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What is Gastrointestinal Stromal Tumor (GIST)?

GIST is a rare cancer of the GI track. It belongs to the general class of cancers called sarcomas. Sarcomas are a group of rare cancers that occur in connective tissues, bones, and muscle tissues. Sarcomas are derived from "mesenchymal cells", which are a general class of cells that includes fibroblasts, muscle cells, blood vessel lining cells (=endothelial cells)

About 40-70% of GISTs arise from the stomach, 20-40% arise from the small intestine, and 5-15% from the colon and rectum. GISTs can also be found in the esophagus (<5%), omentum (<5%), mesentery, or retroperitoneum.

GIST should not be confused with more common cancers (carcinomas) of the GI tract, such as stomach or colon carcinomas; carcinomas may occur in the same parts of the body, but their origins and treatments are complet ely different.

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How is GIST diagnosed?

When GIST tumors are first discovered, the most common symptoms are:

• Vague abdominal discomfort or pain.
• Presence of a palpable abdominal mass.
• Feeling of abdominal fullness.
• Secondary symptoms resulting from tumor bleeding and associated anemia.

A biopsy is commonly used to aid in the diagnosis of cancer and GIST. Tissue samples are prepared from the biopsy sample. One method that the pathologist uses to classify tissues is called immunohistochemistry. Using this technique, the pathologist applies various "antibodies" to the tissues. These antibodies react with specific proteins on the cell surface which are characteristic of particular types of cells. The most important antibody that is applied when GIST is suspected is the antibody to the KIT protein. When these antibodies bind to their specific target on the cell surface they produce a "stain" or change in color of the sample. So when the KIT antibody is applied, if the cell surface has the KIT protein present on the surface, the sample will "stain positive". This is what is known as "KIT positive" and means that this cell has KIT receptors on its surface. Note: the term c-Kit or CD117 may be used instead of KIT.

In making the diagnosis, the pathologist will also study the shape and appearance of the tumor cells under the microscope. The diagnosis of GIST is best made by a pthologist with experience in studying sarcomas.

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How is GIST treated?

GIST is usually treated with either surgery or with a new type of cancer drug called Gleevec. One of the current challenges facing patients with GIST and their doctors, is deciding between surgery or Gleevec and when one is more appropriate than the other. Certainly, both surgery and Gleevec may be appropriate for some patients. For patients with extensive metastatic disease, Gleevec is the fairly easy choice, but for new patients when no metastases are present, the choices are more complex.

GIST is very resistant to traditional types of chemotherapy and radiation. They have little place in treating GIST.

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What is metastatic GIST?

GIST cancers begin as localized (single) tumors growing somewhere along the GI tract. Like most cancers, GISTs can shed cancer cells which spread the disease to other sites. This process is called metastasis and the new lesions are called metastases. (The original lesion is called the "primary".) GISTs usrally metastasize to nearby sites in the body, such as the peritoneal cavity and liver. GIST metastases growing at these other sites are still GISTs-a liver metastasis, for example, is still a GIST, not a "liver cancer". GIST metastases, like GIST primaries, are sensitive to drugs like Gleevec.

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What is Gleevec?

Gleevec is a pill that is taken either once or twice daily, depending on the dose. A patient normally takes 4 to 8 pills (400-800 milligrams) daily.

Gleevec is different from traditional chemotherapy in that it is very selective. Traditional chemotherapy kills all cells that are dividing quickly. This is what causes so many of the side effects of traditional chemotherapy. In addition to the cancer cells, this type of chemotherapy also kills many of the body's normal cells. Gleevec is much more selective and as a result has fewer and less severe side effects. It was designed to block (inhibit) the activity of a mutant type of enzyme (an enzyme is a specific type of protein) that causes Chronic Myeloid Leukemia (CML). This enzyme is called Bcr/Abl. In addition to blocking Bcr/Abl, Gleevec also blocks several other enzymes. These include:

• KIT.
• Platelet Derived Growth Factor Receptors (PDGFR-alpha and PDGFR-beta).
• Various forms of the Abl enzymes.

The blockage of aberrant KIT signaling (and in some cases PDGFR-alpha) usually stops GIST cells from dividing and often induces GIST cells to die (apoptosis).

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How do I find a doctor?

It is our opinion that nothing can take the place of an experienced GIST team of doctors. This may include a Pathologist, Oncologist, and a Surgeon. GIST is such a rare type of cancer that few doctors have much experience in treating it. The hospitals with top Sarcoma treatment centers are likely to have more experience with GIST. This is especially true with the hospitals that conducted or are conducting clinical trials with Gleevec. They have seen many more GIST patients and are more familiar with their unique needs, with treatment options, managing side effects, monitoring considerations, and what to do if the initial treatment fails.

In cooperation with the Connective Tissue Oncology Society (CTOS) our website has started a list of GIST specialists. While it does not include all GIST specialists, we hope you find it useful.

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What should I do if Gleevec stops working for me?

• Get to one of the top GIST centers for further evaluation.
• Don't stop Gleevec too soon.

Initial treatment with Gleevec can sometimes result in swelling of tumors that are responding to Gleevec.
Even if Gleevec is unable to totally stop tumor growth, it may slow growth. In these cases consideration should be given to continuing Gleevec therapy in the absence of other options (for instance, until arrangements can be made to start a different clinical trial).

Imatinib (Gleevec) Discontinuation Can Result in "PET Flare"
Reactivation of active GIST disease in patients who discontinue Gleevec has been demonstrated by PET scans. This phenomenon known as a "PET flare", has been shown to occur in as little as 11 days. Therefore, it is generally advisable not to terminate Gleevec as long as the patient is tolerating the drug, especially if there is evidence that only limited progressive disease is present. Chances are good that Gleevec will continue to shrink or stabilze most sites of disease even in a patient that has developed a limited focus of clonal resistance to Gleevec.¹

Be aware of a special type of progression called a "nodule within a mass." Dose escalation does not seem to affect these specific nodules, which clinically, at least, appear to represent new clones of resistant disease. If local treatments can be utilized, such as radiofrequency ablation or surgical resection of the limited resistant clone, consideration should be given to that approach. Continuation of the Gleevec to maintain control of the remainder of the sensitive disease is also critical.¹

Managing GIST Progression: A conversation With Charles D. Blanke, MD

Novel Pattern of GIST Progression: What It Looks Like, What It Means

• A dose increase can be beneficial in some cases.
• Consider Other Clinical Trials
• Find a well informed patient group like the Life Raft Group.

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