Neoadjuvant Therapy for Gastric Cancer

Neoadjuvant Therapy for Gastric Cancer

ABSTRACT: Gastric cancer is a global health issue. Most cases are diagnosed at an advanced stage with poor prognosis. Current therapies have a modest impact on survival. Surgery remains the only potentially curative treatment, but is associated with a high rate of locoregional recurrence and distant metastases. Total gastrectomy for proximal cancers is complicated by postoperative morbidity and quality-of-life impairment. Combined-modality therapy may improve outcomes in this disease. Adjuvant therapy for gastric cancer has now become the standard in the Western world. However, adjuvant therapy improves survival by only a few months and is associated with high morbidity. Neoadjuvant therapy is commonly used for esophageal and gastroesophageal junction cancers, but is still regarded as investigational in gastric cancer. Several small phase II studies indicate the feasibility of neoadjuvant strategies. The incorporation of novel, targeted agents into neoadjuvant programs and an assessment of biologic changes within the tumor may refine therapy. This article provides a concise review of the literature on neoadjuvant therapy for gastric cancer and suggests avenues for further investigation.

Gastric cancer is a global health
issue. Worldwide, it is the second
most common cause of
cancer-related mortality.[1] In the
United States, gastric cancer is the
eighth most common cause of cancer-
related death.[2] Cancer of the gastric
antrum has decreased in incidence
in the United States and western Europe;
however, this has been countered
by an increased incidence of
cancer of the gastric cardia.[3-5] In
the Far East, particularly Japan, there
has been a notable improvement in
mortality associated with this disease.[
6] This has been partially
attributed to early detection of tumors
by screening and surveillance

Cancers of the distal stomach are
more common in Asia, and exhibit
the following characteristics: (1) They
are associated with Helicobacter pylori
infection, (2) they follow a chronic
atrophic gastritis/metaplasia/dysplasia
sequence, and (3) upon histology, they
are usually the intestinal type.[1,7]

On the other hand, cancers of the
proximal stomach have been associated
with improved socioeconomic
conditions and are less often associated
with H pylori.[1,7] Proximal tumors
are associated with early
hematogenous spread as compared to
slower progression and locoregional
spread in the case of distal tumors.[7]
There has been a recent increase in
the incidence of proximal gastric and
gastroesophageal junction cancers.
The reasons for this increase are unknown.[

Siewert and Stein classified adenocarcinoma
of esophagogastric junction
(AEG) into three distinct entities based
on anatomic origin: (1) adenocarcinoma
of the distal esophagus invading
the gastroesophageal junction (AEG
type I tumors), (2) carcinoma of the
gastric cardia immediately at the gastroesophageal
junction (AEG type II
tumors), and (3) subcardial gastric carcinoma
infiltrating the gastroesophageal
junction (AEG type III tumors).[8]
AEG type II and III tumors are more
likely to be undifferentiated and have a
worse prognosis.[1] Thus, although
gastric cancer is referred to as one entity,
there is heterogeneity due to epidemiologic,
clinical, and therapeutic
differences between cardiac, antral, and
gastroesophageal junction cancers.

In the United States and Europe,
potentially curative resections (with
negative margins, R0) are possible in
only about 50% of newly diagnosed
gastric cancer patients.[9-11] For patients
with locally advanced tumors
(stages II, IIIA, or IIIB) even after
gastric resection with curative intent,
the recurrence rate is as high as 40%
to 65%.[12] As most cases are diagnosed
at an advanced stage, there is
clearly a need to develop innovative
treatment strategies that will downstage
the tumor, increase the R0 resection
rate, and decrease the risk of
recurrence after surgery.

Adjuvant chemoradiation is commonly
used postoperatively for gastric
cancer. The ability to deliver adjuvant
chemoradiation is adversely influenced
by the 25% to 46% postoperative morbidity
seen after gastrectomy with
lymphadenectomy.[13,14] Only 64%
of patients completed adjuvant chemoradiotherapy
in the important Intergroup 0116 trial.[15] Neoadjuvant therapy for
gastric cancer is emerging as a promising
approach. This article discusses the
rationale for neoadjuvant therapy and
the available therapeutic options. A brief
overview of current staging and operative
and adjuvant strategies is presented
below as a preface to this discussion.

Staging Strategies
National Comprehensive Cancer
Network (NCCN) guidelines recommend
a multidisciplinary approach to
staging that includes a complete history
and physical examination, laboratory
studies (complete blood count,
platelet count, and serum biochemistry),
chest radiography, and computed tomography
(CT) of the abdomen and
pelvis. Laparoscopy has also been added
to these guidelines as a category 2B
recommendation (nonuniform consensus
among panel members).[16]

Table 1 depicts the various staging
modalities available for gastric cancer,
along with accuracy, advantages, and
disadvantages. The use of positronemission
tomography (PET) for staging,
detecting recurrence, and evaluating
response to therapy in gastric cancer is
evolving. A recent study in esophageal
cancer suggests that quantitative measurements
of tumor 18F-fluorodeoxyglucose
(FDG) uptake may predict histopathologic
tumor response and patient
outcome as early as 2 weeks after
initiation of preoperative chemotherapy.[
17] This may be a useful investigational
tool in gastric cancer as part of a
neoadjuvant strategy. The recent availability
of integrated CT/PET imaging
is likely to refine staging of these tumors
in the future.

Japanese investigators use a computer-
based program (the Maruyama
program) to predict lymph node stations
at risk for metastasis in particular
cases. The cases are sorted on the basis
of similarity with seven specified variables:
age (± 5 years), sex, Borrmann
type of the tumor, greatest dimension
of the tumor as measured on the luminal
surface (± 2.5 cm), location of the
tumor, estimated tumor depth, and histology.
Comparison is made with a database
of 3,843 gastric cancer patients
at the National Cancer Center Hospital
in Tokyo who had been treated by D2
or more extensive lymphadenectomy.
The program then predicts the percentage
likelihood of disease at each
of the 16 lymph node stations around
the stomach on the basis of actual
patient experience.[18] This information
could be used prospectively to
enroll higher-stage patients into neoadjuvant

The Role of Surgery

Surgical resection remains the only
curative therapy for this disease. The
debate continues regarding the optimal
extent of lymph node dissection
required for maximal therapeutic benefit.
Extended lymphadenectomy remains
the standard of care in the Far
East at the cost of acceptable postoperative
morbidity.[19] Similar results
could not be reproduced in Western
trials and no survival advantage was
attributed to D2 dissections in the
Dutch Gastric Cancer Group trial.[14]
Similar results were noted in the Medical
Research Council (MRC) trial
from the United Kingdom.[13] The
results of randomized control trials
comparing D1 with D2 dissections
are depicted in Table 2. These randomized
trials did not reveal any survival
advantage for D2 dissection.
Morbidity and mortality associated
with D2 dissection was significantly
higher in these randomized trials.
Five-year survival after D1/D2 dissection
remains dismal at 30% to 45%.
Thus, no phase III study in the Western
population has proved the therapeutic
advantage of D2 dissection.

Cochrane database review done by
McCulloch et al revealed survival benefit
of D2 dissections in T3 or more
advanced lesions.[20] Subgroup analysis
of the MRC trial suggests a survival
advantage for stage II and III
patients or those with N1 disease.[13]
The Dutch Gastric Group trial indicated
a survival benefit for N2 patients.[
14] Siewert et al, in a large
prospective multicenter observational
trial, found that the pathologic subgroup
of pT2, N1 and pT3, N0 had a
significant survival benefit with extended
lymph node dissection.[21]

The extent of gastrectomy may also
impact on postoperative morbidity and
quality of life. Due to high incidence
of locoregional failure, multifocal disease,
and submucosal pattern of
spread, total gastrectomy with at least
a 5-cm gastric margin is recommended
for proximal gastric tumors.[9]
Subtotal gastrectomy is often the procedure
of choice for distal (antral)
tumors.[22] Although total gastrectomy
is superior in terms of margin-free
resection, this procedure is associated
with postoperative morbidity of dumping
syndrome, malabsorption, anemia,
osteoporosis, and malnutrition. Quality-
of-life impairment results from
these difficulties.

Davies et al demonstrated that gastric
cancer patients who underwent
subtotal gastrectomy enjoyed superior
quality of life at the end of 1 year
as compared with total gastrectomy
patients.[23] Proximal gastric resection
is associated with a higher risk of
anastomotic leakage and bile-acid reflux.
This complication may be prevented
by jejunal interposition.[9]
Based on the above observations, it
may be worthwhile to investigate neoadjuvant
therapy followed by proximal
gastrectomy as a possible
alternative to total gastrectomy for
proximal gastric cancers.

A recent trial by Bosing et al revealed
a dismal 14% 5-year survival
in patients with AEG type III tumors,
despite surgery.[24] Linitis plastica and
signet-ring histology are other gastric
cancer subtypes that have a poor outcome
with surgical therapy alone.[25]
Thus, patients with stages II, IIIA, or
IIIB (locally advanced) proximal
tumors or those with aggressive histology
are likely to benefit from neoadjuvant
therapy, as surgery alone is
usually not curative in these cases.

The Role of Adjuvant Therapy

The use of postoperative adjuvant
chemoradiotherapy for gastric cancer
gained popularity after a randomized
trial by Macdonald et al.[15] The trial
showed improved survival in the adadjuvant
therapy arm receiving 45 Gy
of radiotherapy and three cycles of
fluorouracil (5-FU) and leucovorin
compared to surgery alone. Median
overall survival in the surgery-only
group was 27 months, as compared
with 36 months in the chemoradiotherapy
group (P = .005). Critics of
this trial note that over half of the
patients received inadequate lymphadenectomy
(most had D0 dissection);
hence, adjuvant therapy may
have been advantageous for these patients,
many of whom possibly had
residual nodal disease. In the Western
world, adjuvant therapy is considered
standard of care since the rate of R0
resection (microscopically negative
postoperative margins) remains suboptimal.
The role of adjuvant therapy
after D2 dissection is unproven.

Neoadjuvant Therapy
Neoadjuvant therapy has a number
of theoretical advantages. First,
neoadjuvant therapy may shrink and
"downstage" the tumor, hence allowing
complete resection of cancers
previously considered inoperable.
Second, radiation treatment volumes
are more precise and tissues are better
oxygenated when radiation is administered
preoperatively. Third, postoperative
morbidity and significant
weight loss of up to 10% precludes
administration of adjuvant therapy in
more than 30% of patients.[26] Neoadjuvant
therapy, including chemotherapy
and radiation, is better tolerated and
feasible in most patients. This strategy
offers patients the maximum benefit of
all available modalities of treatment.

Fourth, neoadjuvant therapy provides
a unique mechanism to assess in vivo
response to chemotherapeutic agents
and an opportunity to study molecular
changes with therapy.

Neoadjuvant therapies may include
preoperative chemotherapy, preoperative
external-beam radiation therapy
(EBRT), concurrent chemoradiotherapy
(chemo-RT), and intraperitoneal
chemotherapy. These modalities are
discussed below.

Preoperative Chemotherapy
Selected phase II trials using preoperative
chemotherapy are shown in
Table 3. Studies that reported median
overall survival and included either
D2 dissection or comprehensive staging
workup were selected. These trials
demonstrated that chemotherapy
delivered in the preoperative setting
is feasible and well-tolerated. These
small trials suggest an improved R0
resection rate and a favorable median
survival compared with historical controls
(median survival of patients who
underwent surgery alone in the Intergroup
0116 trial was 27 months).[15]
An observation by Lowy et al was
that the chemotherapy responders had
a twofold improvement in overall survival
compared to nonresponders.[27]
Although promising, a final answer
regarding the efficacy of neoadjuvant
chemotherapy can only be provided
by a well-powered phase III study.

Currently, three large phase III trials
investigating the role of neoadjuvant
therapy are under way. These
include the MRC Adjuvant Gastric
Infusional Chemotherapy (MAGIC)
trial, the Swiss Study SAKK 43/99,
and the multinational European trial
EORTC (European Organisation for
Research and Treatment of Cancer)

The MAGIC trial accrued 503 gastric
cancer patients between 1994 and
2002.[13] Patients had stage II or more
advanced gastric cancer and were randomized
to perioperative chemotherapy
with three preoperative and three
postoperative cycles of epirubicin
(Ellence), cisplatin, and 5-FU (the CSC
arm) or surgery alone. The preliminary
results of the trial are depicted in
Table 4. The R0 resection rate was significantly
higher in the CSC arm with
no significant difference in postoperative
complications or length of postoperative
hospital stay. Progression-free
survival was superior in the CSC arm
as compared with the surgery-alone arm
(hazard ratio = 0.70, 95% confidence
interval [CI] = 0.56-0.88, P = .002).
The trend toward improved survival
awaits trial completion.

Two elements of the study design
of the MAGIC trial deserve mention.
First, about 11% of patients had distal
esophageal cancer. A prior Intergroup
study in esophageal cancer revealed
no survival advantage with preoperative
chemotherapy; however, there are
limited data in gastric cancer.[29] This
may confound study results. In addition,
neither endoscopic ultrasonography
nor diagnostic laparoscopy was
performed to accurately assess stage of
disease preoperatively. Despite these
problems, the MAGIC trial is the first
well-powered, randomized, controlled
phase III trial that demonstrates the safety
and feasibility of perioperative chemotherapy.
Final efficacy results of this
study are eagerly anticipated.

The Swiss study SAKK 43/99 compares
preoperative docetaxel (Taxotere),
cisplatin, and 5-FU followed by
surgery, vs surgery followed by the
same chemotherapy regimen. The
EORTC 40954 trial compares surgery
plus preoperative cisplatin, leucovorin,
and 5-FU with surgery alone. The
results of these trials will help establish
whether there is a benefit of neoadjuvant
chemotherapy and may
provide information regarding the superiority
of specific neoadjuvant chemotherapy

Preoperative EBRT
The rationale for neoadjuvant radiation
is reduction of local and regional
recurrences. External-beam radiation
therapy also has a palliative role for the
management of bleeding tumors. The
location and extent of tumor is best
imaged in the preoperative setting. As
mentioned earlier, delivery of radiation
therapy preoperatively may enhance
efficacy, reduce treatment volumes, and
decrease toxicity. Almost one-third of
the radiation fields had to be redesigned
in the postoperative adjuvant setting in
the Intergroup 0116 trial.[15] Preoperative
EBRT allows the patient a better
chance of receiving all available therapies,
as postoperative morbidity after
gastrectomy is not insignificant.

Table 5 shows trials comparing preoperative
radiation plus surgery with
surgery alone. These studies used
EBRT doses between 20 and 40 Gy.
However, more current combinedmodality
regimens utilize EBRT doses
up to 45 Gy (Table 6). Zhang et al
demonstrated a significant improvement
in 5-year survival after 40 Gy
was given preoperatively.[52] There did
not appear to be an increase in postoperative
morbidity related to the therapy;
these studies indicated a trend
toward improved survival.


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