What is stomach cancer

Stomach cancer or gastric cancer, occurs when cells in the stomach grow abnormally and develop into tumors, which could become harmful if left untreated ¹.

The stomach is a J-shaped pouch like organ in the left upper abdomen. It is part of the digestive system, which processes nutrients (vitamins, minerals, carbohydrates, fats, proteins, and water) in foods that are eaten and helps pass waste material out of the body. Food moves from the throat to the stomach through a hollow, muscular tube called the esophagus. The esophagus joins the stomach at the gastroesophageal junction, which is just beneath the diaphragm (the thin sheet of breathing muscle under the lungs). After leaving the stomach, partly-digested food passes into the small intestine and then into the large intestine.

The stomach wall has 5 layers:

The stomach wall is made up of several layers of mucous membrane, connective tissue with blood vessels and nerves, and muscle fibers (see Figure 4).

• The innermost layer is the mucosa. This is where stomach acid and digestive enzymes are made. Most stomach cancers start in this layer.
• Next is a supporting layer called the submucosa.
• Outside of this is the muscularis propria, a thick layer of muscle that moves and mixes the stomach contents.
• The outer 2 layers, the subserosa and the outermost serosa, wrap the stomach.

The layers are important in determining the stage (extent) of the cancer and in helping to determine a person’s prognosis (outlook). As a cancer grows from the mucosa into deeper layers, the stage becomes more advanced and the prognosis is not as good.

Stomach cancer should not be confused with other cancers that can occur in the abdomen, like cancer of the colon (large intestine), liver, pancreas, or small intestine because these cancers may have different symptoms, different outlooks, and different treatments.

Stomach cancer represents 1.7% of all new cancer cases in the U.S. In 2017, it is estimated that there will be 28,000 new cases of stomach cancer and an estimated 10,960 people will die of this disease ². For stomach cancer, death rates increase with age. Stomach cancer is the fifteenth leading cause of cancer death in the United States. The number of deaths was 3.2 per 100,000 men and women per year based on 2010-2014 deaths. Stomach cancer is more common in men than women and among other races and ethnicities than non-Hispanic whites. Stomach cancer is most frequently diagnosed among people aged 65-74. Age, diet and stomach disease, including infection with Helicobacter pylori can affect the risk of developing stomach cancer. The number of new cases of stomach cancer was 7.3 per 100,000 men and women per year based on 2010-2014 cases.

The incidence and mortality of gastric cancer have fallen dramatically in US and elsewhere over the past 70 years ³. Nonetheless, gastric cancer remains a major public health issue as the fourth most common cancer and the second leading cause of cancer death worldwide ⁴. In 2000, about 880 000 people were diagnosed with gastric cancer and approximately 650 000 died of the disease ⁵. In Japan, gastric cancer remains the most common type of cancer among both men and women. Age-standardized incidence rates in Japan are 69.2 per 100 000 in men and 28.6 per 100 000 in women ⁶. In contrast to the increasing incidence of proximal tumors in the West, distal tumors continue to predominate in Japan. However, even in Japan, the proportion of proximal stomach cancers has increased among men ⁷.

The wall of the stomach is made up of 3 layers of tissue: the mucosal (innermost) layer, the muscularis (middle) layer, and the serosal (outermost) layer. Stomach cancer begins in the cells lining the mucosal layer and spreads through the outer layers as it grows. Almost all stomach cancers are adenocarcinomas (cancers that begin in cells that make and release mucus and other fluids) ⁸. Other types of gastric cancer are gastrointestinal carcinoid tumors, gastrointestinal stromal tumors, and lymphomas ⁸.

Infection with bacteria called Helicobacter pylori is a common cause of gastric cancer.

The two main tumor sites of gastric adenocarcinoma are proximal (cardia) and distal (noncardia). Despite a decline in distal gastric cancers, proximal tumors have been increasing in incidence since the 1970s, especially among males in the Western countries ⁹, ¹⁰. These gastric tumor types predominate in populations from different geographic locations, racial and socio-economic groups. They may also differ in genetic susceptibility, pathologic profile, clinical presentation, and prognosis. The observed differences between gastric cancers by anatomic site suggest that they are distinct diseases with different etiologies.

• Gastric cancer is often diagnosed at an advanced stage because there are no early signs or symptoms.
• Since symptoms of stomach cancer often do not appear until the disease is advanced, only about 1 in 5 stomach cancers in the United States is found at an early stage, before it has spread to other areas of the body.

Stomach cancer mostly affects older people – two-thirds of people who have it are over age 65. Your risk of getting it is also higher if you

• Have had a Helicobacter pylori infection ¹¹, ¹², which is a type of bacteria that lives in and affects the mucous lining of the stomach
• Have chronic gastritis, a long-term inflammation of the stomach
• Are a man
• Eat lots of salted, smoked, or pickled foods
• Smoke cigarettes
• Have a family history of stomach cancer
• A diet low in fruits and vegetables
• Pernicious anaemia ¹³, a decrease in red blood cells when the intestines cannot properly absorb vitamin B12

It is hard to diagnose stomach cancer in its early stages ¹.

Indigestion and stomach discomfort can be symptoms of early cancer, but other problems can cause the same symptoms. In advanced cases, there may be blood in your stool, vomiting, unexplained weight loss, jaundice, or trouble swallowing. Doctors diagnose stomach cancer with a physical exam, blood and imaging tests, an endoscopy, and a biopsy.

Because it is often found late, it can be hard to treat stomach cancer. Treatment options include surgery, chemotherapy, radiation or a combination.

Can stomach cancer be found early ?

Screening is testing for a disease, such as cancer, in people without symptoms. In countries such as Japan, where stomach cancer is very common, mass screening of the population has helped find many cases at an early, curable stage. This may have reduced the number of people who die of this disease, but this has not been proven.

Studies in the United States have not found that routine screening in people at average risk for stomach cancer is useful, because this disease is not that common. On the other hand, people with certain stomach cancer risk factors may benefit from screening. If you have any questions about your stomach cancer risk or about the benefits of screening, please ask your doctor.

Some of the tests that could be used for screening, such as upper endoscopy, are described in Stomach Cancer Diagnosis.

Because routine screening for stomach cancer is not done in the United States, most people with this disease are not diagnosed until they have certain signs and symptoms that point to the need for medical tests.

Types of stomach cancers

Different types of stomach cancer include:

Adenocarcinoma

About 90% to 95% of cancers of the stomach are adenocarcinomas ¹⁴. When the term stomach cancer or gastric cancer is used, it almost always refers to an adenocarcinoma. These cancers develop from the cells that form the innermost lining of the stomach (known as the mucosa).

Lymphoma

These are cancers of the immune system tissue that are sometimes found in the wall of the stomach. About 4% of stomach cancers are lymphomas. The treatment and outlook depend on the type of lymphoma. For more detailed information, see Non-Hodgkin Lymphoma.

Gastrointestinal stromal tumor (GIST)

These are rare tumors that start in very early forms of cells in the wall of the stomach called interstitial cells of Cajal. Some of these tumors are non-cancerous (benign); others are cancerous. Although GISTs can be found anywhere in the digestive tract, most are found in the stomach. For more information, see Gastrointestinal Stromal Tumor (GIST).

Carcinoid tumor

These are tumors that start in hormone-making cells of the stomach. Most of these tumors do not spread to other organs. About 3% of stomach cancers are carcinoid tumors. These tumors are discussed in more detail in Gastrointestinal Carcinoid Tumors.

Other cancers

Other types of cancer, such as squamous cell carcinoma, small cell carcinoma, and leiomyosarcoma, can also start in the stomach, but these cancers are very rare.

Development of stomach cancer

Stomach cancers tend to develop slowly over many years. Before a true cancer develops, pre-cancerous changes often occur in the inner lining (mucosa) of the stomach. These early changes rarely cause symptoms and therefore often go undetected.

Cancers starting in different sections of the stomach may cause different symptoms and tend to have different outcomes. The cancer’s location can also affect the treatment options. For example, cancers that start at the gastroesophageal junction are staged and treated the same as cancers of the esophagus. A cancer that starts in the cardia of the stomach but then grows into the gastroesophageal junction is also staged and treated like a cancer of the esophagus.

Stomach cancers can spread (metastasize) in different ways. They can grow through the wall of the stomach and invade nearby organs. They can also spread to the lymph vessels and nearby lymph nodes. Lymph nodes are bean-sized structures that help fight infections. The stomach has a very rich network of lymph vessels and nodes. As the stomach cancer becomes more advanced, it can travel through the bloodstream and spread to organs such as the liver, lungs, and bones. If cancer has spread to the lymph nodes or to other organs, the patient’s outlook is not as good.

Incidence and mortality of stomach cancer

The age-adjusted incidence rate for gastric cancer in the United States for the years 2004 to 2008 was 7.7 persons per 100,000 population. Incidence among men is twice as high as among women ¹⁵. Mortality rates for gastric cancer have been declining worldwide in recent decades, most prominently in the United States ¹⁶. Mortality rates for white males in the United States were approximately 40 deaths per 100,000 population in 1930, compared with 4.6 deaths per 100,000 population for the years 2003 to 2007. The death rate from gastric cancer for black males was 2.3 times higher than for whites for the years 2003 to 2007 ¹⁷. The annual number of new cases seems to be steady in recent years; in 2017, it is estimated that 28,000 Americans will be diagnosed with gastric cancer and 10,960 persons will die of it ¹⁸. Gastric cancer is the fourth most common cancer in the world ¹⁹. Worldwide, the estimated number of cases per year in 2008 was 988,000, and the estimated number of deaths was 736,000. Age-standardized annual incidence rates vary widely across the world: from 3.9 to 42.4 cases per 100,000 in men, and from 2.2 to 18.3 cases per 100,000 in women. More than 70% of cases occur in developing countries, and 50% of the cases occur in Eastern Asia ¹⁹.

Most cancers in the United States are advanced at diagnosis, which is reflected in an overall 5-year survival rate of 29.9% from 2005 to 2011 ²⁰. Carcinomas localized to the mucosa or submucosa (“early” cancers) have a much better prognosis; the 5-year survival rate is more than 95% in Japan and more than 65% in the United States. In high-risk populations, secondary prevention measures linked to screening programs have been instituted ²¹. In Japan, endoscopic resection techniques have been refined and could possibly be responsible for drastic reductions in mortality rates in the presence of steady incidence rates. This hypothesis, however, has not been tested in clinical trials.

Who is at Risk of Stomach Cancer ?

Anything that increases your risk of getting a disease is called a risk factor. Having a risk factor does not mean that you will get cancer; not having risk factors doesn’t mean that you will not get cancer. Talk with your doctor if you think you may be at risk. Risk factors for gastric cancer include the following:

Having any of the following medical conditions:

• Helicobacter pylori (H. pylori) infection of the stomach.
• Chronic gastritis (inflammation of the stomach).
• Pernicious anemia.
• Intestinal metaplasia (a condition in which the normal stomach lining is replaced with the cells that line the intestines).
• Familial adenomatous polyposis (FAP) or gastric polyps.

• Eating a diet high in salted, smoked foods and low in fruits and vegetables.
• Eating foods that have not been prepared or stored properly.
• Being older or male.
• Smoking cigarettes.

Having a mother, father, sister, or brother who has had stomach cancer. Only a small percentage of stomach cancers are caused by hereditary diffuse gastric cancer syndrome. But it is very important to recognize it, because most people who inherit this condition eventually get stomach cancer. A personal history of invasive lobular breast cancer before age 50 as well as having close family members who have had stomach cancer suggests that they might be at risk for having this syndrome. These people can talk to a genetics professional about getting genetic testing. If the testing shows the person has a mutation (abnormal change) in the CDH1 gene, many doctors will recommend they have their stomach removed before the cancer develops.

People at elevated risk for gastric cancer include elderly patients with atrophic gastritis or pernicious anemia, patients with sporadic gastric adenomas ¹³, familial adenomatous polyposis ²², or hereditary nonpolyposis colon cancer ²³ and immigrant ethnic populations from countries with high rates of gastric carcinoma ²⁴, ²⁵. Workers in the rubber and coal industries are also at increased risk ²⁶.

Risk factors for gastric cancer include the presence of precursor conditions such as chronic atrophic gastritis and intestinal metaplasia, pernicious anemia, and gastric adenomatous polyps. Genetic factors include a family history of gastric cancer, Li Fraumeni syndrome, and Type A blood type ²⁶. Environmental factors include low consumption of fruits and vegetables; consumption of salted, smoked, or poorly preserved foods; cigarette smoking; and radiation exposure ²⁷, ²⁸, ²⁶.

There is consistent evidence that Helicobacter pylori infection, also known as H. pylori infection, of the stomach is strongly associated with both the initiation and promotion of carcinoma of the gastric body and antrum and of gastric lymphoma ²⁹, ¹¹, ¹². The International Agency for Research on Cancer classifies Helicobacter pylori infection as a cause of noncardia gastric carcinoma and gastric low-grade B-cell mucosa-associated lymphoid tissue or MALT lymphoma (i.e., a Group 1 human carcinogen) ³⁰, ³¹.

Compared with the general population, people with duodenal ulcer disease may have a lower risk of gastric cancer ³².

Figure 1. Stomach

Figure 2. Parts of the stomach

Figure 3. Stomach mucus and gastric acid secreting cells

Figure 4. Layers of the stomach

Stomach cancer prevention

Cancer prevention is action taken to lower the chance of getting cancer. By preventing cancer, the number of new cases of cancer in a group or population is lowered. Hopefully, this will lower the number of deaths caused by cancer.

To prevent new cancers from starting, scientists look at risk factors and protective factors. Anything that increases your chance of developing cancer is called a cancer risk factor; anything that decreases your chance of developing cancer is called a cancer protective factor.

Some risk factors for cancer can be avoided, but many cannot. For example, both smoking and inheriting certain genes are risk factors for some types of cancer, but only smoking can be avoided. Regular exercise and a healthy diet may be protective factors for some types of cancer. Avoiding risk factors and increasing protective factors may lower your risk but it does not mean that you will not get cancer.

Different ways to prevent cancer are being studied, including:

• Changing lifestyle or eating habits.
• Avoiding things known to cause cancer.
• Taking medicines to treat a precancerous condition or to keep cancer from starting.

Smoking cessation

Based on solid evidence, smoking is associated with an increased risk of stomach cancer ³³, ³⁴, ³⁵. Tobacco use can increase the risk of cancers of the proximal stomach, the portion of the stomach closest to the esophagus ³⁶. Tobacco use also increases the risk for many other types of cancer and is responsible for about one-third of all cancer deaths in the United States.

The 2004 Surgeon General’s report identifies cigarette smoking as a cause of stomach cancer, with an average relative risk (RR) in former smokers of 1.2 and in current smokers of 1.6 ³⁷. Compared with persistent smokers, the risk of stomach cancer decreases among former smokers with time since cessation. This pattern of observations makes it reasonable to infer that cigarette smoking prevention or cessation would result in a decreased risk of gastric cancer.

Magnitude of Effect: A systematic review and meta-analysis showed a 60% increase in gastric cancer in male smokers and a 20% increase in gastric cancer in female smokers compared with nonsmokers ³³.

H. Pylori infection eradication

Based on solid evidence, H. pylori infection is associated with an increased risk of gastric cancer. A meta-analysis of seven randomized studies, all conducted in areas of high-risk gastric cancer and all but one conducted in Asia, suggests that treatment of H. pylori may reduce stomach cancer risk (from 1.7% to 1.1% a 65% reduction in cancer rsik) ³⁸. Only two studies assessed gastric cancer incidence as the primary study outcome, and two different studies were double blinded. It is unclear how generalizable the results may be to the North American population.

In the initial report from a clinical trial, 3,365 randomized subjects were followed in an intention-to-treat analysis; it was shown that short-term treatment with amoxicillin and omeprazole reduced the incidence of gastric cancer by 39% during a period of 15 years following randomization, with similar but not statistically significant reductions for gastric cancer mortality ³⁹.

Magnitude of Effect: Risk of cancer may be reduced; effect on cancer mortality is not known.

If your doctor thinks you might have H. pylori infection, there are several ways to test for this:

• The simplest way is a blood test that looks for antibodies to H. pylori. Antibodies are proteins the body’s immune system makes in response to an infection. A positive H pylori antibody test result can mean either that you are infected with H pylori or that you had an infection in the past that is now cleared.

• Another approach is to have an endoscopy procedure to take a biopsy sample of the stomach lining. This sample can be used for chemical tests for this kind of bacteria. Doctors can also identify H. pylori in biopsy samples viewed under a microscope. The biopsy sample can also be cultured (placed in a substance that promotes bacterial growth) to see if H. pylori grows out of the sample.

• There is also a special breath test for the bacteria. For this test, you drink a liquid containing urea. If H. pylori is present, it will chemically change the urea. A sample of your breath is then tested for these chemical changes.

Interventions With Inadequate Evidence as to Whether They Reduce the Risk of Stomach Cancer

Diet

The dramatic decline of stomach cancer in the past several decades is thought to be a result of people reducing many of the known dietary risk factors. This includes greater use of refrigeration for food storage rather than preserving foods by salting, pickling, and smoking. To help reduce your risk, avoid a diet that is high in smoked and pickled foods and salted meats and fish.

A diet high in fresh fruits and vegetables can also lower stomach cancer risk. Citrus fruits (such as oranges, lemons, and grapefruit) may be especially helpful, but grapefruit and grapefruit juice can change the blood levels of certain drugs you take, so it’s important to discuss this with your health care team before adding grapefruit to your diet.

Although some small studies suggested that drinking tea, particularly green tea, may help protect against stomach cancer, most large studies have not found such a link.

Being overweight or obese may add to the risk of stomach cancer. On the other hand, being physically active may help lower your risk.

Based on fair evidence, excessive salt intake and deficient dietary consumption of fresh fruits and vegetables are associated with an increased risk of gastric cancer. Dietary intake of vitamin C contained in vegetables, fruits, and other foods of plant origin is associated with a reduced risk of gastric cancer. Diets high in whole-grain cereals, carotenoids, allium compounds, and green tea are also associated with a reduced risk of this cancer. However, it is uncertain if changing one’s diet to include more vegetables, fruits, and whole grains would reduce the risk of gastric cancer.

Epidemiologic evidence from case-control and cohort studies suggests that increased intake of fresh fruits and vegetables is associated with decreased gastric cancer rates ⁴⁰, ²⁶.

The American Cancer Society ⁴¹ recommends that people eat a healthy diet, with an emphasis on plant foods. This includes eating at least 2½ cups of vegetables and fruits every day. Choosing whole-grain breads, pastas, and cereals instead of refined grains, and eating fish, poultry, or beans instead of processed meat and red meat may also help lower your risk of cancer. However, no randomized clinical trials have been done to establish a causal association.

Dietary supplements

Because of the evidence for an inverse association between gastric cancer and dietary intake of fruits and vegetables, especially those rich in antioxidants, there has been interest in dietary supplementation with antioxidants.

Dietary indices of micronutrient intake have been calculated and indicate possible protective effects of beta carotene, vitamin A, vitamin E, selenium, vitamin C or foods that contain these compounds. A chemoprevention trial in China reported a statistically significant reduction in the gastric cancer mortality rate after supplementation with beta carotene, vitamin E, and selenium ⁴². The population studied, however, may have been nutritionally deficient, raising questions of generalizability to other populations such as that of the United States. In addition, the experimental design did not permit assessment of the relative effects of beta carotene, vitamin E, and selenium.

Likewise, there was a randomized placebo-controlled trial of 200 mg of oral allitridium (a component of garlic) every day combined with 100 mcg of oral selenium every other day for 1 month of each year over a 3-year period in Qixia County (Shandong Province, China), an area with low intake of garlic and low selenium content in their garlic compared with other areas of China ⁴³. Although designed as a double-blinded trial, allitridium causes a distinctive odor of garlic. A total of 5,033 people, who met at least one of the following criteria: (1) medical history of stomach disorder, (2) family history of tumor, (3) history of smoking, or (4) history of alcohol consumption, were randomly assigned. The study, published in a Chinese medical journal, was not well described. After a follow-up for as many as 11 years, there were a total of 23 gastric cancer cases in the allitridium/selenium group and 30 cases in the placebo group. Only 60% of the gastric cancers were diagnosed by histopathology. There was a qualitative difference in outcome by sex: relative risk men = 0.36; relative risk women = 1.14. Given the problems with design and reporting of the study, the evidence of benefit (including men) is weak and may not be generalizable to Western countries.

In a randomized, double-blind, chemoprevention trial in Venezuela among a population at increased risk for gastric cancer, a combination of antioxidant vitamins (vitamins C, E, and beta carotene) failed to modify progression or regression of precancerous gastric lesions ⁴⁴. Another potential explanation for the lack of benefit of vitamin supplementation in this trial was the high prevalence of advanced premalignant lesions and the high H. pylori infection rate ⁴⁵.

A secondary analysis of the Alpha-Tocopherol Beta Carotene trial conducted on male smokers in Finland evaluated the effect of supplementation on gastric cancer incidence ⁴⁶. No protective effects for these supplements against gastric cancer were observed. Six-year follow-up results of a study of 976 Colombian patients have been reported. Patients were randomly assigned to receive eight different treatments that included vitamin supplements and anti-Helicobacter therapy either alone or in combination versus placebo. Among the 79 patients who received anti-Helicobacter therapy, a borderline statistically significant regression of intestinal metaplasia when compared with a placebo was noted. However, the combinations of antibiotics and vitamins did not confer additional benefits. More importantly, the progression rate of intestinal metaplasia was comparable irrespective of the treatments received. The progression rate was 23% in the placebo group and 17% in antibiotic recipients ⁴⁷.

A 2008 Cochrane review examined randomized trials of antioxidant dietary supplements for the prevention of gastrointestinal cancers, including gastric cancer ⁴⁸. Twenty trials were identified that assessed the preventive effects of antioxidant supplements or vitamin C on gastrointestinal cancer. With regard to gastric cancer, there were 12 comparisons of one or more micronutrients with placebo: beta-carotene alone (4 trials); vitamin C alone (1 trial); vitamin E alone (1 trial); vitamin A plus beta-carotene (1 trial); beta-carotene plus vitamin C (1 trial); beta-carotene plus vitamin E (1 trial); beta-carotene plus vitamins C and E (1 trial); selenium plus vitamins C and E (1 trial); and beta-carotene, vitamins C and E, and selenium (1 trial). None of the comparisons showed a statistically significant effect on the incidence of gastric cancer. The overall summary estimate across all trials of antioxidants showed no statistically significant effect. Approximately 0.51% of participants in the combined antioxidant groups developed gastric cancer versus 0.38% in the placebo groups after treatment of 2.1 to 12 years and follow-up for as many as 14.1 years. In the combined analysis of all 20 trials of antioxidants for the prevention of gastrointestinal cancers, a fixed effects model showed an increase in overall mortality of antioxidants compared with a placebo, but not in a random effects model ⁴⁹.

Symptoms of stomach cancer

Stomach cancer has few or no symptoms in the early stages, making early detection difficult.

These and other signs and symptoms may be caused by gastric cancer or by other conditions.

In the early stages of gastric cancer, the following symptoms may occur:

• Indigestion and stomach discomfort.
• A bloated feeling after eating.
• Mild nausea.
• Loss of appetite.
• Heartburn or Dyspepsia (pain or discomfort in the upper abdomen).

However, these are also symptoms of common conditions affecting the stomach like acid gatroesophageal reflux (GERD) or gastritis. They may also occur with other types of cancer.

In more advanced stages of gastric cancer, the following signs and symptoms may occur:

• Blood in the stool.
• Low red blood cell count (anemia).
• Vomiting.
• Weight loss for no known reason.
• Stomach pain.
• A sense of fullness in the upper abdomen after eating a small meal.
• Jaundice (yellowing of eyes and skin).
• Ascites (build-up of fluid in the abdomen).
• Trouble swallowing.

Check with your doctor if you have any of these problems.

The main reason why stomach cancer is often discovered late is because many, even doctors, may not immediately suspect stomach cancer. Less common symptoms of stomach cancer, which tend to present in the more advanced stages, include black stools (a sign of bleeding in stomach).

Stomach cancer diagnosis

Tests that examine the stomach and esophagus are used to detect (find) and diagnose gastric cancer.

The following tests and procedures may be used:

• Physical exam and history : An exam of the body to check general signs of health, including checking for signs of disease, such as lumps or anything else that seems unusual. A history of the patient’s health habits and past illnesses and treatments will also be taken.

• Blood chemistry studies : A procedure in which a blood sample is checked to measure the amounts of certain substances released into the blood by organs and tissues in the body. An unusual (higher or lower than normal) amount of a substance can be a sign of disease.

• CEA (carcinoembryonic antigen) assay: Tests that measure the level of CEA in the blood. This substance is released into the bloodstream from both cancer cells and normal cells. When found in higher than normal amounts, it can be a sign of gastric cancer or other conditions.

• Complete blood count (CBC): A procedure in which a sample of blood is drawn and checked for the following:
  + The number of red blood cells, white blood cells, and platelets.
  + The amount of hemoglobin (the protein that carries oxygen) in the red blood cells.
  + The portion of the sample made up of red blood cells.

• Upper endoscopy : A procedure to look inside the esophagus, stomach, and duodenum (first part of the small intestine) to check for abnormal areas. An endoscope (a thin, lighted tube) is passed through the mouth and down the throat into the esophagus, stomach, and first part of the small intestine.

• Endoscopic ultrasound (EUS): A procedure in which an endoscope is inserted into the body, usually through the mouth or rectum. An endoscope is a thin, tube-like instrument with a light and a lens for viewing. A probe at the end of the endoscope is used to bounce high-energy sound waves (ultrasound) off internal tissues or organs and make echoes. The echoes form a picture of body tissues called a sonogram. This procedure is also called endosonography.
• Barium swallow : A series of x-rays of the esophagus and stomach. The patient drinks a liquid that contains barium (a silver-white metallic compound). The liquid coats the esophagus and stomach, and x-rays are taken. This procedure is also called an upper GI series.

• CT scan (CAT scan): A procedure that makes a series of detailed pictures of areas inside the body, taken from different angles. The pictures are made by a computer linked to an x-ray machine. A dye may be injected into a vein or swallowed to help the organs or tissues show up more clearly. This procedure is also called computed tomography, computerized tomography, or computerized axial tomography.

• PET scan (positron emission tomography scan): A procedure to find malignant tumor cells in the body. A small amount of radioactive glucose (sugar) is injected into a vein. The PET scanner rotates around the body and makes a picture of where glucose is being used in the body. Malignant tumor cells show up brighter in the picture because they are more active and take up more glucose than normal cells do. A PET scan and CT scan may be done at the same time. This is called a PET-CT.

• Biopsy : The removal of cells or tissues so they can be viewed under a microscope to check for signs of cancer. A biopsy of the stomach is usually done during the endoscopy. The sample of tissue may be checked to measure how many human epidermal growth factor receptor 2 (HER2) genes there are and how much human epidermal growth factor receptor 2 (HER2) protein is being made. If there are more human epidermal growth factor receptor 2 (HER2) genes or higher levels of human epidermal growth factor receptor 2 (HER2) protein than normal, the cancer is called human epidermal growth factor receptor 2 (HER2) positive. human epidermal growth factor receptor 2 (HER2)-positive gastric cancer may be treated with a monoclonal antibody that targets the human epidermal growth factor receptor 2 (HER2) protein.

Figure 5. Upper endoscopy

Stomach cancer survival rate ²

The prognosis of patients with gastric cancer is related to tumor extent and includes both nodal involvement and direct tumor extension beyond the gastric wall ⁵⁰, ⁵¹. Tumor grade may also provide some prognostic information ⁵².

In localized distal gastric cancer, more than 50% of patients can be cured. However, early-stage disease accounts for only 10% to 20% of all cases diagnosed in the United States. The remaining patients present with metastatic disease in either regional or distant sites. The overall survival rate in these patients at 5 years ranges from almost no survival for patients with disseminated disease to almost 50% survival for patients with localized distal gastric cancers confined to resectable regional disease. Even with apparent localized disease, the 5-year survival rate of patients with proximal gastric cancer is only 10% to 15%. Although the treatment of patients with disseminated gastric cancer may result in palliation of symptoms and some prolongation of survival, long remissions are uncommon.

Number of New Cases and Deaths per 100,000: The number of new cases of stomach cancer was 7.3 per 100,000 men and women per year. The number of deaths was 3.2 per 100,000 men and women per year. These rates are age-adjusted and based on 2010-2014 cases and deaths.

Lifetime Risk of Developing Cancer: Approximately 0.8 percent of men and women will be diagnosed with stomach cancer at some point during their lifetime, based on 2012-2014 data.

Prevalence of This Cancer: In 2014, there were an estimated 95,764 people living with stomach cancer in the United States.

Percent Surviving 5 Years after being diagnosed with stomach cancer: 30.6%. Relative survival statistics compare the survival of patients diagnosed with cancer with the survival of people in the general population who are the same age, race, and sex and who have not been diagnosed with cancer. Because survival statistics are based on large groups of people, they cannot be used to predict exactly what will happen to an individual patient. No two patients are entirely alike, and treatment and responses to treatment can vary greatly.

Stomach Cancer Stages

The stage of a cancer is a description of how far the cancer has spread. Cancer stage at diagnosis, which refers to extent of a cancer in the body, determines treatment options and has a strong influence on the length of survival. In general, if the cancer is found only in the part of the body where it started it is localized (sometimes referred to as stage 1). If it has spread to a different part of the body, the stage is regional or distant. The earlier stomach cancer is caught, the better chance a person has of surviving five years after being diagnosed. For stomach cancer, 27.1% are diagnosed at the local stage. The 5-year survival for localized stomach cancer is 67.2%.

There are actually 2 types of stages for stomach cancer:

1. The clinical stage of the cancer is the doctor’s best estimate of the extent of the cancer, based on the results of physical exams, endoscopy, biopsies, and any imaging tests (such as CT scans) that have been done.
2. If surgery is done, the pathologic stage can be determined using the same test results used for the clinical stage, plus what is found from tissues removed during surgery.

The clinical stage is used to help plan treatment. Sometimes, though, the cancer has spread further than the clinical stage estimates. Because the pathologic stage is based on what was found at surgery, it can more accurately predict the patient’s outlook. The staging described here is the pathologic stage.

There are three ways that cancer spreads in the body

Cancer can spread through tissue, the lymph system, and the blood:

1. Tissue. The cancer spreads from where it began by growing into nearby areas.
2. Lymph system. The cancer spreads from where it began by getting into the lymph system. The cancer travels through the lymph vessels to other parts of the body.
3. Blood. The cancer spreads from where it began by getting into the blood. The cancer travels through the blood vessels to other parts of the body.

Cancer may spread from where it began to other parts of the body.

When cancer spreads to another part of the body, it is called metastasis. Cancer cells break away from where they began (the primary tumor) and travel through the lymph system or blood.

• Lymph system. The cancer gets into the lymph system, travels through the lymph vessels, and forms a tumor (metastatic tumor) in another part of the body.
• Blood. The cancer gets into the blood, travels through the blood vessels, and forms a tumor (metastatic tumor) in another part of the body.

The metastatic tumor is the same type of cancer as the primary tumor.

For example, if gastric cancer spreads to the liver, the cancer cells in the liver are actually gastric cancer cells. The disease is metastatic gastric cancer, not liver cancer.

A staging system is a way for members of the cancer care team to describe the extent of a cancer’s spread. The system most often used to stage stomach cancer in the United States is the American Joint Commission on Cancer (AJCC) TNM classification system ⁵³. The TNM classification system for staging contains 3 key pieces of information:

• T describes the size of the original (primary) tumour and whether it has invaded nearby tissue (how far it has grown into the wall of the stomach and into nearby organs).
• N describes the spread to nearby (regional) lymph nodes.
• M indicates whether the cancer has metastasized (spread) to distant parts of the body. The most common sites of distant spread of stomach cancer are the liver, the peritoneum (the lining of the space around the digestive organs), and distant lymph nodes. Less common sites of spread include the lungs and brain.

Numbers or letters appear after T, N, and M to provide more details about each of these factors:

• The numbers 0 through 4 indicate increasing severity.
• The letter X means “cannot be assessed” because the information is not available.
• The letters “is” refer to carcinoma in situ, which means the tumor is only in the top layer of mucosa cells and has not yet invaded deeper layers of tissue.

This system is for staging all stomach cancers except those starting in either the gastroesophageal junction (where the stomach and the esophagus meet) or in the cardia (the first part of the stomach) and growing into the gastroesophageal junction. Those cancers are staged (and often treated) like cancers of the esophagus.

The AJCC staging system provides a detailed summary of how far a stomach cancer has spread. But for treatment purposes, doctors are often more concerned about whether the tumor can be removed (resected) with surgery.

• Resectable cancers are those the doctor believes can be completely removed during surgery.
• Unresectable cancers can’t be removed completely. This might be because the tumor has grown too far into nearby organs or lymph nodes, it has grown too close to major blood vessels, it has spread to distant parts of the body, or the person is not healthy enough for surgery.

There is no distinct dividing line between resectable and unresectable in terms of the TNM stage of the cancer, but earlier stage cancers are more likely to be resectable.

T categories of stomach cancer

Nearly all stomach cancers start in the innermost layer of the stomach wall (the mucosa). The T category describes how far through the stomach’s 5 layers the cancer has invaded.

Layers of the stomach

• The innermost layer is the mucosa. The mucosa has 3 parts: epithelial cells, which lie on top of a layer of connective tissue (the lamina propria), which is on top of a thin layer of muscle (the muscularis mucosa).
• Under the mucosa is a supporting layer called the submucosa.
• Below this is the muscularis propria, a thick layer of muscle that moves and mixes the stomach contents.
• The next 2 layers, the subserosa and the outermost serosa, act as wrapping layers for the stomach.

 

Table 1. Primary Tumor (T)

TX	Primary tumor cannot be assessed.
T0	No evidence of primary tumor.
Tis	Carcinoma in situ: intraepithelial tumor without invasion of the lamina propria.
T1	Tumor invades lamina propria, muscularis mucosae, or submucosa.
T1a	Tumor invades lamina propria or muscularis mucosae.
T1b	Tumor invades submucosa.
T2	Tumor invades muscularis propria. (a)
T3	Tumor penetrates subserosal connective tissue without invasion of visceral peritoneum or adjacent structures. (b,c)
T4	Tumor invades serosa (visceral peritoneum) or adjacent structures. (b,c)
T4a	Tumor invades serosa (visceral peritoneum).
T4b	Tumor invades adjacent structures.

a ) A tumor may penetrate the muscularis propria with extension into the gastrocolic or gastrohepatic ligaments, or into the greater or lesser omentum, without perforation of the visceral peritoneum covering these structures. In this case, the tumor is classified T3. If there is perforation of the visceral peritoneum covering the gastric ligaments or the omentum, the tumor should be classified T4.

b ) The adjacent structures of the stomach include the spleen, transverse colon, liver, diaphragm, pancreas, abdominal wall, adrenal gland, kidney, small intestine, and retroperitoneum.

c ) Intramural extension to the duodenum or esophagus is classified by the depth of the greatest invasion in any of these sites, including the stomach.

[Source ⁵³]

Table 2. Regional Lymph Nodes (N)

NX	Regional lymph node(s) cannot be assessed.
N0	No regional lymph node metastasis.b
N1	Metastases in 1–2 regional lymph nodes.
N2	Metastases in 3–6 regional lymph nodes.
N3	Metastases in ≥7 regional lymph nodes.
N3a	Metastases in 7–15 regional lymph nodes.
N3b	Metastases in ≥16 regional lymph nodes.

[Source ⁵³]

Table 3. Distant Metastasis

M0	No distant metastasis.
M1	Distant metastasis.

[Source ⁵³]

The following stages are used for stomach cancer:

Once the T, N, and M categories have been determined, this information is combined and expressed as a stage, using the number 0 (zero) and the Roman numerals I through IV (see below Table 4. Anatomic Stage/Prognostic Groups). This is known as stage grouping. Some stages are split into substages, indicated by letters.

Stage 0 (Carcinoma in Situ): Tis, N0, M0

In stage 0, abnormal cells are found in the inside lining of the mucosa (innermost layer) of the stomach wall. These abnormal cells may become cancer and spread into nearby normal tissue. Stage 0 is also called carcinoma in situ.

Stage I Stomach cancer

In stage I, cancer has formed in the inside lining of the mucosa (innermost layer) of the stomach wall. Stage I is divided into stage IA and stage IB, depending on where the cancer has spread.

• Stage IA: Cancer may have spread into the submucosa (layer of tissue next to the mucosa) of the stomach wall.
• Stage IB: Cancer: may have spread into the submucosa (layer of tissue next to the mucosa) of the stomach wall and is found in 1 or 2 lymph nodes near the tumor; or has spread to the muscle layer of the stomach wall.

Stage II Stomach cancer

Stage II gastric cancer is divided into stage IIA and stage IIB, depending on where the cancer has spread.

Stage IIA: Cancer:

• has spread to the subserosa (layer of tissue next to the serosa) of the stomach wall; or
• has spread to the muscle layer of the stomach wall and is found in 1 or 2 lymph nodes near the tumor; or
• may have spread to the submucosa (layer of tissue next to the mucosa) of the stomach wall and is found in 3 to 6 lymph nodes near the tumor.

Stage IIB: Cancer:

• has spread to the serosa (outermost layer) of the stomach wall; or
• has spread to the subserosa (layer of tissue next to the serosa) of the stomach wall and is found in 1 or 2 lymph nodes near the tumor; or
• has spread to the muscle layer of the stomach wall and is found in 3 to 6 lymph nodes near the tumor; or
• may have spread to the submucosa (layer of tissue next to the mucosa) of the stomach wall and is found in 7 or more lymph nodes near the tumor.

Stage III Stomach cancer

Stage III gastric cancer is divided into stage IIIA, stage IIIB, and stage IIIC, depending on where the cancer has spread.

Stage IIIA: Cancer has spread to:

• the serosa (outermost) layer of the stomach wall and is found in 1 or 2 lymph nodes near the tumor; or
• the subserosa (layer of tissue next to the serosa) of the stomach wall and is found in 3 to 6 lymph nodes near the tumor; or
• the muscle layer of the stomach wall and is found in 7 or more lymph nodes near the tumor.

Stage IIIB: Cancer has spread to:

• nearby organs such as the spleen, transverse colon, liver, diaphragm, pancreas, kidney, adrenal gland, or small intestine, and may be found in 1 or 2 lymph nodes near the tumor; or
• the serosa (outermost layer) of the stomach wall and is found in 3 to 6 lymph nodes near the tumor; or
• the subserosa (layer of tissue next to the serosa) of the stomach wall and is found in 7 or more lymph nodes near the tumor.

Stage IIIC: Cancer has spread to:

• nearby organs such as the spleen, transverse colon, liver, diaphragm, pancreas, kidney, adrenal gland, or small intestine, and may be found in 3 or more lymph nodes near the tumor; or
• the serosa (outermost layer) of the stomach wall and is found in 7 or more lymph nodes near the tumor.

Stage IV Stomach cancer

In stage IV, cancer has spread to distant parts of the body.

Recurrent Gastric Cancer

Recurrent gastric cancer is cancer that has recurred (come back) after it has been treated. The cancer may come back in the stomach or in other parts of the body such as the liver or lymph nodes.

Table 4. Anatomic Stage/Prognostic Groups

Stage	T	N	M
[Source 53]
0	Tis	N0	M0
IA	T1	N0	M0
IB	T2	N0	M0
	T1	N1	M0
IIA	T3	N0	M0
	T2	N1	M0
	T1	N2	M0
IIB	T4a	N0	M0
	T3	N1	M0
	T2	N2	M0
	T1	N3	M0
IIIA	T4a	N1	M0
	T3	N2	M0
	T2	N3	M0
IIIB	T4b	N0	M0
	T4b	N1	M0
	T4a	N2	M0
	T3	N3	M0
IIIC	T4b	N2	M0
	T4b	N3	M0
	T4a	N3	M0
IV	Any T	Any N	M1

Figure 6. Stomach cancer stages

Stomach Cancer Survival Rates by Stage

Survival rates are often used by doctors as a standard way of discussing a person’s prognosis (outlook).

The 5-year survival rate refers to the percentage of patients who live at least 5 years after their cancer is diagnosed. Of course, many of these people live much longer than 5 years (and many are cured).

To get 5-year survival rates, doctors have to look at people who were treated at least 5 years ago. Improvements in treatment since then may result in a better outlook for people now being diagnosed with stomach cancer.

Survival rates are often based on previous outcomes of large numbers of people who had the disease, but they cannot predict what will happen in any particular person’s case. Many other factors may affect a person’s outlook, such as their general health, the location of the cancer in the stomach, the treatment received, and how well the cancer responds to treatment. Your doctor can tell you how these survival rates may apply to you.

The survival rates that follow come from the National Cancer Institute’s Surveillance, Epidemiology and End Results Program (SEER) database. They are based on people diagnosed with stomach cancer and treated with surgery between 1991 and 2000. Survival rates for patients not treated with surgery are likely to be lower. It is also important to note that these are observed survival rates. People with cancer can die of other things and these rates do not take that into account.

The rates below are based on the stage of the cancer at the time of diagnosis. When looking at survival rates, it’s important to understand that the stage of a cancer does not change over time, even if the cancer progresses. A cancer that comes back or spreads is still referred to by the stage it was given when it was first found and diagnosed, but more information is added to explain the current extent of the cancer.

The overall 5-year relative survival rate of all people with stomach cancer in the United States is about 29%. The 5-year relative survival rate compares the observed survival of people with stomach cancer to that expected for people without stomach cancer. Since some people may die from other causes, this is a better way to see the impact of cancer on survival.

This survival rate has improved gradually over the last 30 years. One reason the overall survival rate is poor in the United States is that most stomach cancers are diagnosed at an advanced rather than an early stage. The stage of the cancer has a major effect on a patient’s prognosis (outlook for survival).

Figure 7. New Stomach Cancer Cases, Deaths and 5-Year Relative Survival

[Source ²]

Figure 8. 5 Year Relative Survival Rate by Stomach Cancer Stage at Diagnosis

[Source ²]

Table 5. The 5-year survival rates by stage for stomach cancer treated with surgery

Stage	5 year observed survival
Stage IA	71%
Stage IB	57%
Stage IIA	46%
Stage IIB	33%
Stage IIIA	20%
Stage IIIB	14%
Stage IIIC	9%
Stage IV	4%

[Source ²]

Stomach cancer treatment

Five types of standard treatment are used:

Surgery

Surgery is a common treatment of all stages of gastric cancer. The following types of surgery may be used:

• Subtotal gastrectomy: Removal of the part of the stomach that contains cancer, nearby lymph nodes, and parts of other tissues and organs near the tumor.
• The spleen may be removed. The spleen is an organ in the upper abdomen that filters the blood and removes old blood cells.
• Total gastrectomy: Removal of the entire stomach, nearby lymph nodes, and parts of the esophagus, small intestine, and other tissues near the tumor. The spleen may be removed. The esophagus is connected to the small intestine so the patient can continue to eat and swallow.

If the tumor is blocking the stomach but the cancer cannot be completely removed by standard surgery, the following procedures may be used:

• Endoluminal stent placement: A procedure to insert a stent (a thin, expandable tube) in order to keep a passage (such as arteries or the esophagus) open. For tumors blocking the passage into or out of the stomach, surgery may be done to place a stent from the esophagus to the stomach or from the stomach to the small intestine to allow the patient to eat normally.
• Endoluminal laser therapy: A procedure in which an endoscope (a thin, lighted tube) with a laser attached is inserted into the body. A laser is an intense beam of light that can be used as a knife.
• Gastrojejunostomy: Surgery to remove the part of the stomach with cancer that is blocking the opening into the small intestine. The stomach is connected to the jejunum (a part of the small intestine) to allow food and medicine to pass from the stomach into the small intestine.

Chemotherapy

Chemotherapy is a cancer treatment that uses drugs to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. When chemotherapy is taken by mouth or injected into a vein or muscle, the drugs enter the bloodstream and can reach cancer cells throughout the body (systemic chemotherapy). When chemotherapy is placed directly into the cerebrospinal fluid, an organ, or a body cavity such as the abdomen, the drugs mainly affect cancer cells in those areas (regional chemotherapy). The way the chemotherapy is given depends on the type and stage of the cancer being treated.

Radiation therapy

Radiation therapy is a cancer treatment that uses high-energy x-rays or other types of radiation to kill cancer cells or keep them from growing. There are two types of radiation therapy:

• External radiation therapy uses a machine outside the body to send radiation toward the cancer.
• Internal radiation therapy uses a radioactive substance sealed in needles, seeds, wires, or catheters that are placed directly into or near the cancer.

The way the radiation therapy is given depends on the type and stage of the cancer being treated. External radiation therapy is used to treat gastric cancer.

Chemoradiation

Chemoradiation therapy combines chemotherapy and radiation therapy to increase the effects of both. Chemoradiation given after surgery, to lower the risk that the cancer will come back, is called adjuvant therapy. Chemoradiation given before surgery, to shrink the tumor (neoadjuvant therapy), is being studied.

Targeted therapy

Targeted therapy is a type of treatment that uses drugs or other substances to identify and attack specific cancer cells without harming normal cells. Monoclonal antibody therapy is a type of targeted therapy used in the treatment of gastric cancer.

Monoclonal antibody therapy uses antibodies made in the laboratory from a single type of immune system cell. These antibodies can identify substances on cancer cells or normal substances that may help cancer cells grow. The antibodies attach to the substances and kill the cancer cells, block their growth, or keep them from spreading. Monoclonal antibodies are given by infusion. They may be used alone or to carry drugs, toxins, or radioactive material directly to cancer cells. For stage IV gastric cancer and gastric cancer that has recurred, monoclonal antibodies, such as trastuzumab or ramucirumab, may be given. Trastuzumab blocks the effect of the growth factor protein HER2, which sends growth signals to gastric cancer cells. Ramucirumab blocks the effect of the protein VEGF and may prevent the growth of new blood vessels that tumors need to grow.

The prognosis (chance of recovery) and treatment options depend on the following:

• The stage of the cancer (whether it is in the stomach only or has spread to lymph nodes or other places in the body).
• The patient’s general health.

When gastric cancer is found very early, there is a better chance of recovery. Gastric cancer is often in an advanced stage when it is diagnosed. At later stages, gastric cancer can be treated but rarely can be cured. Taking part in one of the clinical trials being done to improve treatment should be considered.

Radical surgery represents the standard form of therapy that has curative intent. However, the incidences of local failure in the tumor bed and regional lymph nodes, and distant failures via hematogenous or peritoneal routes, remain high ⁵⁴. As such, adjuvant external-beam radiation therapy with combined chemotherapy has been evaluated in the United States.

In a phase III Intergroup trial, 556 patients with completely resected stage IB to stage IV (M0) adenocarcinoma of the stomach and gastroesophageal junction were randomly assigned to receive surgery alone or surgery plus postoperative chemotherapy (5-fluorouracil [5-FU] and leucovorin) and concurrent radiation therapy (45 Gy) ⁵⁵. With 5 years’ median follow-up, a significant survival benefit was reported for patients who received adjuvant combined modality therapy. Median survival was 36 months for the adjuvant chemoradiation therapy group and 27 months for the surgery-alone arm ⁵⁵. Three-year overall survival rates were 50%, and relapse-free survival rates were 48% with adjuvant chemoradiation therapy versus 3-year overall survival rates of 41% and relapse-free survival rates of 31% for surgery alone ⁵⁵. The rate of distant metastases was 18% for the surgery-alone arm and 33% for the chemoradiation-therapy arm ⁵⁵.

Investigators in Europe evaluated the role of preoperative and postoperative chemotherapy without radiation therapy ⁵⁶. In the randomized phase III trial ⁵⁶, patients with stage II or higher adenocarcinoma of the stomach or of the lower third of the esophagus were assigned to receive three cycles of epirubicin, cisplatin, and continuous infusion 5-FU before and after surgery or to receive surgery alone. Compared with the surgery group, the perioperative chemotherapy group had a significantly higher likelihood of progression-free survival (hazard ratio for progression, 0.66) and of overall survival (hazard ratio for death, 0.75). Five-year OS was 36.3%, 29 to 43 for the perioperative chemotherapy group and 23%, 16.6 to 29.4 for the surgery group ⁵⁶.

Stage 0 Gastric Cancer

Standard treatment options:

• Surgery.

Stage 0 is gastric cancer confined to mucosa. Experience in Japan, where stage 0 is diagnosed frequently, indicates that more than 90% of patients treated by gastrectomy with lymphadenectomy will survive beyond 5 years. An American series has confirmed these results ⁵⁷.

Stage I Gastric Cancer

Standard treatment options:

One of the following surgical procedures:

• Distal subtotal gastrectomy (if the lesion is not in the fundus or at the cardioesophageal junction).
• Proximal subtotal gastrectomy or total gastrectomy, both with distal esophagectomy (if the lesion involves the cardia). These tumors often involve the submucosal lymphatics of the esophagus.
• Total gastrectomy (if the tumor involves the stomach diffusely or arises in the body of the stomach and extends to within 6 cm of the cardia or distal antrum).

Regional lymphadenectomy is recommended with all of the above procedures. Splenectomy is not routinely performed ⁵⁸.

Postoperative chemoradiation therapy for patients with node-positive (T1 N1) and muscle-invasive (T2 N0) disease ⁵⁵.

Surgical resection including regional lymphadenectomy is the treatment of choice for patients with stage I gastric cancer ⁵⁸. If the lesion is not in the cardioesophageal junction and does not diffusely involve the stomach, subtotal gastrectomy is the procedure of choice, since it has been demonstrated to provide equivalent survival when compared with total gastrectomy and is associated with decreased morbidity ⁵⁹. When the lesion involves the cardia, proximal subtotal gastrectomy or total gastrectomy (including a sufficient length of esophagus) may be performed with curative intent. If the lesion diffusely involves the stomach, total gastrectomy is required. At a minimum, surgical resection should include greater and lesser curvature perigastric regional lymph nodes. Note that in patients with stage I gastric cancer, perigastric lymph nodes may contain cancer.

In patients with node-positive (T1 N1) and muscle-invasive (T2 N0) disease, postoperative chemoradiation therapy may be considered. A prospective multi-institution phase III trial evaluated postoperative combined chemoradiation therapy versus surgery alone in 556 patients with completely resected stage IB to stage IV (M0) adenocarcinoma of the stomach and gastroesophageal junction and reported a significant survival benefit with adjuvant combined modality therapy ⁵⁵. With a median follow-up of 5 years, median survival was 36 months for the adjuvant chemoradiation therapy group and 27 months for the surgery-alone arm. Three-year overall survival rates were 50%, and relapse-free survival rates were 48% with adjuvant chemoradiation therapy versus 3-year overall survival rates of 41% and relapse-free survival rates of 31% for surgery alone. However, only 36 patients in the trial had stage IB tumors (18 patients in each arm) ⁶⁰. Since the prognosis is relatively favorable for patients with completely resected stage IB disease, the effectiveness of adjuvant chemoradiation therapy for this group is less clear.

Stage II Gastric Cancer

Standard treatment options:

1)One of the following surgical procedures:

• Distal subtotal gastrectomy (if the lesion is not in the fundus or at the cardioesophageal junction).
• Proximal subtotal gastrectomy or total gastrectomy (if the lesion involves the cardia).
• Total gastrectomy (if the tumor involves the stomach diffusely or arises in the body of the stomach and extends to within 6 cm of the cardia).

Regional lymphadenectomy is recommended with all of the above procedures. Splenectomy is not routinely performed ⁵⁸.

2) Postoperative chemoradiation therapy ⁵⁵.
3) Perioperative chemotherapy ⁵⁶.
4) Postoperative chemotherapy.

Surgical resection with regional lymphadenectomy is the treatment of choice for patients with stage II gastric cancer ⁵⁸. If the lesion is not in the cardioesophageal junction and does not diffusely involve the stomach, subtotal gastrectomy is the procedure of choice. When the lesion involves the cardia, proximal subtotal gastrectomy or total gastrectomy may be performed with curative intent. If the lesion diffusely involves the stomach, total gastrectomy and appropriate lymph node resection may be required. The role of extended lymph node (D2) dissection is uncertain ⁶¹ and in some series is associated with increased morbidity ⁶².

Postoperative chemoradiation therapy may be considered for patients with stage II gastric cancer. A prospective multi-institution phase III trial evaluated postoperative combined chemoradiation therapy versus surgery alone in 556 patients with completely resected stage IB to stage IV (M0) adenocarcinoma of the stomach and gastroesophageal junction and reported a significant survival benefit with adjuvant combined modality therapy ⁵⁵. With a median follow-up of 5 years, median survival was 36 months for the adjuvant chemoradiation therapy group and 27 months for the surgery-alone arm. Three-year overall survival rates were 50%, and relapse-free survival rates were 48% with adjuvant chemoradiation therapy versus 3-year overall survival rates of 41% and relapse-free survival rates of 31% for surgery alone.The rate of distant metastases was 32% for the surgery-alone arm and 40% for the chemoradiation therapy arm.

Investigators in Europe evaluated the role of preoperative and postoperative chemotherapy without radiation therapy ⁵⁶. In the randomized phase III trial, patients with stage II or higher adenocarcinoma of the stomach or of the lower third of the esophagus were assigned to receive three cycles of epirubicin, cisplatin, and continuous infusion fluorouracil (ECF) before and after surgery or to receive surgery alone. Compared with the surgery group, the perioperative chemotherapy group had a significantly higher likelihood of progression-free survival (hazard ratio for progression, 0.66) and of overall survival (hazard ratio for death, 0.75). Five-year overall survival was 36.3%, 29 to 43 for the perioperative chemotherapy group and 23%, 16.6 to 29.4 for the surgery group ⁵⁶.

Japanese investigators randomly assigned 1,059 patients with stage II or III gastric cancer who had undergone a D2 gastrectomy to receive either 1 year of S-1, an oral fluoropyrimidine not available in the United States, or follow-up after surgery alone ⁶³. Patients were randomly assigned in a 1:1 fashion. The 3-year overall survival rate was 80.1% in the S-1 group and 70.1% in the surgery-only group. The hazard ratio for death in the S-1 group, as compared with the surgery-only group, was 0.68 ⁶³.

Subsequently, investigators in Asia evaluated the role of capecitabine/oxaliplatin as adjuvant therapy after gastric cancer resection. In the CLASSIC trial, 37 centers in South Korea, China, and Taiwan randomly assigned 1,035 patients with stage IIA, IIB, IIIA, or IIIB gastric cancer who had undergone a curative D2 gastrectomy to receive adjuvant chemotherapy (eight 3-week cycles of capecitabine plus oxaliplatin) or follow-up post-surgery alone ⁶⁴. The 3-year disease-free survival rate was 74% in the chemotherapy group and 59% in the surgery-alone group (hazard ratio, 0.56). The 3-year overall survival was 83% in the chemotherapy group and 78% in the surgery-alone group (hazard ratio, 0.72) ⁶⁴.

Stage III Gastric Cancer

Standard treatment options:

1. Radical surgery. Curative resection procedures are confined to patients who do not have extensive nodal involvement at the time of surgical exploration.
2. Postoperative chemoradiation therapy ⁵⁵.
3. Perioperative chemotherapy ⁵⁶.
4. Postoperative chemotherapy.

All patients with tumors that can be resected should undergo surgery. As many as 15% of selected stage III patients can be cured by surgery alone, particularly if lymph node involvement is minimal (<7 lymph nodes).

Postoperative chemoradiation therapy may be considered for patients with stage III gastric cancer. A prospective multi-institution phase III trial evaluating postoperative combined chemoradiation therapy versus surgery alone in 556 patients with completely resected stage IB to stage IV (M0) adenocarcinoma of the stomach and gastroesophageal junction reported a significant survival benefit with adjuvant combined modality therapy ⁵⁵. With a median follow-up of 5 years, median survival was 36 months for the adjuvant chemoradiation therapy group and 27 months for the surgery-alone arm. Three-year overall survival rates were 50%, and relapse-free survival rates were 48% with adjuvant chemoradiation therapy versus 3-year overall survival rates of 41% and relapse-free survival rates of 31% for surgery alone.

Investigators in Europe evaluated the role of preoperative and postoperative chemotherapy without radiation therapy ⁵⁶. In the randomized phase III trial, patients with stage II or higher adenocarcinoma of the stomach or of the lower third of the esophagus were assigned to receive three cycles of epirubicin, cisplatin, and continuous infusion 5-fluorouracil (ECF) before and after surgery or to receive surgery alone. Compared with the surgery group, the perioperative chemotherapy group had a significantly higher likelihood of progression-free survival (hazard ratio for progression, 0.66) and of overall survival (hazard ratio for death, 0.75). Five-year overall survival was 36.3%, 29 to 43 for the perioperative chemotherapy group and 23%, 16.6 to 29.4 for the surgery group ⁵⁶.

Japanese investigators randomly assigned 1,059 patients with stage II or III gastric cancer who had undergone a D2 gastrectomy to receive either 1 year of S-1, an oral fluoropyrimidine not available in the United States, or follow-up after surgery alone ⁶³. Patients were randomized in a 1:1 fashion. The 3-year overall survival rate was 80.1% in the S-1 group and 70.1% in the surgery-only group. The hazard ratio for death in the S-1 group, as compared with the surgery-only group, was 0.68 ⁶³.

Subsequently, investigators in Asia evaluated the role of capecitabine/oxaliplatin as adjuvant therapy after gastric cancer resection. In the CLASSIC trial , 37 centers in South Korea, China, and Taiwan randomly assigned 1,035 patients with stage IIA, IIB, IIIA, or IIIB gastric cancer who had undergone a curative D2 gastrectomy to receive adjuvant chemotherapy (eight 3-week cycles of capecitabine plus oxaliplatin) or follow-up post-surgery alone ⁶⁴. The 3-year disease-free survival rate was 74% in the chemotherapy group and 59% in the surgery-alone group. The 3-year overall survival was 83% in the chemotherapy group and 78% in the surgery-alone group ⁶⁴.

Stage IV and Recurrent Gastric Cancer

Standard treatment options:

1.)Palliative chemotherapy with:

• Fluorouracil (5-FU) ⁶⁵.
• Epirubicin, Cisplatin, and 5-FU (ECF) ⁶⁶.
• Epirubicin, Oxaliplatin, and Capecitabine (EOX) ⁶⁷.
• Cisplatin and 5-FU (CF) ⁶⁸.
• Docetaxel, Cisplatin, and 5-FU (DCF) ⁶⁹.
• Etoposide, Leucovorin, and 5-FU (ELF) ⁷⁰.
• 5-FU, Doxorubicin, and Methotrexate (FAMTX) ⁶⁸.

2.) Trastuzumab, cisplatin, and either 5-FU or capecitabine in patients with HER2-positive tumors (3+ on immunohistochemistry [IHC] or fluorescence in situ hybridization [FISH]-positive).

3.) Endoluminal laser therapy, endoluminal stent placement, or gastrojejunostomy, may be helpful to patients with gastric obstruction ⁷¹.

4.) Palliative radiation therapy may alleviate bleeding, pain, and obstruction.

5.) Palliative resection should be reserved for patients with continued bleeding or obstruction.

Standard chemotherapy versus best supportive care for patients with metastatic gastric cancer has been tested in several clinical trials, and there is general agreement that patients who receive chemotherapy live for several months longer on average than patients who receive supportive care ⁷², ⁷³, ⁷⁴. During the last 20 years, multiple randomized studies evaluating different treatment regimens (monotherapy vs. combination chemotherapy) have been performed in patients with metastatic gastric cancer with no clear consensus emerging as to the best management approach. A meta-analysis of these studies demonstrated an hazard ratio of 0.83 for overall survival in favor of combination chemotherapy ⁷⁵.

Of all the combination regimens, Epirubicin, Cisplatin, and 5-FU (ECF) is often considered the reference standard in the United States and Europe. In one European trial, 274 patients with metastatic esophagogastric cancer were randomly assigned to receive either ECF or 5-FU, doxorubicin, and methotrexate (FAMTX) ⁷⁶. The group who received ECF had a significantly longer median survival (8.9 vs. 5.7 months) than the FAMTX group ⁷⁶. In a second trial that compared ECF with mitomycin, cisplatin, and 5-FU (MCF), there was no statistically significant difference in median survival (9.4 vs. 8.7 months) ⁶⁶.

Oxaliplatin and capecitabine are often substituted for cisplatin and 5-FU within the ECF regimen as a result of data from the REAL-2 trial ⁶⁷. This randomized trial of 1,002 patients with advanced esophageal, gastroesophageal junction, or gastric cancer utilized a 2 × 2 design to demonstrate noninferior median overall survival in patients treated with capecitabine rather than 5-FU (hazard ratio death = 0.86) and in patients treated with oxaliplatin in place of cisplatin (hazard ratio death = 0.92).

An international collaboration of investigators randomly assigned 445 patients with metastatic gastric cancer to receive docetaxel, cisplatin, and 5-FU (DCF) or Cisplatin, and 5-FU ⁷⁷. Time-to-treatment progression was the primary endpoint. Patients who received DCF experienced a significantly longer time-to-treatment progression (5.6 months vs. 3.7 months). The median overall survival was significantly longer for patients who received DCF versus patients who received CF (9.2 months vs. 8.6 months) ⁷⁷. There were high toxicity rates in both arms. Febrile neutropenia was more common in patients who received DCF (29% vs. 12%), and the death rate on the study was 10.4% for patients on the DCF arm and 9.4% for patients on the CF arm ⁷⁸.

Whether the CF regimen should be considered as an index regimen for the treatment of patients with metastatic gastric cancer is the subject of debate ⁷⁸. The results of a study that randomly assigned 245 patients with metastatic gastric cancer to receive CF, FAMTX, or ELF demonstrated no significant difference in response rate, progression-free survival, or overall survival between the arms ⁶⁸. Grades 3 and 4 neutropenia occurred in 35% to 43% of patients on all arms, but severe nausea and vomiting was more common in patients in the CF arm and occurred in 26% of those patients ⁶⁸.

Trastuzumab

In an open-label, international phase III trial, patients with HER2-positive metastatic, inoperable locally advanced, or recurrent gastric or GE junction cancer were randomly assigned to chemotherapy with or without the anti-HER2 monoclonal antibody trastuzumab.[18] HER2 positivity was defined as either 3+ staining by IHC or a HER2 to CEP17 ratio of two or more using FISH. Tumors from 3,665 patients were HER2 tested; of the patients, 810 were positive (22%) and 594 met eligibility criteria for randomization. Chemotherapy consisted of cisplatin plus 5-FU or capecitabine chosen at the investigator’s discretion. The study treatment was administered every 3 weeks for six cycles, and trastuzumab was continued every 3 weeks until disease progression, unacceptable toxicity, or withdrawal of consent. Crossover to trastuzumab at disease progression was not permitted. Median overall survival was 13.8 months in patients assigned to trastuzumab and 11.1 months in patients assigned to chemotherapy alone ⁷⁹. There was no significant difference in rates of any adverse event, and cardiotoxic effects were equally rare in both arms.

Second-line Chemotherapy

When patients develop progression of disease after first-line chemotherapy, there is no standard treatment option. Investigators in Korea randomly assigned patients with advanced gastric cancer who had received one or two prior chemotherapy regimens involving both a fluoropyrimidine and a platinum agent to either salvage chemotherapy or best supportive care in a 2:1 fashion ⁸⁰. Salvage chemotherapy consisted of either docetaxel (60 mg/m2 every 3 weeks) or irinotecan (150 mg/m2 every 2 weeks) and was left to the discretion of the treating physicians. Of the 202 patients enrolled, 133 received salvage chemotherapy and 69 received best supportive care. Median overall survival was 5.3 months in the group that received salvage chemotherapy and 3.8 months in the group that received best supportive care. There was no difference in median OS between docetaxel and irinotecan (5.2 months vs. 6.5 months ⁸⁰.

Ramucirumab

Ramucirumab is a fully humanized monoclonal antibody directed against the vascular endothelial growth factor receptor-2. In the international, phase III, placebo-controlled, REGARD trial, 355 patients with stage IV gastric or gastroesophageal junction cancer who had progressed on a first-line fluorouracil- or platinum-containing regimen were randomly assigned in a 2:1 fashion to ramucirumab or placebo ⁸¹. Patients who were assigned to ramucirumab had a significantly improved median overall survival of 5.2 months compared with patients assigned to the placebo who had a median overall survival of 3.8 months. Rates of hypertension were higher in the ramucirumab group than in the placebo group. Ramucirumab is an acceptable treatment in cisplatin or 5-fluorouracil refractory, stage IV, gastric cancer ⁸¹.

In the international, double-blinded, phase III RAINBOW trial, 665 patients were randomly assigned to receive paclitaxel (80 mg/m2) on days 1, 8, and 15 every 28 days with ramucirumab (8 mg/kg) added on days 1 and 15 or a placebo added on days 1 and 15 ⁸². Patients assigned to ramucirumab had a significant improvement in median overall survival of 9.6 months compared with patients assigned to a placebo who had a median overall survival of 7.4 months. Grade 3 or higher neutropenia, fatigue, hypertension, and abdominal pain were more common in the ramucirumab group. The combination of paclitaxel and ramucirumab is an acceptable second-line-chemotherapy regimen in patients with stage IV gastric or gastroesophageal junction cancer ⁸².

Treatment options under clinical evaluation:

Palliative chemotherapy with:

• Irinotecan and cisplatin.
• Folic acid, 5-FU, and irinotecan (FOLFIRI).
• Leucovorin, 5-FU, and oxaliplatin (FOLFOX).

Phase II studies evaluating irinotecan-based or oxaliplatin-based regimens demonstrate similar response rates and time-to-treatment progression to those found with ECF or CF, but the former may be less toxic ⁸³, ⁸⁴, ⁸⁵, ⁸⁶, ⁸⁷, ⁸⁸. There are conflicting data regarding relative efficacy of any one regimen for another. Ongoing studies are evaluating these newer regimens.

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