ONCOLOGY.
No. 9
Neoadjuvant Therapy for Gastric Cancer
By MANPREET K. CHADHA, MD
Department of Medicine
State University of New York
University at Buffalo
Erie County Medical Center
BORIS W. KUVSHINOFF, MD,
Attending Surgeon
Division of Gastrointestinal Surgery
Department of Surgery
MILIND M. JAVLE, MD
Attending Physician
Department of Medicine
Roswell Park Cancer Institute
Buffalo, New York |
August 1, 2005
Preoperative Chemo-RT
Given the benefit of single-modality
treatment (chemotherapy or radiation)
preoperatively in gastric cancer
and the experience using preoperative
chemo-RT in other gastrointestinal
malignancies, such as esophageal
and rectal cancer, preoperative chemo-
RT strategies for gastric cancer appear
logical. However, experience in
this area is rather limited. Trials investigating
preoperative chemo-RT
for gastric cancer are depicted in
Table 6. These studies indicate that
combined-modality therapy, consisting
of chemo-RT followed by surgery, is
well tolerated, without significant increase
in morbidity or mortality. These
studies utilized cisplatin and 5-FU-
based regimens. It is possible that use
of newer radiation sensitizers such as
docetaxel, irinotecan (Camptosar),
oxaliplatin (Eloxatin), or gemcitabine
(Gemzar), alone or in combination, may
yield higher pathologic responses.
In these studies, complete response
was correlated with improved survival.
The trial by Ajani et al (Table 3)
deserves special mention.[46] These
investigators utilized a three-step approach
in which patients first received
two cycles of chemotherapy consisting
of 5-FU and cisplatin, followed a
month later by EBRT of 45 Gy and
infusional 5-FU prior to surgery. The
approach yielded an encouraging 70%
R0 resection rate and a pathologic
complete response rate of 30%.The
median survival in this study population
was 33.7 months, with a median
survival time of 63.9 months in patients
with a complete response. The
trial results support the hypothesis that
a two-step preoperative approach
leads to superior pathologic response,
which in turn leads to improved clinical
outcome.
Will aggressive neoadjuvant
approaches allow limited gastric
resection? Future phase III trials
are necessary to answer this question.
Perioperative
Intraperitoneal Therapy
Intraperitoneal chemotherapy is an
attractive treatment modality for gastric
cancer for several reasons. Even
after extended lymphadenectomy, the
peritoneum remains a major site of
failure. Locoregional recurrence rates
are as high as 40% to 50%, suggesting
that peritoneal implantation is frequent
in this cancer.[30] It is also
postulated that manipulation of gastric
cancer during surgery may result
in the release of free cells into the
peritoneal cavity; these cells get
trapped in fibrin and proliferate under
the influence of cytokines released
during surgical stress and wound healing.
Using intraperitoneal chemotherapy
in the perioperative period can
eradicate tumor cells prior to entrapment
in the fibrin and development
of fibrosis.
Because hyperthermia and chemotherapy
have been shown to be synergistic,
perioperative intraperitoneal
hyperthermic chemoperfusion (IHCP)
may be advantageous for management
of gastric cancer.[31,32] Continuous
IHCP can be performed following temporary
closure of the abdomen or with
an open abdomen technique. Peritoneal
perfusate is maintained at 41 oC to
42 oC and uniform drug distribution is
ensured mechanically.[30]
Selected randomized control trials
of perioperative intraperitoneal chemotherapy
in locally advanced gastric
cancers with R0 resection are
shown in Table 7. Sugarbaker et al
performed a meta-analysis of perioperative
intraperitoneal therapy trials.[
30] Their data suggest improved
overall survival in the perioperative
intraperitoneal chemotherapy group
vs surgery alone. Maximal benefit
was noted in stage III or IV gastric
cancer.
As seen earlier, some trials of preoperative
chemotherapy (Table 3) also
included postoperative intraperitoneal
therapy. This is an interesting approach
that can be considered for gastric
cancer patients with a high
likelihood of peritoneal dissemination,
such as those with linitis plastica or
locally advanced signet-ring carcinoma
of the stomach. Clearly, administration
of intraperitoneal therapy is
complicated and adds some morbidity.
Therefore, this approach should
be limited to centers with high levels
of expertise in the context of a clinical
trial.
New Approaches
It is clear that the efficacy of traditional
chemotherapeutic agents is limited
in gastric cancer. Newer agents
such as docetaxel, irinotecan, oxaliplatin,
and capecitabine (Xeloda) are
active in metastatic gastric cancer and
may represent promising options for
neoadjuvant therapy.[33-38] Another
agent of interest is pemetrexed
(Alimta), which is a multitargeted antifolate
that inhibits multiple enzymes
important in folate metabolism. Preliminary
results of a phase II investigation
of single-agent pemetrexed in
patients with locally advanced or
metastatic gastric cancer showed a
response rate of 28% with an acceptable
adverse event profile in patients
treated with folic acid and B12
supplementation.[39]
Novel agents including trastuzumab
(Herceptin), cyclooxygenase inhibitors,
antiangiogenic agents, matrix
metalloproteinase inhibitors, and
EGFR-specific inhibitors such as gefitinib
(Iressa), erlotinib (Tarceva), and
cetuximab (Erbitux) are currently being
investigated in gastric cancer.
These agents offer hope for the development
of more effective regimens,
both as single agents and in combination.
Once their activity in gastric
cancer is established, studies incorporating
these agents into neoadjuvant
strategies should be conducted.
In the future, neoadjuvant approaches
may need to be tailored to
the individual patient. The use of metabolic-
based imaging such as FDGPET
may identify early responders
and thereby serve to exclude patients
from further ineffective systemic therapy.
Such patients can then go on to
receive immediate surgery. Further,
patients who progress on neoadjuvant
therapy may be spared aggressive surgical
intervention, as this subgroup
historically does very poorly regardless
of therapy. The availability of
tissue pre- and postchemotherapy with
neoadjuvant therapy allows the possipossibility
of performing proteomic and
other biologic assays which may help
further to refine this therapy.
Conclusions
Current data suggest the possibility
of diverse neoadjuvant strategies
that are worthy of further investigation
for the management of gastric
cancer. These strategies include neoadjuvant
chemotherapy, chemoradiation,
radiotherapy, and perioperative
intraperitoneal therapy. At this point
in time, it is unclear which of these
options offer therapeutic superiority.
Choice of an individual modality is
dictated by clinical presentation. Neoadjuvant
chemoradiation improves
R0 resection rates and should be considered
for large, proximal tumors
that cannot be removed with a margin-
free resection. This therapy, in
combination with limited surgical resection,
may be considered for proximal
gastric cancer patients who are
not candidates for total gastrectomy.
Perioperative intraperitoneal therapy
can be considered for positive peritoneal
cytology. External-beam radiation
therapy is useful for palliation of
bleeding gastric tumors. Incorporation
of targeted approaches may further
improve the outcome of gastric
cancer patients. Results of ongoing
phase III trials in this regard are eagerly
awaited.
RICHARD M. GOLDBERG, MD and BERT O'NEIL, MD
BRIAN G. CZITO, MD and CHRISTOPHER G. WILLETT, MD
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