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
antibiotics, and increased screening in some countries. these pathways may play an important role in influencing
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
chemoradiation and a European study using preoperative right gastroepiploic branch, which supplies the lower portion
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.
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
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
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.
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
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
women. Worldwide, however, gastric cancer rates are about Diet rich in pickled vegetables, salted fish, salt, and smoked
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
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.
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
does not seem to hold for tumors originating in the cardia. Gastritis, Acute Gastroenteritis, Viral
Previous gastric surgery
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
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
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
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
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
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
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
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%.
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.
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
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
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
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%)
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.
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
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
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
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,
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
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
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
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
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