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					Gastric Cancer: Introduction                                     gastric surface is adjacent to the left lobe of the liver and the
Background                                                       anterior abdominal wall. The left portion of the stomach is
Gastric cancer was once the second most common cancer in         adjacent to the spleen, the left adrenal gland, the superior
the world. In most developed countries, however, rates of        portion of the left kidney, the ventral portion of the
stomach cancer have declined dramatically over the past half     pancreas, and the transverse colon.
century. In the United States, stomach malignancy is             The site of stomach cancer is classified on the basis of its
currently the 14th most common cancer.                           relationship to the long axis of the stomach. Approximately
Decreases in gastric cancer have been attributed in part to      40% of cancers develop in the lower part, 40% in the middle
widespread use of refrigeration, which has had several           part, and 15% in the upper part; 10% involve more than one
beneficial effects: increased consumption of fresh fruits and    part of the organ. Most of the decrease in gastric cancer
vegetables; decreased intake of salt, which had been used as     incidence and mortality in the United States has involved
a food preservative; and decreased contamination of food by      cancer in the lower part of the stomach; the incidence of
carcinogenic compounds arising from the decay of                 adenocarcinoma in the cardia has actually shown a gradual
unrefrigerated meat products. Salt and salted foods may          increase.
damage the gastric mucosa, leading to inflammation and an        Pathophysiology
associated increase in DNA synthesis and cell proliferation.     Ooi et al identified 3 oncogenic pathways that are
Other factors likely contributing to the decline in stomach      deregulated in the majority (>70%) of gastric cancers: the
cancer rates include lower rates of chronicHelicobacter          proliferation/stem cell, NF-kappa β, and Wnt/beta-catenin
pylori infection, thanks to improved sanitation and use of       pathways. Their study suggests that interactions between
                                                        1
antibiotics, and increased screening in some countries.          these pathways may play an important role in influencing
                                                                                                          4
Nevertheless, gastric cancer is still the second most common     disease behavior and patient survival.
cause of cancer-related death in the world, and it remains       Understanding the vascular supply of the stomach allows
difficult to cure in Western countries, primarily because most   understanding of the routes of hematogenous spread. The
patients present with advanced disease. Even patients who        vascular supply of the stomach is derived from the celiac
present in the most favorable condition and who undergo          artery. The left gastric artery, a branch of the celiac artery,
curative surgical resection often die of recurrent disease.      supplies the upper right portion of the stomach. The
However, 2 studies have demonstrated improved survival           common hepatic artery branches into the right gastric artery,
with adjuvant therapy: a US study using postoperative            which supplies the lower portion of the stomach, and the
                  2
chemoradiation and a European study using preoperative           right gastroepiploic branch, which supplies the lower portion
                                    3
and postoperative chemotherapy.                                  of the greater curvature.
Anatomic aspects                                                 Understanding the lymphatic drainage can clarify the areas at
The molecular biology responsible for carcinogenesis, tumor      risk for nodal involvement by cancer. The lymphatic drainage
biology, and response to therapy in stomach cancer are           of the stomach is complex. Primary lymphatic drainage is
active areas of investigation but are not addressed in this      along the celiac axis. Minor drainage occurs along the splenic
review. Instead, this article focuses on clinical management,    hilum, suprapancreatic nodal groups, porta hepatis, and
which first requires a thorough understanding of gastric         gastroduodenal areas.
anatomy.                                                         Frequency
Stomach and duodenum, coronal section.                           United States
The stomach begins at the gastroesophageal junction and          The American Cancer Society estimates that 21,130 cases of
ends at the duodenum. The stomach has 3 parts: the               gastric cancer will be diagnosed in 2009 (12,820 in men,
uppermost part is the cardia; the middle and largest part is     8,310 in women) and that 10,620 persons will die of the
                                                                          5
the body, or fundus; and the distal portion, the pylorus,        disease. Gastric cancer is the seventh leading cause of
connects to the duodenum. These anatomic zones have              cancer deaths.
distinct histologic features. The cardia contains                International
predominantly mucin-secreting cells. The fundus contains         Once the second most common cancer worldwide, stomach
mucoid cells, chief cells, and parietal cells. The pylorus is    cancer has dropped to fourth place, after cancers of the lung,
composed of mucus-producing cells and endocrine cells.           breast, and colon and rectum. However, stomach cancer
The stomach wall is made up of 5 layers. From the lumen out,     remains the second most common cause of death from
the layers include the mucosa, the submucosa, the                cancer. The American Cancer Society estimates that in 2007
muscularis layer, the subserosal layer, and the serosal layer.   there were an estimated one million new cases, nearly 70%
The peritoneum of the greater sac covers the anterior surface    of them in developing countries, and about 800,000 deaths.
of the stomach. A portion of the lesser sac drapes posteriorly   Tremendous geographic variation exists in the incidence of
over the stomach. The gastroesophageal junction has limited      this disease around the world. Rates of the disease are
or no serosal covering. The right portion of the anterior        highest in Asia and parts of South America and lowest in
                1
North America. The highest death rates are recorded in            esophageal varices or at the anastomosis after surgery;
Chile, Japan, South America, and the former Soviet Union.         intrahepatic jaundice caused by hepatomegaly; extrahepatic
Mortality/Morbidity                                               jaundice; and inanition resulting from starvation or cachexia
The 5-year survival rate for curative surgical resection ranges   of tumor origin.
from 30-50% for patients with stage II disease and from 10-       Physical
25% for patients with stage III disease. Because these            All physical signs are late events. By the time they develop,
patients have a high likelihood of local and systemic relapse,    the disease is almost invariably too far advanced for curative
some physicians offer them adjuvant therapy. The operative        procedures.
mortality rate for patients undergoing curative surgical          Signs may include a palpable enlarged stomach with
resection at major academic centers is less than 3%.              succussion splash; hepatomegaly; periumbilical metastasis
Race                                                              (Sister Mary Joseph nodule); and enlarged lymph nodes such
The rates of gastric cancer are higher in Asian and South         as Virchow nodes (ie, left supraclavicular) and Irish node
American countries than in the United States. Japan, Chile,       (anterior axillary). Blumer shelf (ie, shelflike tumor of the
and Venezuela have developed a very rigorous early                anterior rectal wall) may also be present. Some patients
screening program that detects patients with early stage          experience weight loss, and others may present with melena
disease (ie, low tumor burden). These patients appear to do       or pallor from anemia.
quite well. In fact, in many Asian studies, patients with         Paraneoplastic syndromes such as dermatomyositis,
resected stage II and III disease tend to have better outcomes    acanthosis nigricans, and circinate erythemas are poor
than similarly staged patients treated in Western countries.      prognostic features.
Some researchers suggest that this reflects a fundamental         Other associated abnormalities also include peripheral
biologic difference in the disease as it manifests in Western     thrombophlebitis and microangiopathic hemolytic anemia.
countries.                                                        Causes
In the United States, Asian and Pacific Islander males and        Gastric cancer may often be multifactorial, involving both
females have the highest incidence of stomach cancer,             inherited        predisposition       and        environmental
                                                                           6
followed by black, Hispanic, white, American Indian, and Inuit    factors. Environmental      factors    implicated      in  the
populations.                                                      development of gastric cancer include diet, Helicobacter
Sex                                                               pylori infection, previous gastric surgery, pernicious anemia,
In the United States, gastric cancer affects slightly more men    adenomatous polyps, chronic atrophic gastritis, and radiation
than women; the American Cancer Society estimates that in         exposure.
2009, 12,820 new cases will occur in men and 8,310 in             Diet
         5
women. Worldwide, however, gastric cancer rates are about         Diet rich in pickled vegetables, salted fish, salt, and smoked
                                    1
twice as high in men as in women.                                 meats correlate with an increased incidence of gastric cancer.
Age                                                               A diet that includes fruits and vegetables rich in vitamin C
Most patients are elderly at diagnosis. The median age for        may have a protective effect.
gastric cancer in the United States is 70 years for males and     Smoking
74 years for females. The gastric cancers that occur in           Smoking is associated with an increased incidence of
younger patients may represent a more aggressive variant or       stomach cancer in a dose-dependent manner, both for
may suggest a genetic predisposition to development of the        number of cigarettes and for duration of smoking.
disease.                                                          Smoking increases the risk of cardiac and noncardiac forms of
                                                                                    8
Clinical                                                          stomach cancer. Cessation of smoking reduces the risk.
History                                                           Meta-analysis of 40 studies estimated that the risk was
In the United States, about 25% of stomach cancer patients        increased by approx 1.5- to 1.6-fold and was higher in men.
present with localized disease, 31% present with regional         Helicobacter pylori infection
disease, and 32% present with distant metastatic disease; the     Chronic bacterial infection with H pylori is the strongest risk
remainder of cases surveyed were listed as unstaged.              factor for stomach cancer.
Early disease has no associated symptoms; however, some           H pylori may infect 50% of the world's population, but many
patients with incidental complaints are diagnosed with early      fewer than 5% of infected individuals develop cancer. It may
gastric cancer. Most symptoms of gastric cancer reflect           be that only a particular strain of H pylori is strongly
advanced disease. Patients may complain of indigestion,           associated with malignancy, probably because it is capable of
nausea or vomiting, dysphagia, postprandial fullness, loss of     producing the greatest amount of inflammation. In addition,
appetite, melena, hematemesis, and weight loss.                   full malignant transformation of affected parts of the
Late complications include pathologic peritoneal and pleural      stomach may require that the human host have a particular
effusions; obstruction of the gastric outlet, gastroesophageal    genotype of interleukin (IL) to cause the increased
junction, or small bowel; bleeding in the stomach from            inflammation and an increased suppression of gastric acid
secretion. For example, IL-17A and IL-17F are inflammatory          esophageal or gastric cancers. No significant difference was
cytokines that play a critical role in inflammation. Wu et al       observed for increased risk of esophageal or gastric cancers
found that carriage of IL-17F 7488GA and GG genotypes were          between the bisphosphonate cohort and the control group.
                                                      10
associated with an increased risk of gastric cancer.                Differential Diagnoses
H pylori infection is associated with chronic atrophic gastritis,   Esophageal Cancer     Gastroenteritis, Bacterial
and patients with a history of prolonged gastritis have a
                                                                    Esophageal Stricture Malignant Neoplasms of the illium
sixfold increased risk of developing gastric cancer.
Interestingly, this association is particularly strong for tumors   Esophagitis           Lymphoma, Non-Hodgkin
located in the antrum, body, and fundus of the stomach but          Gastric Ulcers        Gastritis, Atrophic
                                                              11
does not seem to hold for tumors originating in the cardia.         Gastritis, Acute      Gastroenteritis, Viral
Previous gastric surgery
                                                                    Gastritis, Chronic
Prev\ surgery is implicated as a risk factor. The rationale is
that surgery alters the normal pH of the stomach, which may         Workup
lead to metaplastic and dysplastic changes in luminal cells.        Laboratory Studies
Retrospective studies demonstrate that a small percentage of        The goal of obtaining laboratory studies is to assist in
patients who undergo gastric polyp removal have evidence of         determining optimal therapy.
invasive carcinoma within the polyp. This discovery has led         A CBC count can identify anemia, which may be caused by
some researchers to conclude that polyps might represent            bleeding, liver dysfunction, or poor nutrition. Approximately
premalignant conditions.                                            30% of patients have anemia.
Genetic factors                                                     Electrolyte panels and liver function tests also are essential to
Some 10% of stomach cancer cases are familial in origin.            better characterize the patient's clinical state.
Genetic factors involved in gastric cancer remain poorly            Carcinoembryonic antigen (CEA) is increased in 45-50% of
understood, though specific mutations have been identified          cases.
in a subset of gastric cancer patients. For example, germline       Cancer antigen (CA) 19-9 is elevated in about 20% of cases.
truncating mutations of the E-cadherin gene (CDH1) are              Imaging Studies
detected in 50% of diffuse-type gastric cancers, and families       Esophagogastroduodenoscopy has a diagnostic accuracy of
that harbor these mutations have an autosomal dominant              95%. This relatively safe and simple procedure provides a
                                                       13
pattern of inheritance with a very high penetrance.                 permanent color photographic record of the lesion. This
Other hereditary syndromes with a predisposition for                procedure is also the primary method for obtaining a tissue
stomach cancer include hereditary nonpolyposis colorectal           diagnosis of suspected lesions. Biopsy of any ulcerated lesion
cancer,Li-Fraumeni        syndrome, familial        adenomatous     should include at least 6 specimens taken from around the
polyposis, and Peutz-Jeghers syndrome.                              lesion because of variable malignant transformation. In
Epstein-Barr virus                                                  selected cases, endoscopic ultrasound may be helpful in
The Epstein-Barr virus may be associated with an unusual            assessing depth of penetration of the tumor or involvement
(<1%) form of stomach cancer, lymphoepithelioma-like                of adjacent structures.
carcinoma.                                                          Double-contrast upper GI series and barium swallows may be
Pernicious anemia                                                   helpful in delineating the extent of disease when obstructive
Pernicious anemia associated with advanced atrophic                 symptoms are present or when bulky proximal tumors
gastritis and intrinsic factor deficiency is a risk factor for      prevent passage of the endoscope to examine the stomach
gastric carcinoma.                                                  distal to an obstruction (more common with
Gastric ulcers                                                      gastroesophageal [GE]-junction tumors). These studies are
Gastric cancer may develop in the remaining portion of the          only 75% accurate and should for the most part be used only
stomach following a partial gastrectomy for gastric ulcer.          when upper GI endoscopy is not feasible.
Benign gastric ulcers may themselves develop into                   Chest radiograph is done to evaluate for metastatic lesions.
malignancy.                                                         CT scan or MRI of the chest, abdomen, and pelvis assess the
Obesity                                                             local disease process as well as evaluate potential areas of
Obesity increases the risk of gastric cardia cancer.                spread (ie, enlarged lymph nodes, possible liver metastases).
Radiation exposure                                                  Endoscopic ultrasound allows for a more precise
Survivors of atomic bomb blasts have had an increased rate          preoperative assessment of the tumor stage. Endoscopic
of stomach cancer. Other populations exposed to radiation           sonography is becoming increasingly useful as a staging tool
may also have an increased rate of stomach cancer.                  when the CT scan fails to find evidence of T3, T4, or
Bisphosphonates                                                     metastatic disease. Institutions that favor neoadjuvant
A large cohort study examined whether use of oral                   chemoradiotherapy for patients with locally advanced
bisphosphonates was associated with an increased risk of            disease rely on endoscopic ultrasound data to improve
                                                                    patient stratification.
Histologic Findings                                                2. N0 - No regional lymph node metastases
Adenocarcinoma of the stomach constitutes 90-95% of all            3. N1 - Metastasis in 1-6 regional lymph nodes
gastric malignancies. The second most common gastric               4. N2 - Metastasis in 7-15 regional lymph nodes
malignancies are lymphomas. Gastrointestinal stromal               5. N3 - Metastasis in more than 15 regional lymph nodes
tumors formerly classified as either leiomyomas or                 Distant metastasis
leiomyosarcomas account for 2% of gastric neoplasms.               1. MX - Distant metastasis (M) cannot be assessed
Carcinoids (1%), adenoacanthomas (1%), and squamous cell           2. M0 - No distant metastasis
carcinomas (1%) are the remaining tumor histologic types.          3. M1 - Distant metastasis
Adenocarcinoma of the stomach is subclassified according to        Prognostic features
histologic description as follows: tubular, papillary, mucinous,   Two important factors influencing survival in resectable
or signet-ring cells, and undifferentiated lesions.                gastric cancer are depth of cancer invasion through the
Pathology specimens are also classified by gross appearance.       gastric wall and presence or absence of regional lymph node
In general, researchers consider gastric cancers ulcerative,       involvement.
polypoid, scirrhous (ie, diffuse linitis plastica), superficial    In about 5% of primary gastric cancers, a broad region of the
spreading, multicentric, or Barrett ectopic adenocarcinoma.        gastric wall or even the entire stomach is extensively
Researchers also employ a variety of other classification          infiltrated by malignancy, resulting in a rigid thickened
schemes. The Lauren system classifies gastric cancer               stomach, termed linitis plastica. Patients with linitis plastica
                                                                                                        16
pathology as either Type I (intestinal) or Type II (diffuse). An   have an extremely poor prognosis.
appealing feature of classifying patients according to the         Margins positive for presence of cancer are associated with a
Lauren system is that the descriptive pathologic entities have     very poor prognosis.
clinically relevant differences.                                   The greater the number of involved lymph nodes, the more
Intestinal, expansive, epidemic-type gastric cancer is             likely the patient is to develop local and systemic failure after
associated with chronic atrophic gastritis, retained glandular     surgery.
structure, little invasiveness, and a sharp margin. The            In a study by Shen and colleagues, the depth of tumor
pathologic presentation classified as epidemic by the Lauren       invasion and gross appearance, size, and location of the
system is associated with most environmental risk factors,         tumor were 4 pathologic factors independently correlated
carries a better prognosis, and shows no familial history.         with the number of metastatic lymph nodes associated with
The second type, diffuse, infiltrative, endemic cancer,            gastric cancer.
consists of scattered cell clusters with poor differentiation      Lee and colleagues found that surgical stage, as estimated
and dangerously deceptive margins. Margins that appear             during curative resection for gastric cancer, complemented
clear to the operating surgeon and examining pathologist           the pathologically determined stage for determining
often are determined retrospectively to be involved. The           prognosis. Survival was significantly poorer among patients
endemic-type tumor invades large areas of the stomach. This        with pathologic Stages II, IIIa, and IIIb disease in whom
type of tumor is also not recognizably influenced by               intraoperative staging overestimated the extent of
                                                                                        18
environment or diet, is more virulent in women, and occurs         pathological stage.
more often in relatively young patients. This pathologic entity    Staging
is associated with genetic factors (such as E-cadherin), blood     1. Stage 0 - Tis, N0, M0
groups, and a family history of gastric cancer.                    2. Stage IA - T1, N0 or N1, M0
Staging                                                            3. Stage IB - T1, N2, M0 or T2a/b, N0, M0
The 2006 American Joint Committee on Cancer (AJCC) Cancer          4. Stage II - T1, N2, M0 or T2a/b, N1, M0 or T2, N0, M0
Staging Manual presents the following TNM classification           5. Stage IIIA - T2a/b, N2, M0 or T3, N1, M0 or T4, N0, M0
                                       15
system for staging gastric carcinoma:                              6. Stage IIIB - T3, N2, M0
Primary tumor                                                      7. Stage IV - T1-3, N3, M0 or T4, N1-3, M0, or any T, any N,
1. TX - Primary tumor (T) cannot be assessed                             M1
2. T0 - No evidence of primary tumor                               Survival rates
3. Tis - Carcinoma in situ, intraepithelial tumor without          1. Stage 0 - Greater than 90%
     invasion of lamina propria                                    2. Stage Ia - 60-80%
4. T1 - Tumor invades lamina propria or submucosa                  3. Stage Ib - 50-60%
5. T2 - Tumor invades muscularis propria or subserosa              4. Stage II - 30-40%
6. T3 - Tumor penetrates serosa (ie, visceral peritoneum)          5. Stage IIIa - 20%
     without invasion of adjacent structures                       6. Stage IIIb - 10%
7. T4 - Tumor invades adjacent structures                          7. Stage IV - Less than 5%.
Regional lymph nodes                                               Spread patterns
1. NX - Regional lymph nodes (N) cannot be assessed
Cancer of the stomach can spread directly, via lymphatics, or      12% with D2 and D1 dissections, respectively — a statistically
hematogenously.                                                    insignificant difference — and postoperative mortality rates
                                                                                                 22
Direct extension into the omenta, pancreas, diaphragm,             of 2.2% and 3%, respectively.
transverse colon or mesocolon, and duodenum is common.             D2 dissections are recommended by the National
If the lesion extends beyond the gastric wall to a free            Comprehensive Cancer Network over D1 dissections. A
peritoneal (ie, serosal) surface, then peritoneal involvement      pancreas- and spleen - preserving D2 lymphadenectomy is
is frequent.                                                       suggested, as it provides greater staging information, and
The visible gross lesion frequently underestimates the true        may provide a survival benefit while avoiding its excess
extent of the disease.                                             morbidity when possible.
The abundant lymphatic channels within the submucosal and          Outcome
subserosal layers of the gastric wall allow for easy               The 5-year survival rate for a curative surgical resection
microscopic spread.                                                ranges from 60-90% for patients with stage I, 30-50% for
The submucosal plexus is prominent in the esophagus and            patients with stage II disease, and 10-25% for patients with
the subserosal plexus is prominent in the duodenum,                stage III disease.
allowing proximal and distal spread.                               Because these patients have a high likelihood of local and
Lymphatic drainage is through numerous pathways and can            systemic relapse, some physicians offer adjuvant therapy.
involve multiple nodal groups (eg, gastric, gastroepiploic,        Consultations
celiac,    porta     hepatic,      splenic,   suprapancreatic,     Specialists recommend obtaining consultations freely in the
pancreaticoduodenal, paraesophageal, and paraaortic lymph          management of most malignancies, and gastric carcinoma is
nodes).                                                            no exception. The gastroenterologist, surgical oncologist,
Hematogenous spread commonly results in liver metastases.          radiation oncologist, and medical oncologist work closely as a
Treatment                                                          team.
Surgical Care                                                      Follow-up
Type of surgery                                                    Deterrence/Prevention
In general, most surgeons in the United States perform a           A diet that includes fruits and vegetables rich in vitamin C
total gastrectomy (if required for negative margins), an           may have a protective effect.
esophagogastrectomy for tumors of the cardia and                   Complications
gastroesophageal junction, and a subtotal gastrectomy for          Direct mortality rate within 30 days after a surgical procedure
tumors of the distal stomach.                                      for gastric cancer has been reduced substantially over the
A randomized trial comparing subtotal with total gastrectomy       last 40 years. Most major centers report a direct mortality
for distal gastric cancer revealed similar morbidity, mortality,   rate of 1-2%.
                           19
and 5-year survival rates.                                         Early postoperative complications include anastomotic
Because of the extensive lymphatic network around the              failure, bleeding, ileus, transit failure at the anastomosis,
stomach and the propensity for this tumor to extend                cholecystitis (often occult sepsis without localizing signs),
microscopically, traditional teaching is to attempt to maintain    pancreatitis, pulmonary infections, and thromboembolism.
5-cm surgical margin proximally and distally to the 1˚ lesion.     Further surgery may be required for anastomotic leaks.
Lymph node dissection                                              Late mechanicophysiologic complications include dumping
The extent of the lymph node dissection is somewhat                syndrome, vitamin B-12 deficiency, reflux esophagitis, and
controversial.                                                     bone disorders, especially osteoporosis.
Many studies demonstrate that nodal involvement indicates          Postgastrectomy patients often are immunologically
a poor prognosis, and more aggressive surgical approaches to       deficient, as measured by blastogenic and delayed cutaneous
attempt to remove involved lymph nodes are gaining                 hypersensitivity responses.
popularity.                                                        Prognosis
Two randomized trials compared D1 (perigastric lymph               Unfortunately, only a minority of patients with gastric cancer
nodes) with D2 (hepatic, left gastric, celiac, and splenic         who undergo a surgical resection will be cured of their
arteries, as well as those in the splenic hilum)                   disease.      Most     patients     have      a     recurrence.
lymphadenectomy in patients who were treated for curative          Patterns of failure
intent. In the largest of these trials, postoperative morbidity    Several studies have investigated the patterns of failure after
(43% versus 25%) and mortality (10% versus 4%) were higher         surgical resection alone. Studies that depend solely on the
in the D2 group.                                                   physical examination, laboratory studies, and imaging studies
Most critics argue that these studies were underpowered and        may overestimate the percentage of patients with distant
overestimated benefit. In addition, a recent randomized trial      failure and underestimate the incidence of local failure,
found a much lower rate of complications than those earlier        which is more difficult to detect.
trials. Degiuli et al reported complication rates of 17.9% and
A reoperation series from the University of Minnesota may         Numerous randomized clinical trials comparing combination
offer a more accurate understanding of the biology of the         chemotherapy in the postoperative setting to surgery alone
disease. In this series of patients, researchers surgically       did not demonstrate a consistent survival benefit.
reexplored patients 6 months after the initial surgery and        Recent meta-analyses have shown a hint of statistical benefit.
meticulously recorded the patterns of disease spread. The         In one meta-analysis of 13 randomized trials, adjuvant
total local-regional failure rate approached 67%. The gastric     systemic chemotherapy was associated with a significant
bed was the site of failure in 54% of these cases, and the        survival benefit (odds ratio for death, 0.80; 95% CI, 0.66-
regional lymph nodes were the site of failure in 42%.             0.97). In subgroup analysis, there was a trend toward a larger
Approximately 26% of patients had evidence of distant             magnitude of effect for trials in which at least two thirds of
                                                                                                           29
failure. The patterns of failure included local tumor regrowth,   the patients had node-positive disease.
tumor bed recurrences, regional lymph node failures, and          A postoperative chemoradiation study was prompted in part
distant failures (ie, hematogenous failures and peritoneal        by the patterns of local failure often preceding systemic
spread). Primary tumors involving the gastroesophageal            spread.
junction tended to fail in the liver and the lungs. Lesions       Adjuvant chemoradiotherapy
                                             23
involving the esophagus failed in the liver.                      A randomized phase III study performed in the United States,
Adjuvant therapy                                                  Intergroup 0116, demonstrated a survival benefit associated
The pattern of failure prompted a number of investigations        with postoperative chemoradiotherapy compared with
                                                                                  2
into adjuvant therapy. The rationale behind radiotherapy is       surgery alone.
to provide additional local-regional tumor control. Adjuvant      In this study, patients underwent an en bloc resection.
chemotherapy is used either as a radiosensitizer or as            Patients with T3 and/or N+ adenocarcinoma of the stomach
definitive treatment for presumed systemic metastases.            or gastroesophageal junction were randomized to receive a
Adjuvant radiotherapy                                             bolus of 5-fluorouracil (5-FU) and leucovorin (LV) and
Moertel and colleagues randomized postoperative patients          radiotherapy or observation.
with advanced gastric cancer to receive 40 Grays (Gy) of          Patients who received the adjuvant chemoradiotherapy
radiotherapy or 40 Gy of radiotherapy with 5-FU as a              demonstrated improved disease-free survival (from 32% to
radiosensitizer and demonstrated improved survival                49%) and improved overall survival rates (from 41% to 52%)
                                                   24
associated with the combined-modality therapy.                    compared to those who were merely observed.
The British Stomach Cancer Group reported lower rates of          This regimen is considered the standard of care in the United
local recurrence in patients who received postoperative           States.
                                                           25
radiotherapy than in those who underwent surgery alone.           Neoadjuvant chemotherapy
The update of the initial Gastrointestinal Tumor Study Group      Neoadjuvant chemotherapy may allow downstaging of
series revealed higher 4-year survival rates in patients with     disease to increase resectability, decrease micrometastatic
unresectable gastric cancer who received combined-modality        disease burden prior to surgery, allow patient tolerability
therapy than in those who received chemotherapy alone             prior to surgery, determine chemotherapy sensitivity, reduce
(18% vs 6%).                                                      the rate of local and distant recurrences, and ultimately
In a series from the Mayo Clinic, patients were randomized to     improve survival.
receive postoperative radiotherapy with 5-FU or surgery           A European randomized trial also demonstrated survival
alone, and improved survival was demonstrated in patients         benefit when patients were treated with 3 cycles of
                                          27
receiving adjuvant therapy (23% vs 4%).                           preoperative chemotherapy (epirubicin, cisplatin, and 5-
Intraoperative radiotherapy                                       fluorouracil) followed by surgery and then 3 cycles of
Some authors suggest that intraoperative radiotherapy             postoperative chemotherapy compared with surgery alone.
(IORT) shows promising results.                                   The benefit was comparable to that obtained with
                                                                                                                  3
This alternative method of delivering radiotherapy allows for     postoperative chemoradiation in the US trial. However, the
a high dose to be given in a single fraction while in the         Gastric Chemotherapy Group for Japan did not demonstrate
operating room so that other critical structures can be           significant survival benefit with neoadjuvant chemotherapy.
avoided.                                                          Choice of preoperative and postoperative chemotherapy
The National Cancer Institute randomized patients with            versus postoperative chemotherapy and radiation remains
grossly resected stage III/IV gastric cancer to receive either    controversial, and an ongoing United States Intergroup study,
20 Gy of IORT or 50 Gy of postoperative external beam             CALGB 80101, will look more closely at that question.
radiation. Local failure was delayed in the patients treated      Advanced unresectable disease
with IORT (21 mo vs 8 mo). Although the median survival           Many patients present with distant metastases,
duration also was higher (21 mo vs 10 mo), this figure did not    carcinomatosis, unresectable hepatic metastases, pulmonary
                                28
reach statistical significance.                                   metastases, or direct infiltration into organs that cannot be
Adjuvant chemotherapy                                             resected completely.
In the palliative setting, radiotherapy provides relief from       11.1 months in the chemotherapy group (hazard ratio, 0.74,
                                                                               35
bleeding, obstruction, and pain in 50-75% of patients. The         P = .0046).
median duration of palliation is 4-18 months.                      Although modest, this 2.7-month improvement in overall
Surgical procedures such as wide local excision, partial           survival is clinically meaningful in this group of patients, who
gastrectomy, total gastrectomy, simple laparotomy,                 have a poor prognosis. In addition to the impact on overall
gastrointestinal anastomosis, and bypass also are performed        survival, trastuzumab improved all of the secondary end
with palliative intent, with a goal of allowing oral intake of     points, including progression-free survival (increased from
food and alleviating pain.                                         5.2 mo to 6.7 mo; P = .002) and overall response rate
Platinum-based chemotherapy, in combinations such as               (increased from 34.5% to 47%; P =.0017).
epirubicin/cisplatin/5-FU      or      docetaxel/cisplatin/5-FU,   Trastuzumab was approved in October of 2010 for the
represents the current first-line regimen. Other active            treatment of HER2-overexpressing metastatic gastric or
regimens include irinotecan and cisplatin and other                gastroesophageal        junction    adenocarcinoma.       It   is
combinations with oxaliplatin and irinotecan.                      administered in combination with cisplatin and capecitabine
Results of cisplatin-based chemotherapy have been largely          or 5-fluorouracil in patients who have not received prior
discouraging, with median time to progression of 3-4 months        treatment for metastatic disease. The trastuzumab dose
and overall survival of approximately 6-9 months despite           consists of an initial cycle of 8 mg/kg intravenously (IV)
reported response rates of up to 45%. Early results reported       infused over 90 minutes, followed by subsequent cycles of 6
in 2007 by Japanese clinicians suggest some improvement in         mg/kg IV infused over 30-90 minutes every 3 weeks.
both response rates and survival with the oral                     Treatment is continued until the disease progresses.
fluoropyrimidine S-1 used alone or in combination with
           30
cisplatin. (S-1 combines 3 investigational drugs: tegafur, a
prodrug of 5-FU; gimeracil, an inhibitor of fluorouracil
degradation; and oteracil or potassium oxanate, a GI tract
adverse-effect modulator.) These results remain to be
confirmed by ongoing studies in Europe and North America.
Bevacizumab, a monoclonal antibody against vascular
endothelial growth factor (VEGF) is currently being evaluated
                                    31
for use in advanced gastric cancer.
Novel treatment strategies may be guided by the use of gene
signatures. Kim et al reported that combined overexpression
of MYC, EGFR, and FGFR2 predicts a poor response of
metastatic gastric cancer to treatment with cisplatin and
fluorouracil.
Ishido et al reported that in patients receiving S-1
chemotherapy after gastrectomy for advanced gastric cancer,
intratumoral mRNA expression of thymidylate synthase (TS)
is an independent prognostic factor for response to
chemotherapy. In 39 patients who received postoperative S-
1, recurrence-free survival and overall survival were
significantly longer in patients with low TS expression than in
those with high TS expression (P=0.021 and 0.016,
respectively), whereas in 40 patients treated with surgery
                                                     34
only, TS expression did not correlate with survival.
Overexpression of human epidermal growth factor receptor 2
(HER2) is a significant negative prognostic factor for gastric
cancer. In the international ToGA trial (trastuzumab with
chemotherapy in HER2-positive advanced gastric cancer),
about 22% of patients with advanced gastric cancer were
found to have tumors that overexpressed HER2. In this phase
III trial, 594 patients with HER2-positive advanced gastric
cancer were randomized to receive standard chemotherapy
alone or chemotherapy plus trastuzumab (Herceptin). Overall
survival with trastuzumab was 13.8 months, compared with

				
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