32 THE NEW ENGLAND JOURNAL OF MEDICINE July 6, 1995

REVIEW ARTICLE

to data from the Surveillance, Epidemiology, and End

Results Program, there has been a steady rise in the in-
MEDICAL PROGRESS cidence of adenocarcinoma of the proximal stomach
and the gastroesophageal junction, whereas the inci-
dence of distal cancers has remained largely unchanged
GASTRIC CARCINOMA or has decreased slightly.7 Moreover, the incidence of
adenocarcinoma of the gastroesophageal junction and
CHARLES S. FUCHS, M.D., the gastric cardia has increased at a rate exceeding
AND ROBERT J. MAYER, M.D. 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

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-
that gastroesophageal and proximal gastric adenocar-
cinomas have a common pathogenesis that is most like-
ly different from that of distal gastric cancers.
mon cause of cancer-related deaths in the world.1 In
1995, 22,800 Americans will be given a diagnosis of Pathological Features
gastric carcinoma, and 14,700 will die of the disease.2 More than 90 percent of stomach cancers have been
This review discusses recent developments in our un- reported to be adenocarcinomas, and the remainder
derstanding of the epidemiology and pathogenesis of are predominantly non-Hodgkin’s lymphomas or leio-
gastric carcinoma, methods of diagnosis and staging, myosarcomas.11 Differentiation between adenocarcino-
and approaches to treatment and palliation. ma and lymphoma is critical, since the prognosis and
treatment for these two cancers differ considerably.11
EPIDEMIOLOGY AND BIOLOGY
Gastric adenocarcinomas can be subdivided into two
Incidence categories: an intestinal type characterized by cohesive
In 1930, gastric carcinoma was the leading cause of neoplastic cells forming glandlike tubular structures,
cancer-related deaths among American men and the and a diffuse type in which cell cohesion is absent, so
third most common cause among women.3 Over the that individual cells infiltrate and thicken the stomach
subsequent 50 years, the incidence rates for gastric car- wall without forming a discrete mass.12 Intestinal-type
cinoma in the United States dropped from 33 to 10 cas- lesions are frequently ulcerative, occur in the distal
es per 100,000 men and from 30 to 5 per 100,000 wom- stomach more often than the diffuse type, and are often
en.4 At present, the disease rarely occurs before the age preceded by a prolonged precancerous phase.13 Diffuse
of 40 years, but its incidence increases steadily thereaf- carcinomas occur more often in young patients, develop
ter and peaks in the seventh decade. In the United throughout the stomach but especially in the cardia,
States, African Americans, Hispanic Americans, and and are associated with a worse prognosis. Although
Native Americans are 1.5 to 2.5 times more likely to the intestinal type tends to predominate in geographic
have gastric carcinoma than are whites.5 The disease regions with a high incidence of gastric carcinoma and
remains approximately twice as common in men as in is less likely to be found in areas where the frequency
women. is declining, the incidence of diffuse lesions is similar in
The declining incidence of gastric carcinoma has most populations throughout the world.13,14 The decline
been observed throughout the world, although patterns in the incidence of gastric cancer during this century
vary widely (Fig. 1).1 The incidence is highest in Japan, appears to be largely attributable to a decrease in the
China, South America, and Eastern Europe. In Japan, number of intestinal-type lesions. Although the identi-
gastric carcinoma remains the most frequent cancer in fication of all adenocarcinomas as either diffuse or in-
both sexes and accounts for 20 to 30 percent of all in- testinal is not always possible, these two types of gas-
cident cancers.6 As in other industrialized countries, tric cancer appear to represent disorders with different
however, the incidence of gastric cancer in Japan has epidemiologic and etiologic factors.
been dropping steadily since 1960.
In 1930, most cases of gastric carcinoma in the Unit- Precursor Conditions
ed States originated in the distal stomach (gastric body Studies of specimens obtained at surgery or autopsy
and antrum), and the reduction in the incidence of gas- have suggested that gastric cancers often develop in the
tric cancer from 1930 through 1976 largely reflects a context of other conditions (Table 1). Chronic atrophic
decline in distal lesions. Since 1976, however, according gastritis and its associated abnormality, intestinal meta-
plasia, are the lesions most closely linked to an in-
From the Division of Medical Oncology, Dana–Farber Cancer Institute (C.S.F., creased risk of gastric cancer — specifically, the intes-
R.J.M.); the Channing Laboratory, Department of Medicine, Brigham and Wom- tinal type.15 Atrophic gastritis usually begins as a
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- multifocal process in the distal stomach.16 As foci coa-
tute, 44 Binney St., Boston, MA 02115. lesce, a state of reduced gastric acid production results,

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Vol. 333 No. 1 MEDICAL PROGRESS 33

Men Women with long-term, drug-induced achlor-

Japan Japan
hydria.25-28
Although an association between
Costa Rica Costa Rica gastric ulcer and gastric cancer has
China China
been alleged, observational studies
of patients with benign gastric ulcers
Brazil Brazil treated medically do not support
Yugoslavia Yugoslavia this association.29,30 In contrast, dis-
tal gastrectomy for benign disorders,
Poland Poland particularly peptic ulcer disease, is
Germany Germany associated with an increased risk of
gastric cancer. Recent meta-analyses
England England indicate that this relative risk re-
U.S., black U.S., black mains low until 15 to 20 years after
resection of the distal stomach but
Canada Canada
increases steadily thereafter to the
U.S., white U.S., white range of approximately 1.5 to 3.31,32
This delay in the development of
0 10 20 30 40 50 60 70 80 0 10 20 30 40 50 60 70 80 gastric cancer may reflect the time
required for a gradual progression of
Annual Incidence of Gastric Cancer
(cases per 100,000 population) normal mucosa to intestinal meta-
plasia to dysplasia and cancer result-
Figure 1. Annual Incidence of Gastric Cancer in Selected Countries. ing from prolonged achlorhydria
Data are from the International Agency for Research on Cancer.1 and enterogastric reflux after antrec-
tomy. Some investigators have advo-
which may progress to metaplasia, dysplasia, and ulti- cated endoscopic screening for patients who have un-
mately carcinoma.17 Pathological studies indicate that dergone a distal gastrectomy. Given the small relative
intestinal metaplasia frequently accompanies intestin- risk associated with partial gastrectomy, however, as
al-type gastric cancer, whereas the prevalence of intes- well as the absence of prospective data supporting such
tinal metaplasia among patients with diffuse-type can- costly surveillance, routine screening does not appear
cers remains similar to that in the general population.18 to be justified.33,34
Several investigators have demonstrated that the prev- Epidemiologic studies have consistently demonstrat-
alence of atrophic gastritis and intestinal metaplasia is ed an association between Helicobacter pylori infection
highest in regions of the world that have the highest and the risk of gastric cancer. An analysis of data from
rates of gastric cancer.19,20 Furthermore, atrophic gas- 13 countries showed a strong correlation between the
tritis and gastric carcinoma share a variety of environ- incidence of gastric cancer and the prevalence of H. py-
mental risk factors that are highly prevalent in regions lori infection.35 Prospective serologic studies have re-
of the world where gastric cancer remains endemic. ported that persons with H. pylori infection have a
These observations suggest that atrophic gastritis and three- to sixfold higher risk of gastric cancer than those
intestinal metaplasia represent an important interme- without infection.36-38 This association seems largely re-
diate step in the pathogenesis of endemic, intestinal- stricted to intestinal-type cancers and cancers of the
type gastric cancer. Nonetheless, both conditions have distal stomach.39-41 These studies have failed to demon-
been reported in otherwise healthy adults who do not strate an association between gastric cancer and peptic
subsequently have gastric cancer, indicating that nei-
ther atrophic gastritis nor achlorhydria alone is suffi- Table 1. Risk Factors for Gastric Cancer.
cient to cause gastric carcinoma.
Most observational studies of patients with perni- Precursor conditions
cious anemia have demonstrated that this condition is Chronic atrophic gastritis and intestinal metaplasia
Pernicious anemia
associated with a two- to threefold excess risk of stom- Partial gastrectomy for benign disease
21-23
ach cancer. An excess risk of gastric carcinoid tu- Helicobacter pylori infection
mors has also been reported in such patients, which Ménétrier’s disease
Gastric adenomatous polyps
may be the result of prolonged acid suppression, hyper- Barrett’s esophagus
23,24
gastrinemia, and neuroendocrine hyperplasia. Con- Genetic and environmental factors
sequently, there has been concern that the iatrogenic Family history of gastric cancer
achlorhydria induced by parietal-cell histamine-recep- Blood type A
tor antagonists and gastric proton-pump inhibitors Hereditary nonpolyposis colon cancer syndrome
Low socioeconomic status
may result in an increase in the incidence of intestinal- Low consumption of fruits and vegetables
type gastric cancer and gastric carcinoids. To date, Consumption of salted, smoked, or poorly preserved
foods
however, no study has reported an increased risk of ei- Cigarette smoking
ther gastric carcinoma or gastric carcinoid in patients

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34 THE NEW ENGLAND JOURNAL OF MEDICINE July 6, 1995

ulcer disease, suggesting that the association of H. py- tion. In striking contrast, the increasing incidence of
lori infection with gastric cancer is independent of the adenocarcinoma of the distal esophagus and gastric
link between the infection and ulcer disease.37 The pre- cardia has been reported to be greater among higher
cise role of H. pylori infection in gastric carcinogenesis socioeconomic classes, a finding that remains largely
remains unclear, although it is associated with the de- unexplained.8
velopment of chronic atrophic gastritis.42 Nevertheless, The marked decline in the incidence of gastric can-
gastric carcinoma develops in only a small proportion cer in the United States and other industrialized coun-
of infected persons, again suggesting that genetic or en- tries suggests that environmental exposures, which can
vironmental cofactors are required. The effect of pre- vary over time, play an important part in the pathogen-
vention or treatment of H. pylori infection on the risk of esis of the disease. Studies of people emigrating from
gastric cancer is unknown. areas of high risk to areas of low risk also point to a
Numerous case reports link gastric cancer with hy- substantial environmental influence.54,55 Among Japa-
pertrophic gastropathy (i.e., Ménétrier’s disease), al- nese immigrants in Hawaii, the risk of gastric cancer
though the rarity of Ménétrier’s disease has made it has remained high, even among those who adopted a
difficult to determine the strength of this associa- Western diet.54 For their second- and third-generation
tion.43,44 Similarly, considerable evidence indicates an offspring, however, the rates of the disease have pro-
increased risk of gastric cancer among patients with ad- gressively declined, approaching the rates in the native
enomatous polyps of the stomach.45 The malignant po- population. Similar observations have been noted among
tential of adenomas appears to be directly related to Eastern European immigrants living in the United
the size of the polyp and the degree of dysplasia. States.55 Furthermore, an analysis of Colombians mi-
Although the precursor lesions noted above have grating from geographic regions of high risk to those of
been largely linked to distal gastric carcinoma, the low risk demonstrated that the excess risk among the
marked rise in the incidence of adenocarcinoma of the immigrants was restricted to the intestinal form of gas-
gastric cardia and distal esophagus appears to be tric carcinoma.56 These studies suggest that exposure
strongly correlated with an increase in the incidence of to one or more environmental factors early in life con-
Barrett’s esophagus.46 The incidence of cancer in pa- tributes to the development of intestinal-type gastric
tients with Barrett’s esophagus has been estimated to cancer, with diet the most likely cause.
be 0.8 percent per year.47 Future investigation may ex- Data on the relation between diet and the risk of gas-
plain the recent increase in the incidence of adenocar- tric cancer have been difficult to interpret, since most
cinoma among patients with Barrett’s epithelium and of the studies have been retrospective and have relied
provide a basis for identifying patients at risk. on patients’ recall of early dietary habits. Nonetheless,
these studies have generally demonstrated that diets
Genetic and Environmental Risk Factors rich in fruits and vegetables are associated with a re-
Considerable evidence supports the role of genetic duced risk of gastric cancer57-71 and that diets rich in
factors in the pathogenesis of gastric cancer. Clustering salted, smoked, or poorly preserved foods are associat-
of this disease within families has been reported for ed with an increased risk of the disease.57,63,66-68,71 Stud-
centuries, most notably in the Bonaparte family. Napo- ies in Japan suggest that the recent decline in deaths
leon, his father, Charles, and his grandfather Joseph all from gastric cancer has been accompanied by a parallel
died of the disease, as did several of Napoleon’s sib- decline in per capita consumption of salted and dried
lings.48 Patients with hereditary nonpolyposis colorectal foods, as well as a parallel increase in the consumption
cancer (i.e., Lynch syndrome II), an autosomal domi- of fresh fruits and vegetables.18 Excessive dietary salt
nant disorder with a high degree of penetrance, are at has been associated with gastric atrophy in animals72
increased risk for gastric cancer.49 In addition to these and with atrophic changes in gastric mucosa in hu-
well-defined, rare syndromes, case–control studies indi- mans.73 Consumption of highly salted and pickled
cate that first-degree relatives (e.g., a parent or sibling) foods over a long period may therefore lead to atrophic
of patients with gastric cancer have a two- to threefold gastritis, making gastric mucosa more susceptible to
increase in the risk of contracting the disease.50,51 Fur- the development of carcinoma.
ther support for a genetic influence comes from several Foods that are relatively rich in nitrates, nitrites, and
studies reporting an increased risk of gastric cancer secondary amines can combine to form N-nitroso com-
among persons with blood type A; the risk appears to pounds, which have been shown to induce gastric tu-
be more pronounced for diffuse lesions than for the in- mors in animals.74 Moreover, anaerobic bacteria, which
testinal type.52 often colonize stomachs already affected by atrophic
Throughout the world, the risk of gastric cancer gastritis and intestinal metaplasia, may convert ni-
is inversely associated with socioeconomic status.5,18,53 trates and nitrites to potentially carcinogenic nitroso
Although the link between a higher risk of gastric can- compounds.17 Nitrates and nitrites were previously
cer and lower socioeconomic status appears to be in- used to preserve meat, fish, and vegetables; during this
dependent of occupational exposure, it is difficult to century, however, the nitrate and nitrite content of
ascertain the relative contribution of other potential foods in the United States and other industrialized na-
confounding factors, such as overcrowding, poor sani- tions has declined by 75 percent.18 Despite the muta-
tation, inadequate preservation of food, and poor nutri- genicity of N-nitroso compounds, epidemiologic data

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Vol. 333 No. 1 MEDICAL PROGRESS 35

on dietary nitrates and nitrites have been inconsistent, growth-factor systems, including the K-sam oncogene.
and the role of these compounds in gastric carcinogen- These disparities between mutations associated with
esis remains unclear.75 the intestinal and diffuse types of gastric cancer under-
Long-term use of refrigeration and improved meth- score the unique pathogenesis of each.
ods for preserving food have been associated with a de-
DIAGNOSIS
creased risk of gastric cancer, and it has been proposed
that their widespread use may account for the decline Clinical Presentation
in the incidence of the disease during this century.18,58,76 When superficial and surgically curable, gastric car-
Refrigeration increases the availability of fruits and cinoma typically produces no symptoms. Consequently,
vegetables, obviates the need for salting or similar at the time of presentation, the disease is often locally
methods of food preservation, and may prevent the advanced or metastatic.85 As the tumor becomes more
contamination of food by bacteria and fungi capable of extensive, an insidious upper abdominal discomfort
activating various procarcinogens. may develop, ranging in intensity from a vague sense
Several cohort and case–control studies have shown of postprandial fullness to a severe, steady pain. Ano-
a 1.5- to 3.0-fold increase in the risk of gastric cancer rexia, often with slight nausea, is quite common but
among smokers, although most studies have failed to usually not the presenting symptom. Weight loss is also
demonstrate a clear dose–response relation.59,60,65,77-80 frequently reported at the time of presentation. Ab-
Similarly, several studies have demonstrated an in- dominal pain and weight loss were the most frequent
creased risk of gastric dysplasia and other potentially initial symptoms in a review of 18,365 patients per-
premalignant lesions among smokers.81 Studies of the formed by the American College of Surgeons (Table
relation between alcohol consumption and the risk of 2).86 Vomiting occurs more often when the tumor in-
gastric cancer have been largely inconclusive.59,65,68,77 vades the pylorus, whereas dysphagia may be the main
In summary, it appears likely that the intestinal type symptom associated with a lesion of the cardia. Hema-
of gastric cancer is related largely to environmental fac- temesis or melena is reported by 20 percent of patients,
tors prevalent early in life. Exposure to H. pylori infec- although frank gastrointestinal hemorrhage is uncom-
tion or a diet deficient in fruits and vegetables and rich mon and more likely to be associated with leiomyoma
in highly salted or poorly preserved foods may lead to and leiomyosarcoma. There are no physical findings
gastric mucosal damage and atrophic gastritis.17 Fur- associated with early gastric cancer, and the presence
ther mucosal injury by intraluminal bacteria, bacterial of a palpable abdominal mass generally indicates long-
activation of procarcinogens, or consumption of other standing growth and regional extension.
carcinogens may lead to the development of metapla- Gastric carcinomas spread by direct extension
sia, dysplasia, and ultimately carcinoma. Consequently, through the stomach wall to perigastric tissue, occa-
the worldwide decline in distal, intestinal-type gastric sionally adhering to or invading adjacent structures,
cancer may be the result of the diminishing prevalence such as the pancreas, colon, or liver. Direct extension
of many of these environmental factors, brought about, into the colon may be associated with foul-smelling
in part, by improved refrigeration and food storage. In emesis or the passage of recently ingested material in
contrast, proximal, diffuse-type gastric cancer, which is the stool.87 The disease may also spread by lymphatic
equally prevalent in both high- and low-risk regions of vessels to intraabdominal lymph nodes and supracla-
the world, may be associated with other factors that are vicular nodes (Virchow’s node). A tumor that spreads
still unrecognized. Future epidemiologic studies should along the peritoneal surfaces may result in a periumbil-
analyze proximal and distal cancers separately to iden- ical nodule (Sister Mary Joseph’s node), an enlarged
tify etiologic factors that account for these different dis- ovary (Krukenberg’s tumor), a mass in the cul-de-sac
eases. (Blumer’s shelf ), or frank peritoneal carcinomatosis
and malignant ascites. The liver is the most common
MOLECULAR FEATURES
The role of oncogenes and tumor-suppressor genes Table 2. Symptoms at the Time of the Initial
in the pathogenesis of gastric cancer has recently re- Diagnosis among 18,365 Patients with Gas-
ceived considerable attention. As in studies of colorec- tric Cancer.*
tal cancer, allelic deletions of the MCC (mutated in
SYMPTOM FREQUENCY (%)
colon cancer), APC (adenomatous polyposis coli), and
p53 tumor-suppressor genes have been reported in 33, Weight loss 61.6
34, and 64 percent of gastric cancers, respectively.82 Abdominal pain 51.6
Unlike both colon and pancreatic cancers, gastric can- Nausea 34.3
cer rarely involves mutations in the ras oncogene.83 Anorexia 32.0
Abnormalities of several growth factors and receptor Dysphagia 26.1
systems have also been identified in gastric cancer. Pa- Melena 20.2
tients with intestinal-type cancers have an increased Early satiety 17.5
Ulcer-type pain 17.1
frequency of overexpression of epidermal growth-factor
Lower-extremity edema 5.9
receptor, erbB-2, and erbB-3.84 In contrast, diffuse le-
sions have been linked to abnormalities of fibroblast *Data are from Wanebo et al.86

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36 THE NEW ENGLAND JOURNAL OF MEDICINE July 6, 1995

site of hematogenous dissemination, although pulmo- penetration and the presence of nodal metastases with
nary metastases are also seen. Laboratory tests may an accuracy of approximately 85 and 70 percent, re-
demonstrate anemia (in 42 percent of patients), hypo- spectively — higher than that of preoperative CT scan-
proteinemia (in 26 percent), abnormal liver function ning.103,104 Because of the inability to examine the en-
(in 26 percent), and fecal occult blood (in 40 percent).88 tire abdomen with ultrasonic endoscopy, however, the
Patients with gastric carcinoma infrequently present sensitivity of this technique cannot approach that of
with various paraneoplastic conditions, such as mi- CT scanning in detecting distant metastases. Without
croangiopathic hemolytic anemia,89 membranous ne- additional data on the effect of ultrasonic endoscopy on
phropathy,90 the sudden appearance of seborrheic kera- the clinical outcome, routine use of this technique can-
toses (the Leser–Trélat sign),91 filiform and papular not be recommended.105
pigmented lesions in skin folds and mucous membranes
(acanthosis nigricans),92 chronic intravascular coagula- Tumor Markers
tion leading to arterial and venous thrombi (Trous- Despite the initial enthusiasm about serologic tumor
seau’s syndrome),93 and in rare cases, dermatomyosi- markers, they have not been useful in diagnosing gas-
tis.94 tric carcinoma at an early stage. Carcinoembryonic an-
tigen levels are less frequently elevated in patients with
Diagnostic Studies gastric carcinoma than in those with colorectal carcino-
An upper gastrointestinal series is often the first di- ma. Although elevated levels (5 ng per deciliter) have
agnostic test performed to evaluate symptoms related been reported in 40 to 50 percent of patients with met-
to the upper gastrointestinal tract. Double-contrast astatic gastric carcinomas, similar elevations are noted
techniques allow improved visualization of mucosal de- in only 10 to 20 percent of patients with surgically re-
tail and may indicate diminished distensibility of the sectable disease.106 Serum carcinoembryonic antigen
stomach, which may be the only indication of a diffuse therefore has no role in the diagnosis of gastric carci-
infiltrative carcinoma.95 For lesions between 5 and 10 noma, although it may be valuable in the postoperative
mm in diameter, however, false negative rates as high follow-up of patients.
as 25 percent have been reported.96 Differentiating a The alpha-fetoprotein level, a marker more common-
benign tumor from a malignant ulcer or even a lym- ly used for germ-cell and hepatocellular tumors, and
phoma may be impossible, and knowing the anatomi- the CA 19-9 level, a marker often associated with pan-
cal location of the ulcer is not enough to predict the creatic cancer, are elevated in 30 percent of patients
presence or absence of a tumor.95 with gastric carcinoma.106 Like carcinoembryonic anti-
Less than 3 percent of all gastric ulcers that are eval- gens, however, these tumor markers are most often el-
uated by endoscopy and biopsy are malignant.97,98 evated in patients with incurable disease and are there-
Thus, if the radiographic features of an ulcer appear fore not useful for early detection.
benign and complete healing can be demonstrated on
a repeated examination, endoscopy may not be neces- Screening
sary. Endoscopy and biopsy should be performed, how- Although it is difficult to justify population-based
ever, if an upper gastrointestinal examination indicates surveillance in the United States, screening for gastric
the possible presence of a tumor or if a lesion has not cancer has been advocated in geographic regions where
completely healed within approximately six weeks. the prevalence of the disease remains high. In Japan,
Fiberoptic endoscopy and biopsy have been reported annual screening by radiography or endoscopy has been
to have a diagnostic accuracy of 95 percent.96,99,100 recommended for persons 50 years of age or older. In
Since the accuracy increases with the number of biop- Japanese programs using endoscopy to screen for gas-
sies, multiple biopsies are recommended.100 Gastric tric cancer, 40 to 60 percent of newly diagnosed tumors
carcinomas may be difficult to distinguish from gastric are in an early stage, and such screening has been al-
lymphomas, and because of the submucosal location of leged to account for the recent decline in deaths from
lymphoid neoplasms, it is important to obtain biopsy the disease in Japan.107 A case–control study in Vene-
specimens at an adequate depth. zuela, however, failed to demonstrate a reduction in
Computed tomographic (CT) scans of the abdomen mortality among persons undergoing screening radiog-
can delineate the extent of the primary tumor, as well raphy.108 To date, screening for gastric cancer has not
as the presence of nodal or distant metastases. Com- been evaluated in a prospective, controlled study.
parisons of the findings on CT scans with the findings
at laparotomy, however, indicate that preoperative Staging and Prognosis
scans often underestimate the extent of disease, princi- The pathological stage of gastric cancer remains the
pally because of radiographically undetectable metasta- most important determinant of the prognosis. Analyses
ses to the lymph nodes, liver, and omentum.101,102 Inves- from multiple clinical trials confirm the importance of
tigators have recently used a high-frequency ultrasound the depth at which the tumor has penetrated the stom-
probe attached to the end of an endoscope to assess the ach wall and the presence or absence of metastases to
condition of patients with gastric cancer. Preoperative regional lymph nodes or distant organs in predicting
ultrasonic endoscopy can determine the depth of tumor disease-free and overall survival.85 The American Joint

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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

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38 THE NEW ENGLAND JOURNAL OF MEDICINE July 6, 1995

gressive surgical procedure in Japan. Japanese investi- is being studied, but the value of this treatment re-
gators have espoused an extended resection of lymph mains uncertain.136
nodes, including the resection of nodes within 3 cm of
the tumor (R1) and of nodes adjacent to the left gas- Chemotherapy
tric, splenic, common hepatic, and celiac arteries (R2 Several drugs, when used as single agents, have been
and R3). Retrospective studies from Japan suggest associated with a reduction of more than 50 percent in
that extended lymphadenectomy can improve surviv- measurable tumor mass (i.e., an “objective response”)
al.107,123 Two small, prospective trials, however, failed in over 15 percent of patients. Fluorouracil, which has
to demonstrate a benefit of extensive lymphadenecto- been examined most extensively, produces a response
my, which was associated with substantial morbidi- rate of approximately 20 percent.137 Other drugs with
ty.124,125 The potential difference in stage-specific sur- reported activity include mitomycin, cisplatin, doxoru-
vival between Japan and Western countries may be bicin, the chloroethylnitrosoureas (carmustine and se-
explained, in part, by the higher incidence of proximal mustine), methotrexate, and trimetrexate.85 Complete
and diffuse-type tumors in Western societies. Further- responses with single agents are rare, however, and
more, the less extensive nodal dissection employed in partial regressions have been relatively brief.
the United States probably results in an underestima- Various combinations of active drugs have been re-
tion of the full extent of disease, thereby generating ported to improve the response rate among patients
lower rates of stage-specific survival.126 The value of with advanced gastric carcinoma. A combination of flu-
radical lymph-node resection continues to be debated orouracil, doxorubicin, and mitomycin has been associ-
and is currently being evaluated in randomized, con- ated with a 30 to 40 percent response rate and, until re-
trolled trials. cently, was the most widely prescribed regimen for
In the absence of ascites or extensive metastatic dis- patients with advanced disease.138 Despite an initial re-
ease, patients who are believed to be surgically incur- sponse rate of 64 percent when a combination of etopo-
able should be considered for palliative gastric resec- side, doxorubicin, and cisplatin was used by German in-
tion, which can be performed with acceptably low risks vestigators,139 in subsequent trials this regimen was
of morbidity and mortality.127 Although the approxi- considerably less effective and extremely toxic.140,141 A
mate median survival remains only 8 to 12 months af- combination of fluorouracil, doxorubicin, and high-dose
ter palliative resection, the procedure can provide relief methotrexate was associated with a significant improve-
from obstruction, bleeding, and pain.128-130 When resec- ment in the response rate, as compared with either eto-
tion is not possible, a bypass of the obstructing lesion poside, doxorubicin, and cisplatin140 or fluorouracil, dox-
can be performed, although symptomatic relief is often orubicin, and mitomycin.142 Despite these higher rates
limited and transient.128-130 of response to chemotherapy in patients with a malig-
A variety of endoscopic methods are available for the nant condition once thought untreatable, the median
palliation of symptoms related to obstruction. Laser ab- survival associated with multidrug therapy has general-
lation of tumor tissue can be effective, although relief ly ranged from 6 to 10 months, and the overall effect of
appears to be transient, and repeated treatments are such treatment, as compared with less toxic, single-drug
required.131 The use of plastic and expansile metal therapy, on survival remains debatable.143 Future trials
stents has been associated with a success rate higher should also consider the effect of systemic chemothera-
than 85 percent among selected patients with gastroe- py on the quality of life of patients with advanced gas-
sophageal tumors or tumors in the cardia.132,133 tric cancer, so that specific treatment recommendations
can be formulated.
Radiotherapy The results of biologic and clinical studies have indi-
Gastric carcinoma is relatively resistant to radio- cated that chemotherapy may augment the effect of ra-
therapy, requiring doses of external-beam irradiation diotherapy when the two approaches are used concur-
that exceed the tolerance of surrounding structures, rently.144 Such results suggest that chemotherapeutic
such as bowel mucosa and the spinal cord, if adequate agents may function as radiation sensitizers. A trial
control of the primary tumor is to be achieved. Conse- conducted by the Gastrointestinal Tumor Study Group
quently, for patients with locally recurrent or metastat- reported that, as compared with radiotherapy alone,
ic disease, moderate doses of external-beam irradiation the combination of intravenous fluorouracil and radio-
are used only to palliate symptoms and not to improve therapy improved the survival of patients with locally
survival.134 advanced gastric carcinoma.145 This benefit appeared
Because of the high incidence of local and regional to be restricted to patients whose primary gastric tu-
recurrent disease, several attempts have been made to mors had been resected. In this setting, simultaneous
use radiotherapy prophylactically after a curative re- chemotherapy and radiotherapy may decrease the bur-
section. To date, prospective, controlled trials have den of residual microscopic disease after resection,
failed to demonstrate a survival benefit for patients re- thereby preventing both local and regional recurrence
ceiving radiotherapy alone after a curative resection.135 and distant metastasis.
The use of high-energy irradiation during gastrectomy The administration of chemotherapy shortly after a

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Vol. 333 No. 1 MEDICAL PROGRESS 39

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