

endoscopic biopsy and stratified for longitudinal study, because the lesions are not 

typically removed, unlike other premalignant 

processes (e.g., the adenomatous polyp). 

Further adenocarcinoma of the esophagus 

remains the cancer with the most rapidly 

rising incidence in the United States, so an 

accurate estimate of the prevalence of its 

precursor lesions and evaluation of their 

population distribution are essential. Such a 

research initiative would allow for the 

establishment of risk stratification (molecular, environmental, and epidemiological) for 

these lesions. An additional benefit of this 

initiative is the potential to measure patientcentered issues, such as the impact of 

identifying these premalignant lesions on 

functional status and quality of life. Finally, 

establishment of risk stratification allows a 

concentration of resources directed at 

individuals and populations at risk of disease 

progression. 

Priority 2: Establish risk stratification for 

these premalignant lesions by the formation 

of a multi-institutional cohort registry of 

patients drawn from screening studies and 

current surveillance practices. 

Rationale: Establishment of a cohort of 

subjects with upper gastrointestinal 

premalignant lesions would provide 

opportunities for addressing the natural 
78 Report of the Stomach/Esophageal Cancers Progress Review Group 

history of these lesions, opportunities for 

further risk stratification of patients with 

these lesions, and opportunities for 

investigating the genetic and biologically 

controlling events in the carcinogenic 

process. This, in turn, would provide opportunities for intervention studies aimed at 

preventing disease progression and would 

serve as a resource for evaluating and 

developing novel invasive and noninvasive 

diagnostic technology applications. 

Importantly, the premalignant lesions of 

these cancers remain in situ, which allow 

them to be followed and studied over time. 

This makes them a good model for studying 

carcinogenesis in these and other cancers. 

Priority 3: Establish noninvasive 

technologies, such as serum markers and 

imaging techniques, for screening and 

surveillance of these premalignant lesions. 

Rationale: At present, there is little or no 

funding on a national level for development 

of new technologies that has enormous 

potential for identifying these early lesions. 

Accurate identification of these lesions, 

especially in asymptomatic people, would 

allow real population screening, which 

would give us true prevalence figures and let 

us see the geographic and population 

variability of these lesions. Unlike some 

other malignant processes, higher risk 

populations for these diseases are identifiable, and the malignancies are associated 

with larger organ field defects that can be 

more reliably studied (e.g., long-segment 

Barrett’s esophagus). Additionally, the same 

new technologies can probably be used for 

earlier detection and treatment of these 

curable premalignant and early malignant 

lesions, which should reduce the morbidity 

and mortality of these cancers. 

Infrastructure Needed To 

Accomplish Priorities 

Partnership Platforms

• No single center possesses the resources 

necessary for addressing any of these 

three priorities. Moreover, single center 

studies, by nature, preferentially exclude 

community-based individuals with these 

lesions. Interinstitutional cooperation is 

mandatory. 

• Development of imaging technologies 

capable of identifying premalignant 

lesions and indicators of neoplastic 

progression are likely to require funding 

and collaboration from industry as well 

as from NIH. 

Resources Needed To Overcome 

Limitations of Previous Research and To 

Capitalize on Existing Opportunities 

• All three priorities require coordination 

of cross-institutional, cross-disciplinary, 

multicenter studies designed by 

interested investigators in this field, 

including epidemiologists, 

gastrointestinal endoscopists, basic 

scientists, and pathologists. 

• Central to this process is a multiinstitutional registry that would include 

epidemiological and biological information, as well as a tissue repository of 

well-characterized individuals with these 

premalignant lesions. Without such an 

infrastructure, many testable hypotheses 

and recommended studies cannot be 

performed. 
Appendix B: Breakout Reports 79 

Localized Malignant 

Co-Chairs: Coit, Daniel and Lawrence, Theodore; Haller, Daniel G.

Participants: 

Brooks, Jo Ann 

Burgart, Lawrence

Chak, Amitabh 

Chow, Wong-Ho 

Conley, Barbara 

Conner, Jerry 

Dehdashti, Farrokh

Fontham, Elizabeth T.H. 

Forastiere, Arlene 

Fox, James 

Helft, Paul

Ilson, David 

Karpey, Martin 

Lines, Stephen 

Powell, Steven 

Rothenberg, Mace 

Rowland, Julia 

Sandler, Robert

Sharma, Prateek

Stoner, Gary 

Van Dam, Jacques

Weston, Allan

Overview/Background 

Information/Barriers 

Patients with localized malignancies of the 

stomach and esophagus have a wide variety 

of biologic and anatomic features at 

presentation. In addition to traditional 

staging for each tumor (based on 

characteristics of the primary tumor, lymph 

nodes, and distant metastases), there are at 

least three distinct anatomic sites 

(esophagus, GE junction, stomach) and two 

histologies (adenocarcinoma and squamous 

cell). This heterogeneity makes clinical 

research in patients with localized 

malignancies in these sites even more 

challenging. 

Surgery is the mainstay of treatment for 

tumors of the upper gastrointestinal tract, 

with a wide variety of outcomes depending 

not only on tumor stage, surgical expertise, 

and technique, but also on the increasingly 

common application of multimodality 

treatments. 

For esophageal cancer, surgery alone 

remains a standard for most patients, but 

with a low likelihood of cure, even in 

apparently localized disease. 

Chemoradiation may significantly 

downstage tumors and cure some patients, 

and may be considered as sole treatment for 

patients when nonsurgical palliation alone is 

considered. Many patients treated with 

curative intent now receive chemotherapy, 

radiation, and surgery, although the relative 

contribution of each modality to ultimate 

outcome remains uncertain. 

For patients with gastric cancer, cure rates 

vary widely, depending on the stage and site 

of tumor, with distal lesions having higher 

cure rates than proximal lesions with surgery 

alone. Based on the recent U.S. intergroup 

trial results, a standard of care for patients 

with gastric cancer who are at risk for 

recurrence following complete resection is 

postoperative adjuvant chemoradiation. 

Future trials are being designed to assess 

the optimal sequence of treatments 

(preoperative vs. postoperative) and the 

modifications of systemic treatment to 

reduce the risk of distant failure. 

While the incidence of both squamous cell 

carcinoma of the esophagus and adenocarcinoma of the distal stomach appears to 

be decreasing, adenocarcinoma of the gastric 

cardia and gastroesophageal junction appear 

to be increasing more rapidly than any other 

human cancer. Some of the precursor lesions 

for this entity have been identified (gastric 
80 Report of the Stomach/Esophageal Cancers Progress Review Group 

intestinal metaplasia, esophageal Barrett’s 

epithelium), but the host factors governing 

progression to malignancy are not fully 

characterized. Furthermore, once the 

carcinoma is diagnosed, long-term prognosis 

is poor, even after multimodality therapy for 

apparent localized disease. The effects of 

patient, tumor, and treatment-related factors 

in outcome are not well understood. 

Patients with esophageal and gastric cancers 

are older and often present with significant 

medical comorbidities that can limit 

treatment options. These comorbidities often 

define a patient’s tolerance of and recovery 

from intensive treatment programs. These 

patients often have unique functional 

problems arising from both disease and 

treatment-related morbidity. Long-term 

survival data do not adequately describe 

these outcomes of treatment in this group of 

patients. 

Compared to clinical research in other 

tumors, there has been relatively little work 

in predictive and prognostic markers, even 

retrospectively, to select optimal therapy for 

individual patients or groups of patients. 

Barriers to clinical research in these tumors 

include the lack of biologic markers, strong 

biases on the part of both patients and 

physicians for or against certain therapies, 

and suboptimal mechanisms - beyond the 

national cooperative groups - for collection 

of data and for testing of hypotheses in this 

relatively uncommon malignancy. 

Three Scientific Priorities and 

Rationales 

Priority 1: Optimize available treatment 

modalities and promote the development of 

novel targeted therapeutics, e.g., 

radiosensitizing agents, systemic agents, 

and minimally invasive resection and 

ablation techniques. Develop predictors of 

response that may affect treatment 

selection, including molecular and imaging 

predictors of partial or complete response 

to both conventional and novel therapies. 

Rationale: Treatment approaches for 

esophageal and stomach tumors have 

become more complex, with more patients 

receiving surgery, chemotherapy, and 

radiation. However, it remains unclear 

whether all patients require such treatments. 

In particular, the role of nonsurgical local 

modalities (such as endoscopic mucosal 

resection, stenting and photodynamic 

therapy) in patients with esophageal cancer 

needs to be further evaluated. To understand 

which patients would best benefit from what 

are now considered standard treatments, the 

role of chemoradiation in gastric and 

esophageal cancers needs to be explored. 

Advances in biologic markers and imaging 

should be exploited to better help in patient 

selection and determining response to 

therapy. Some intermediate measures of 

success (including serial biopsy before, 

during, and after treatment as well as 

imaging) would enable clinical researchers 

to assess efficacy of traditional and targeted 

biologic therapies outside of the framework 

of large-scale randomized trials. 

Priority 2: Apply and refine patientcentered methods to assess specific short 

and long-term tumor-and treatment-related 

quality of life issues in patients with 

localized esophageal and gastric cancer. 

These would include assessment of pain, 

nutrition, swallowing, fatigue, and 

diarrhea as well as quality and cost of care 

issues. 

Rationale: Information characterizing longterm functional outcome is scant even 

though good data exist describing patterns of 

recurrence and survival of patients treated 

for localized gastric and esophageal cancers. 

These patients have unique functional 

problems related to both disease and 

treatment-related morbidity. While some 

data exist for quality of life outcomes, 
Appendix B: Breakout Reports 81 

additional organ-specific instruments need 

to be developed, validated, and applied. In 

addition, assessment of quality and cost of 

care as well as patient preferences should be 

incorporated into clinical trial design. 

Priority 3: Define host and tumor 

characteristics to best predict relapse and 

survival for patients with localized cancer 

of the esophagus or stomach. These 

include genetic, molecular, biochemical, 

imaging, and other clinical factors, 

 as well as patient sociodemographic 

characteristics. Unique characteristics of 

esophageal and stomach cancers permit the 

serial sampling of tumor before, during, 

and after treatment. 

Rationale: Currently, the treatment patterns 

for large groups of patients with esophageal 

or gastric tumors are largely based on 

empirical data. The problem is that the 

different primary sites should be considered 

as distinct diseases. Molecular and genetic 

markers should be obtained to rationally 

select both the need for and type of therapy 

for the individual patient or subset of 

patients. With the introduction of new 

chemotherapeutic agents and targeted 

biologic therapies, predictive markers for 

response or resistance are important in 

designing treatment programs and in 

predicting toxicity of therapy. Esophageal 

and stomach cancers offer ease of access for 

serial biopsies to assess the impact of 

therapy, which makes them unique for these 

purposes. 

Infrastructure Needed To 

Accomplish Priorities 

Partnership Platforms 

Cooperative groups 

• Collaboration with NIDDK 

• Department of Defense; Department of 

Veterans Affairs, Research Wing 

Expected Resources To Overcome 

Limitations of Previous Research and To 

Capitalize on Existing Opportunities 

• Cooperative national database of patients 

with gastric and esophageal cancers 

• National tissue bank for study of 

molecular profile of gastric and 

esophageal cancer 

• National multi-institutional consortium 

for gastric and esophageal cancer 
82 Report of the Stomach/Esophageal Cancers Progress Review Group 

Late Malignant 

Co-Chairs: Holland, Jimmie and Wang, Kenneth; Jatoi, Aminah

Participants: 

Ajani, Jaffer 

Bloom, Bernard 

Buttar, Navtej 

Fischman, Alan 

Frazzitta, Bart 

Gammon, Marilie 

MacDonald, John 

Mori, Yuriko 

Okunieff, Paul 

Patterson, Reese 

Richmond, Ellen 

Sonnenberg, Amnon 

Taylor, Philip 

Tepper, Joel 

Ward, Mary 

Welch, Michael 

Wojcik, Brian 

Overview/Background 

Information/Barriers 

Among the approximately 30,000 U.S. 

patients diagnosed annually with gastric or 

esophageal cancer, the vast majority will 

eventually face widespread metastatic 

disease, thereby confronting the prospect of 

an incurable cancer and a limited life. 

Curative therapy for these cancers can be 

achieved only rarely. The primary 

considerations for these cancers have been 

palliative therapies and treatments designed 

to extend survival. 

Palliation. Palliative therapy for upper 

gastrointestinal tumors has focused on 

maintaining the patency of the lumen in 

order to allow nutrition, medications, and 

salivary secretions to pass. The most 

commonly applied methods of achieving 

this goal have been the placement of stents 

to alleviate severe dysphagia, as well as 

chemotherapy and radiation. Gastric cancers 

rarely obstruct because of the larger 

diameter of the lumen in the stomach. 

Modern stents can be made from flexible 

plastic materials, metallic expandable mesh, 

metallic stents that are coated with a plastic 

material, or metallic mesh stents that contain 

flaps to prevent reflux of ingested material. 

Metallic stents have become commonly used 

in the esophagus because of their ease of 

placement and longer-term palliation of 

dysphagia. Thermal ablative therapies, such 

as Nd:YAG laser therapy or photodynamic 

therapy, have also been used to open the 

esophageal lumen and may be tolerated 

better, but often they do not offer durable 

palliation. Gastric and esophageal cancers 

also affect nutritional status, which can be 

enhanced by novel enteral access devices 

such as percutaneous jejunostomy and 

gastrostomy. 

Chemotherapy. Chemotherapy has 

provided patients a survival advantage. In 

three previous trials, chemotherapy was 

compared to best supportive care, and 

although benefits were modest, a statistically 

significant survival advantage was observed 

among chemotherapy-treated patients in 

each of these trials. 

This survival advantage has spawned 

renewed interest in testing other 

chemotherapeutic agents in this setting. 

However, recent studies suggest two 

recurrent and concerning themes. First, 

conventional chemotherapy appears to be 

reaching a plateau with respect to its 

efficacy. For example, a promising 

treatment regimen for stomach cancers is 

combined administration of epirubicin, 

cisplatin, and 5-fluorouracil. This regimen 

yielded a response rate as high as 70% in 

previous phase II trials. However, the 

treatment regimen provides only a modest 
Appendix B: Breakout Reports 83 

survival advantage over a previously used 

regimen of 5-fluorouracil, adriamycin, and 

methotrexate. The median survival times for 

these regimens were 8.9 versus 5.7 months, 

respectively. 

Second, high toxicity rates remain a major 

problem. The testing of newer drugs, such as 

the taxanes and camptothecans, in combination with other agents, has provided 

response rates that approach 50%, but only 

at the cost of severe toxicity that also occurs 

in approximately 50% of patients. Thus, 

although the modest benefits of chemotherapy protect from nihilism, there is a 

clear mandate to explore other strategies to 

improve treatment efficacy and to reduce 

toxicity. 

Patient Concerns. Patients with late stage 

esophageal or gastric cancer are 

experiencing the physical symptoms of 

poorly controlled disease such as anorexia, 

pain, bleeding, fatigue, and obstruction, and 

the recognition that therapies are not 

curative. This combination of physical and 

existential concerns (anxiety, depression, 

seeking of the meaning of life and death) 

lead to levels of distress that are substantial 

and are experienced not only by the patient, 

but by the family as well. While there has 

been increasing attention to the control of 

symptoms near the end of life, few studies 

have addressed the problems of patients with 

tumors of these two sites. The interruption 

of gastrointestinal function adversely affects 

nearly every aspect of daily living and limits 

meaningful social interactions with family 

and others, which often occur around food. 

There is a range of assessment tools 

available that validly measure subjective 

symptoms: pain, nausea and vomiting, 

dysphagia, fatigue, anxiety, depression, and 

delirium related to treatment toxicities. It is 

important to review this body of information 

and its relevance to these tumors, 

particularly in relation to late stage disease, 

when these symptoms are the most common. 

More importantly, it is critical that patients 

with esophageal and gastric tumors be 

studied in late stages to determine the 

complex distressing symptoms and to 

conduct symptom-control trials using the 

modalities currently available, while also 

exploring novel interventions. 

Three Scientific Priorities and 

Rationale for Each 

Priority 1: Develop specific, molecularly 

targeted therapies for late-stage gastroesophageal cancers based on knowledge of 

molecular pathways important in tumor 

progression, response to therapy, and 

normal tissue tolerance. Identify molecular 

markers that could be assessed by 

nationally available bioinformatics 

resources to define patients who would 

respond to nonsurgical treatments. 

Rationale: Current therapies for late-stage 

gastroesophageal cancer are unsatisfactory. 

It is important to develop new therapies that 

decrease mortality and minimize damage to 

normal tissue. Molecular markers of 

susceptibility to these toxicities are being 

discovered, and biological modulators are 

becoming clinically available. Because of 

their accessibility, gastroesophageal cancers 

are ideal candidates for testing novel 

therapies and for identifying surrogate 

markers of response. The accessibility also 

means that tissue can be acquired serially, 

which would enhance the ability to establish 

tissue databanks to study these diseases. 

Priority 2: Design and conduct clinical 

trials by multidisciplinary investigators to 

test the efficacy of new diagnostic and 

treatment modalities for late-stage 

gastroesophageal cancers. These should 

include measurements of QoL, costeffectiveness, best supportive care, and 

patient education in the non-curative 

management of late disease. 
84 Report of the Stomach/Esophageal Cancers Progress Review Group 

Rationale: Currently, there are very few 

clinical trials for advanced-stage gastroesophageal cancers, and virtually no 

symptom management studies related to 

these cancers. 

Priority 3: Develop validated tumor models 

for late-stage gastroesophageal cancers to 

facilitate the development and testing of 

new drugs that would allow effective 

treatment of advanced tumors. 

Rationale: Tumor models of late-stage 

disease are necessary to elucidate biological 

and genetic mechanisms of cancer 

progression. They are needed to test the 

efficacy of therapeutic agents and permit the 

application of genomics and proteomics. 

Infrastructure Needed To 

Accomplish Priorities 

Partnership Platforms

Establish partnerships for research and 

education with other governmental agencies, 

cooperative groups, community oncologists, 

private foundations, relevant professional 

organizations, industry, and patient 

advocacy groups—particularly the National 

Coalition of Cancer Survivorship. 

Expected Resources To Overcome 

Limitations of Previous Research and To 

Capitalize on Existing Opportunities 

• Investigate and define optimal 

information networks, including the NCI 

Office of Communication, to: 

– Inform patients 

– Educate physicians about the 

standards of care for advanced 

disease (e.g., physicians need to 

anticipate B12 deficiency, the need 

for bone-density scans, and the 

possibility of H. pylori infection). It 

may be possible to approach this 

objective by modifying widely 

disseminated Clinical Practice 

Guidelines. 

• Develop an Internet-based information 

system for public distribution. It should 

include information about post-operative 

complications, nutritional needs, etc. 
Appendix C 

Stomach/Esophageal Cancers PRG Members 

Appendix C: Stomach/Esophageal Cancers PRG Members 85 

Appendix C: Stomach/Esophageal Cancers PRG Members 

Timothy J. Eberlein, M.D. 

PRG Co-Chair 

Bixby Professor and Chair 

Washington University School of Medicine 

Brian J. Reid, M.D., Ph.D. 

PRG Co-Chair 

Head, Gastrointestinal Oncology Program 

Fred Hutchinson Cancer Research Center 

Ernest T. Hawk, M.D., M.P.H. 

PRG Executive Director 

Chief, Gastrointestinal and Other 

 Cancers Research Group 

National Cancer Institute 

Jaffer A. Ajani, M.D. 

Professor of Medicine 

Department of Gastrointestinal 

 Medical Oncology 

University of Texas M.D. Anderson 

 Cancer Center 

Martin J. Blaser, M.D. 

Chairman, Department of Medicine 

New York University School of Medicine 

Jo Ann Brooks, Ph.D. 

Assistant Professor 

Department of Thoracic Surgery 

Indiana University Medical Center 

Donald O. Castell, M.D. 

Professor of Medicine 

Medical University of South Carolina 

Daniel Coit, M.D., F.A.C.S. 

Chief, Gastric and Mixed Tumor Service 

Memorial Sloan-Kettering Cancer Center 

Pelayo Correa, M.D. 

Boyd Professor, Department of Pathology 

Louisiana State University Health 

 Sciences Center 

Thomas R. DeMeester, M.D. 

Professor and Chairman, Department of Surgery 

Keck School of Medicine 

University of Southern California 

M. Brian Fennerty, M.D. 

Professor of Medicine 

Division of Gastroenterology 

Oregon Health and Sciences University 

Arlene A. Forastiere, M.D., Ph.D. 

Professor, Department of Oncology 

Sidney Kimmel Comprehensive Cancer Center 

Johns Hopkins University 

Karen J. Goodman, Ph.D. 

Assistant Professor 

Department of Epidemiology 

University of Texas Health Science Center 

 at Houston School of Public Health 

Stanley R. Hamilton, M.D. 

Professor and Head, Department of Pathology 

Division of Pathology and Laboratory Medicine 

University of Texas M.D. Anderson 

 Cancer Center 

Jimmie Holland, M.D. 

Chairman, Department of Psychiatry and 

 Behavioral Sciences 

Memorial Sloan-Kettering Cancer Center 

Theodore S. Lawrence, M.D., Ph.D. 

Professor and Chairman 

Department of Radiation Oncology 

University of Michigan 

Douglas S. Levine, M.D. 

Executive Director of Clinical Research 

AstraZeneca 

David Lieberman, M.D. 

Chief, Divison of Gastroenterology 

Oregon Health and Sciences University 

Stephen Meltzer, M.D. 

Professor of Medicine 

University of Maryland Hospital 

Cherie Nichols, M.B.A. 

Director 

Office of Science Planning and Assessment 

National Cancer Institute 
86 Report of the Stomach/Esophageal Cancers Progress Review Group 

Roy C. Orlando, M.D. 

Professor of Medicine and Physiology 

Tulane University Health Sciences Center 

Dawn Provenzale, M.D. 

Associate Professor and Director of 

 Gastrointestinal Outcomes Research 

Duke University Medical Center 

Anil K. Rustgi, M.D. 

T. Grier Miller Associate Professor of 

 Medicine and Genetics 

Chief of Gastroenterology 

University of Pennsylvania 

Richard Sampliner, M.D. 

Professor of Medicine 

Arizona Health Sciences Center 

University of Arizona 

Robert Tell, M.S.H.A 

Patient Advocate 

Joel Tepper, M.D. 

Professor and Chairman 

Department of Radiation Oncology 

University of North Carolina at Chapel Hill 

 School of Medicine 

Jacques Van Dam, M.D., Ph.D. 

Professor and Clinical Chair 

Division of Gastroenterology 

Stanford University Medical Center 

Thomas Vaughan, M.D. 

Head, Program in Epidemiology 

Fred Hutchinson Cancer Research Center 

Kenneth K. Wang, M.D. 

Associate Professor of Medicine 

Mayo Clinic 

Michael Welch, Ph.D. 

Professor, Department of Radiology 

Washington University Medical School 
Appendix D 

Stomach/Esophageal Cancers PRG 

Roundtable Participants 

*PRG Members 

Appendix D: Stomach/Esophageal Cancers PRG Roundtable Participants 87 

Appendix D: Stomach/Esophageal Cancers PRG Roundtable 

Participants 

Timothy J. Eberlein, M.D.* 

PRG Co-Chair 

Bixby Professor and Chair 

Department of Surgery 

Director, Alvin J. Siteman Cancer Center 

Washington University School of Medicine 

660 South Euclid Avenue, Campus Box 8109 

St. Louis, MO 63110 

Telephone: (314) 362-8086 

Fax: (314) 454-1898 

E-mail: eberleint@msnotes.wustl.edu 

Brian J. Reid, M.D., Ph.D.* 

PRG Co-Chair 

Head, Gastrointestinal Oncology Program 

Public Health Sciences Division 

Fred Hutchinson Cancer Research Center 

1100 Fairview Avenue North, Mailstop C1-157 

Seattle, WA 98109 

Telephone: (206) 667-6792 

Fax: (206) 667-6132 

E-mail: bjr@fhcrc.org 

Ernest T. Hawk, M.D., M.P.H.* 

PRG Executive Director 

Chief, Gastrointestinal and Other 

 Cancers Research Group 

Division of Cancer Prevention 

National Cancer Institute 

Executive Plaza North, Room 2141 

6130 Executive Boulevard 

Bethesda, MD 20892-7322 

Telephone: (301) 594-2684 

Fax: (301) 435-6344 

E-mail: hawke@mail.nih.gov 

Jaffer A. Ajani, M.D.* 

Professor of Medicine 

Department of Gastrointestinal 

 Medical Oncology 

University of Texas M.D. Anderson 

 Cancer Center 

1515 Holcombe Boulevard, Box 426 

Houston, TX 77030-4009 

Telephone: (713) 792-2828 

Fax: (713) 745-1163 

E-mail: jajani@mail.mdanderson.org 

David Beer, Ph.D. 

Professor, Department of Surgery 

University of Michigan Medical School 

MSRB2, B560, Box 0686 

1150 West Medical Center Drive 

Ann Arbor, MI 48109-6860 

Telephone: (734) 763-0325 

Fax: (734) 763-0323 

E-mail: dgbeer@umich.edu 

Leslie Bernstein, Ph.D. 

Chair in Cancer Research, AFLAC, Inc. 

Professor, Keck School of Medicine 

University of Southern California 

1975 Zonal Avenue, KAM 506 

Los Angeles, CA 90033 

Telephone: (323) 442-1619 

Fax: (323) 442-1992 

E-mail: lbern@hsc.usc.edu 

Martin J. Blaser, M.D.* 

Chairman, Department of Medicine 

New York University School of Medicine 

550 First Avenue, Room NBV-16N1 

New York, NY 10016 

Telephone: (212) 263-6394 

Fax: (212) 263-7700 

E-mail: martin.blaser@med.nyu.edu 

Bernard Bloom, Ph.D. 

Research Professor, Department of Medicine 

University of Pennsylvania 

3615 Chestnut Street 

Philadelphia, PA 19104-2676 

Telephone: (215) 898-7178 

Fax: (215) 573-8684 

E-mail: bsbloom@mail.med.upenn.edu 

Patricia Blount, M.D. 

Affiliate Investigator 

Fred Hutchinson Research Cancer Center 

1100 Fairview Avenue North, Room C1-157 

Seattle, WA 98109 

Telephone: (425) 401-6689 

Fax: (425) 401-6689 

E-mail: pblount@fhcrc.org 
*PRG Members 

88 Report of the Stomach/Esophageal Cancers Progress Review Group 

Jon C. Bowersox, M.D., Ph.D. 

Director of Medical Affairs 

Johnson and Johnson/Ethicon 

 Endo-Surgery, Inc. 

4545 Creek Road, ML-21 

Cincinnati, OH 45242 

Telephone: (513) 337-3108 

Fax: (513) 337-7328 

E-mail: jbowersox@eesus.jnj.com 

Jo Ann Brooks, Ph.D.* 

Assistant Professor 

Department of Thoracic Surgery 

Indiana University Medical Center 

545 Barnhill Drive, Room EH 215 

Indianapolis, IN 46202 

Telephone: (317) 274-3940 

Fax: (317) 278-3996 

E-mail: jbrooksb@iupui.edu 

Lawrence Burgart, M.D. 

Pathologist, Department of Anatomic Pathology 

Mayo Clinic 

200 First Street, S.W. 

Rochester, MN 55905 

Telephone: (507) 284-3883 

Fax: (507) 284-1599 

E-mail: lburgart@mayo.edu 

Navtej Buttar, M.D. 

Researcher 

Mayo Clinic 

200 First Street, S.W. 

Rochester, MN 55905 

Telephone: (507) 266-0132 

Fax: (507) 255-7612 

E-mail: buttar.navtej@mayo.edu 

Kevin M. Callahan, Ph.D. 

Deputy Director 

Office of Science Planning and Assessment 

National Cancer Institute 

Building 31, Room 11A03 

31 Center Drive 

Bethesda, MD 20892-2590 

Telephone: (301) 402-7519 

Fax: (301) 435-3876 

E-mail: kc92t@nih.gov 

Alan J. Cameron, M.D. 

Professor, Department of Medicine 

Mayo Clinic 

200 First Street, S.W. 

Rochester, MN 55905 

Telephone: (507) 288-3198 

Fax: (507) 284-0538 

E-mail: gutguy@prodigy.net 

Donald O. Castell, M.D.* 

Professor of Medicine 

Medical University of South Carolina 

Clinical Science Building, Suite 202 

96 Jonathan Lucas Street 

Charleston, SC 29425 

Telephone: (843) 792-7522 

Fax: (843) 792-8395 

E-mail: castell@musc.edu 

Amitabh Chak, M.D. 

Assistant Professor 

Case Western Reserve University 

University Hospitals of Cleveland 

11100 Euclid Avenue 

Cleveland, OH 44106-8066 

Telephone: (216) 844-5386 

Fax: (216) 983-0347 

E-mail: axc22@po.cwru.edu 

Wong-Ho Chow, Ph.D. 

Senior Investigator 

Occupational Epidemiology Branch, DCEG 

National Cancer Institute 

Executive Plaza South, Room 8100 

6120 Executive Boulevard 

Rockville, MD 20852 

Telephone: (301) 435-4708 

Fax: (301) 402-1819 

E-mail: choww@mail.nih.gov 

Adrian J. Christie, M.D. 

Director, Department of Pathology 

St. John Macomb Hospital 

11800 East 12 Mile Road 

Warren, MI 48093-3494 

Telephone: (810) 573-5026 

Fax: (810) 573-5007 

E-mail: adrianjchristie@aol.com 
*PRG Members 

Appendix D: Stomach/Esophageal Cancers PRG Roundtable Participants 89 

Daniel Coit, M.D., F.A.C.S.* 

Chief, Gastric and Mixed Tumor Service 

Memorial Sloan-Kettering Cancer Center 

1275 York Avenue 

New York, NY 10021-6007 

Telephone: (212) 639-6325 

Fax: (212) 717-3400 

E-mail: coitd@mskcc.org 

Barbara Conley, M.D. 

Chief, Diagnostics Research Branch, CDP 

National Cancer Institute 

Executive Plaza North, Room 6035A 

6130 Executive Boulevard 

Rockville, MD 20852 

Telephone: (301) 496-1591 

Fax: (301) 402-7819 

E-mail: conleyb@mail.nih.gov 

Jerry Conner 

2607 Rock Port Circle 

Garland, TX 75044 

Telephone: (972) 530-2317 

E-mail: jerryc@appleisp.net 

Pelayo Correa, M.D.* 

Boyd Professor, Department of Pathology 

Louisiana State University Health 

 Sciences Center 

1901 Perdido Street 

New Orleans, LA 70112 

Telephone: (504) 568-6035 

Fax: (504) 599-1278 

E-mail: correa@lsuhsc.edu 

James Corrigan, Ph.D. 

Chief, Program Assessment Branch 

Office of Science Planning and Assessment 

National Cancer Institute 

Building 31, Room 11A03 

31 Center Drive, MSC 2590 

Bethesda, MD 20892-2590 

Telephone: (301) 496-5515 

Fax: (301) 435-3876 

E-mail: corrigan@mail.nih.gov 

Phillip Daschner 

Program Administrator 

Division of Cancer Biology 

National Cancer Institute 

Executive Plaza North, Room 5014 

6130 Executive Boulevard 

Rockville, MD 20852 

Telephone: (301) 496-9740 

Fax: (301) 496-2025 

E-mail: daschnep@mail.nih.gov 

Sandy Dawsey, M.D. 

Senior Investigator 

Cancer Prevention Studies Branch 

National Cancer Institute 

6116 Executive Boulevard, Suite 705 

Bethesda, MD 20892-8314 

Telephone: (301) 594-2930 

Fax: (301) 435-8644 

E-mail: dawseys@mail.nih.gov 

Farrokh Dehdashti, M.D. 

Associate Professor of Radiology 

Washington University School of Medicine 

510 South Kingshighway Boulevard 

St. Louis, MO 63110 

Telephone: (314) 362-7418 

Fax: (314) 362-1032 

E-mail: dehdashtif@mir.wustl.edu 

Thomas R. DeMeester, M.D.* 

Professor and Chairman, Department of Surgery 

Keck School of Medicine 

University of Southern California 

1510 San Pablo Street, Suite 514 

Los Angeles, CA 90033-4612 

Telephone: (323) 442-5925 

Fax: (323) 442-5872 

E-mail: demeester@surgery.hsc.usc.edu 

Molla Donaldson, Ph.D. 

Senior Scientist for Quality of Care 

 Research and Policy 

Outcomes Research Branch, AOP 

National Cancer Institute 

Executive Plaza North, Room 4028 

6130 Executive Boulevard 

Rockville, MD 20852 

Telephone: (301) 435-1638 

Fax: (301) 435-3710 

E-mail: molla.donaldson.@nih.gov 
*PRG Members 

90 Report of the Stomach/Esophageal Cancers Progress Review Group 

Deborah Duran, Ph.D. 

PRG Coordinator 

Office of Science Planning and Assessment 

National Cancer Institute 

Building 31, Room 11A03 

31 Center Drive, MSC 2590 

Bethesda, MD 20892-2590 

Telephone: (301) 496-5515 

Fax: (301) 435-3876 

E-mail: durande@mail.nih.gov 

Gary Falk, M.D. 

Staff Gastroenterologist, 

Department of Gastroenterology 

Center for Swallowing and 

 Esophageal Disorders 

The Cleveland Clinic Foundation 

9500 Euclid Avenue, Desk A-30 

Cleveland, OH 44195 

Telephone: (216) 444-1762 

Fax: (216) 444-6302 

E-mail: falkg@ccf.org 

M. Brian Fennerty, M.D.* 

Professor of Medicine 

Division of Gastroenterology 

Oregon Health and Sciences University 

3181 S.W. Sam Jackson Park Road, MC PV-310 

Portland, OR 97201-3098 

Telephone: (503) 494-3787 

Fax: (503) 494-7556 

E-mail: fennerty@ohsu.edu 

Alan J. Fischman, M.D., Ph.D. 

Director, Nuclear Medicine Division 

Massachusetts General Hospital 

Professor 

Harvard Medical School 

55 Fruit Street, Tilton 201 

Boston, MA 02114 

Telephone: (617) 726-8353 

Fax: (617) 726-6165 

E-mail: fischman@pet.mgh.harvard.edu 

Elizabeth T.H. Fontham, Ph.D. 

Professor and Chairman, Department of 

 Public Health and Preventive Medicine 

Louisiana State University Health 

 Sciences Center 

1600 Canal Street, Suite 800 

New Orleans, LA 70112 

Telephone: (504) 599-1396 

Fax: (504) 568-6905 

E-mail: efonth@lsuhsc.edu 

Arlene A. Forastiere, M.D., Ph.D.* 

Professor, Department of Oncology 

Sidney Kimmel Comprehensive Cancer Center 

Johns Hopkins University 

1650 Orleans Street, Room G-90 

Baltimore, MD 21231 

Telephone: (410) 955-9818 

Fax: (410) 614-9861 

E-mail: af@jhmi.edu 

James Fox, D.V.M. 

Professor and Director 

Division of Comparative Medicine 

Massachusetts Institute of Technology 

Building 16, Room 825 

77 Massachusetts Avenue 

Cambridge, MA 02139 

Telephone: (617) 253-1735 

Fax: (617) 252-1877 

E-mail: jgfox@mit.edu 

Bart Frazzitta 

11 Crane Court 

Manalapan, NJ 07726 

Telephone: (732) 446-9509 

Fax: (732) 446-0005 

E-mail: chiefomni@aol.com 

Marilie D. Gammon, Ph.D. 

Associate Professor 

Department of Epidemiology 

University of North Carolina at Chapel Hill 

2102C McGavran-Greenberg Hall 

Pittsboro Road, Campus Box 7400 

Chapel Hill, NC 27599-7435 

Telephone: (919) 966-7421 

Fax: (919) 966-2089 

E-mail: gammon@email.unc.edu 
*PRG Members 

Appendix D: Stomach/Esophageal Cancers PRG Roundtable Participants 91 

Irene Georgakoudi, Ph.D. 

Research Scientist, Spectroscopy Laboratory 

Massachusetts Institute of Technology 

77 Massachusetts Avenue, Room 6-014 

Cambridge, MA 02139 

Telephone: (617) 253-9487 

Fax: (617) 253-4513 

E-mail: ireneg@mit.edu 

Karen J. Goodman, Ph.D.* 

Assistant Professor 

Department of Epidemiology 

University of Texas Health Science Center 

 at Houston School of Public Health 

1200 Herman Pressler, Room W906 

Houston, TX 77030 

Telephone: (713) 500-9268 

Fax: (713) 500-9329 

E-mail: kgoodman@sph.uth.tmc.edu 

Ramaswamy Govindan, M.D. 

Assistant Professor, Department of Medicine 

Washington University School of Medicine 

Wohl Hospital, Room 108 

4960 Childrens’ Place 

St. Louis, MO 63110 

Telephone: (314) 362-4819 

Fax: (314) 362-7086 

E-mail: rgovinda@im.wustl.edu 

Daniel G. Haller, M.D. 

Professor, Department of Medicine 

University of Pennsylvania 

3400 Spruce Street, 16 Penn Tower 

Philadelphia, PA 19104-4202 

Telephone: (215) 662-6318 

Fax: (215) 349-5326 

E-mail: daniel.haller@uphs.upenn.edu 

Frank A. Hamilton, M.D., M.P.H. 

Chief, Digestive Diseases Program 

National Institute of Diabetes and 

 Digestive and Kidney Diseases 

2 Democracy Plaza, Room 669 

6707 Democracy Boulevard 

Bethesda, MD 20892-5450 

Telephone: (301) 594-8877 

Fax: (301) 480-8300 

E-mail: fh14e@nih.gov

Stanley R. Hamilton, M.D.* 

Professor and Head, Department of Pathology 

Division of Pathology and Laboratory Medicine 

University of Texas M.D. Anderson 

 Cancer Center 

1515 Holcombe Boulevard, Box 85 

Houston, TX 77030 

Telephone: (713) 792-2040 

Fax: (713) 792-4094 

E-mail: shamilto@mdanderson.org 

James Hayman, M.D. 

Associate Professor, Department of 

 Radiation Oncology 

University of Michigan Medical School 

Box UH-B2C490-0010 

1500 East Medical Center Drive 

Ann Arbor, MI 48109 

Telephone: (734) 936-4288 

Fax: (734) 763-7370 

E-mail: hayman@umich.edu 

Paul Helft, M.D. 

Assistant Professor, Department of Medicine 

Division of Hematology/Oncology 

Indiana University Cancer Pavilion 

535 Barnhill Drive, Room 414 

Indianapolis, IN 46202 

Telephone: (317) 278-6942 

Fax: (317) 278-4190 

E-mail: phelft@iupui.edu 

Donald Henley, M.A. 

5944 McDonie Avenue 

Woodland Hills, CA 91367 

Telephone: (818) 883-1249 

Fax: (818) 883-0833 

E-mail: donehenley@aol.com 

Jimmie Holland, M.D.* 

Chairman, Department of Psychiatry 

 and Behavioral Sciences 

Memorial Sloan-Kettering Cancer Center 

1242 Second Avenue 

New York, NY 10021 

Telephone: (212) 639-3004 

Fax: (212) 717-3763 

E-mail: hollandj@mskcc.org 
*PRG Members 

92 Report of the Stomach/Esophageal Cancers Progress Review Group 

Mark C. Hornbrook, Ph.D. 

Associate Director 

Center for Health Research, Northwest Region 

Kaiser Permanente 

3800 North Interstate Avenue 

Portland, OR 97227-1110 

Telephone: (503) 335-6746 

Fax: (503) 335-2428 

E-mail: mark.c.hornbrook@kpchr.org 

Scott Hundahl, M.D., F.A.C.S. 

Medical Director, The Queen’s Cancer Institute 

The Queen’s Medical Center and 

 University of Hawaii 

1301 Punchbowl Street, Tower 6 

Honolulu, HI 96813 

Telephone: (808) 537-7353 

Fax: (808) 537-7080 

E-mail: shundahl@queens.org 

David Ilson, M.D., Ph.D. 

Associate Attending Physician 

Memorial Sloan-Kettering Cancer Center 

1275 York Avenue, Suite H912 

New York, NY 10021 

Telephone: (212) 639-8306 

Fax: (212) 717-3320 

E-mail: ilsond@mskcc.org 

Aminah Jatoi, M.D. 

Assistant Professor 

Mayo Clinic 

200 First Street, S.W. 

Rochester, MN 55905 

Telephone: (570) 284-3902 

Fax: (570) 538-1803 

E-mail: jatoi.aminah@mayo.edu 

Martin Karpeh, M.D. 

Associate Attending Surgeon 

Memorial Sloan-Kettering Cancer Center 

1275 York Avenue 

New York, NY 10021 

Telephone: (212) 639-8056 

Fax: (212) 794-5847 

E-mail: karpehm@mskcc.org 

Eric Knisley 

Vice President and General Manager 

Fujinon Incorporated 

10 High Point Drive 

Wayne, NJ 07470 

Telephone: (973) 633-5600 

Fax: (973) 633-8818 

E-mail: eric.knisley@fujinon.com 

Rakesh Kumar, Ph.D. 

Professor 

University of Texas M.D. Anderson 

 Cancer Center 

1515 Holcombe Boulevard, Box 108 

Houston, TX 77030-4009 

Telephone: (713) 745-3558 

Fax: (713) 745-2050 

E-mail: rkumar@mdanderson.gov 

Theodore S. Lawrence, M.D., Ph.D.* 

Professor and Chairman 

Department of Radiation Oncology 

University of Michigan 

B2C502 University Hospital 

1500 East Medical Center Drive 

Ann Arbor, MI 48109 

Telephone: (734) 647-9955 

Fax: (734) 763-7371 

E-mail: tsl@umich.edu 

Lawrence Leichman, M.D. 

Chief, Division of Medical Oncology 

Albany Medical College 

47 New Scotland Avenue 

Buffalo, NY 14263 

Telephone: (518) 262-8269 

Fax: (518) 262-6556 

E-mail: leichml@mail.amc.edu 

Douglas S. Levine, M.D.* 

Executive Director of Clinical Research 

AstraZeneca 

725 Chesterbrook Boulevard, Suite E-3C 

Wayne, PA 19087-5677 

Telephone: (610) 695-4306 

Fax: (610) 695-1162 

E-mail: doug.levine@astrazeneca.com 
*PRG Members 

Appendix D: Stomach/Esophageal Cancers PRG Roundtable Participants 93 

David Lieberman, M.D. 

Chief, Divison of Gastroenterology 

Oregon Health and Sciences University 

Portland VAMC P3-GI 

3710 S.W. Veterans Hospital Road 

Portland, OR 97207 

Telephone: (503) 273-5318 

Fax: (503) 220-3426 

E-mail: lieberma@ohsu.edu 

Stephen Lines 

Program Manager 

AstraZeneca 

725 Chesterbrook Boulevard, Suite E-2C 

Wayne, PA 19078 

Telephone: (610) 695-1253 

Fax: (610) 695-1245 

E-mail: stephen.lines@astrazeneca.com 

Joe Lipscomb, Ph.D. 

Chief, Outcomes Research Branch, DCCP 

National Cancer Institute 

Executive Plaza North, Room 4005 

6130 Executive Boulevard 

Rcokville, MD 20852 

Telephone: (301) 402-3590 

Fax: (301) 435-3710 

E-mail: jl300p@nih.gov 

Calum MacAulay, Ph.D. 

Head, Cancer Imaging Department 

British Columbia Cancer Agency 

601 West 10th Avenue 

Vancouver, British Columbia V5Z 1L3 

Canada 

Telephone: (604) 877-6098, ext. 3109 

Fax: (604) 877-6077 

E-mail: cmacaula@bccancer.bc.ca 

John MacDonald, M.D. 

Medical Director and Chief 

Gastrointestinal Oncology Services 

St. Vincent’s Comprehensive Cancer Center 

325 West 15th Street 

New York, NY 10011 

Telephone: (212) 604-6011 

Fax: (212) 604-6039 

E-mail: jmacdona@salick.com 

Susan Mayne, Ph.D. 

Associate Professor 

Yale University School of Medicine 

P.O. Box 208034 

60 College Street 

New Haven, CT 06520-8034 

Telephone: (203) 785-6274 

Fax: (203) 785-6980 

E-mail: susan.mayne@yale.edu 

Stephen Meltzer, M.D.* 

Professor of Medicine 

University of Maryland Hospital 

22 South Greene Street, Room N3W62 

Baltimore, MD 21201 

Telephone: (410) 706-3375 

Fax: (410) 706-1325 

E-mail: smeltzer@medicine.umaryland.edu 

Margo Michaels, M.P.H. 

Survivor and Public Education Section 

Office of Education and Special Initiatives 

National Cancer Institute 

6116 Executive Boulevard, Suite 202 

Bethesda, MD 20852-8334 

Telephone: (301) 594-8993 

Fax: (301) 594-7063 

E-mail: micham@mail.nih.gov 

Yuriko Mori, M.D. 

Postdoctoral Fellow 

University of Maryland, Baltimore 

655 West Baltimore Street 

Bressler Research Building, Room 8-012 

Baltimore, MD 21201 

Telephone: (410) 706-3375 

Fax: (410) 706-1325 

E-mail: ymori001@umaryland.edu 

Steven Moss, M.D. 

Associate Professor of Medicine 

Rhode Island Hospital 

Brown University 

593 Eddy Street, Room APC 445 

Providence, RI 02903 

Telephone: (401) 444-6713 

Fax: (401) 444-2939 

E-mail: steven_moss@brown.edu 
*PRG Members 

94 Report of the Stomach/Esophageal Cancers Progress Review Group 

Cherie Nichols, M.B.A.* 

Director 

Office of Science Planning and Assessment 

National Cancer Institute 

Building 31, Room 11A03 

31 Center Drive 

Bethesda, MD 20892-2590 

Telephone: (301) 496-5515 

Fax: (301) 435-3876 

E-mail: nicholsc@mail.nih.gov 

Olof Nyren, M.D., Ph.D. 

Professor of Clinical Epidemiology 

Department of Medical Epidemiology 

Karolinska Institute 

Box 286, S-171 77 

Berzelius vag 15C 

S-171 77 Stockholm 

Sweden 

Telephone: 46-8-728-6195 

Fax: 46-8-314-975 

E-mail: olof.nyren@mep.ki.se 

Paul Okunieff, M.D. 

Professor and Chair 

Department of Radiation Oncology 

University of Rochester 

601 Elmwood Avenue, Box 647 

Rochester, NY 14642 

Telephone: (585) 275-5575 

Fax: (585) 275-1531 

E-mail: paul_okunieff@urmc.rochester.edu 

Roy C. Orlando, M.D.* 

Professor of Medicine and Physiology 

Tulane University Health Sciences Center 

1430 Tulane Avenue, SL-35 

New Orleans, LA 70112-2699 

Telephone: (504) 588-5606 

Fax: (504) 587-2188 

E-mail: rorlando@tulane.edu 

Reese Patterson 

6005 Glenmary Road 

Knoxville, TN 37919 

Telephone: (865) 588-8169 

Richard Peek, M.D. 

Associate Professor of Medicine 

Division of Gastroentology 

Vanderbilt University School of Medicine 

C-2104 Medical Center North 

1161 21st Avenue South 

Nashville, TN 37232 

Telephone: (615) 322-5200 

Fax: (615) 343-6229 

E-mail: richard.peek@mcmail.vanderbilt.edu 

Steven Powell, M.D. 

Associate Professor of Medicine 

Digestive Health Center of Excellence 

University of Virginia Health Systems 

P.O. Box 800708 

Charlottesville, VA 22908-0708 

Telephone: (434) 243-2718 

Fax: (434) 924-0491 

E-mail: powell@virginia.edu 

Dawn Provenzale, M.D.* 

Associate Professor and Director of 

 Gastrointestinal Outcomes Research 

Duke University Medical Center 

508 Fulton Street, Building 16, Room 70 

Durham, NC 27705 

Telephone: (919) 286-2287 

Fax: (919) 416-5839 

E-mail: prove002@mc.duke.edu 

Lewis Queirolo, Ph.D. 

440 Eagle Crest Road 

Camano Island, WA 98282 

Telephone: (360) 387-4652 

Fax: (360) 285-6471 

E-mail: lew.queirolo@noaa.gov 

Linda Rabeneck, M.D. 

Professor of Medicine and Director 

Division of Gasteroenterology 

University of Toronto 

238 Davenport Road, Suite 319 

Toronto, Ontario M5R 1J6 

Canada 

Telephone: (416) 471-3407 

Fax: (416) 323-6129 

E-mail: rabeneck@bcm.tmc.edu 
*PRG Members 

Appendix D: Stomach/Esophageal Cancers PRG Roundtable Participants 95 

Ellen S. Richmond, M.S., R.N., C.S., 

 A.O.C.N. 

Program Director and Clinical Trials 

 Nurse Specialist 

Gastrointestinal and Other Cancer 

 Research Group 

National Cancer Institute 

Executive Plaza North, Room 2148 

6130 Executive Boulevard 

Rockville, MD 20852 

Telephone: (301) 435-2466 

Fax: (301) 435-6344 

E-mail: er115z@nih.gov 

Luz Rodriguez, M.D. 

Surgical Oncologist and Staff Physican 

Genetics Branch, CCR 

National Cancer Institute 

National Naval Hospital 

Building 8, Room 5101 

8901 Wisconsin Avenue 

Bethesda, MD 20889 

Telephone: (301) 435-1460 

Fax: (301) 496-0047 

E-mail: rodrigul@mail.nih.gov 

Yvonne Romero, M.D. 

Consultant, Division of Gastroenterology 

 and Hepatology 

Mayo Clinic 

200 First Street, S.W. 

Rochester, MN 55905 

Telephone: (507) 284-8714 

Fax: (507) 284-0538 

E-mail: romero.yvonne@mayo.edu 

Mace Rothenberg, M.D. 

Ingram Associate Professor of Cancer Research 

Vanderbilt-Ingram Cancer Center 

Vanderbilt University 

777 Preston Research Building 

Nashville, TN 37232-6307 

Telephone: (615) 343-8422 

Fax: (615) 343-7602 

E-mail: mace.rothenberg@ mcmail.vanderbilt.edu 

William Rothman, M.S.A.K. 

University of Michigan School of Public Health 

2861 Stratford Street 

Oak Park, MI 48237 

Telephone: (248) 968-2437 

E-mail: wroth@mich.com 

Julia Rowland, Ph.D. 

Director, Office of Cancer Survivorship, DCCPS 

National Cancer Institute 

Executive Plaza North, Room 4086 

6130 Executive Boulevard 

Rockville, MD 20852 

Telephone: (301) 402-2964 

Fax: (301) 594-5070 

E-mail: rowlandj@mail.nih.gov 

Anil K. Rustgi, M.D.* 

T. Grier Miller Associate Professor of 

 Medicine and Genetics 

Chief of Gastroenterology 

University of Pennsylvania 

415 Curie Boulevard 

Philadelphia, PA 19104 

Telephone: (215) 898-0154 

Fax: (215) 573-5412 

E-mail: anil2@mail.med.upenn.edu 

Richard Sampliner, M.D.* 

Professor of Medicine 

Arizona Health Sciences Center 

University of Arizona 

P.O. Box 245028 

1501 North Campbell Avenue, Room 6406 

Tucson, AZ 85724-5018 

Telephone: (520) 626-6119 

Fax: (520) 629-4737 

E-mail: samplinr@u.arizona.edu 

Robert Sandler, M.D. 

Professor of Medicine and Epidemiology 

University of North Carolina at Chapel Hill 

719 Burnett Womack Building, CB 7080 

Chapel Hill, NC 27599-7080 

Telephone: (919) 966-0090 

Fax: (919) 966-2478 

E-mail: rsandler@med.unc.edu 
*PRG Members 

96 Report of the Stomach/Esophageal Cancers Progress Review Group 

Florin M. Selaru, M.D. 

Faculty Research Associate 

University of Maryland, Baltimore 

655 West Baltimore Street, BRB 8-012 

Baltimore, MD 21201 

Telephone: (410) 706-3375 

Fax: (410) 706-1325 

E-mail: fselaru001@medicine.umaryland.edu 

Prateek Sharma, M.D. 

Assistant Professor, Gastrointestinal Section 

University of Kansas Medical School and 

 VA Medical Center 

4801 East Linwood Boulevard 

Kansas City, MO 64128 

Telephone: (816) 861-4700, ext. 6737 

Fax: (816) 922-4692 

E-mail: psharma@kumc.edu 

David Shibata, M.D. 

Assistant Professor of Surgery 

University of Maryland School of Medicine 

22 South Greene Street, Room N4W58 

Baltimore, MD 21201 

Telephone: (410) 328-7320 

Fax: (410) 328-8118 

E-mail: dshibata@smail.umaryland.edu 

Debra Silberg, M.D., Ph.D. 

Assistant Professor 

University of Pennsylvania 

415 Curie Boulevard, 650 CRB 

Philadelphia, PA 19104 

Telephone: (215) 898-0157 

Fax: (215) 573-2024 

E-mail: silberg@mail.med.upenn.edu 

Michael V. Sivak, Jr., M.D. 

Chief, Division of Gastroenterology 

Case Western Reserve University 

School of Medicine 

University Hospitals of Cleveland 

11100 Euclid Avenue, Wehrn 253 

Cleveland, OH 44106 

Telephone: (216) 844-7344 

Fax: (216) 844-7371 

E-mail: mvs4@po.cwru.edu 

Amnon Sonnenberg, M.D., M.Sc. 

Staff Physician 

University of New Mexico 

New Mexico VA Health Care System 

VA Medical Center, Room 111F 

1501 San Pedro Drive, S.E. 

Albuquerque, NM 87108 

Telephone: (505) 265-1711, ext. 4513 

Fax: (505) 256-5751 

E-mail: sonnbrg@unm.edu 

Rhonda Souza, M.D. 

Assistant Professor of Medicine 

Gastrointestinal Department 

Dallas VA Medical Center 

University of Texas Southwestern 

 Medical School 

4500 South Lancaster Road, MC 111B1 

Dallas, TX 75287 

Telephone: (214) 857-0301 

Fax: (214) 857-0328 

E-mail: rsouza@airmail.net 

Stuart Spechler, M.D. 

Chief, Division of Gastroenterology 

Dallas VA Medical Center 

University of Texas Southwestern 

 Medical School 

4500 South Lancaster Road 

Dallas, TX 75216 

Telephone: (214) 374-7799 

Fax: (214) 857-1571 

E-mail: sjspechler@aol.com 

Sudhir Srivastava, Ph.D., M.P.H. 

Chief, Cancer Biomarkers Research Group, DCP 

National Cancer Institute 

Executive Plaza North, Room 3142 

6130 Executive Boulevard 

Rockville, MD 20852 

Telephone: (301) 435-1594 

Fax: (301) 402-8990 

E-mail: ss1a@nih.gov 
*PRG Members 

Appendix D: Stomach/Esophageal Cancers PRG Roundtable Participants 97 

Gary Stoner, Ph.D. 

Professor and Chairman 

Division of Environmental Health Sciences 

Cancer Hospital and Research Institute 

Ohio State University School of Public Health 

300 West 10th Avenue, Room 1148B 

Columbus, OH 43210-1240 

Telephone: (614) 293-3268 

Fax: (614) 293-3333 

E-mail: stoner.21@osu.edu 

Philip R. Taylor, M.D., Sc.D. 

Chief, Cancer Prevention Studies Branch, CCR 

National Cancer Institute 

6116 Executive Boulevard, Room 705 

Rockville, MD 20852 

Telephone: (301) 594-2932 

Fax: (301) 435-8645 

E-mail: phil_taylor@nih.gov 

Robert Tell, M.S.H.A.* 

Patient Advocate 

29401 Windmill Court 

Farmington Hills, MI 48334 

Telephone: (248) 626-6410 

E-mail: rt259@columbia.edu 

Joel Tepper, M.D.* 

Professor and Chairman 

Department of Radiation Oncology 

University of North Carolina at Chapel Hill 

 School of Medicine 

Clinical Cancer Center, Room 1043 

101 Manning Drive, Campus Box 7512 

Chapel Hill, NC 27599-7512 

Telephone: (919) 966-0400 

Fax: (919) 966-7681 

E-mail: tepper@radonc.unc.edu 

Nelia A. Tobey, Ph.D. 

Research Professor of Medicine 

SL 35-Gastroenterology Department 

Tulane University School of Medicine 

1430 Tulane Avenue 

New Orleans, LA 70112 

Telephone: (504) 568-0811, ext. 5847 

Fax: (504) 587-2188 

E-mail: ntobey@tulane.edu 

George Triadafilopoulos, M.D. 

Professor of Medicine 

Department of Gastroenterology 111-G1 

Stanford University 

Palo Alto VA Health Care System 

3801 Miranda Avenue 

Palo Alto, CA 94304-6187 

Telephone: (650) 493-5000, ext. 64485 

Fax: (650) 856-8024 

E-mail: vagt@stanford.edu 

Annabelle Uy, M.S. 

Program Analyst 

Office of Science Planning and Assessment 

National Cancer Institute 

Building 31, Room 11A03 

31 Center Drive, MSC 2590 

Bethesda, MD 20892-2590 

Telephone: (301) 496-5515 

Fax: (301) 435-3876 

E-mail: uya@mail.nih.gov 

Jacques Van Dam, M.D., Ph.D.* 

Professor and Clinical Chair 

Division of Gastroenterology 

Stanford University Medical Center 

300 Pasteur Drive, Room H-1121, MC 5202 

Stanford, CA 94305-5202 

Telephone: (650) 736-0431 

Fax: (650) 723-8305 

E-mail: jvandam@stanford.edu 

Thomas Vaughan, M.D.* 

Head, Program in Epidemiology 

Fred Hutchinson Cancer Research Center 

P.O. Box 19024 

1100 Fairview Avenue North 

Seattle, WA 98109 

Telephone: (206) 667-4738 

Fax: (206) 667-4787 

E-mail: tvaughan@u.washington.edu 

Andrew von Eschenbach, M.D. 

Director 

National Cancer Institute 

Building 31, Room 11A48 

31 Center Drive 

Bethesda, MD 20892-2590 

Telephone: (301) 496-5615 

Fax: (301) 402-0338 

E-mail: togashim@mail.nih.gov 
*PRG Members 

98 Report of the Stomach/Esophageal Cancers Progress Review Group 

Kenneth K. Wang, M.D.* 

Associate Professor of Medicine 

Mayo Clinic 

Main Alfred Building, Room 430 

200 First Street, S.W. 

Rochester, MN 55905 

Telephone: (507) 284-2174 

Fax: (507) 255-7612 

E-mail: wang.kenneth@mayo.edu 

Timothy C. Wang, M.D. 

Chief, Gastroenterology Division 

University of Massachusetts Medical School 

Lazare Research Center, Suite 208 

364 Plantation Street 

Worcester, MA 01605 

Telephone: (508) 856-4778 

Fax: (508) 856-4770 

E-mail: timothy.wang@umassmed.edu 

Mary H. Ward, Ph.D. 

Tenure-track Investigator 

Occupational Epidemiology Branch, DCEG 

National Cancer Institute 

Executive Plaza South, Room 8104 

1620 Executive Boulevard 

Rockville, MD 20852 

Telephone: (301) 435-4713 

Fax: (301) 402-1819 

E-mail: wardm@mail.nih.gov 

Michael Welch, Ph.D.* 

Professor, Department of Radiology 

Washington University Medical School 

Campus Box 8225 

510 South Kingshighway Boulevard 

St. Louis, MO 63110 

Telephone: (314) 362-8436 

Fax: (314) 362-8399 

E-mail: welchm@mir.wustl.edu 

Allan Weston, M.D. 

Chief, Gastrointestinal-Hepatology Section 

Kansas City VA Medical Center 

4801 East Linwood Boulevard 

Kansas City, MO 64128 

Telephone: (816) 861-4700 

Fax: (816) 922-4692 

E-mail: allan.weston@med.va.gov 

Christopher Willett, M.D. 

Professor, Department of Radiation Oncology 

Massachusetts General Hospital 

Harvard Medical School 

100 Blossom Street, Cox 3 

Boston, MA 02114 

Telephone: (617) 724-1548 

Fax: (617) 726-3603 

E-mail: cwillett@partners.org 

Brian Wojcik, Ph.D. 

Scientific Review Administrator 

Division of Examural Activities 

National Cancer Institute 

6116 Executive Boulevard, Room 8013 

Rockville, MD 20852 

Telephone: (301) 402-2785 

Fax: (301) 496-6497 

E-mail: bw134s@nih.gov 

Anna Wu, Ph.D. 

Professor, Keck School of Medicine 

University of Southern California 

1441 Eastlake Avenue, MC9175 

Los Angeles, CA 90089 

Telephone: (323) 865-0484 

Fax: (323) 865-0139 

E-mail: annawu@hsc.usc.edu 

NIH Pu

blication Number 03-5314

December 2002

T916