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Gastric Cancer: The Basics

Ryan P. Smith, MD and Eric Shinohara, MD, MSCI
Updated by: Lara Bonner Millar, MD
The Abramson Cancer Center of the University of Pennsylvania
Last Modified: January 27, 2011

What is the stomach?

Gastric cancer is cancer of the stomach. The stomach is the organ that holds and stores food. It is located just underneath (deep to) the lower portion of the rib cage on the left side. It is connected to the mouth and throat by the esophagus. The stomach contains acid and is quite muscular. Due to the motion of the stomach and the acid, quite a bit of digestion takes place in the stomach. The partially digested food is then emptied into the small intestine so that absorption of the nutrients from food can take place. Although the stomach obviously cannot be directly visualized, it can be seen via an endoscopy procedure using a fiber-optic camera (see below).

What is gastric cancer?

The definition of a tumor is a mass of quickly and abnormally growing cells. Tumors can be either benign or malignant. Benign tumors have uncontrolled cell growth, but without any invasion into normal tissues and without any spread. A malignant tumor is called cancer when these tumor cells gain the propensity to invade tissues and spread locally as well as to distant parts of the body. In this sense, gastric cancer occurs when cells in the lining of the stomach grow uncontrollably and form tumors that can invade normal tissues and spread to other parts of the body.

Cancers are described by the types of cells from which they arise. Over 90% of gastric cancers arise from the lining of the stomach. Since this lining has glands, the cancer that comes from it is called adenocarcinoma. Although there are other cancers that can arise in the stomach (lymphomas-from lymph tissue, leiomyosarcoma-from muscle tissue, squamous cell carcinoma-from lining without glands), the vast majority are adenocarcinomas. Hence, these are the most commonly studied.

Am I at risk for gastric cancer?

In the United States, there are about 22,000 gastric cancers annually; with about 11,00 deaths attributed to this disease each year Interestingly, its incidence has drastically decreased since 1930. Although it is presumed that this is due to some sort of dietary or environmental factor(s), the exact reason behind this decrease is not known. One theory is that the advent of refrigeration led to decreased use of nitrites, "smoking" of foods, and other such forms of food preservation. It also decreased food contamination. Gastric cancer is approximately twice as common in men and more common in Blacks than Caucasians. It is rare to see gastric cancer before the age of 40, and its incidence increases with age thereafter. There are two types of gastric cancer, the intestinal type and the diffuse type; the latter carries a worse prognosis.

Although gastric cancer has greatly decreased in the United States, on a worldwide scale its incidence is still high, and it is the second leading cause of cancer death worldwide, behind lung cancer. Its highest incidence is in East Asia (e.g.-Japan, China), presumably because of a diet consisting of heavily smoked, salted, and pickled foods. Interestingly, first generation immigrants from these countries have a decreased incidence of stomach cancer after moving to the United States, but it is still higher than the general American population. However, the incidence greatly declines in second and third generation Japanese and Chinese immigrants to the United States, pointing to the fact that there does not appear to be an inherently genetic component in Eastern Asians' preponderance to gastric cancer, but rather an environmental component.

As mentioned above, diets heavily salted, smoked, or pickled are associated with an increased risk of disease, while diets rich in fruits, vegetables, and dietary fiber are associated with a decreased risk of cancer. The incidence of gastric cancers also increases with decreasing socioeconomic status, likely due to a number of social, occupational, and cultural factors. Tobacco use has also been associated with an increase in gastric cancers. There does not appear to be a link with alcohol consumption.

There does appear to be a genetic link in some cases of gastric cancer, and there are some genetic diseases such as hereditary nonpolyposis colorectal cancer, familial adenomatous polyposis, and Peutz Jeghers syndrome which all predispose to gastric cancer. It also appears that people with blood type A are at increased risk for gastric cancer for an unknown reason.

Studies have also linked infection with Helicobacter pylori with gastric cancer. H. pylori is associated with gastric ulcers and chronic atrophic gastritis, which may explain the high incidence of gastric cancer in patients infected with H. pylori. However, the exact role of H. pylori in the development of gastric cancer remains unclear. It is theorized that H. pylori causes a gastritis or inflammation of the stomach, which can lead to a loss of secretory cells in the stomach, also known as strophic gastritis. It is believed that this process of atrophy can lead to gastric cancer. H. pylori has also been linked to lymphomas of the stomach.

Pernicious anemia, an autoimmune disease where the stomach does not produce stomach acid, has also been linked to gastric cancer. Drugs which cause a decrease in stomach acid production have not been linked to an increased risk of gastric cancer.

It should be noted that, although these risk factors are listed above, the majority of gastric cancers develop without any one obvious predisposing cause. In other words, there is no extremely strong cause effect relationship with any risk factor, in contrast, for example, to that between smoking and lung cancer.

How can I prevent gastric cancer?

Because there is no one risk factor directly associated with gastric cancer, there is no strict lifestyle change that can greatly decrease a person's risk of developing gastric cancer. However, eating a "Western" type diet, without heavily smoked or salted foods and rich in fruits and vegetables will likely decrease a person's risk. Also, smoking cessation will likely decrease gastric cancer risk (though smoking should be stopped for numerous other health reasons). Some have advocated the consumption of foods with high level of antioxidants and vitamin C to prevent gastric cancers, though this has not been definitively proven. Since H. pylori infections have been linked to the development of gastric cancers, the quick treatment of H. pylori infections may decrease the numbers of gastric cancers, though whether treating H. Pylori actually reduces the risk of gastric cancer remains controversial. The decision to treat H. pylori should be discussed with your physician.

What screening tests are available?

There are no established programs for primary prevention of gastric cancer in the United States. There are no plans to initiate a screening program in the United States, simply because the incidence of gastric cancer is fairly low, and thus the yield from gastric cancer screening would be far too low to approach cost-effectiveness. A few populations may be exceptions (e.g.-patients with known atrophic gastritis, a chronic inflammation of the stomach lining), but overall screening for gastric cancer in the United States would likely cause more problems than it would solve (i.e. a lot of false positives, or false alarms). Currently, screening for H. Pylori is not recommended for areas with a relatively low incidence of gastric cancer, such as in the United States.

In some Japanese centers, where gastric cancer is much more prevalent, screening has been more successful. A variety of tests have been used in these screening programs, with the ability to accurately identify gastric cancers in over 90% of patients who actually have it. These tests include double-contrast barium radiographs (so-call "upper GIs" or "barium swallows") and upper endoscopies. An upper endoscopy (or an "EGD") is a test done using a camera at the end of a long tube that is placed down the patient's throat to the stomach itself. The physician performing the EGD is able to directly visualize the stomach. Many abnormalities can be detected with an EGD-most importantly, ulcers and cancers. Patients are sedated during the procedure, so discomfort is kept to a minimum.

More recently, studies have verified the use of a newer blood test that could be used for screening for gastric cancer. This analyzes the presence of enzymes in the blood called the serum pepsinogen I/II ratio, which is low in patients at risk for atrophic gastritis and gastric cancer. However, this is still in the earlier stage of testing and needs to be verified.

What are the signs of gastric cancer?

The symptoms of gastric cancer are often nonspecific, and the majority of people will unfortunately present with advanced disease. The vast majority of gastric cancer patients present with vague complaints such as upper abdominal discomfort or indigestion, loss of appetite, occasional vomiting, belching, or decreased ability to eat a large meal. Unfortunately, these symptoms are often the exact symptoms that patients experience when they have peptic ulcer disease or gastritis. Therefore, patients can be treated for benign diseases, such as ulcers, without the diagnosis of gastric cancers being made. This is not incorrect management, as gastritis and peptic ulcer disease are much more common than gastric cancer. However, if symptoms persist or do not respond to treatment, further investigations should follow.

Up to 25% of people with gastric cancer will have a history of gastric ulcers. Other symptoms, such as vomiting blood or problems with swallowing, are less common, but should be investigated without delay. Additional symptoms that generally apply to cancer patients are unexplained weight loss as well as fatigue and weakness, with or without anemia. Again, these symptoms are, unfortunately, nondescript, and do not necessarily apply to cancer in general or gastric cancer specifically. Advanced disease can present with lymph node involvement with masses in the area of the belly button, the underarms, or the clavicle. People with advanced disease may also present with abdominal swelling.

How is gastric cancer diagnosed and staged?

Diagnosis

Upper endoscopy, as described above, is routinely used for the initial diagnosis and staging of patients with gastric cancer. Using endoscopy, the diagnosis can be obtained in over 95% of cases. Many times, ultrasound during endoscopy is used to attempt to identify how deep into the wall of the stomach the cancer has penetrated. In addition, ultrasound can identify spread to lymph nodes in many cases. Depth of wall invasion and presence of lymph node spread are two very important components of treatment, as the surgeon uses this information to determine if he or she can operate.

Other procedures are needed to determine the stage of the disease. CT scans ("CAT scans") of the abdomen and chest are done, not only to rule out spread to distant organs, like the liver and lungs, but also to determine the spread to lymph nodes close to the stomach that could not be identified by ultrasound. Other tests to rule out abdominal spread of disease outside of the stomach itself are PET scans, which use radioactive solutions to identify tumors, and laparoscopy. Laparoscopy is a surgical procedure that involves puncturing the abdominal cavity with a fiber optic camera and directly viewing the organs and tissues in the stomach's area and the entire abdominal cavity. Although PET scans and laparoscopy are fairly new introductions to the staging of gastric cancer, CT scans, endoscopy, and ultrasound are more generally accepted as required in order to properly identify the extent of disease, and all will likely be done in a patient diagnosed with gastric cancer.

Other, more routine tests done before treatment include blood screening tests, to insure that overall blood counts are within normal limits, and that a patient's liver, kidneys, and overall health are normal.

All of these tests are important to determine the extent of the disease, which allows the disease to be staged. The stage provides a guideline for the optimal treatment of the gastric cancer as well as the prognosis.

Staging

The staging of a cancer basically describes how much it has grown before the diagnosis is made, documenting the extent of disease. Unfortunately, gastric cancer often presents as a more advanced disease because of lack of early diagnosis, due mainly to the lack of specific associated symptoms. Before the staging systems are introduced, here's some background on how cancers grow and spread, and therefore become more advanced in stage.

Cancers cause problems because they spread and can disrupt the functioning of normal organs. One way gastric cancer can spread is by local extension to invade through the stomach wall and into adjacent structures. These surrounding structures include the soft tissues and fat surrounding the stomach as well as other organs such as the spleen, pancreas, large intestine, small intestine, liver, and large blood vessels.

Gastric cancer can also spread by accessing the lymphatic system. The lymphatic circulation is a complete circulation system in the body (somewhat like the blood circulatory system) that drains into various lymph nodes. When cancer cells access this lymphatic circulation, they can travel to lymph nodes and start new sites of cancer. This is called lymphatic spread. Gastric cancers have a propensity to undergo lymphatic spread because there are many small lymphatic vessels contained within the stomach wall. The first lymph nodes that cancer cells spread to are the "perigastric" nodes along the sides of the stomach itself. They can then spread to lymph nodes adjacent to the liver, spleen, pancreas, and aorta.

Gastric cancers can also spread through the bloodstream. Cancer cells gain access to distant organs via the bloodstream and the tumors that arise from these cells are called metastases. Because of the stomach's blood supply, the most common organ it spreads to is the liver, though tumors can also spread to the lung or other organs less commonly.

A fourth way gastric cancer can spread is throughout the entire abdomen, the so-called peritoneal cavity. Although rare, once cancer cells grow outside of the stomach itself, there is nothing stopping cells from spreading to any surface in the entire abdominal cavity.

There are two accepted staging systems in gastric cancer. They both detail the extent of disease by describing the growth of tumor in the stomach itself as well as the presence and extent of spread to the lymph nodes. The TNM systems are used to describe many types of cancers. They have three components: T-describing the extent of the "primary" tumor (the tumor in the stomach itself); N-describing the spread to the lymph nodes; M-describing the spread to other organs (i.e.-metastases).

The "T" stage is as follows:

  • Tis-"in-situ cancer"-very superficial tumor, without invasion of the stomach wall
  • T1-tumor invades into only the superficial portions of the stomach wall
    • T1a: invades lamina propria or muscularis mucosa
    • T1b: invades submucosa
  • T2-tumor invades into muscular layers of the stomach wall
  • T3-tumor extends through the stomach wall into the subserosal connective tissue without invasion of the visceral peritoneum or adjacent structures
  • T4-tumor extends outside the stomach wall and invades the visceral peritoneum or adjacent structures

The "N" stage is as follows:

  • N0-no spread to lymph nodes
  • N1-tumor spread to 1-2 lymph nodes
  • N2-tumor spread to 3-6 lymph nodes
  • N3-tumor spread to more than 6 lymph nodes
    • N3a: spread to 7-15 lymph nodes
    • N3b: spread to 16 or more lymph nodes

The "M" stage is as follows:

  • M0-no tumor spread to other organs
  • M1-tumor spread to other organs

The overall stage is based on a combination of these T, N, and M parameters:

  • Stage IA-T1N0M0
  • Stage IB-T1N1M0 or T2N0M0
  • Stage IIA-T1N2M0 or T2N1M0 or T3N0M0
  • Stage IIB-T1N3 or T2N2M0 or T3N1M0 or T4aN0M0
  • Stage IIIA-T2N3 or T3N2 or T4aN1M0
  • Stage IIIB- T4bN0M0 or T4bN1M0 or T4aN2M0 or T3N3M0
  • Stage IV-any T, any N, M1

Though complicated, this staging systems help physicians determine the extent of the cancer, and therefore make treatment decisions regarding a patient's cancer. The stage of cancer, or extent of disease, is based on information gathered through various tests done as the diagnosis and work-up of the cancer is being performed.

What are the treatments for gastric cancer?

Currently, all curative treatments for gastric cancer involve surgery (surgical resection of all of the cancer). The smallest amount of surgery that is possible while still taking out all of the cancer is what is normally performed. Generally, tumors which are localized to the part of the stomach closest to the esophagus (proximal stomach) are treated with a gastrectomy (removal of the entire stomach). A partial gastrectomy is the removal of only a portion of the stomach, in contrast to a total gastrectomy, which is done when the tumor is larger. Partial gastrectomies may be appropriate for those tumors located further from the esophagus, in the distal portion of the stomach. For partial gastrectomy, the surgical margin around the gastric cancer needs to be 5 cm, i.e., there needs to be 5 cm of normal stomach tissue around the tumor in the portion of the stomach removed. Diffuse disease involving the stomach is also an indication for a total gastrectomy. Also, the surgeon performs a complete dissection of the lymph nodes, removing as many as possible. How extensive of a lymph node dissection to perform is controversial, with contradictory data from the United States compared with Japan. However, it is import that an experienced surgeon performs the dissection as it is a difficult surgery. Obviously, when the stomach or a portion of the stomach is removed, the two ends must be rejoined. This is done by various procedures, all attempting to eliminate as many of the side effects of the surgery as possible, such as inability to eat larger meals and the so-called "dumping syndrome." Dumping syndrome results from the stomach being removed and the result of the small intestine filling too rapidly with undigested food. Symptoms include nausea, vomiting, bloating, diarrhea, and even shortness of breath. These symptoms can usually be managed with dietary modifications.

Although surgery is always required for curative treatment, it is often not enough to achieve cure in many cases. The majority of cases of early gastric cancer are cured by surgery alone. However, in most patients with more advanced cases of gastric cancer, such as those with positive lymph nodes or tumors which have invaded the deep layers of the stomach or beyond, the cancer will come back if only surgery is done. Up to two-thirds of these patients recur, with cancer coming back in their lymph nodes or other organs. To combat this, radiation therapy and chemotherapy are recommended in many patients. It is felt that any patient with stage IB or higher gastric cancer (involvement of deeper portions of the stomach wall or any lymph nodes involved with cancer) will benefit from additional therapy with concurrent radiation and chemotherapy.

Radiation therapy makes the use of high energy x-rays to kill cancer cells. It does this by damaging the DNA in tumor cells. Normal cells in our body can repair radiation damage much quicker than tumor cells, so while tumor cells are killed by radiation, many normal cells are not. This is the basis for the use of radiation therapy in cancer treatment. Radiation is delivered using large machines that produce the high energy x-rays. After radiation oncologists set up the radiation fields ("radiation fields" are the areas of the body that will be treated by radiation), treatment is begun. Radiation is given 5 days a week for approximately 5 weeks at a radiation treatment center. The treatment takes just a few minutes each day and is completely painless. The typical radiation field used in the treatment of gastric cancer includes portions of the upper abdomen. In other words, it is designed to kill tumor cells in the area that the surgery was performed. Typical side effects include nausea and vomiting (though this should be less of a problem since the stomach has already been removed) and diarrhea.

Chemotherapy is defined as drugs that are used to kill tumor cells. The large advantage in using chemotherapy is that, since it is a medicine, is travels through the entire body. Hence, if some tumor cells have spread outside of what surgery or radiation can treat, they can potentially be killed by chemotherapy. Similar to radiation, some normal cells are damaged during treatment, resulting in side effects. The standard chemotherapy used in the treatment of gastric cancer is called 5-FU, coupled with another drug called leucovorin. This type of chemotherapy is delivered through the vein. Side effects from 5-FU and leucovorin include nausea, diarrhea, skin changes, and sores of the mouth. Although other chemotherapy drugs (cisplatin, oxaloplatin, epirubicin) are being investigated for the treatment of gastric cancer, 5-FU plus leucovorin remains the standard. Sometimes chemotherapy and radiation are used prior to surgery, but a large trial has demonstrated that surgery follow by radiation with chemotherapy appears to be the best current treatment. The value of radiation and chemotherapy was demonstrated in a large study first reported in 2001, and updated in 2009 by MacDonald et al. These authors reported a much better outcome in patients with Stage IB or greater gastric cancer who were treated with radiation and chemotherapy after potentially curable surgery. This study has established the "standard of care" in the United States, and is detailed as follows:

  • Surgery: to remove all of the cancer, as well as removal of the lymph nodes in the area of the stomach
  • Radiation: to the area of the upper abdomen, 5 days per week for 5 weeks; usually starts 4-6 weeks after surgery, to allow for recovery from surgery, but may be delayed by a few weeks if chemotherapy is started first, prior to combining the two treatments.
  • Chemotherapy: using 5-FU and leucovorin combination therapy, given during the radiation and also after the radiation is completed; can sometimes be started for a few weeks prior to the start of radiation therapy, to allow for local healing if needed

There has also been a study demonstrating the benefit of preoperative chemotherapy followed by surgery and postoperative chemotherapy, a regimen often used in people who may not tolerate radiation with chemotherapy. The type of chemotherapy advised in this setting is epirubicin, cisplatin and 5-fluorouracil (ECF). About 20% of gastric cancers overproduce a protein called HER-2; in such cases the addition of Herceptin, a biological agent, to chemotherapy has been shown to improve survival for patients with advanced disease.

Follow-up testing for gastric cancer

Once someone completes treatment for gastric cancer (including surgery +/- radiation and chemotherapy), he or she needs to be closely followed by his or her cancer physicians. This close follow-up is required for a couple of reasons. First, it needs to be insured that the patient recovers from the cancer treatment itself. This includes ensuring that the patient has no vomiting or diarrhea and has healed from surgery. Also, symptoms of "dumping syndrome" need to be addressed with dietary modifications. In addition, because of the removal of the stomach or a portion of the stomach, gastric cancer patients are prone to a certain type of anemia, resulting from not having enough vitamin B-12. This will be monitored for the patient's entire life, as this anemia does not usually occur until years after the surgery.

The other major reason a patient needs to be followed closely is to make sure their cancer does not recur. Recurrence can be detected using physical exam, repeat, periodic endoscopies, and CT scans. At first, patients will have follow-up visits and tests fairly often. The longer the patient is free of disease, the less often he or she will have to go for check-ups.

References

Calvo FA, Martinez-Monge R, Ortiz de Urbina D, Gunderson LL. Stomach Cancer. Clinical Radiation Oncology. Edited by Gunderson LL, Tepper JE. Philadelphia; 2000: 652-686.

Hofmann M, Stoss O, Shi D, et al. Assessment of a HER2 scoring system for gastric cancer: results from a validation study. Histopathology 2008; 52(7):797-805.

Karpeh MS, Kelsen DP, Tepper J. Cancer of the Stomach. In Cancer: Principles and Practice of Oncology (6th Edition). Edited by DeVita, Jr VT, Hellman S, Rosenberg SA. Philadelphia: Lippincott Williams & Wilkins; 2001: 1092-1126

Lawrence, Jr. W. Gastric Cancer. Clinical Oncology. Edited by Lenhardt, Jr. RE, Osteen RT, Gansler T. Atlanta: American Cancer Society; 2001: 345-356.

MacDonald JS, Smalley SR, Benedetti J, et al. Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction. NEJM 2001; 345 (10): 725-730.

Smalley SR. New Developments in Radiotherapy for Gastric Cancer. ASTRO Refresher Course, Copyright American Society for Therapeutic Radiology and Oncology, 2002

Van Cutsem E, Kang Y, Chung H, et al. Efficacy results from the ToGA trial: A phase III study of trastuzumab added to standard chemotherapy (CT) in first-line human epidermal growth factor receptor 2 (HER2)-positive advanced gastric cancer (GC). J Clin Oncol 2009; 27(18S)