SEMINAR

Seminar

Gastric cancer

Peter Hohenberger, Stephan Gretschel

The past decade has seen many advances in knowledge about gastric cancer. Notably, tumour biology and lymphatic
spread are now better understood, and treatment by surgical and medical oncologists has become more standardised.
Since refrigerators have replaced other methods of food conservation, Helicobacter pylori has become a factor in the
cause of gastric cancer. Cancers that arise at the oesophagogastric junction might be further examples of wealth-
associated disease. To tailor treatment better, the western hemisphere needs to borrow from the East by establishing
screening programmes for early diagnosis, through careful surgical resection, and through detailed analysis of tumour
spread. In Europe and the USA, most patients reach treatment with cancers already at an advanced stage. For these
patients, three important randomised trials are underway that evaluate combined therapy. Cytostatic drugs, especially
angiogenesis inhibitors have proved disappointing; however, basic research efforts to detect familial gastric cancers
and to assess minimally residual disease look more hopeful.

Cancer of the stomach is a disease for which treatment
and attitudes vary in different regions of the world. That
an organ cancer should show varying causative factors in
different parts of the world is not unusual; however, with
gastric cancer, it is not only the incidence of the disease,
but also the approach to early diagnosis and treatment
that varies greatly between the western and the eastern
hemispheres. Information from Asia about the disease has
been used in Europe for teaching purposes and study
guidance.
Our understanding of the causes of this cancer of the
stomach, knowledge about tumour spread, and the ability
to detect it have greatly improved. Management
guidelines have been published.1 Surgical treatment has
been standardised, and treatment programmes tailored to
the individual patient have resulted from new technology
and a molecular understanding of tumour dissemination.
This review summarises these advances, with an emphasis
on publications since 1995, outlines remaining areas of
controversy, and provides pointers to what might soon be
achievable.
Epidemiology
Worldwide, gastric cancer is the second largest cause of
cancer-related death. The disease is most common in
Japan and China; in Europe the annual incidence is 12–15
per 100 000, with Portugal at the top end of this range.2,3
In the USA, the incidence is low and the death rate for
gastric cancer is 5·2 deaths per 100 000 compared with 90
per 100 000 in Japan.4 During the past 50 years, incidence
of and mortality from gastric cancer have decreased
worldwide, especially in developed countries (figure 1).2,5,6
These improvements are explained by better living
conditions and increased consumption of fresh fruit,
vitamins, and vegetables, rather than by improvements in
Lancet 2003; 362: 305–15
Division of Surgery and Surgical Oncology, Robert Roessle Hospital
at the Max Delbrück Center for Molecular Medicine, Charité,
Humboldt University at Berlin, Germany (Prof P Hohenberger MD,
S Gretschel MD)
Correspondence to: Prof Peter Hohenberger, Division of Surgery and
Surgical Oncology, Robert Roessle Hospital and Tumour Institute at
the Max Delbrück Center for Molecular Medicine, Charité, Campus
Berlin-Buch, Humboldt University, D-13125 Berlin, Germany
(e-mail: hohenberger@rrk-berlin.de)
treatment. Incidence of tumours in the proximal stomach
or cardia has increased during the past two decades,
whereas the incidence of distal tumours is actually
dropping.2,7 A strong association between gastric cancer
and age exists, irrespective of ethnic group and sex
(figure 2).2,8 Improvements in survival have been most
striking in Japan and Korea, where up to 40% of tumours
are detected early by screening programmes.
Studies on the development of gastric cancer suggest
that genetic predisposition, infection, and diet are part of
a complex interaction. While assessment of classic risk
factors such as smoking, alcohol intake, or drinking green
tea show inconsistent results.9 Regular users of aspirin and
other non-steroidal anti-inflammatory drugs (NSAIDs)
were at a decreased risk of non-cardia gastric
adenocarcinoma (odds ratio [OR] 0·46; 95% CI
0·31–0·68), but not of gastric cardia adenocarcinoma
(0·80) when compared with never users, although
whether the association is causal remains unclear.
In 1965, Laurén10 described two histological subtypes of
gastric cancer, diffuse and intestinal (figure 3). Since then,
differentiation between intestinal and “glandular or
gastric” types has become more distinct in recent years.
The intestinal type usually arises in the distal part of the
stomach and is found in elderly patients. Its development
was assumed to follow from chronic atrophic gastritis via
metaplasia of the glands induced by exogenous factors.
Population-based case-control studies from Spain11 and
Sweden12 ascribed a cancer-promoting effect to nitrates
and nitrose compounds. However, there is no proof from
prospective studies that the more common use of
refrigerators instead of salting, smoking, and pickling for
food conservation explains the drop in the incidence of
gastric cancer of intestinal type. The World Cancer
Research Fund notes convincing evidence for an inverse
relation between fruit and vegetable intake and gastric
cancer.13 However, evidence from interventional studies
that increased intake of vitamins and tracer elements can
prevent cancer is weak. Results of a Swedish population-
Search strategy
We searched the MEDLINE database (years 1995 to July,
2002) with the keywords: gastric cancer, stomach cancer,
epidemiology, Helicobacter pylori, D2-lymphadenectomy,
adjuvant, neoadjuvant, randomized trial, minimal residual
disease.

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 SEMINAR

35
White men
32·5
White women
30
Black men
27·5 Black women

25

22·5
Rate per 100 000

20

17·5

15

12·5

10

7·5

2·5

0
73
74
75
76
77
78
79
80
81
82
83
84
85
86
87
88
89
90
91
92
93
94
95
96
97
98
99
19
19
19
19
19
19
19
19
19
19
19
19
19
19
19
19
19
19
19
19
19
19
19
19
19
19
19
Year of diagnosis
Figure 1: Incidence of gastric cancer in the USA from 1973 to 1999
Data from SEER Cancer Statistics Review.5

based case-control study showed that there was no
reduction in risk of cancer of the gastric cardia, and that
more than 25 000 individuals would need to increase their
food and vegetable consumption to prevent one
oesophageal cancer per year.14
Cancer of intestinal type can also arise without
metaplasia, and the sequence of atrophic gastritis to
intestinal metaplasia to dysplasia to carcinoma has been
challenged by the postulated role for Helicobacter pylori.
180
White men
160
White women
140 Black men
Rate per 100 000
Examination of very small early carcinomas also raises
doubts about the importance of dysplasia as a
precancerous lesion, because at the periphery of
carcinomas that were less than 5 mm in size no precursor
dysplasias were noted.15
By comparison with the intestinal type, the diffuse type of
gastric cancer is more common in young patients, and
people with blood group A are predisposed to the disease.
The incidence of genetically associated diffuse cancers is
assumed to be 5–10%.16 Germline mutations of the CDH1
gene that encodes E-cadherin, an epithelial cell adhesion
molecule, were identified in few families with hereditary
diffuse gastric carcinoma in a pattern suggestive of
autosomal dominant inheritance with incomplete

Black women penetrance. Prophylactic gastrectomy revealed

120
intramucosal signet-ring cell adenocarcinoma in regions of
100 the stomach that had not been detected with endoscopy.
These findings have opened up a debate about the merits of
80
prophylactic total gastrectomy for gene mutation carriers.
60 In diffuse-type cancer, minute signet-ring tumours develop
40
de novo from stem cells in the proliferative cell zone at the
neck region of gastric glands.17 Intestinal metaplasia,
20 dysplasia, and adenocarcinoma arise coincidentally,18 which
0 implies that no precursor is present for any of these
malignant diseases and development of the intestinal type
00–04
05–09
10–14
15–19
20–24
25–29
30–34
35–39
40–44
45–49
50–54
55–59
60–64
65–69
70–74
75–79
80–84

85

from signet-cell cancer might be a time-dependent event.19

Age at diagnosis (years) Role of H pylori

In 1983, Marshall and Warren20 detected a gram-negative
Figure 2: Age dependent incidence of gastric cancer in the bacillus, now called H pylori, which has since been
USA associated with gastric ulcer disease. Infection is most
Data from SEER Cancer Statistics Review.5 likely to take place during childhood via the faeco-oral

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 SEMINAR

carcinoma,30,31 whereas individuals with extensive corpus

gastritis develop hypochlorhydria and gastric atrophy.
Host factors seem to play a crucial part since interleukin-1
(IL-1) gene cluster polymorphisms suspected of
enhancing production of IL-1 are associated with an
increased risk of both hypochlorhydria induced by
H pylori and gastric cancer. IL-1 is a proinflammatory
cytokine and a powerful inhibitor of gastric acid secretion.
Host genetic factors that affect IL-1 might determine
why some individuals infected with H pylori develop
gastric cancer and others do not.
IL-1 is not the only molecular factor that might be
relevant to H pylori infection. For example, the adherence
of H pylori to the gastric mucosa involves specific bacterial
adhesins and host receptors. The Lewis (b) blood-group
antigen mediates H pylori attachment to gastric mucosa.
H pylori infection has been shown to induce formation of

Reproduced with permission from Armed Forces Institute of Pathology

sialyl-Lewis X antigens in gastric epithelium in humans
and in rhesus monkeys.32 The ability of many H pylori
strains to adhere to sialylated glycoconjugates expressed
during chronic inflammation might thus contribute to the
virulence and extraordinary chronicity of H pylori
infection and account for the existence of H pylori strains
of differing virulence, especially cagA-positive strains.33
CagA positive strains are able to colonise both the gastric
and duodenal mucosa. With PCR, H pylori virulence
genes were analysed and it could be shown that strains
coexpressing cagA, s1m1 vacA, and babA2 genes worsened
inflammation significantly.34 Soluble glycoproteins
presenting the Lewis (b) antigen or antibodies to it inhibit
bacterial binding. Gastric tissues that do not express
Lewis (b) do not bind H pylori, and the bacteria do not
Figure 3: Histological subtypes of gastric cancer bind to this antigen when it is substituted with a terminal
(A) Gastric carcinoma of intestinal type. Normal mucosa is replaced by GalNAc--1-3 residue, the blood group A determinant.
infiltrating tubular profiles. Haematoxylin and eosin, 200. (B) Signet-ring This finding suggests that the availability of H pylori
cell gastric carcinoma of the diffuse type. There is diffuse infiltration of
the mucosa by signet ring cells. The gastric pits appear normal and there receptors might be reduced in individuals of blood group
is no evidence of gastritis or intestinal metaplasia. Haematoxylin and A and B phenotypes, compared with blood group O
eosin, 200. individuals.35
H pylori substantially impairs the bioavailability of
route, and transmission is from person to person.21–24 vitamin C, which together with the reduced vitamin C
Prevalence of the bacteria is high in Asia and Eastern intake of H pylori-positive people, greatly reduces
Europe and low in Western and Northern Europe as well concentrations of vitamin C in plasma. The reduced
as in North America. In a population-based case-control circulating concentrations of vitamin C in people infected
study, 72% of 190 patients with gastric adenocarcinomas with H pylori may be a causative factor in gastric cancer, as
were seropositive by IgG ELISA and 91% by immunoblot well as other diseases associated with antioxidant
assay, versus 55% in 144 controls. 71% of non-cardia deficiency.36 Successful eradication of H pylori improves
adenocarcinomas were attributable to H pylori. Results secretion of vitamin C into gastric juice, which might
from Japan and the UK suggest that in patients younger increase protection against gastric cancer.37 Results of a
than 40 years, 45–55% of all gastric cancers might be randomised, placebo-controlled trial in a Colombian
associated with this infection. Serological investigations population of people at high risk of gastric cancer showed
might be misleading: elderly patients with mucosal that vitamin C, beta-carotene, and H pylori eradication
atrophy develop seroreversion. Initial analysis showed that were statistically significant in promoting regression of
89% of histological sections of patients with stomach precursor lesions.38
cancer of intestinal type contained H pylori in non- Despite recent advances in knowledge about differences
cancerous tissue compared with 32% in diffuse type in carcinogenesis of gastric cancer subtypes, genetic
cancer;25 however, results of serological analysis showed alterations between H pylori positive and non-H pylori
an association between H pylori and both types of gastric associated cancers could not be verified.15,39
cancer.26,27 The association between cancer of the gastric
cardia and H pylori infection is ambiguous. Progress in diagnosis
H pylori infection is associated with various clinical Patients in eastern countries are mainly those with early
outcomes, including gastric cancer and duodenal ulcer cancers, whereas western patients are usually treated
disease. There is also evidence that infection in children when the cancer is at an advanced stage. This difference
and adults leads to different pathology.28 This variation in might have contributed to confusion in histopathological
outcome seems to be related to the severity and the classification of the disease (panel 1 and 2), and made
anatomical distribution of the gastritis attributable to comparison of treatment results from the two regions
H pylori.29 Patients who have duodenal ulcer with antrum- difficult.40 In the west, inflammatory and regenerative
dominant H pylori gastritis and only very low-grade corpus changes of the mucosa of the stomach were classified as
H pylori gastritis retain normal (or even high) acid dysplasia, as were well-differentiated adenocarcinomas. In
secretion, and they very rarely develop gastric follow-up studies, people who had gastric mucosa biopsy

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SEMINAR

Panel 1: TNM staging system and appearance of Panel 3: Vienna classification of epithelial
gastric cancer (5th edn, 1997) neoplasia of the gastrointestinal tract36
Primary tumour (T) Category comments
Tis Carcinoma in situ, intraepithelial tumour (see 1 Negative for neoplasia
Vienna classification) 2 Indefinitive for neoplasia
T1 Tumour invades lamina propria (T1a) or 3 Non-invasive low-grade neoplasia
submucosa (T1b) 4 Non-invasive high-grade neoplasia
T2 Tumour invades muscularis propria or 4·1 High-grade adenoma
subserosa; extension into omenta or 4·2 Non-invasive carcinoma
gastrohepatic ligaments is classified T2, until 4·3 Suspicious for invasive carcinoma
perforation of the visceral peritoneum has 5 Invasive neoplasia
occurred 5·1 Intramucosal carcinoma
T3 Tumour penetrates serosa 5·2 Submucosal carcinoma or beyond
T4 Tumour invades adjacent structures
judged. Now, endoscopic ultrasonography is accepted as
Lymph-node metastases (N)
superior to conventional CT. However, CT with gastric
Histological examination of a regional lymphadectomy
distention of 600–800 mL of water (hydro-CT) might be
specimen will ordinarily include 15 or more nodes
a complementary investigation and should be noted
N0 No regional lymph-node metastases
(table 1). Endoluminal ultrasonography is used with
NX Less than 15 investigated lymph nodes
rotating or sectorial scanners of 7·5 MHz or 12 MHz.
N1 1–6 regional lymph-node metastases
Rotating scanners improve orientation, while the sectorial
N2 7–15 regional lymph-node metastases
probes allow biopsies to be taken. The gastric fundus is a
N3 More than 15 regional lymph-node metastases
difficult area to assess as is the lesser gastric curvature
M1 Metastases in retropancreatic, mesenteric, or
where the scanner cannot be positioned exactly. In early
para-aortic nodes
gastric cancer, rotating miniprobes of higher resolution
Distant metastases (M) (20 MHz) can be used to separate mucosal from
M0 No distant metastases submucosal invasion.43 Endoluminal ultrasonography
M1 Distant metastases cannot reliably discriminate a T2 from a T3 lesion,
especially if the carcinoma invades the greater or lesser
specimens classified as high-grade dysplasia, up to 75% of omentum; however, even high-resolution CT cannot
the patients developed a cancer within a median time of differentiate between T1 and T2 lesions.
8 months. There were no similar reports from Japan, Routine detection of early gastric cancer is a rare event.
Korea, or Asia. As a consequence of this finding, reported Therefore, workers have investigated indigo-carmine
by the British Society of Gastroenterology first in 1990 staining of the mucosa applied locally via the endoscope,
with confirmative reports later on,41 the Vienna or fluorescein given intravenously (chromoendoscopy).
classification of epithelial neoplasia of the gastrointestinal Results of this work might allow detection of early cancer
tract (oesophagus, stomach, colorectum) was introduced even if the lesion does not belong to either the protruded
in 1998.42 Differences between western and Japanese or the depressed type.44
pathologists’ diagnostic classification of gastrointestinal
epithelial neoplastic lesions could largely be resolved by Limited resection in early gastric cancer
the adoption of a terminology based on cytological and In early gastric cancer, 5 year survival can be better than
architectural severity and invasion status (panel 3). Here, 90% if treated in experienced hands. In Japan, screening
high-grade dysplasia, non-invasive carcinoma, and endoscopy results in the detection of up to 40% of gastric
suspected invasive carcinoma are integrated into one cancers at an early stage; in Europe the proportion is less
term. Although it might be advantageous to use these than 15%. In early cancers, lymphnode metastasis is
categories to initiate adequate follow-up, local unusual; up to 4% for the mucosal type T1a and about
endoscopical, or surgical treatment it is local staging 23% for the submucosal type T1b. If morphological
about the depth of invasion that is the essential factors (size, growth type, ulceration, grading) are
prerequisite for any treatment decision. considered, T1 tumours with a very low risk of lymph-
node metastases can be selected.45 Results from a study in
Endoscopical ultrasound for local staging Japan46 of more than 5000 patients with early gastric
Flexible endoscopy is the method of choice to establish cancer who had gastrectomy with lymph-node dissection,
the diagnosis of gastric cancer, and biopsies are needed for showed that none out of 1230 well-differentiated
confirmation. Early gastric cancer (ie, confined to the intramucosal cancers of less than 30 mm diameter was
mucosa [T1a]) might be treated locally in some cases, and associated with metastases. None of the 929 lesions
thus the depth of infiltration to the gastric wall without ulceration was associated with nodal metastases
(T-category) is of utmost importance, because it allows irrespective of tumour size. In submucosal cancers, there
the risk of lymphatic dissemination of the tumour to be was a correlation between tumour size greater than
30 mm and lymphatic-vascular involvement and increased
Panel 2: TNM staging system stage classification CT EUS Hydro-CT Lap
N0 N1 N2 N3 T category 25–66% 71–92% 51% 47%
M0 T1 Ia Ib II IV N category 25–68% 55–87% 51% 60–90%
T2 Ib II IIIa IV M category 65–72% ·· 79% 80–90%
T3 II IIIa IIIb IV EUS=endogastric ultrasonography. Lap=laparoscopy (with laparoscopic
T4 IIIa IV IV IV ultrasonography).
M1 IV IV IV IV Table 1: Accuracy of four diagnostic methods to assess TNM
features in patients with gastric carcinoma

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risk of nodal metastases. In these patients with smaller
tumours, total gastrectomy with clearance of the
lymphatic drainage area is not recommended. In Japan,
surgeons favour endoscopic mucosal resection, which is
thought to have high curative potential and to avoid the
need for further radical surgery; however, such an
approach should only be done if very accurate local
staging has been achieved.47 Furthermore, the risk of
missing lymph-node metastases is about 2·5%.
Early endoscopic mucosal resection techniques used
norepinephrine to raise lesions, which were then resected
with an electrical sling: R0-resection rates ranged from
45–65%. Techniques evolved to use a panendoscope to
obtain a specimen with a large 20 mm circular cap under
full suction.48 After resection of 167 specimens from 97
lesions in 85 patients, 93% of elevated lesions were
resected completely; however, in flat or depressed lesions
only 53% of the tumours could be removed by a single
approach with clear margins. Endoscopic mucosal
resection is often impossible for lesions located at the
gastric cardia or lesser curvature, but these difficulties
might be overcome by combining endoscopic and
laparoscopic mucosal resection. The area of the removed
specimen could be as large as 5050 mm. 5-year follow-
up results with laparoscopic resection in the lesion-lifting
method (ie, laparascopic resection of the tumour-bearing
segment with a linear cutter after the gastric wall has been
lifted with a T-shaped metal stab inserted beneath the
tumour while it is under endoscopical control), showed
that only one patient needed gastrectomy for tumour
invasion to the submucosal layer, and two developed
intragastric recurrence near the staple line.49 The Japan
Gastric Cancer Association issued treatment guidlelines in
March, 2001, for doctors, patients, and their families.50
Assessment of abdominal spread in advanced
cancers
Lymph-node metastases arise in up to 44% of patients
with T2 tumours, and 64% in those with T3 cancers.
Surgical clearance of the lymphatics is essential if a
curative approach is to be taken, or if patients are to have
preoperative chemotherapy.
Knowledge of the presence and extent of nodal spread
is helpful in planning treatment. A CT scan, however,
does not provide much information, and only the size of
nodes can be used as a criterion. Endoluminal
ultrasonography can assess lymph nodes close to the
gastric wall, and features such as a rounded shape,
hypoechoic patterns, and a size larger than 1 cm suggest
metastasis. Rarely, analysis of transgastric biopsy samples
can prove tumour infiltration, and within this context,
laparoscopy has had a new lease of life. Laparoscopy had
been used for around four decades for the staging of
gastrointestinal cancer,51 but its use diminished with the
arrival of CT and MRI in the mid sixties. However, since
1990, laparoscopy has been used again because of new
techniques, such as combining the procedure with
pneumoperitoneum, the use of trocars, and the
development of specialised instruments, 30 viewing
optics, and laparoscopic ultrasound probes.52,53 The
sequence of staging laparascopy is shown in panel 4.
Laparoscopic staging can achieve a 92% rate of detection
for advanced gastric cancer, compared with only 58%
with CT and 63% with endoscopic ultrasonography
(table 1). Workers in several prospective series52–56 have
reported that up to a third of patients had a tumour at a
more advanced stage than had been expected, and the
treatment plan had to be changed. Even if the tumour is at
the dorsal part of the stomach, it can be assessed directly
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SEMINAR
Panel 4: Laparoscopic staging of gastric cancer54
After inflation of the pneumo-peritoneum, a visual turnaround
of the abdominal cavity is done and peritoneal or liver surface
is inspected for small tumour deposits. Assessment of
serosal invasion (T3) can be based on direct view and biopsy.
Thereafter, the lesser sac is opened to explore local
resectability in tumours of the dorsal part of the stomach.
Lavage of the bursa is done; thereafter, laparoscopic
ultrasonography under direct view allows a thorough
examination of subdiaphragmal liver segments not
assessable to transcutaneous ultrasonography. Perigastric
lymph nodes, the coeliac axis and nodes along the
hepatoduodenal ligament are examined. Most important,
suspicious lymph nodes can be excised or biopsied.
by opening the lesser sac via the minor omentum or the
gastrocolic ligament. Laparoscopic staging done by a
skilled surgeon immediately before treatment surgery
seems to be the best diagnostic tool to guide decisions
about surgical resection or palliative measures.55,56 If the
staging laparoscopy is done as a separate procedure,
lavage of the omental sac or the abdominal cavity can be
used for peritoneal washing. Intraperitoneal free cancer
cells imply a very poor prognosis in gastric carcinoma;
however, there is no consensus on how these patients
should be managed.
Cancer of the oesphagogastric junction
By contrast with the diminishing frequency of gastric
cancer, the rate of carcinoma at the oesphagogastric
junction is rising, especially in industrialised countries. In
Europe, increased incidence of this type of cancer has
been reported in Denmark, Italy, and the UK.2,7,57,58 The
frequency of adenocarcinoma of the gastric cardia
increased 29·1% to 52·2% from 1984 to 1993
(p<0·0001). This tumour type is distinct from cancer of
the lower oesophagus or Barrett’s carcinoma. Only a small
subgroup of these cancers is promoted by
gastroesophageal reflux, so antireflux surgery will not
prevent them. In a population-based retrospective cohort
study in Sweden, 67 000 patients with gastro-oesophageal
reflux disease were compared with 11 000 who underwent
anti-reflux surgery. The standardised incidence ratio of
gastric cardia adenocarcinoma was 2·4 ( 95% CI 1·7–3·3)
in men who did not have surgery and 5·3 (95% CI
3·0–8·7) in those who had undergone surgery.59 The
cancer risk pattern in women was similar, but the number
of cases was very much smaller. Associations have also
been reported between cancer of the gastric cardia and
H pylori infection and Epstein-Barr virus.60,61
Irrespective of the cause, cancer of the gastric cardia is
characterised by poor prognosis, which might be partly
due to the fact that tumours are located at the border of
three areas of lymphatic drainage—mediastinal,
abdominal, and retroperitoneal. Furthermore, there is no
peritoneal cover in the dorsal part of the cardia. Lymph-
node metastases might develop early and at locations such
as the left renal vein and para-aortic nodes—regions not
routinely cleared during surgery for gastric cancer.62,63 A
delay in diagnosis might occur with cancers in oesophago-
gastric junction because the subcardial area cannot be
easily viewed by endoscopy, and because symptoms
caused by tumour stenosis occur only at a late stage in the
disease. Carcinomas of the gastro-oesophageal junction
might arise from the distal oesophagus, the true cardia or
the subcardial region.
Siewert and Stein64 have proposed a classification based
on the different origins of oesophago-gastric tumours.
309
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Number Regimen R0- Survival In a Dutch randomised trial, 56 patients were allocated
of resection time either up to four cycles of 5-fluorouracil, adriamycin, and
patients rate (%) (months) methotrexate (FAMTX) before surgery or to surgery only.
Ajani73 56 Preop FAMTX, postop 61 15* 12 patients (44%) could not complete chemotheraphy
5-FU/CDDP because of tumour progression toxicity, or both. This
48 Preop and postop EAP 77 16† small trial revealed no benefit for chemotherapy, and the
Fink74 49 Preop PLF 76 36*
Dutch investigators concluded future trials should use
Kang75 107 Surgery vs PEF and 61 vs 78 30 vs 42*
surgery (p=0·049) p=0·11 more active regimens.76 Although some workers have
Songun76 56 Surgery vs preop 62 vs 56, 13·1 vs reported success in the downstaging locally advanced
FAMTX and surgery (ns) 12·8 (ns) cancer and also long survival rates in patients with
77
Skoropad 78 Surgery vs preop RT Data not 9 vs 21 (ns) otherwise unresectable cancers, surgical staging was not
20 Gy IORT+surgery shown done to confirm the unresectability of lesions.79,80
Zhang78 370 Surgery vs 40 Gy and 79 vs 89 20 vs 30
surgery (p=0·01) (10 yr)
Three large phase 3 trials are underway to assess the
p=0·0094 usefulness of neoadjuvant treatment. The MAGIC trial in
Preop=preoperative. Postop=postoperative. FAMTX=5-fluorouracil, doxorubicin,
the UK compared surgery alone with ECF (epirubicin,
methotrexate. CDDP=cisplatin. EAP=etoposide, doxorubicin, cisplatin. cisplatin, and 5-fluorouracil). Most recently, preliminary
PEF=cisplatin, etoposide, 5-fluorouracil. PLF=cisplatin, leucovorin, fluorouracil. data of this trial involving 503 patients were released.81
RT=radiotherapy. ns=not significant. IORT=intraoperative radiotherapy. *Median
survival time. †Mean survival time.
The authors reported an increased R0 resection rate of
79% after combined modality therapy compared with 69%
Table 2: Results of neaodjuvant treatment concepts for locally
after resection alone (p<0·02). Pathological examination of
advanced gastric cancer
the resection specimens suggested a downsizing of the
tumour. Perioperative complication rates seemed not to be
Type I represents adenocarcinoma of the distal raised. Whereas progression-free survival was improved
oesophagus with the centre of the tumour lying 2·5 cm significantly, there was no advantage in overall survival
above the anatomical cardia. Such tumours should be after a minimum of 1 year follow-up in all patients. The
treated by subtotal resection of the oesophagus including Swiss study, SAKK 43/99, compares surgery plus
the cardia and gastric fundus together with removal of the preoperative TCF (taxotere, cisplatin, and 5-fluorouracil)
lymph nodes to the coeliac axis. The type II tumour is true with surgery followed by the same chemotherapy regimen.
carcinoma of the cardia with centres in the region 1 cm A multinational European trial (EORTC 40954) compares
above and 2 cm below the anatomical cardia. surgery alone with surgery after neoadjuvant PLF
Gastrectomy, splenectomy, and resection of the distal part (cisplatin, leucovorin, and 5-fluorouracil).
of the oesophagus is recommended for type 2. Type 3 To identify patients who should receive palliative care
cancer is a gastric carcinoma with its centre 2–5 cm below rather than neoadjuvant treatment, staging laparoscopy
the anatomical cardia and should be treated by total with inspection of the bursa omentalis should be done to
gastrectomy including splenectomy and removal of a short identify peritoneal spread.
part of the distal oesophagus. Lymphatic clearance is
recommended caudally to the coeliac axis, hilus of the Gastric resection and lymphatic clearance
spleen, and para-aortic nodes. This classification system Whether the optimum surgery for gastric cancer in the
has been endorsed by the International Society for distal half of the stomach is subtotal or total gastrectomy is
Diseases of the Oesophagus and the International Gastric not clear. The Italian Gastrointestinal Tumour Study
Cancer Association. Group randomly allocated 624 patients with cancer in the
It is essential that the type of lesion is known before distal half of the stomach to subtotal gastrectomy (n=320)
planning a patient’s treatment. Because gastric cardia or total gastrectomy (n=304). Both procedures included
cancer is a three-compartment tumour, it is not surprising a second-level lymphadenectomy. Inclusion criteria were a
that incomplete resections, either for ascending intramural tumour with a proximal edge at least 6 cm from the cardia,
spread to the oesophagus or transmural spread to the and no intraperitoneal or distant spread. At 5 years, the
pericardiac soft tissues affects prognosis.65,66 survival probability was 65·3% for patients with subtotal
and 62·4% for those with total gastrectomy. Subtotal
Neoadjuvant treatment options gastrectomy with lymphadenectomy of compartments one
In western countries, when patients with cancer of the and two has been associated with a better nutritional status
stomach are referred for treatment, they are likely to have and quality of life, and it should be the procedure of
locally advanced disesase: 44% of patients in the UK- choice.82
lymphadenectomy study had pT3 tumours,67 59% in a Lymph-node metastasis decisively affects prognosis in
German study had stage III or IV disease,68 as did 67% of stomach cancer. Operative clearance of the lymphatics is of
18 365 patients in the American College of Surgeons’ utmost importance and requires a thorough surgical
study.69 In the presence of advanced disease, complete training if it is to be done effectively and safely. Removal of
resection of the tumour and its lymphatic spread can be the perigastric lymph nodes only is called D1 resection. D2-
achieved in fewer than 50% of patients. Furthermore, lymphadenectomy adds removal of the lymphatic chains
median survival rates at 5 years are, at best, around 30% along the coeliac axis, the common hepatic and splenic
because of locoregional recurrence and systemic artery, and at the hilus of the spleen, and this procedure has
metastases.70–72 Consequently, several trials have sought to been recommended by the Japanese Society for Research
assess whether patients benefit from preoperative in Gastric Cancer, the European Society of Surgical
chemotherapy to downstage the tumour, and eliminate Oncology, the International Gastric Cancer Association,
micrometastases and intraoperative spillage of tumour and the US National Comprehensive Cancer Network.
cells. Unfortunately, encouraging results of phase 2 trials The D2 procedure is done to achieve: accurate staging and
have not been reported in full, while data from randomised regional disease control, and because of potential benefit to
trials do not lend support to the neoadjuvant approach, a subgroup of patients with occult disease in D2 nodes. D2
even if chemotherapy is combined with preoperative or lymphadenectomy is safe if done by a skilled surgeon, and if
intraoperative radiation treatment (table 2). splenectomy and pancreatic resection are avoided.

310 THE LANCET • Vol 362 • July 26, 2003 • www.thelancet.com

For personal use. Only reproduce with permission from The Lancet.

Rights were not granted to include this
image in electronic media. Please
refer to the printed journal.
Figure 4: Multidirectional lymphatic network of the stomach
and its relation to the pancreas, liver, mediastinum, and
retroperitoneum
Figure from Inoue83
Lymphatic drainage of the stomach is multidirectional
and involves a wide net of lymphatic channels. Detailed
descriptions of these pathways go back to the 1930s
(figure 4).83 Skip metastases can occur in up to 20% of
patients and the aim of clearing one lymph-node station
beyond the last node occupied by cancer led to the
development of D2 lymphadenectomy.
Results of eight prospective, non-randomised trials
showed substantial survival advantages for D2 over D1
lymphadenectomy, especially in patients with stage
2 and 3a disease.84 However, morbidity and mortality are
associated with D2 lymphadenectomy, most often
explained by lesions to the pancreatic tail or because the
pancreas needs to be resected to achieve complete
removal of the lymph nodes at the splenic hilus (table 3).
Three randomised, controlled trials have been done
in the past years to assess whether D2 lymphadenectomy
in combination with total gastrectomy really yields a
substantial survival advantage. A Dutch multicentre
trial85 used instructors from Japan and strict quality
control to ensure that D2 lymphadenectomy was done
accurately. However, all three trials showed increased
morbidity with D2 lymphadenectomy and improved
survival rates were not evident. Pancreatic fistula and
pancreatitis resulting from splenectomy and resection
of the pancreatic tail were the main contributors to
morbidity. In a subgroup of patients without splenectomy
or resection of the pancreatic tail, D2 lymphadenectomy
was associated with a drop in local recurrence rates in
the Dutch trial,85 and the best 5-year survival rates in
a UK trial.71 Splenectomy is an especially adverse
prognostic factor of its own and suppression of
T-cell function is thought to be one of the linking
factors.88 Therefore, splenectomy should be done only
in cases of locally advanced tumour of the upper third
of the stomach, tumours of the greater curvature,
and those of the gastric cardia. The incidence of lymph-
node metastases is between 10% and 25%, and if
splenectomy is advised, the pancreas should be
preserved.89
THE LANCET • Vol 362 • July 26, 2003 • www.thelancet.com
For personal use. Only reproduce with permission from The Lancet.
SEMINAR
Patients Morbidity (%) Mortality (%) 5-year
(D1/D2) (D1/D2) (D1/D2) survival (%)
(D1/D2)
Bonenkamp85,86 380/331 25/43 4/10 45/47
Cuschieri67,71 200/200 28/46 6·5/13 35/33
Dent87 22/21 15/30 0/0 78/76
(3 years)
Table 3: Comparison of morbidity, mortality, and 5-year survival
in randomised trials of D1 versus D2 lymphadenectomy
Individualised assessment of lymphatic spread
To avoid unnecessary removal of lymph nodes that are
not at risk of tumour, two approaches have been pursued.
The first technique uses a computerised database of
information to convert a large amount of information and
experience to a treatment decision for an individual
patient. The second approach uses information derived
from dissection of the sentinel node.
Maruyama and his co-workers developed a computer
program (Kampschoer and colleagues)90 to calculate the
probability of nodal spread to each individual lymph-node
station, using histopathological features of the primary
tumour. At first, the program used information from about
2000 patients from the National Cancer Centre of Tokyo;
however, the program is continuously updated and it
now includes data from more than 8000 patients. Depth of
infiltration, tumour size, tumour location, grading, typing,
and macroscopic appearance are used to predict the
probability of nodal metastases. Application of this program
in Germany and Italy resulted in a diagnostic accuracy
of 74% and 94%, respectively.91,92 However, the point at
which lymph-node dissection should be done is not clear.
Maruyama and colleagues initially recommended a cutpoint
of 18%; however, if this recommendation was used, up to a
fifth of patients would have incomplete operations.
In the 1950s, Weinberg93 was the first to identify
perigastric lymphatic vessels and nodes by injecting blue
dye (figure 4). Later, activated carbon was favoured
for lymphatic mapping. In a prospective randomised
evaluation of preoperative endoscopic vital staining with
CH40 before D2 lymph-node dissection, the rate of
metastatic nodes was substantially higher in patients who
had staining versus those who did not.94 The success of
isolated drainage of CH40 led to the use of this approach
for endolymphatic chemotherapeutic treatment of nodal
metastases via absorption of mitomycin C.95 None of these
methods was able to detect the first draining lymph-
node—ie, the so-called sentinel node, which has been
shown to be a marker of lymph-node metastases in
melanoma and breast cancer by several studies from the
USA and Europe. Because the stomach has four main
lymphatic drainage directions (coeliac axis, liver,
mediastinum, and retroperitoneum) more prospective data
are needed before drainage directions revealed by blue dye
or 99Tc colloid can be allowed to affect decisions about
removal or non-removal of lymph nodes in patients with
cancer of the stomach. If non-stained or non-radiolucent
areas are not removed, nodes occupied by cancer could be
left behind. Table 4 shows that the detection rate of the
initial draining (ie, sentinel) node ranges from 95% to
100%. However, the sensitivity of detecting nodes involved
by cancer as controlled by full D2 lymphadenectomy is in
the range of 90% depending on the stage of tumours
recruited. Although this approach seems promising, it is
yet to be fully tested. Future procedures might see patients
with T1 or small T2 lesions undergoing lymphadenectomy
limited to the area indicated by the sentinel node
procedure.
311
SEMINAR
Number of Method Detection Sensitivity Node
patients rate (%) (%)
and T
category
Kitagawa96 127 T1 m99Tc 95% 92%
18 T2 Sn-colloid
Ichikura97 62 T1/2 dye 100% 87%
ICG
Hiratsuka 98
44 T1 dye 99% 90%
30 T2 ICG
ICG=indocyan green
Table 4: Results of sentinel node detection gastric cancer
Reconstruction after total gastrectomy
Replacement of the resected stomach should prevent
reflux from the intestine to the oesophagus and thus
prevent oesophagitis. Furthermore, measures should be
taken to avoid postoperative malabsorption and
maldigestion, because total gastrectomy leads to impaired
nutritional status and loss of more than 10% of the
preoperative weight. Reconstruction of the alimentary
canal after gastric resection has long been a point of
debate and prospective randomised trials have been done
to assess whether a J-shaped pouch reservoir constructed
from the proximal jejunum is needed to replace the
stomach.99,100 Furthermore, investigators also sought to
determine whether any reconstruction should be
positioned as a Roux-en-Y oesophago-jejunostomy or
whether the duodenal passage should be maintained.
Because it is a technically simple procedure, Roux-en-Y
oesophago-jejunostomy is the preferred type of
anastomosis. A comparison of a J-pouch replacement for
the stomach with straight anastomosis shows that
functional results seem to be superior in the pouch group
during the first year after surgery.99,100 However, patients
who had this more sophisticated reconstruction procedure
did not avoid weight loss or show an improved quality of
life. Results of a randomised comparison of J-pouch
reconstruction with or without maintainence of the
duodenal passage in 120 patients showed that there are no
significant differences between the procedures with
respect to anastomotic dehiscence rates, general
complications, mortality, operation time, or bodyweight,
Visick scoring,101 or Spitzer index.102,103 Differences
between the procedures seemed to represent only an early
adaptive process, and advantages could not be seen
during longer follow-up.
Adjuvant treatment
Many studies have investigated the use of postoperative
adjuvant systemic chemotherapy. Results of a meta-
analysis104 showed that there is no evidence of a survival
advantage with this treatment. However, some data from
non-randomised trials and one small randomised trial
suggest that postoperative intraperitoneal chemotherapy
remains worthy of investigation.105,106
Recently, workers from a US multi-institutional
randomised trial of 556 patients claimed that adjuvant
radiochemotherapy improved postoperative median
overall survival from 27 months to 36 months (p<0·005,
hazard ratio 1·35) as well as relapse-free survival (1·52)
after a medium follow-up of 3 years.107 Improvement in
survival rates could be shown through all stages of disease
and was attributed to the 45 Gy of radiotherapy and three
cycles of 5-fluorocacil (425 mg/m2) and leucovorin
(20 mg/m2) that were given in addition to resection of
non-metastatic gastric cancer with curative intent.
Initially, the investigators considered this regimen a
standard of care; however, during the study they
312
For personal use. Only reproduce with permission from The Lancet.
concluded that the quality of surgical treatment was
positive poor.108 A substantial proportion of patients had had D0
patients resections—ie, no clearance of the lymphatics. A
(%)
comparison of 5-year survival rates in patients with
17% different stage cancers showed that surgery and
postoperative radiochemotherapy had the same rate of
24%
success as those achieved in the randomised trials for D1
14% or D2 lymphadenectomy alone.109 Only 10% of patients
had received a D2 lymphadenectomy, and as a result
64% of controls had recurrence, which involved regional
sites in 72%, local sites in 29%, and distant sites in 18%.
Recently, surgical information about treatment of various
lymph node stations was re-analysed. The Maruyama
program to estimate the likelihood of disease in
undissected regional node stations was applied,84 and
survival probability was calculated by Cox’s multivariate
regression. As a result, 54% of patients had undergone a
D0 lymphadenectomy and the index of unresected
disease proved to be an independent prognostic factor,
even after adjustment for linked variables such as T stage
or the number of positive nodes.108 In this trial, surgical
undertreatment undermined survival estimates—the
results could be interpreted as has having treated residual
disease by radiochemotherapy in a significant subgroup
of patients. After R0 resection of cancer of the stomach
and adequate lymphadenectomy, adjuvant treatment
cannot be recommended outside of prospective
randomised trials.
Assessment of minimal residual disease as a
prognostic factor
Apart from macrometastases in lymph nodes and other
distant sites, micrometastases and single disseminated
tumour cells are detected in bone marrow, blood, and
lymph nodes in patients with gastric cancer. Tumour cell
clusters of less than 2 mm with stromal reaction from
surrounding tissue are called micrometastases. Minimal
residual disease is represented by single disseminated
tumour cells detected by cytological examination,
immunohistochemical analysis, or RT-PCR. Cytology
detects one epithelial cell per 100 cells, immuno-
histochemical techniques detect one cell per 105 cells;
however, RT-PCR allows detection of one epithelial cell
per 107 cells.110 The higher the sensitivity, the less
specificity should be expected. There is much debate
about whether these cells represent true metastatic cells
and precursors of overt metastases, or whether they have a
limited life span and are merely a sign of shedded tumour
cells. Recently, the tumorigenic potential of epithelial cells
has been proven in animal experiments in studies with
cells derived from oesophageal nodal metastases and
prostate cancer.111,112 Characterisation of those cells
showed less expression of proliferation markers (p120 and
CK67) and HLA class 1 receptors are downregulated and
might contribute to less activation of T-cell mediated
destruction.113
In gastric cancer, disseminated epithelial cells can be
detected by antibodies against cytokeratin-18 and
urokinase-type plasminogen activator (uPA).114 The
detection rate of epithelial cells in bone marrow or lymph
nodes that stain negative in conventional haematoxylin
and eosin (pN0) depends on the stage of disease;
however, it was also reported for early cancer of
submucosal type.115 Carcinoembryonic antigen-mRNA
positive cells were detected in an increased range after
surgical manipulation.116 The presence of disseminated
tumour cells in bone marrow is indicative of systemic
disease even in early stages of cancer of the stomach. The
extent of tumour-cell detection in bone marrow correlates
THE LANCET • Vol 362 • July 26, 2003 • www.thelancet.com

Panel 5: Potential advances in the treatment and
diagnosis of gastric cancer in the next 5–10 years
● increase to 50% the proportion of gastric cancers in the
western hemisphere that are diagnosed early by improved
endoscopic methods
● explore the incidence of inherited gastric cancer and
locate the genomic defect
● eradication of H pylori, thus eliminating one causal agent
● development of a vaccine against highly-invasive, tumour-
inducing strains of H pylori
● clarification of the mechanisms of individualised reaction
to H pylori infection (interleukins, vascular endothelial
growth factor)
● ‘proof of principle’ that eradication of H pylori prevents
development of gastric cancer
● identification of the lymphatic drainage basin by combined
endoscopic and laparoscopic sentinel node procedure in
T1b and T2 tumours, leading to limited lymphadenectomy
in most patients
● establish a clear indication for neoadjuvant treatment and
select patients by expected reponse to treatment
● develop a method to fight peritoneal carcinosis (intra-
abdominal antibodies, migration factor inhibitors, anti-
proliferative substances)
● characterisation of single tumour cells in bone marrow as
a basis for directed adjuvant therapy
with prognosis in patients who undergo resection of
curative intent. Therefore, epithelial cells in bone marrow
could be a selection criteria for adjuvant treatment if there
were active drugs or efficient strategies.117 However, by no
means should the detection of these cells direct a patient
to treatment of purely palliative intent. At present, the
detection of disseminated epithelial cells in patients with
gastric cancer is an area of intense research but does not
yet have clinical consequences.
Panel 5 shows the possibilities for future developments
in treatment of gastric cancer.
Conflict of interest statement
None declared.
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