32 THE NEW ENGLAND JOURNAL OF MEDICINE
REVIEW ARTICLE
MEDICAL PROGRESS
GASTRIC CARCINOMA
CHARLES S. FUCHS, M.D.,
AND ROBERT J. MAYER, M.D.
D ESPITE a marked decline in the incidence of gas-
tric carcinoma in many industrialized nations,
cancer of the stomach remains the second most com-
mon cause of cancer-related deaths in the world.1 In
1995, 22,800 Americans will be given a diagnosis of
gastric carcinoma, and 14,700 will die of the disease.2
This review discusses recent developments in our un-
derstanding of the epidemiology and pathogenesis of
gastric carcinoma, methods of diagnosis and staging,
and approaches to treatment and palliation.
EPIDEMIOLOGY AND BIOLOGY
Incidence
In 1930, gastric carcinoma was the leading cause of
cancer-related deaths among American men and the
third most common cause among women.3 Over the
subsequent 50 years, the incidence rates for gastric car-
cinoma in the United States dropped from 33 to 10 cas-
es per 100,000 men and from 30 to 5 per 100,000 wom-
en.4 At present, the disease rarely occurs before the age
of 40 years, but its incidence increases steadily thereaf-
ter and peaks in the seventh decade. In the United
States, African Americans, Hispanic Americans, and
Native Americans are 1.5 to 2.5 times more likely to
have gastric carcinoma than are whites.5 The disease
remains approximately twice as common in men as in
women.
The declining incidence of gastric carcinoma has
been observed throughout the world, although patterns
vary widely (Fig. 1).1 The incidence is highest in Japan,
China, South America, and Eastern Europe. In Japan,
gastric carcinoma remains the most frequent cancer in
both sexes and accounts for 20 to 30 percent of all in-
cident cancers.6 As in other industrialized countries,
however, the incidence of gastric cancer in Japan has
been dropping steadily since 1960.
In 1930, most cases of gastric carcinoma in the Unit-
ed States originated in the distal stomach (gastric body
and antrum), and the reduction in the incidence of gas-
tric cancer from 1930 through 1976 largely reflects a
decline in distal lesions. Since 1976, however, according
From the Division of Medical Oncology, Dana–Farber Cancer Institute (C.S.F.,
R.J.M.); the Channing Laboratory, Department of Medicine, Brigham and Wom-
en’s Hospital (C.S.F.); and Harvard Medical School (C.S.F., R.J.M.) — all in
Boston. Address reprint requests to Dr. Fuchs at the Dana–Farber Cancer Insti-
tute, 44 Binney St., Boston, MA 02115.
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July 6, 1995
to data from the Surveillance, Epidemiology, and End
Results Program, there has been a steady rise in the in-
cidence of adenocarcinoma of the proximal stomach
and the gastroesophageal junction, whereas the inci-
dence of distal cancers has remained largely unchanged
or has decreased slightly.7 Moreover, the incidence of
adenocarcinoma of the gastroesophageal junction and
the gastric cardia has increased at a rate exceeding
that of any other cancer, including melanoma and lung
cancer. Similar trends in proximal gastric cancers have
been observed in Europe.8-10 These findings suggest
that gastroesophageal and proximal gastric adenocar-
cinomas have a common pathogenesis that is most like-
ly different from that of distal gastric cancers.
Pathological Features
More than 90 percent of stomach cancers have been
reported to be adenocarcinomas, and the remainder
are predominantly non-Hodgkin’s lymphomas or leio-
myosarcomas.11 Differentiation between adenocarcino-
ma and lymphoma is critical, since the prognosis and
treatment for these two cancers differ considerably.11
Gastric adenocarcinomas can be subdivided into two
categories: an intestinal type characterized by cohesive
neoplastic cells forming glandlike tubular structures,
and a diffuse type in which cell cohesion is absent, so
that individual cells infiltrate and thicken the stomach
wall without forming a discrete mass.12 Intestinal-type
lesions are frequently ulcerative, occur in the distal
stomach more often than the diffuse type, and are often
preceded by a prolonged precancerous phase.13 Diffuse
carcinomas occur more often in young patients, develop
throughout the stomach but especially in the cardia,
and are associated with a worse prognosis. Although
the intestinal type tends to predominate in geographic
regions with a high incidence of gastric carcinoma and
is less likely to be found in areas where the frequency
is declining, the incidence of diffuse lesions is similar in
most populations throughout the world.13,14 The decline
in the incidence of gastric cancer during this century
appears to be largely attributable to a decrease in the
number of intestinal-type lesions. Although the identi-
fication of all adenocarcinomas as either diffuse or in-
testinal is not always possible, these two types of gas-
tric cancer appear to represent disorders with different
epidemiologic and etiologic factors.
Precursor Conditions
Studies of specimens obtained at surgery or autopsy
have suggested that gastric cancers often develop in the
context of other conditions (Table 1). Chronic atrophic
gastritis and its associated abnormality, intestinal meta-
plasia, are the lesions most closely linked to an in-
creased risk of gastric cancer — specifically, the intes-
tinal type.15 Atrophic gastritis usually begins as a
multifocal process in the distal stomach.16 As foci coa-
lesce, a state of reduced gastric acid production results,
Vol. 333 No. 1
Men
Japan Japan
Costa Rica Costa Rica
China China
Brazil Brazil
Yugoslavia Yugoslavia
Poland Poland
Germany Germany
England England
U.S., black U.S., black
Canada Canada
U.S., white U.S., white
0 10 20 30 40 50 60 70 80
Annual Incidence of Gastric Cancer
(cases per 100,000 population)
Figure 1. Annual Incidence of Gastric Cancer in Selected Countries.
Data are from the International Agency for Research on Cancer.1
which may progress to metaplasia, dysplasia, and ulti-
mately carcinoma.17 Pathological studies indicate that
intestinal metaplasia frequently accompanies intestin-
al-type gastric cancer, whereas the prevalence of intes-
tinal metaplasia among patients with diffuse-type can-
cers remains similar to that in the general population.18
Several investigators have demonstrated that the prev-
alence of atrophic gastritis and intestinal metaplasia is
highest in regions of the world that have the highest
rates of gastric cancer.19,20 Furthermore, atrophic gas-
tritis and gastric carcinoma share a variety of environ-
mental risk factors that are highly prevalent in regions
of the world where gastric cancer remains endemic.
These observations suggest that atrophic gastritis and
intestinal metaplasia represent an important interme-
diate step in the pathogenesis of endemic, intestinal-
type gastric cancer. Nonetheless, both conditions have
been reported in otherwise healthy adults who do not
subsequently have gastric cancer, indicating that nei-
ther atrophic gastritis nor achlorhydria alone is suffi-
cient to cause gastric carcinoma.
Most observational studies of patients with perni-
cious anemia have demonstrated that this condition is
associated with a two- to threefold excess risk of stom-
21-23
ach cancer. An excess risk of gastric carcinoid tu-
mors has also been reported in such patients, which
may be the result of prolonged acid suppression, hyper-
23,24
gastrinemia, and neuroendocrine hyperplasia. Con-
sequently, there has been concern that the iatrogenic
achlorhydria induced by parietal-cell histamine-recep-
tor antagonists and gastric proton-pump inhibitors
may result in an increase in the incidence of intestinal-
type gastric cancer and gastric carcinoids. To date,
however, no study has reported an increased risk of ei-
ther gastric carcinoma or gastric carcinoid in patients
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MEDICAL PROGRESS 33
Women with long-term, drug-induced achlor-
hydria.25-28
Although an association between
gastric ulcer and gastric cancer has
been alleged, observational studies
of patients with benign gastric ulcers
treated medically do not support
this association.29,30 In contrast, dis-
tal gastrectomy for benign disorders,
particularly peptic ulcer disease, is
associated with an increased risk of
gastric cancer. Recent meta-analyses
indicate that this relative risk re-
mains low until 15 to 20 years after
resection of the distal stomach but
increases steadily thereafter to the
range of approximately 1.5 to 3.31,32
This delay in the development of
0 10 20 30 40 50 60 70 80 gastric cancer may reflect the time
required for a gradual progression of
normal mucosa to intestinal meta-
plasia to dysplasia and cancer result-
ing from prolonged achlorhydria
and enterogastric reflux after antrec-
tomy. Some investigators have advo-
cated endoscopic screening for patients who have un-
dergone a distal gastrectomy. Given the small relative
risk associated with partial gastrectomy, however, as
well as the absence of prospective data supporting such
costly surveillance, routine screening does not appear
to be justified.33,34
Epidemiologic studies have consistently demonstrat-
ed an association between Helicobacter pylori infection
and the risk of gastric cancer. An analysis of data from
13 countries showed a strong correlation between the
incidence of gastric cancer and the prevalence of H. py-
lori infection.35 Prospective serologic studies have re-
ported that persons with H. pylori infection have a
three- to sixfold higher risk of gastric cancer than those
without infection.36-38 This association seems largely re-
stricted to intestinal-type cancers and cancers of the
distal stomach.39-41 These studies have failed to demon-
strate an association between gastric cancer and peptic
Table 1. Risk Factors for Gastric Cancer.
Precursor conditions
Chronic atrophic gastritis and intestinal metaplasia
Pernicious anemia
Partial gastrectomy for benign disease
Helicobacter pylori infection
Ménétrier’s disease
Gastric adenomatous polyps
Barrett’s esophagus
Genetic and environmental factors
Family history of gastric cancer
Blood type A
Hereditary nonpolyposis colon cancer syndrome
Low socioeconomic status
Low consumption of fruits and vegetables
Consumption of salted, smoked, or poorly preserved
foods
Cigarette smoking
The New England Journal of Medicine
34 THE NEW ENGLAND JOURNAL OF MEDICINE
ulcer disease, suggesting that the association of H. py-
lori infection with gastric cancer is independent of the
link between the infection and ulcer disease.37 The pre-
cise role of H. pylori infection in gastric carcinogenesis
remains unclear, although it is associated with the de-
velopment of chronic atrophic gastritis.42 Nevertheless,
gastric carcinoma develops in only a small proportion
of infected persons, again suggesting that genetic or en-
vironmental cofactors are required. The effect of pre-
vention or treatment of H. pylori infection on the risk of
gastric cancer is unknown.
Numerous case reports link gastric cancer with hy-
pertrophic gastropathy (i.e., Ménétrier’s disease), al-
though the rarity of Ménétrier’s disease has made it
difficult to determine the strength of this associa-
tion.43,44 Similarly, considerable evidence indicates an
increased risk of gastric cancer among patients with ad-
enomatous polyps of the stomach.45 The malignant po-
tential of adenomas appears to be directly related to
the size of the polyp and the degree of dysplasia.
Although the precursor lesions noted above have
been largely linked to distal gastric carcinoma, the
marked rise in the incidence of adenocarcinoma of the
gastric cardia and distal esophagus appears to be
strongly correlated with an increase in the incidence of
Barrett’s esophagus.46 The incidence of cancer in pa-
tients with Barrett’s esophagus has been estimated to
be 0.8 percent per year.47 Future investigation may ex-
plain the recent increase in the incidence of adenocar-
cinoma among patients with Barrett’s epithelium and
provide a basis for identifying patients at risk.
Genetic and Environmental Risk Factors
Considerable evidence supports the role of genetic
factors in the pathogenesis of gastric cancer. Clustering
of this disease within families has been reported for
centuries, most notably in the Bonaparte family. Napo-
leon, his father, Charles, and his grandfather Joseph all
died of the disease, as did several of Napoleon’s sib-
lings.48 Patients with hereditary nonpolyposis colorectal
cancer (i.e., Lynch syndrome II), an autosomal domi-
nant disorder with a high degree of penetrance, are at
increased risk for gastric cancer.49 In addition to these
well-defined, rare syndromes, case–control studies indi-
cate that first-degree relatives (e.g., a parent or sibling)
of patients with gastric cancer have a two- to threefold
increase in the risk of contracting the disease.50,51 Fur-
ther support for a genetic influence comes from several
studies reporting an increased risk of gastric cancer
among persons with blood type A; the risk appears to
be more pronounced for diffuse lesions than for the in-
testinal type.52
Throughout the world, the risk of gastric cancer
is inversely associated with socioeconomic status.5,18,53
Although the link between a higher risk of gastric can-
cer and lower socioeconomic status appears to be in-
dependent of occupational exposure, it is difficult to
ascertain the relative contribution of other potential
confounding factors, such as overcrowding, poor sani-
tation, inadequate preservation of food, and poor nutri-
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July 6, 1995
tion. In striking contrast, the increasing incidence of
adenocarcinoma of the distal esophagus and gastric
cardia has been reported to be greater among higher
socioeconomic classes, a finding that remains largely
unexplained.8
The marked decline in the incidence of gastric can-
cer in the United States and other industrialized coun-
tries suggests that environmental exposures, which can
vary over time, play an important part in the pathogen-
esis of the disease. Studies of people emigrating from
areas of high risk to areas of low risk also point to a
substantial environmental influence.54,55 Among Japa-
nese immigrants in Hawaii, the risk of gastric cancer
has remained high, even among those who adopted a
Western diet.54 For their second- and third-generation
offspring, however, the rates of the disease have pro-
gressively declined, approaching the rates in the native
population. Similar observations have been noted among
Eastern European immigrants living in the United
States.55 Furthermore, an analysis of Colombians mi-
grating from geographic regions of high risk to those of
low risk demonstrated that the excess risk among the
immigrants was restricted to the intestinal form of gas-
tric carcinoma.56 These studies suggest that exposure
to one or more environmental factors early in life con-
tributes to the development of intestinal-type gastric
cancer, with diet the most likely cause.
Data on the relation between diet and the risk of gas-
tric cancer have been difficult to interpret, since most
of the studies have been retrospective and have relied
on patients’ recall of early dietary habits. Nonetheless,
these studies have generally demonstrated that diets
rich in fruits and vegetables are associated with a re-
duced risk of gastric cancer57-71 and that diets rich in
salted, smoked, or poorly preserved foods are associat-
ed with an increased risk of the disease.57,63,66-68,71 Stud-
ies in Japan suggest that the recent decline in deaths
from gastric cancer has been accompanied by a parallel
decline in per capita consumption of salted and dried
foods, as well as a parallel increase in the consumption
of fresh fruits and vegetables.18 Excessive dietary salt
has been associated with gastric atrophy in animals72
and with atrophic changes in gastric mucosa in hu-
mans.73 Consumption of highly salted and pickled
foods over a long period may therefore lead to atrophic
gastritis, making gastric mucosa more susceptible to
the development of carcinoma.
Foods that are relatively rich in nitrates, nitrites, and
secondary amines can combine to form N-nitroso com-
pounds, which have been shown to induce gastric tu-
mors in animals.74 Moreover, anaerobic bacteria, which
often colonize stomachs already affected by atrophic
gastritis and intestinal metaplasia, may convert ni-
trates and nitrites to potentially carcinogenic nitroso
compounds.17 Nitrates and nitrites were previously
used to preserve meat, fish, and vegetables; during this
century, however, the nitrate and nitrite content of
foods in the United States and other industrialized na-
tions has declined by 75 percent.18 Despite the muta-
genicity of N-nitroso compounds, epidemiologic data
Vol. 333 No. 1
on dietary nitrates and nitrites have been inconsistent,
and the role of these compounds in gastric carcinogen-
esis remains unclear.75
Long-term use of refrigeration and improved meth-
ods for preserving food have been associated with a de-
creased risk of gastric cancer, and it has been proposed
that their widespread use may account for the decline
in the incidence of the disease during this century.18,58,76
Refrigeration increases the availability of fruits and
vegetables, obviates the need for salting or similar
methods of food preservation, and may prevent the
contamination of food by bacteria and fungi capable of
activating various procarcinogens.
Several cohort and case–control studies have shown
a 1.5- to 3.0-fold increase in the risk of gastric cancer
among smokers, although most studies have failed to
demonstrate a clear dose–response relation.59,60,65,77-80
Similarly, several studies have demonstrated an in-
creased risk of gastric dysplasia and other potentially
premalignant lesions among smokers.81 Studies of the
relation between alcohol consumption and the risk of
gastric cancer have been largely inconclusive.59,65,68,77
In summary, it appears likely that the intestinal type
of gastric cancer is related largely to environmental fac-
tors prevalent early in life. Exposure to H. pylori infec-
tion or a diet deficient in fruits and vegetables and rich
in highly salted or poorly preserved foods may lead to
gastric mucosal damage and atrophic gastritis.17 Fur-
ther mucosal injury by intraluminal bacteria, bacterial
activation of procarcinogens, or consumption of other
carcinogens may lead to the development of metapla-
sia, dysplasia, and ultimately carcinoma. Consequently,
the worldwide decline in distal, intestinal-type gastric
cancer may be the result of the diminishing prevalence
of many of these environmental factors, brought about,
in part, by improved refrigeration and food storage. In
contrast, proximal, diffuse-type gastric cancer, which is
equally prevalent in both high- and low-risk regions of
the world, may be associated with other factors that are
still unrecognized. Future epidemiologic studies should
analyze proximal and distal cancers separately to iden-
tify etiologic factors that account for these different dis-
eases.
MOLECULAR FEATURES
The role of oncogenes and tumor-suppressor genes
in the pathogenesis of gastric cancer has recently re-
ceived considerable attention. As in studies of colorec-
tal cancer, allelic deletions of the MCC (mutated in
colon cancer), APC (adenomatous polyposis coli), and
p53 tumor-suppressor genes have been reported in 33,
34, and 64 percent of gastric cancers, respectively.82
Unlike both colon and pancreatic cancers, gastric can-
cer rarely involves mutations in the ras oncogene.83
Abnormalities of several growth factors and receptor
systems have also been identified in gastric cancer. Pa-
tients with intestinal-type cancers have an increased
frequency of overexpression of epidermal growth-factor
receptor, erbB-2, and erbB-3.84 In contrast, diffuse le-
sions have been linked to abnormalities of fibroblast
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MEDICAL PROGRESS 35
growth-factor systems, including the K-sam oncogene.
These disparities between mutations associated with
the intestinal and diffuse types of gastric cancer under-
score the unique pathogenesis of each.
DIAGNOSIS
Clinical Presentation
When superficial and surgically curable, gastric car-
cinoma typically produces no symptoms. Consequently,
at the time of presentation, the disease is often locally
advanced or metastatic.85 As the tumor becomes more
extensive, an insidious upper abdominal discomfort
may develop, ranging in intensity from a vague sense
of postprandial fullness to a severe, steady pain. Ano-
rexia, often with slight nausea, is quite common but
usually not the presenting symptom. Weight loss is also
frequently reported at the time of presentation. Ab-
dominal pain and weight loss were the most frequent
initial symptoms in a review of 18,365 patients per-
formed by the American College of Surgeons (Table
2).86 Vomiting occurs more often when the tumor in-
vades the pylorus, whereas dysphagia may be the main
symptom associated with a lesion of the cardia. Hema-
temesis or melena is reported by 20 percent of patients,
although frank gastrointestinal hemorrhage is uncom-
mon and more likely to be associated with leiomyoma
and leiomyosarcoma. There are no physical findings
associated with early gastric cancer, and the presence
of a palpable abdominal mass generally indicates long-
standing growth and regional extension.
Gastric carcinomas spread by direct extension
through the stomach wall to perigastric tissue, occa-
sionally adhering to or invading adjacent structures,
such as the pancreas, colon, or liver. Direct extension
into the colon may be associated with foul-smelling
emesis or the passage of recently ingested material in
the stool.87 The disease may also spread by lymphatic
vessels to intraabdominal lymph nodes and supracla-
vicular nodes (Virchow’s node). A tumor that spreads
along the peritoneal surfaces may result in a periumbil-
ical nodule (Sister Mary Joseph’s node), an enlarged
ovary (Krukenberg’s tumor), a mass in the cul-de-sac
(Blumer’s shelf ), or frank peritoneal carcinomatosis
and malignant ascites. The liver is the most common
Table 2. Symptoms at the Time of the Initial
Diagnosis among 18,365 Patients with Gas-
tric Cancer.*
SYMPTOM FREQUENCY (%)
Weight loss 61.6
Abdominal pain 51.6
Nausea 34.3
Anorexia 32.0
Dysphagia 26.1
Melena 20.2
Early satiety 17.5
Ulcer-type pain 17.1
Lower-extremity edema 5.9
*Data are from Wanebo et al.86
36 THE NEW ENGLAND JOURNAL OF MEDICINE
site of hematogenous dissemination, although pulmo-
nary metastases are also seen. Laboratory tests may
demonstrate anemia (in 42 percent of patients), hypo-
proteinemia (in 26 percent), abnormal liver function
(in 26 percent), and fecal occult blood (in 40 percent).88
Patients with gastric carcinoma infrequently present
with various paraneoplastic conditions, such as mi-
croangiopathic hemolytic anemia,89 membranous ne-
phropathy,90 the sudden appearance of seborrheic kera-
toses (the Leser–Trélat sign),91 filiform and papular
pigmented lesions in skin folds and mucous membranes
(acanthosis nigricans),92 chronic intravascular coagula-
tion leading to arterial and venous thrombi (Trous-
seau’s syndrome),93 and in rare cases, dermatomyosi-
tis.94
Diagnostic Studies
An upper gastrointestinal series is often the first di-
agnostic test performed to evaluate symptoms related
to the upper gastrointestinal tract. Double-contrast
techniques allow improved visualization of mucosal de-
tail and may indicate diminished distensibility of the
stomach, which may be the only indication of a diffuse
infiltrative carcinoma.95 For lesions between 5 and 10
mm in diameter, however, false negative rates as high
as 25 percent have been reported.96 Differentiating a
benign tumor from a malignant ulcer or even a lym-
phoma may be impossible, and knowing the anatomi-
cal location of the ulcer is not enough to predict the
presence or absence of a tumor.95
Less than 3 percent of all gastric ulcers that are eval-
uated by endoscopy and biopsy are malignant.97,98
Thus, if the radiographic features of an ulcer appear
benign and complete healing can be demonstrated on
a repeated examination, endoscopy may not be neces-
sary. Endoscopy and biopsy should be performed, how-
ever, if an upper gastrointestinal examination indicates
the possible presence of a tumor or if a lesion has not
completely healed within approximately six weeks.
Fiberoptic endoscopy and biopsy have been reported
to have a diagnostic accuracy of 95 percent.96,99,100
Since the accuracy increases with the number of biop-
sies, multiple biopsies are recommended.100 Gastric
carcinomas may be difficult to distinguish from gastric
lymphomas, and because of the submucosal location of
lymphoid neoplasms, it is important to obtain biopsy
specimens at an adequate depth.
Computed tomographic (CT) scans of the abdomen
can delineate the extent of the primary tumor, as well
as the presence of nodal or distant metastases. Com-
parisons of the findings on CT scans with the findings
at laparotomy, however, indicate that preoperative
scans often underestimate the extent of disease, princi-
pally because of radiographically undetectable metasta-
ses to the lymph nodes, liver, and omentum.101,102 Inves-
tigators have recently used a high-frequency ultrasound
probe attached to the end of an endoscope to assess the
condition of patients with gastric cancer. Preoperative
ultrasonic endoscopy can determine the depth of tumor
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July 6, 1995
penetration and the presence of nodal metastases with
an accuracy of approximately 85 and 70 percent, re-
spectively — higher than that of preoperative CT scan-
ning.103,104 Because of the inability to examine the en-
tire abdomen with ultrasonic endoscopy, however, the
sensitivity of this technique cannot approach that of
CT scanning in detecting distant metastases. Without
additional data on the effect of ultrasonic endoscopy on
the clinical outcome, routine use of this technique can-
not be recommended.105
Tumor Markers
Despite the initial enthusiasm about serologic tumor
markers, they have not been useful in diagnosing gas-
tric carcinoma at an early stage. Carcinoembryonic an-
tigen levels are less frequently elevated in patients with
gastric carcinoma than in those with colorectal carcino-
ma. Although elevated levels (5 ng per deciliter) have
been reported in 40 to 50 percent of patients with met-
astatic gastric carcinomas, similar elevations are noted
in only 10 to 20 percent of patients with surgically re-
sectable disease.106 Serum carcinoembryonic antigen
therefore has no role in the diagnosis of gastric carci-
noma, although it may be valuable in the postoperative
follow-up of patients.
The alpha-fetoprotein level, a marker more common-
ly used for germ-cell and hepatocellular tumors, and
the CA 19-9 level, a marker often associated with pan-
creatic cancer, are elevated in 30 percent of patients
with gastric carcinoma.106 Like carcinoembryonic anti-
gens, however, these tumor markers are most often el-
evated in patients with incurable disease and are there-
fore not useful for early detection.
Screening
Although it is difficult to justify population-based
surveillance in the United States, screening for gastric
cancer has been advocated in geographic regions where
the prevalence of the disease remains high. In Japan,
annual screening by radiography or endoscopy has been
recommended for persons 50 years of age or older. In
Japanese programs using endoscopy to screen for gas-
tric cancer, 40 to 60 percent of newly diagnosed tumors
are in an early stage, and such screening has been al-
leged to account for the recent decline in deaths from
the disease in Japan.107 A case–control study in Vene-
zuela, however, failed to demonstrate a reduction in
mortality among persons undergoing screening radiog-
raphy.108 To date, screening for gastric cancer has not
been evaluated in a prospective, controlled study.
Staging and Prognosis
The pathological stage of gastric cancer remains the
most important determinant of the prognosis. Analyses
from multiple clinical trials confirm the importance of
the depth at which the tumor has penetrated the stom-
ach wall and the presence or absence of metastases to
regional lymph nodes or distant organs in predicting
disease-free and overall survival.85 The American Joint
Vol. 333 No. 1 MEDICAL PROGRESS 37

Table 3. TNM Classification of Gastric Carcinoma.* chance for a cure. Since resection of the primary lesion
can also offer the most effective means of symptomatic
Primary tumor
Tis Carcinoma in situ
palliation, abdominal exploration with curative intent
T1 Invasion of lamina propria or submucosa should be undertaken, unless there is clear evidence of
T2 Invasion of muscularis propria disseminated disease or other contraindications to sur-
T3 Penetration of the serosa
T4 Invasion of adjacent structures gery.116 For patients with distal tumors, partial gastrec-
Regional lymph-node metastases
tomy with resection of adjacent lymph nodes appears
N0 None to be sufficient. A randomized comparison of total and
N1 Metastases in perigastric lymph node (or nodes) within partial gastrectomy demonstrated higher rates of mor-
3 cm of the edge of the primary tumor bidity and mortality after total gastrectomy, with no
N2 Metastases in perigastric lymph node (or nodes) more than
3 cm from the edge of the primary tumor, along the left difference in overall survival.117 For patients with prox-
gastric, common hepatic, splenic, or celiac arteries imal lesions, larger midgastric lesions, or disease in-
Distant metastases volving the entire stomach, total gastrectomy may be
M0 None necessary. Routine splenectomy for tumors not adher-
M1 Distant metastases
ing to or invading the spleen has been associated with
Stage a higher complication rate and no clear survival bene-
0 Tis N0 M0
I T1 N0–1 M0
fit.118-120
T2 N0 M0 Among patients with gastric tumors who presented
II T1 N2 M0 to more than 700 U.S. hospitals between 1982 and
T2 N1 M0
T3 N0 M0 1987, 7.2 percent died during gastric resection or with-
III T2 N2 M0 in 30 days.86 Although tumors confined to the mucosa
T3 N1–2 M0 without lymph-node involvement (T1N0M0) were as-
T4 N0–1 M0
IV T4 N2 M0 sociated with a survival rate of 60 percent at five years,
T1–4 N1–2 M1 this early-stage disease accounted for less than 10 per-
*According to the American Joint Committee on Cancer.109
cent of all the tumors (Table 4). Two thirds of patients
presented with stage III or IV disease, associated with
survival rates of 13 and 3 percent, respectively, at five
Committee on Cancer has incorporated these factors in years. Among patients whose disease recurred after an
a comprehensive tumor–node–metastasis (TNM) stag- attempted curative resection, the recurrence was local
ing system (Table 3).109 or regional (involving perigastric tissue and lymph
Beyond the stage of disease, intestinal-type cancer is nodes) in approximately 40 percent and systemic in 60
associated with a higher rate of five-year survival than percent. As expected, for most studies, the liver and
diffuse cancer (26 and 16 percent, respectively).86 Sim- peritoneum were the predominant sites of systemic re-
ilarly, poorly differentiated tumors, tumors with abnor- currence.121,122 Metastatic disease beyond the abdomen
mal DNA content (i.e., aneuploidy),110,111 and tumors has been reported in 20 to 40 percent of patients, but
with genetic alterations in proto-oncogenes112,113 or tu- it is rarely the first site of recurrence.
mor-suppressor genes,114,115 all of which are common As compared with data from the United States and
among patients in the United States, have been associ- most European nations, data from the National Can-
ated with a diminished survival rate. The location of cer Center in Japan suggest that Japan has a higher
the primary tumor also appears to predict the outcome. proportion of patients with early-stage disease and
Approximately 37 percent of gastric carcinomas in the substantially improved stage-specific survival (Table
United States originate in the upper third of the stom- 4).107 These improved survival rates may be the result
ach, whereas 20 percent originate in the middle third, of population-based screening, although some observ-
and 30 percent in the lower third86; 12 percent of gas- ers suggest that they also reflect the use of a more ag-
tric carcinomas involve the entire stomach. The rate of
survival five years after resection is approximately 20 to Table 4. Survival after Resection of Gastric Carcinoma among
25 percent for patients with distal tumors, 10 percent Patients at U.S. and Japanese Centers.
for patients with proximal tumors, and less than 5 per-
STAGE OF
cent for those whose entire stomach is involved.86,111 DISEASE UNITED STATES (1982–1987)* JAPAN (1971–1985)†
The diminished survival of patients with proximal tu- 5-YR SURVIVAL 5-YR SURVIVAL
NO . OF CASES (%) (%) NO . OF CASES (%) (%)
mors may reflect the more aggressive, diffuse histologic
features of such lesions or the considerable technical I 2004 (18.1) 50.0 1453 (45.7) 90.7
difficulty of resecting proximal tumors and obtaining II 1796 (16.2) 29.0 377 (11.9) 71.7
sufficiently wide radial margins. III 3945 (35.6) 13.0 693 (21.8) 44.3
IV 3342 (30.1) 3.0 653 (20.6) 9.0
TREATMENT
*The number of cases is based on data on 11,087 patients who underwent pathological stag-
Surgery ing at 700 U.S. hospitals; age-adjusted survival is based on the 10,237 patients who underwent
gastric resection.86
Complete surgical eradication of a gastric tumor, †The number of cases and age-adjusted survival are based on data on 3176 patients who
with resection of adjacent lymph nodes, is the only underwent gastric resection at the National Cancer Center Hospital, Tokyo, Japan.107

The New England Journal of Medicine

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Copyright © 1995 Massachusetts Medical Society. All rights reserved.
38 THE NEW ENGLAND JOURNAL OF MEDICINE
gressive surgical procedure in Japan. Japanese investi-
gators have espoused an extended resection of lymph
nodes, including the resection of nodes within 3 cm of
the tumor (R1) and of nodes adjacent to the left gas-
tric, splenic, common hepatic, and celiac arteries (R2
and R3). Retrospective studies from Japan suggest
that extended lymphadenectomy can improve surviv-
al.107,123 Two small, prospective trials, however, failed
to demonstrate a benefit of extensive lymphadenecto-
my, which was associated with substantial morbidi-
ty.124,125 The potential difference in stage-specific sur-
vival between Japan and Western countries may be
explained, in part, by the higher incidence of proximal
and diffuse-type tumors in Western societies. Further-
more, the less extensive nodal dissection employed in
the United States probably results in an underestima-
tion of the full extent of disease, thereby generating
lower rates of stage-specific survival.126 The value of
radical lymph-node resection continues to be debated
and is currently being evaluated in randomized, con-
trolled trials.
In the absence of ascites or extensive metastatic dis-
ease, patients who are believed to be surgically incur-
able should be considered for palliative gastric resec-
tion, which can be performed with acceptably low risks
of morbidity and mortality.127 Although the approxi-
mate median survival remains only 8 to 12 months af-
ter palliative resection, the procedure can provide relief
from obstruction, bleeding, and pain.128-130 When resec-
tion is not possible, a bypass of the obstructing lesion
can be performed, although symptomatic relief is often
limited and transient.128-130
A variety of endoscopic methods are available for the
palliation of symptoms related to obstruction. Laser ab-
lation of tumor tissue can be effective, although relief
appears to be transient, and repeated treatments are
required.131 The use of plastic and expansile metal
stents has been associated with a success rate higher
than 85 percent among selected patients with gastroe-
sophageal tumors or tumors in the cardia.132,133
Radiotherapy
Gastric carcinoma is relatively resistant to radio-
therapy, requiring doses of external-beam irradiation
that exceed the tolerance of surrounding structures,
such as bowel mucosa and the spinal cord, if adequate
control of the primary tumor is to be achieved. Conse-
quently, for patients with locally recurrent or metastat-
ic disease, moderate doses of external-beam irradiation
are used only to palliate symptoms and not to improve
survival.134
Because of the high incidence of local and regional
recurrent disease, several attempts have been made to
use radiotherapy prophylactically after a curative re-
section. To date, prospective, controlled trials have
failed to demonstrate a survival benefit for patients re-
ceiving radiotherapy alone after a curative resection.135
The use of high-energy irradiation during gastrectomy
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Copyright © 1995 Massachusetts Medical Society. All rights reserved.
July 6, 1995
is being studied, but the value of this treatment re-
mains uncertain.136
Chemotherapy
Several drugs, when used as single agents, have been
associated with a reduction of more than 50 percent in
measurable tumor mass (i.e., an “objective response”)
in over 15 percent of patients. Fluorouracil, which has
been examined most extensively, produces a response
rate of approximately 20 percent.137 Other drugs with
reported activity include mitomycin, cisplatin, doxoru-
bicin, the chloroethylnitrosoureas (carmustine and se-
mustine), methotrexate, and trimetrexate.85 Complete
responses with single agents are rare, however, and
partial regressions have been relatively brief.
Various combinations of active drugs have been re-
ported to improve the response rate among patients
with advanced gastric carcinoma. A combination of flu-
orouracil, doxorubicin, and mitomycin has been associ-
ated with a 30 to 40 percent response rate and, until re-
cently, was the most widely prescribed regimen for
patients with advanced disease.138 Despite an initial re-
sponse rate of 64 percent when a combination of etopo-
side, doxorubicin, and cisplatin was used by German in-
vestigators,139 in subsequent trials this regimen was
considerably less effective and extremely toxic.140,141 A
combination of fluorouracil, doxorubicin, and high-dose
methotrexate was associated with a significant improve-
ment in the response rate, as compared with either eto-
poside, doxorubicin, and cisplatin140 or fluorouracil, dox-
orubicin, and mitomycin.142 Despite these higher rates
of response to chemotherapy in patients with a malig-
nant condition once thought untreatable, the median
survival associated with multidrug therapy has general-
ly ranged from 6 to 10 months, and the overall effect of
such treatment, as compared with less toxic, single-drug
therapy, on survival remains debatable.143 Future trials
should also consider the effect of systemic chemothera-
py on the quality of life of patients with advanced gas-
tric cancer, so that specific treatment recommendations
can be formulated.
The results of biologic and clinical studies have indi-
cated that chemotherapy may augment the effect of ra-
diotherapy when the two approaches are used concur-
rently.144 Such results suggest that chemotherapeutic
agents may function as radiation sensitizers. A trial
conducted by the Gastrointestinal Tumor Study Group
reported that, as compared with radiotherapy alone,
the combination of intravenous fluorouracil and radio-
therapy improved the survival of patients with locally
advanced gastric carcinoma.145 This benefit appeared
to be restricted to patients whose primary gastric tu-
mors had been resected. In this setting, simultaneous
chemotherapy and radiotherapy may decrease the bur-
den of residual microscopic disease after resection,
thereby preventing both local and regional recurrence
and distant metastasis.
The administration of chemotherapy shortly after a
Vol. 333 No. 1 MEDICAL PROGRESS
complete resection in patients at high risk for the re-
currence of disease has been assessed as a means of
eradicating clinically undetectable micrometastases. A
number of studies have investigated whether such pro-
phylactic adjuvant therapy leads to a reduced rate of
recurrence and an increased rate of survival. Although
the results of two small trials suggested a survival ben-
efit for patients who received postoperative chemother-
apy, as compared with those treated with surgery
alone,146,147 many other controlled trials of adjuvant
chemotherapy,135,148-151 chemotherapy combined with ra-
diotherapy,152,153 or chemotherapy combined with im-
munotherapy154,155 have failed to demonstrate such a
benefit for patients who received postoperative therapy.
Although trials in Japan reported a survival advantage
for patients receiving adjuvant therapy, many of these
trials failed to include a prospectively identified control
group treated with surgery alone, and most included
patients at a very early stage of disease.156 A meta-anal-
ysis of 14 randomized, controlled trials, most of which
were conducted in the United States and Europe, con-
cluded that postoperative chemotherapy offers no
survival benefit beyond that associated with curative
resection.157 Consequently, at this time, the administra-
tion of adjuvant chemotherapy in patients who have un-
dergone curative resection cannot be recommended as
a routine practice. A randomized study sponsored by
the National Cancer Institute is comparing surgery
alone with postoperative radiotherapy in combination
with fluorouracil-based chemotherapy. Future trials
may evaluate the use of new combinations of cytotoxic
agents, the delivery of chemotherapy directly to the
peritoneal space, or the administration of chemothera-
py before surgery (i.e., neoadjuvant therapy).
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