Chemoradiation For Resectable Gastric Cancer

Review
Chemoradiation for gastric cancer
Chemoradiation for resectable gastric cancer

Henry Q Xiong, Leonard L Gunderson, James Yao, and Jaffer A Ajani
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The incidence of gastric cancer has been declining in recent

years, however, the disease continues to be a worldwide
public health problem. About two thirds of patients with
gastric cancer undergo surgical resection with curative
intent. R0 resectioncomplete local-regional tumour
removal with negative resection marginsis the only
curative modality. The optimum extent of lymph-node
dissection (D1 vs D2) is controversial. Disease relapse, both
local and distant, is common and the 5-year survival rate is
disappointing. Adjuvant chemotherapy has been studied
extensively in this setting but an effective regimen has not
yet been identified. A recent intergroup study has shown
that postoperative chemoradiation is effective in improving
both disease-free survival (3-year, 48% vs 31%, p<0001)
and overall survival (3-year, 50% vs 41%, p=0005)
compared with surgery alone. Preoperative radiation as a
single adjuvant therapy has also yielded improvements in
local-regional control, disease-free survival, and overall
survival compared with surgery alone. Preoperative
chemotherapy or chemoradiation has been accepted to
have a theoretical advantage over postoperative therapy
and has now been shown to be a feasible option. Its
efficacy, however, remains to be tested.
Lancet Oncol 2003; 4: 498505
Gastric cancer is the second most common cancer worldwide,

although the incidence of the disease has been declining for
the past few decades (figure 1). Each year, roughly 798 000
people are diagnosed with gastric cancer worldwide (99% of
total cancer cases) and 628 000 people die from the disease
(121% of cancer deaths).1 The incidence of gastric cancer
varies substantially among racial and ethnic groups. The
incidence is highest in Japan, Korea, eastern Asia, eastern
Europe, and parts of Latin America. The USA and other
industrialised nations have relatively low incidences of the
disease.
The only potentially curative treatment for gastric cancer
is surgery. However, relapse after surgical resection is
common and accounts for the high mortality rate. Much
effort has been focused on the search for an effective adjuvant
or preoperative therapy to improve cure rates. Several reviews
of adjuvant chemotherapy for gastric cancer have been
published recently.25 In this review we discuss
chemoradiation as a treatment for resectable gastric cancer.
Figure 1. Postoperative x-ray of the digestive system after a gastrectomy

for stomach cancer.
proportion of patients who were treated with some type of

surgery or surgery combined with adjuvant therapy;7
approximately 6165% of patients with localregional disease
underwent surgery. Adjuvant chemotherapy, radiation, or
chemoradiation were used with increasing frequency as
disease progressed from stage IA to IIIB. About 10% of
patients with stage III disease received adjuvant therapy but
only 5% of patients with stage I disease received adjuvant
therapy. However, fewer patients received adjuvant therapy
than in an earlier report.8 A significant proportion of patients
did not receive any treatment. This may be because more than
50% patients with gastric cancer in the USA are older than
Disease progression
HQX and JY are Assistant Professors and JAA is a Professor all in

the Department of Gastrointestinal Medical Oncology at The
University of Texas MD Anderson Cancer Center, TX, USA. LLG is
Professor and Chairman of the Department of Radiation Oncology,
Mayo Clinic Cancer Center, AZ, USA.
The primary treatment for gastric cancer is surgery. For

example, in a study by Wanebo and colleagues, 77% of
patients underwent surgery but only 35% of received
adjuvant chemotherapy or radiation therapy.6 However, the
National Cancer Database in the USA reported a lower
Correspondence: Prof Jaffer A Ajani, Department of

Gastrointestinal Medical Oncology, Box 426, Division of Medicine,
The University of Texas MD Anderson Cancer Center, 1515
Holcombe Boulevard, Houston, TX 77030, USA.
Tel: +1 (713) 792 2828. Fax: +1 (713) 745 1163.
Email: jajani@mail.mdanderson.org
498
THE LANCET Oncology Vol 4 August 2003
http://oncology.thelancet.com
For personal use. Only reproduce with permission from The Lancet.
Review
Table 1. Stage-stratified 5-year overall survival rates in

patients with gastric cancer
Stage
IA
71
IB
56
II
37
IIIA
18
IIIB
11
IV
5
Ref
86
69
55
38
17
16
93
84
69
46
30
10
8*
*Data based on surgical series. Data from the US national registry databasea
significant proportion of patients did not receive cancer-directed therapy which may
confound the survival comparison.
70 yearsa fact that should kept in mind when designing

treatment programmes.
Overall survival for patients with gastric cancer correlate
well with stage (table 1).7,9,10 Completeness of resection is
another major factor that influences survival. In one study,
the 10-year survival rate for patients who had complete localregional tumour removal with negative resection margins
(R0 resection) was 361% compared with 263% for the
overall patient population. The depth of tumour invasion and
presence or absence of lymph-node involvement is also
predictive of patient survival. Table 2 shows the relation
between depth of tumour invasion and survival. The survival
of patients who had lymph-node involvement at the time of
surgery was much lower than that of patients who had no
lymph-node involvement, especially when more than one
lymph node was involved (table 2).11 The ratio of the number
of involved lymph-nodes among the overall lymph nodes that
were removed is another independent prognostic factor. The
poor survival after surgery for patients who had lymph-node
metastases suggests that surgery alone is not adequate and that
additional therapy is needed. Survival is least favourable for
patients with disease extension beyond the gastric wall and
involved nodes.
Patterns of relapse
Understanding patterns of disease relapse is crucial for
designing appropriate adjuvant or preoperative therapy.
Clinical and autopsy studies have revealed a high incidence of
localregional recurrence and distant relapse (primarily liver
Table 2. Survival by depth of tumour invasion and nodal
involvement
Prognostic factor
5-year survival (%)
Depth of invasion10
Mucosa
934
Submucosa
898
Muscle
772
Subserosa
605
Serosa
397
Adjacent organ
87
No of lymph-node metastases11
0
81
13
63
46
46
7+
29
metastases and peritoneal seeding) after resection.1216 Patients

with primary cancer involving the gastroesophageal junction
are more likely to have extra-abdominal spread, primarily
lung metastases, than those whose cancer involved more distal
portions of the stomach.
Localregional recurrences occur commonly within the
region of the gastric bed and nearby lymph nodes (table 3).
Tumour relapse in anastomoses, the gastric remnant, or the
duodenal stump is also frequent. In a reoperation study at the
University of Minnesota (USA), localregional recurrence in
the tumour bed or regional nodes was the only evidence of
relapse in 29% of the 86 patients with relapsed disease (23%
of 105 evaluable patients at risk) and as any component of
relapse in 88%.15 More extensive procedures, including
routine splenectomy, omentectomy, and radical lymph-node
dissection, did not improve survival rates or decrease the
incidence of localregional recurrence.15 As shown in table 4, a
high percentage of patients had subsequent relapse within the
scope of the initial node dissection, even when radical node
dissections were done (figures 2 and 3). This data indicates the
difficulty of achieving a complete lymph-node dissection in
this location.
Patterns of relapse were analysed by stage in a study of 130
patients who underwent resection with curative intent.17
Localregional recurrence was a component of relapse in 49
patients (38%) and the sole component of relapse in 21 (16%
of the 130 patients at risk and 24% of the 88 patients with
disease progression). The incidence of localregional
recurrence by stage was in excess of 35% for T3N0, T4N0,
T3N13, and T4N13 disease. The sites at highest risk for
localregional recurrence included the gastric bed (27 of 130
patients, 21%) and the anastomosis or gastric remnant (33 of
130 patients, 25%). The true incidence of gastric bed, regional
lymph node, and peritoneal relapse may be higher because
this was not a reoperation or autopsy study (see comparative
findings in table 3).
Although patterns of relapse data are more accurate in
autopsy analyses, patient selection is biased. Wisbeck and
colleagues, found in an autopsy series that 39% of patients
who had undergone curative resection with negative margins
subsequently had disease relapse.14 Among those who had
relapse, the first relapse was local in 22%, regional in 19%,
and distant in 59%. The fact that curative resection fails in the
majority of patients underscores the need for effective
adjuvant or preoperative therapy.
Adjuvant chemotherapy
The poor survival of patients who undergo curative resection
alone for gastric cancer is indicative of the need for adjuvant
therapy, especially in patients who have disease that has
extended beyond the gastric wall and show lymph-node
involvement at the time of surgery. Many phase II and III
clinical trials have been done to find an effective adjuvant
chemotherapy and several comprehensive reviews have been
published on this topic. The combination of fluorouracil,
doxorubicin, and mitomycin was initially used for the
treatment of metastatic gastric cancer.17 Coombes and
colleagues studied this regimen in 281 patients who received
adjuvant chemotherapy or no chemotherapy after surgery.
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Review
Table 3. Patterns of localregional relapse in clinical,

reoperation, and autopsy series
Gastric
bed (%)
52
Anastomosis or Abdominal or
stumps (%)
stab wound (%)
60
Lymph nodes
(%)
52
Ref
68
54
13
21
25
14
55
27
43
15
12
They found no significant difference in disease-free or overall

survival between the treatment and control groups.18
Subgroup analysis showed that patients with more advanced
tumours (T3T4) derived some benefit from the treatment.
The European Organization for Research on the Treatment of
Cancer (EORTC) did a similar trial of adjuvant chemotherapy
with fluorouracil, doxorubicin, and mitomycin for patients
with resectable gastric cancer. In this study, disease stage and
completeness of surgery were found to be important
prognostic factors but patients who received chemotherapy
had no survival advantage.19 A delay in disease relapse was
reported for patients who received chemotherapy, but this
had no effect on survival. Similarly, the Southwest Oncology
Group (SWOG) reported that fluorouracil, doxorubicin, and
mitomycin was not an effective adjuvant regimen.20 Many
adjuvant chemotherapy trials of several different regimens
have been done worldwide and the results have been analysed
in recent reviews and meta-analyses. However, there is no
definitive evidence which suggests that chemotherapy, as a
single adjuvant therapy, has any value in prolonging survival.
It is probable that multiple factors account for the failure
to identify successful adjuvant chemotherapy for resected
gastric cancer. Lack of an effective chemotherapeutic regimen
may be the primary one. Fluorouracil, doxorubicin, and
mitomycin and other closely associated regimens, typically
yield a response rate of 35% for patients with advanced
gastric cancer.21 However, complete response is only about
2% and duration of response is generally short. Since these
regimens have no effect on survival of patients with advanced
gastric cancer, their lack of efficacy in the adjuvant setting is
not surprising. Several newer regimens have been tested and
compared with fluorouracil, doxorubicin, and mitomycin,
but none have shown a survival advantage.22
Other shortcomings in prospective randomised trials of
adjuvant therapy may account for the poor results. Surgery for
gastric cancer is a major procedure. A fraction of patients do

not recover enough to receive adjuvant therapy or have
surgical complications that preclude adjuvant therapy.
Furthermore, the timing of adjuvant chemotherapy may be
critical and delays are common in initiating adjuvant therapy.
Finally, most trials have accrued relatively small numbers of
patients, thus reducing their statistical power to detect
differences between the treatment and control groups.
However, whatever the reason, no effective adjuvant systemic
chemotherapy is currently available for resected gastric
cancer.
Chemoradiation
The rationale for using chemoradiation as an adjuvant
therapy for patients who have undergone R0 resection is that
these patients are at risk for localregional recurrence and
distant metastases. Radiation in conjunction with surgery can
improve localregional control and systemic chemotherapy
can suppress or eliminate microscopic distant metastasis and
improve radiation cytotoxicity.
Chemotherapy may function as a radiosensitiser,
improving the effect of radiation via various mechanisms.
DNA is a critical target of radiation, with tumour-kill caused
by double-stranded DNA breaks. This effect is
counterbalanced by DNA repair. Drugs that inhibit DNA
repair could therefore improve radiation cytotoxicity. Several
drugs, including hydroxyurea, fluorouracil, cisplatin, and
irinotecan, are known to inhibit DNA repair or increase
misrepair caused by radiation.2326 Moreover, cells are known
to vary in their responses to radiation as a function of their
specific phase in the cell cycle. Cells in G2/M phase are three
times more sensitive than cells in late S/G1 phase.27
Chemotherapeutic agents that blocks the cell cycle at the G2/M
phase, such as the taxanes, would sensitise that cell population
to the radiation effect.2830 Furthermore, drugs such as
fluorouracil, doxorubicin, and paclitaxel can reduce the
threshold of cells to radiation damage. Thus, tumour cells
exposed to these drugs are more sensitive to the cytotoxic
effect of radiation. Finally, apoptosis is one of the mechanisms
by which cells respond to radiation. Therefore, drugs such as
paclitaxel and gemcitabine that induce apoptosis also improve
the radiation effect.3133
Fluorouracil is the cytotoxic agent most frequently used in
combination with radiation. It is given either as continuous
infusion during radiation or as an interrupted bolus given
Table 4. Operative method versus patterns of relapse15*

Operative
procedure
Method 1 (pre-1950)
Method 2 (1950-1954)
Method 3 (1954 to present)
Total
Relapses/total
number of patients
at risk
Patterns of relapse
N (%)
Localregional
Alone
Component
Peritoneal seeding
Alone
Component
Distant metastasis
Alone
Component
25/36
29/32
26/37
80/105
9 (25)
6 (19)
8 (22)
23 (22)
1 (3)
1 (9)
1 (3)
3 (3)
0
3 (9)
2 (5)
5 (5)
23 (64)
24 (75)
23 (62)
70 (67)
12 (33)
17 (53)
15 (41)
44 (42)
7 (19)
9 (28)
7 (19)
23 (22)
*86 patients with relapse, 80 evaluable by all parameters. Data represent number of patients with relapse; data in parentheses represent percentage of total group at risk who had
complete follow-up. Method 1 (pre 1950): subtotal or total gastrectomy, greater omentectomy, regional node dissection; method 2 (19501954): method 1 plus splenectomy,
total omentectomy, additional node dissection regarding splenic, suprapancreatic, and central celiac axis; method 3 (1954 to present): methods 1 and 2 plus extension of node
dissection to porta hepatis and pancreaticoduodenal (intent: total lymph node dissection of all primary node areas equivalent to D2 or D3 dissection).
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Review
alone or in combination with leucovorin for 34 days during

To overcome some of the problems encountered in these
weeks 1 and 5 of radiation. Paclitaxel has been shown recently trials and to better evaluate adjuvant chemoradiation for
to have activity in conjunction with radiation in patients with resected gastric cancer, an intergroup study was done.40 In
this trial, patients with stage Ib to IV M0 gastric cancer who
gastric cancer.34,35
Initial evidence of the superiority of chemoradiation over underwent curative surgery were randomly assigned to
radiation alone came from a study of unresectable gastro- receive adjuvant chemoradiation or observation alone. A
intestinal cancer.36 In that trial, patients were randomly total of 603 patients were accrued to this study of whom 556
assigned to receive radiation at doses of 3540 Gy over 3545 were evaluable85% had lymph-node metastasis and 68%
weeks plus fluorouracil or placebo. The addition of fluoro- had T3 or T4 lesions. The treatment consisted of one cycle of
uracil prolonged survival compared with radiation alone.
bolus fluorouracil/leucovorin daily for 5 days before
Three subsequent randomised trials evaluated the radiation and two cycles after radiation. During radiation,
effectiveness of chemoradiation for resected gastric cancer, bolus fluorouracil/leucovorin was given on days 14 and on
one of which included only patients with R0 resection the last 3 days. Radiation was given at 45 Gy in 25 fractions
(table 5). Dent and colleagues did a randomised trial of over 5 weeks. The radiation field included the tumour bed,
142 patients who received radiation alone or chemoradiation regional nodes, and 2 cm beyond the proximal and distal
after resection.37 Patients were stratified into division I margins of resection. The tumour bed was defined by
(localised disease, T13) or II (advanced disease, T4 or M1). preoperative computed tomography (CT), barium
No difference in survival was observed between treatment and roentgenography, and surgical clips. Regional nodes
control groups. Bleiberg and colleagues reported a included perigastric, celiac, local para-aortic, spenic,
randomised trial in patients who underwent curative or hepatoduodenal or hepatic-portal, and pancreaticoduodenal
palliative surgery for gastric cancer.38 In that trial, patients lymph nodes. In patients with tumours of the gastrowere randomly assigned to receive radiation, chemoradiation, oesophageal junction, paracardial and paraoesophageal
radiation followed by chemotherapy, or chemoradiation lymph nodes were included, but pancreaticoduodenal
followed by chemotherapy. Statistical differences were lymph nodes were excluded. The 3-year overall survival was
detected in median survival times for the treatment groups, 50% for the treatment group and 41% for the observation
but the differences disappeared when comparisons were group. The 3-year disease-free survival was 48% for the
adjusted for prognostic factors.
treatment group and 31% for the observation group.
The third trial assessed a total of 62 patients who Improvements in overall and disease-free survival were
underwent R0 resection but had poor prognostic features. significant (p=0005 and <0001, respectively). Grade 3 and
Patients were randomly assigned to receive no treatment after 4 toxic effects occurred in 41% and 32% of patients who
resection or radiation (375 Gy in 24 fractions over 45 weeks) received chemoradiation, but treatment-related death was
plus concurrent fluorouracil (15 mg/kg for 3 days during only 1%. The common toxic effects included leucopenia,
week 1 of radiation).39 Of 39 patients assigned adjuvant nausea/vomiting, and diarrhoea. The authors advocated
treatment, 10 had more favourable prognostic features postoperative chemoradiation as standard care after curative
and refused adjuvant treatment. Accordingly, they were resection for patients with gastric cancer at high risk of
observed alongside 23 patients treated
Table 5. Clinical trials of chemoradiation for resected gastric cancer
with surgery alone (a total of 33
patients had surgery alone). The 39
Patients
Treatment
Survival
Ref
patients randomly assigned to receive
142 in total
37
31 (division I)
Surgery
15% at 80 months
concurrent fluorouracil and radiation
35 (division I)
20 Gy plus fluorouracil
14% at 80 months
had better rates of survival (5-year
24 (division II)
Surgery
0% at 80 months
survival rate 23% vs 4%, p=005).
26 (division II)
20 Gy plus chemotherapy
8% at 80 months
When patient outcomes were com115 in total
39
pared by actual treatment received,
30
555 Gy
12 months*
5-year survival rates still favoured the
30
Chemoradiation
10 months*
26
555 Gy plus chemotherapy
15 months*
patients given adjuvant treatment (20%
29
Chemoradiation plus chemotherapy 18 months*
vs 12%) but the difference was not
62 in total
38
significant probably because of the
23 (randomised)
Surgery
4% at 5 years
small numbers of patients.
39 (randomised)
23% at 5 years (p=005*)
These three early trials did not yield
33 (actual treatment)
Surgery
12% at 5 years
a definitive conclusion with regard to
29 (actual treatment)
20% at 5 years
the benefit or lack of benefit of
556 in total
40
275
Surgery
3-yr overall survival 41%
adjuvant chemoradiation. They were
disease-free survival 31%
criticised for enrolling small numbers
281
Chemotherapy, 45 Gy, plus
3-yr overall survival 50%
of patients, for failing to standardise
further chemotherapy
3-yr disease-free survival 48%
surgery, for including patients with
*Differences in the median survival durations were significant but differences in survival disappeared when the
gross residual disease, and for using
comparisons were adjusted for prognostic factors. p=0005. p<0001.
suboptimum doses of fluorouracil and
radiation.
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recurrence. This trial was well designed, accrued large

numbers of patients so that the results are adequately
powered, used surgery alone as control, and involved many
institutions. Therefore, the results are convincing and
applicable for common practice. However, questions have
been raised about the adequacy of the chemotherapy and
surgical components of the study.
Comparison of the patterns of disease relapse in the

treatment and observation groups in the intergroup study
suggested that adjuvant treatment was more effective in
reducing the rate of local recurrence than that of distant
metastasis. However, since all intra-abdominal relapse (nodal,
liver, peritoneal) was classed as regional relapse, the effect of
chemotherapy on liver and peritoneal relapse is uncertain.
110
111
20
2
4sa
1
19
7
12
12
12
5
9
8a
8p
10
11
16b1
4sb
16a2
14a
6
4sb
16a1
13
10
11
16b2
18
4d
4d
4d
17
14v
13
15
1 Right cardial lymph nodes

2 Left cardial lymph nodes
3 Lymph nodes along the lesser curvature
4 Lymph nodes along the greater curvature
4sa Lymph nodes along the short gastric vessels
4sb Lymph nodes along the left gastroepiploic vessels
4d Lymph nodes along the right gastroepiploic vessels
5 Suprapyloric lymph nodes
6 Infrapyloric lymph nodes
7 Lymph nodes along the left gastric artery
8 Lymph nodes along the common hepatic artery
8a Anterosuperior group
8p Posterior group
9 Lymph nodes around the celiac artery
10 Lymph nodes at the splenic hilum
11 Lymph nodes along the splenic artery
12 Lymph nodes in the hepatoduodenal ligament
13 Lymph nodes on the posterior surface of the pancreatic head
14 Lymph nodes at the root of the mesenterium
14a Lymph nodes along the superior
mesenteric artery
14v Lymph nodes along the superior mesenteric vein
15
Lymph nodes along the middle colic vessels
16a1 Lymph nodes around the abdominal aorta (aortic hiatus)
16a2 Lymph nodes around the abdominal aorta (From the upper margin
of the celiac trunk to the lower margin of the left renal vein)
16b1 Lymph nodes around the abdominal aorta (From the lower margin
of the left renal vein to the upper margin of the inferior mesenteric
artery)
16b2 Lymph nodes around the abdominal aorta (From the upper margin
of the inferior mesenteric artery to the aortic bifurcation)
17
Lymph nodes on the anterior surface of the pancreatic head
18
Lymph nodes along the inferior margin of the pancreas
19
Infradiaphragmatic lymph nodes
20
Lymph nodes in the oesophageal hiatus of the diaphragm
105 Paraoesophageal lymph nodes in the upper thorax
106 Tracheal lymph nodes in the thorax
107 Lymph nodes of the tracheal bifurcation
108 Paraoesophageal lymph nodes in the middle thorax
109 Lymph nodes of the pulmonary hilum
110 Paraoesophageal lymph nodes in the lower thorax
111 Supradiaphragmatic lymph nodes
112 Posterior mediastinal lymph nodes
Figure 2. Regional lymph nodes
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In addition, routine CT imaging was not part of interval

evaluation, so the exact patterns of relapse for all patients in
the study are uncertain. It is understood that the two cycles of
fluorouracil/leucovorin chemotherapy given concurrently
with radiation could potentially function as a radiation
enhancer and therefore decrease the risk of tumour-bed and
regional-node relapse within the radiation field. The addition
of three more cycles of chemotherapy (one cycle before and
two cycles after concurrent chemoradiation) did not seem to
decrease the rate of extra-abdominal relapse (14% vs 12% of
patients at risk). Relapse within the abdominal cavity (intraabdominal nodes, liver, or peritoneal), however, was reduced
from 46% of patients at risk who underwent surgery alone
to 24% who underwent chemoradiation. Therefore,
presentation of relapse rates based on patients at risk rather
than patients who relapsed suggests that the three cycles of
AMC
MAC
MCA
CMA
A
AM
AD
MA
M
MC
C
CM
fluorouracil/leucovorin did have an effect on metastatic

disease. The addition of potentially more active chemotherapy
would be appropriate in the treatment group of a subsequent
phase III intergroup trial of postoperative adjuvant therapy.
Some investigators have questioned whether the positive
results obtained in the intergroup study were the result of
adding chemoradiation to less-than-optimum surgery.
However, such arguments are not supported by data showing
the effect of extended node dissection on survival and patterns
of relapse. Although only 10% of patients in the trial
underwent a D2 node dissection, there was no discernable
difference in either disease-free or overall survival according
to extent of nodal dissection (p=080). Extended node
dissection has not improved survival in two large randomised
phase III trials comparing D2 and D1 dissections, but it did
result in increased morbidity in both trials.4245 Moreover,
extent of node dissection did not
reduce the risk of localregional relapse
Additional
in node-dissected sites in a reoperation
lymph node when
series for gastric cancer.16
tumour invades
the oesophagus
1
2
3
4sa
4sb
4d
5
6
7
8a
8p
9
10
11
12
N2
Option
A randomised phase III trial from

Beijing (China) has shown improved
disease-free and overall survival rates
and improved localregional control
when irradiation precedes resection for
adenocarcinoma of the gastric cardia.46
Overall survival at 5 years were 30% in
the 171 patients who received preoperative irradiation (40 Gy in 20
fractions over 4 weeks) and 20% in 199
patients who had only surgical
resection (p=0009). Local relapse was
diagnosed in 39% of patients in the
adjuvant irradiation group and 52% of
the patients who underwent surgery
only (p<0025) and regional node
relapse was identified in 39% of the
adjuvant treatment group and 54% of
the surgery only group (p<0005). No
difference was seen in the rates of
distant metastasis, which were 24% and
25% in the two groups.
N2
Option
N1
Option
Option
Option
N2
N3
Option
N2
N3
13
14a
Option
14v
15
Preoperative therapy
Preoperative radiation
Lymph node*
N3
Option
16a2, b1
N3
16a1, b2
Option
17
Option
18
Option
19
20
Option
N3
Preoperative chemoradiation
Option
N3
N2
N2
N1
Figure 3. Definition of lymph-node dissection based on the Japanese Classification of Gastric

Cancer. D0, no dissection or incomplete dissection of the red lymph nodes; D1, dissection of all the
red lymph nodes; D2, dissection of all the red and blue lymph nodes; D3, dissection of all the red,
blue, and yellow lymph nodes; D4, dissection of all the red, blue, yellow, and green lymph nodes; C,
upper third of the stomach; M, middle third; A, lower third; D, duodenum. If more than one portion is
involved, all involved portions should be described in order of involvement, the first indicating the
portion in which the bulk of the tumour is situated, eg, MC or MCA. When a tumour located in the
lower third (A) extends to the duodenum (D), the disease should be described as AD; option,
optional lymph nodesthe D classification is not affected by excision or non-excision of these
nodes. *Refer to figure 2 for node locations.
An important goal of preoperative

chemoradiation is to reduce the
primary tumour to facilitate R0
resection. Other theoretical benefits
include a potentially earlier effect on
micrometastatic disease and a change
in the ability of tumour cells that may
be shed at the time of surgical resection
to implant and grow at other
locations.40 Moreover, patients may be
diagnosed with rapidly growing
metastatic carcinoma before surgery,
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thus avoiding unnecessary procedures. In addition, some

investigators feel that patients may tolerate preoperative
therapy better than postoperative therapy because after
surgery patients may not receive adequate nutrition
(dependent on the extent of gastric resection). However,
despite compelling reasons in support of this order of
treatment,
preoperative
chemoradiation
remains
investigational.
We reported three consecutive phase II trials of
preoperative chemotherapy for patients with potentially
resectable gastric cancer.41,42,43 Our results show that
preoperative chemotherapy is feasible. Lowy and colleagues
further analysed the results of these three trials and showed
that response to preoperative chemotherapy was the single
most important predictor of overall survival in patients
undergoing surgical resection.44 Response to chemotherapy
was found to be the only independent prognostic factor by
multivariate analysis. Patients who showed a response to
chemotherapy had a more than a two-fold increase in overall
survival rate. This finding supports further evaluation of
preoperative approaches in the treatment of gastric cancer.
Preoperative chemoradiation for potentially resectable
gastric cancer has been tested in phase I/II clinical trials.
Mansfield and co-workers reported a phase II study of
preoperative chemoradiation for potentially resectable gastric
cancer.45 In that trial, patients were treated with continuous
infusion of fluorouracil and 45 Gy of radiation. No additional
systemic chemotherapy was given. 11% achieved complete
response and 41% patients had partial response20% of
patients developed distant metastasis and were not suitable for
gastrectomy. Overall median survival was 34 months and the
disease-specific survival was greater than 60% at 4 years in
patients who underwent resection. Additional studies are
required to assess the possible survival benefit to patients
receiving this regimen as preoperative therapy. Several clinical
trials have been done with cytotoxic agents other than
fluorouracil and cisplatin in conjunction with radiation.
Safran and colleagues reported that patients who received
concurrent paclitaxel and radiation had an overall response of
56%, including complete response in three patients (11%)
with localregional, unresectable gastric cancer.33 The 2-year
progression-free and overall survival were 29% and 31%,
respectively. Several studies have evaluated the combination
of radiation with different chemotherapeutic agents, and
preliminary results have been reported.33 One study reported
that a regimen comprising a continuous infusion of
fluorouracil and weekly paclitaxel with radiation therapy was
well tolerated in patients with carcinoma of the upper
gastrointestinal tract. A further study is needed to evaluate the
addition of paclitaxel to the concurrent chemoradiation
regimens. Another study reported a phase I study of
concurrent irinotecan with radiation in patients with locally
advanced upper gastrointestinal carcinomas. Clearly,
additional studies are needed to put the roles of these agents in
perspective.
Conclusion
The large intergroup study clearly showed the value of
postoperative chemoradiation. Further study is needed to
504
Search strategy and selection criteria

Published data were identified by searches of MEDLINE using
the search terms, gastric cancer, surgery, and radiation.
We also searched the Proceedings of ASCO up to 2001. We
paid most attention to prospective trials of preoperative
radiation and postoperative chemoradiation for resected
gastric cancer. Less weight was given to single-arm trials,
trials for locally advanced or unresectable gastric cancer, and
adjuvant chemotherapy.
develop more effective chemotherapy regimens. The advent of

biological agents that target a specific cellular process provides
a new avenue for further research. The use of chemotherapy
as a radiosensitiser and systemic therapy need to be better
defined. The concept of preoperative chemoradiation is
attractive but remains investigational.
Acknowledgments
This work was supported in part by a grant from the Cantu and
Caporella families.
Conflict of interest
None declared.
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