Gastrointestinal Stromal Tumor – Causes, Diagnosis and Treatment

Gastrointestinal stromal tumor (GIST) is a rare malignancy of the gastrointestinal (GI) tract. Unlike the vast majority of GI cancers such as esophagus, stomach, and colon cancers, which come from epithelial cells (cells that form the inner lining of the GI tract), GIST derives from cells in the mesenchymal tissue (nonepithelial cells) and thus falls into the broad family of tumors called soft-tissue sarcomas.

GISTs represent less than 1 percent of all primary GI cancers. A study using the National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) registry reported less than one case (0.68 case) of GIST per 100,000 people, or about 4,500 to 6,000 total cases annually, in the United States between 1992 and 2000.

Prior to the 1990s, there was much debate as to the type of cell in the GI tract that gave rise to GISTs. In the early 1990s, a significant breakthrough was made when almost all GISTs were discovered to express a protein called c-Kit (also known as CD117). C-Kit belongs to a class of proteins known as kinases that perform crucial functions in regulating the growth of cells. The c-Kit protein is found on the surface of malignant cells that form GISTs. Furthermore, in 80 percent of GISTs, the c-Kit protein contains mutations that render it more active, ultimately resulting in the uncontrolled growth of the malignant cells. The recognition of c-Kit expression as a common feature of GISTs now allows these tumors to be more readily distinguished from other malignancies of the GI tract, such as leiomyosarcomas.

It is now believed that GIST originates from cells in the mesenchymal tissue of the GI tract known as the interstitial cells of Cajal. These cells, which also produce c-Kit, are sometimes described as the “pacemaker” cells of the gut. They have characteristics of both smooth muscle cells and nerve cells and are important in regulating gut contractility (peristalsis), which helps move food through the gastrointestinal tract.

How It Spreads GISTs most frequently occur in the stomach, followed by the small intestine, omentum or mesentery (lining of the abdomen), colon, and esophagus. GISTs usually start in the second layer of the bowel wall and may grow inward (toward the cavity, or lumen, of the bowel, where food passes through) or outward. GISTs typically invade the local surrounding tissues by extension of the primary tumor and metastasize (spread) to distant sites such as the liver and abdominal cavity. GISTs rarely metastasize to the lymph nodes.

What Causes It The exact cause of GIST is unknown. Almost all GISTs express (make) the c-Kit protein on the surface of their cells. In 80 percent of GISTs, a mutation is found in the c-Kit protein that makes it much more active than the normal c-Kit protein. Most often, a mutation is found in a position of the c-Kit gene known as exon 11; less often, a mutation is found in exon 9, 13, or 17. Although the exact mechanism is unknown, it is believed the widespread expression of c-Kit and the presence of c-Kit mutations play a large role in the pathogenesis of GISTs. In rare cases, GISTs do not express the c-Kit protein and instead make a protein called platelet-derived growth factor receptor (PDGFR).

Risk Factors

There are no known risk factors for GIST. The vast majority of GISTs are sporadic (no evidence of inheritance from one generation to the next). However, a few families whose members have a predisposition to developing multiple GISTs have been described. These families were found to have germ line mutations in the c-Kit gene, which get passed on from one generation to the next.

Screening

Due to the low incidence of the disease and the fact that there are no known risk factors, there are no screening programs or recommendations for GIST.

Common Signs and Symptoms

The most common symptom caused by GIST—occurring in 40 percent of cases—is gastrointestinal bleeding, which is manifested as vomiting blood, passage of black tarry stools, or passage of bloody stools, depending on whether the tumor is in the stomach or further down in the intestines. Gastrointestinal bleeding usually causes anemia. When GISTs are large, they can result in bowel obstruction, which causes nausea, vomiting, severe abdominal pain, and constipation.

Diagnosis

The diagnosis of GIST depends on where the tumor is located.

Physical Examination There are few findings on physical examination.

• Paleness, due to anemia.

• Abdominal tenderness, due to bowel obstruction.

• An abdominal mass that can be palpated (felt).

• An enlarged liver (hepatomegaly).

• Fluid in the abdominal cavity (ascites).

Blood and Other Tests

• Fecal occult blood test (test for hidden blood in the stool).

• Complete blood count, which may indicate anemia due to gastrointestinal bleeding.

• Liver function blood tests (transaminases, alkaline phosphatase, bilirubin, and LDH), which may indicate tumor in the liver.

• Levels of serum iron and ferritin, which may indicate anemia.

Imaging

• X-rays of the upper gastrointestinal tract (upper GI series) by standard and double-contrast methods may find GISTs in the esophagus, stomach, and small intestine.

• Chest X-ray can detect tumors that have metastasized to the lungs and the midchest area (mediastinum).

• CT scan of the abdomen detects tumors in the liver and abdominal cavity and, less often, in the stomach, small intestine, and colon. CT scan of the chest detects tumors in the lung and midchest. CT scans define the size and lateral extent of tumors.

• PET scan is a nuclear medicine study that can distinguish whether a mass seen on CT is a GIST, and can occasionally detect tumors that are missed by CT scan. Tumors appear as bright spots on PET scan because they take up the radioactive sugar that is injected into the vein.

• MRI of the abdomen is sometimes used when CT scan with contrast (dye) cannot be used because of allergy to contrast or kidney failure.

Endoscopy and Biopsy

• Esophagoduodenoscopy (EGD) is the key test in the diagnosis of GIST found in the stomach or esophagus. A flexible fiber-optic tube with a camera at the end is passed through the esophagus into the stomach. The entire esophagus and stomach can be visualized with this technique to look for a GIST. If a mass is found in the stomach or esophagus, a piece of tissue from the mass can be biopsied using forceps located at the end of the fiber-optic scope.

• Colonoscopy is similar to EGD except that the flexible fiber-optic scope is passed through the rectum into the colon and is used to visualize the entire colon to look for masses. As in the case of EGD, biopsy of any colonic masses can be obtained during colonoscopy.

• Endoscopic ultrasound is a newer technique that uses an ultrasound probe at the end of an endoscope (such as an EGD) to evaluate the extent of a mass in the stomach or esophagus and to evaluate for any abnormal lymph nodes that may be affected by cancer near the stomach or esophagus.

• CT-guided biopsy is a technique in which a CT scan is used to locate a mass in the chest or abdomen while a needle is simultaneously used to biopsy the mass under the guidance of the CT image. This technique can be used to biopsy a mass in the abdominal cavity that is suspicious for a GIST.

• Pathology review of the tumor samples obtained by biopsy is done by looking at thin sections of the tumor tissue under the microscope. Immunohistochemistry, wherein the tumor tissue is stained by an antibody that recognizes the c-Kit protein, is also performed. Since almost all GISTs express the c-Kit protein, positive staining of the tumor tissue for c-Kit confirms the diagnosis of GIST.

Staging

There is no current staging system for GIST. However, two parameters are often used after removal of a GIST by surgery to determine its aggressiveness and to predict how likely it is to recur. The two parameters are the size of the tumor and its mitotic rate (the number of dividing tumor cells seen under the microscope). Using these two parameters, GISTs are divided into very low risk, low risk, intermediate risk, and high risk.

* HPF denotes high-powered field seen under the microscope.

Treatment Overview

The most important initial treatment decision for patients with GIST is to determine whether the tumor can be completely removed by surgery. If the GIST is not removable by surgery, other treatment options, including targeted therapy, may be considered.

Surgery Surgery is the only realistic means of cure in patients with GIST. Surgery is an option for patients with localized GISTs that have not metastasized to distant sites or invaded adjacent organs or vital structures (such as major blood vessels). When the tumor originates from the omentum or mesentery (lining of the abdominal cavity), surgery may be difficult, since the tumor usually spreads to multiple places in the abdominal cavity. Other factors determine whether a patient with GIST is a candidate for surgery. These include the overall health of the patient and whether the patient can tolerate an extensive operation.

The goal of surgery is complete resection of the tumor, whether it is in the esophagus, stomach, colon, omentum, or mesentery. During surgery, the rest of the abdominal cavity and the liver are explored to make sure there are no residual tumors or occult tumors that were not seen on preoperative imaging studies. GIST is usually encased by a sheath of tissue called a pseudocapsule, so care is taken during surgery to ensure that the tumor does not rupture. Even when GISTs are extending into adjacent organs (for example, a GIST that arises in the stomach and extends to the pancreas), they usually only displace these organs and do not invade them. Therefore, it is often possible to lift the tumor off the adjacent organs during surgery. For tumors in the esophagus or colon, surgery usually involves removing the tumor and portions of the esophagus or colon. For tumors in the stomach, either the entire stomach or a part of it is removed, depending on the size of the tumor. In all cases, the goal is to obtain a negative resection margin—a border of normal tissue surrounding the tumor that does not contain any cancer.

Most GISTs that are localized to one area are removable by surgery. For example, in a large series of patients with GIST published by the Memorial Sloan-Kettering Cancer Center, 85 percent of patients with localized GIST were able to undergo complete resection. Nearly 45 percent of these patients remained free of disease recurrence five years after their surgery.

In general, the likelihood of recurrence after complete resection of a GIST depends on two factors: the size and the mitotic rate (number of dividing cells) of the original tumor. As described in the table above, tumors that are greater than 4 inches (10 cm) in dimension or have a mitotic rate greater than ten per fifty high-powered fields are at high risk of relapse (greater than 50 percent at five years). Tumors that are smaller than 2 inches (5 cm) and have a mitotic rate of less than ten per fifty high-powered fields have a less than 10 percent chance of recurrence at five years. Several studies are investigating the value of administering a drug called imatinib mesylate (Gleevec) following surgery to try to decrease the risk of tumor recurrence (see “Targeted Therapy,” below). In some instances, patients may also receive this same drug prior to their planned surgery, with the goal of shrinking the tumor to allow for a safer operation.

Chemotherapy Traditional chemotherapy agents, in contrast to newer targeted therapies such as imatinib mesylate (Gleevec) and sunitinib (Sutent), are not effective in the treatment of GIST.

Targeted Therapy Metastatic GISTs or locally advanced GISTs that have invaded (grown into) adjacent organs are not resectable by surgery. Prior to the year 2000, there was no known effective treatment for patients with these unresectable tumors. However, the discovery in the late 1990s that almost all GISTs express the c-Kit protein and that the c-Kit protein is abnormally activated in the tumor cells led to the development of a very effective treatment for unresectable GIST.

In the early 2000s, imatinib mesylate (Gleevec) was discovered to specifically bind to (target) the c-Kit molecule and block its function. Imatinib is a small molecule that comes in the form of an oral pill and is easily absorbed by the bowel. It belongs to a new class of drugs called receptor tyrosine kinase inhibitors (RTKIs). Imatinib is a prototype of so-called targeted therapy, in which drugs are designed to specifically target and inactivate proteins (in this case, c-Kit) that are thought to be responsible for the uncontrolled growth of the cancer cells. Imatinib was originally approved for the treatment of chronic myelogenous leukemia (CML) when it was found to effectively block the activity of another protein, called BCR/ABL, which causes CML. In clinical trials, most patients with CML who took imatinib had complete remission of their disease.

Due to its ability to block the activity of c-Kit, imatinib was studied in patients with GIST. In a large multinational clinical trial comparing two doses of imatinib in patients with unresectable GIST, 66 percent of patients had marked shrinkage of their tumors, and another 16 percent had tumors that remained stable on treatment. The median duration of response was twenty-seven months. There was no difference in response rates between the two doses tested (400 mg and 600 mg daily). Based on these positive results, imatinib was approved by the FDA in 2002 for the treatment of unresectable or metastatic GIST.

Imatinib is generally very well tolerated by patients. Its most common side effects are swelling of the area around the eyes, generalized swelling, mild skin rash on the face, and mild decrease in blood counts (decreased red blood count, called anemia, and decreased platelet count). Other side effects include nausea, abdominal bloating and cramping, and diarrhea. All of these side effects are usually mild.

Interestingly, it appears that the type of c-Kit mutation found in a patient’s GIST determines how well the patient responds to imatinib treatment. In a large clinical trial in which patients with unresectable GIST were treated with imatinib, patients whose GIST contained a c-Kit mutation at exon 11 did much better than patients whose tumor contained a c-Kit mutation at exon 9 or no c-Kit mutation at all. A higher percentage of patients with an exon 11 mutation had tumor shrinkage with imatinib treatment; these patients also lived longer than patients with an exon 9 mutation or no mutation. While these sorts of mutational analyses are useful, they are not a part of routine testing at most pathology laboratories.

Despite the effectiveness of imatinib, most advanced GISTs eventually become resistant to imatinib treatment. For patients whose GIST has progressed despite imatinib treatment, another drug, called sunitinib (Sutent), has been found to be effective. Similar to imatinib, sunitinib is a tyrosine kinase inhibitor that targets and blocks the c-Kit protein, in addition to other proteins. Sunitinib also comes in the form of a pill that is taken orally. In a clinical trial comparing sunitinib to placebo in patients whose GIST had progressed despite imatinib, patients who took sunitinib had a longer period of tumor control (shrinkage or stable tumor) compared to those who took placebo. Patients whose GIST contained an exon 9 mutation in c-Kit did much better on sunitinib than patients whose tumor contained an exon 11 mutation. This is opposite of the effect seen with imatinib.

Sunitinib is also generally well tolerated by patients. Its most common side effects include diarrhea, skin discoloration, mouth sores, fatigue, high blood pressure, and decreased blood counts (red blood count and platelet count). Based on its efficacy, sunitinib was approved by the FDA in January of 2006 for the treatment of patients with GIST after disease progression on, or intolerance to, imatinib.

Because of the effectiveness of imatinib in patients with advanced GIST, this agent is being studied in patients whose GIST has been completely removed by surgery, to determine if it can increase the chance of cure in these patients. This type of therapy given after surgery is called adjuvant treatment. Two large clinical trials, one in Europe and the other in the United States, are currently evaluating imatinib as adjuvant therapy for GIST. Both trials are comparing imatinib treatment to no adjuvant treatment in patients with intermediate or high-risk GIST (determined by tumor size and mitotic rate) that has been completely removed by surgery. Results from these studies are not yet available. Furthermore, potentially operable patients whose tumors are very large at the time of diagnosis, may initially start treatment with imatinib for a period of time, with the goal of shrinking the tumor to make eventual surgical resection safer and easier (referred to as neoadjuvant therapy).

Assessing Treatment Response

Two types of scans are usually used to determine whether a patient with GIST is responding to treatment with imatinib or sunitinib—CT and PET scans. Either scan is obtained every three to six months while the patient is on treatment. A CT scan often shows shrinkage of tumors if they are responding to therapy. However, GISTs can sometimes increase in size or remain the same size on the CT scan in early treatment, due to bleeding in the tumor or death and degeneration of tumor cells; thus, this is not indicative of treatment failure. Often, GISTs that are responding to treatment become less bright on CT scan (hypodense) and PET scan (decreased uptake).

Treatment by Stage

 Localized

The standard for patients with localized GIST that has not metastasized to distant organs or invaded adjacent organs is surgery. For GISTs in the stomach, the tumor and either part of the stomach or the entire stomach are removed (gastrectomy). For tumors in the esophagus, small intestine, or colon, portions of the esophagus, intestine, or colon are removed along with the tumor. In all cases, the goal is to achieve a negative margin around the tumor.

Five-Year Survival 35 to 87 percent, depending on the size of the tumor and the mitotic rate

Investigational The adjuvant treatment of patients with completely resected GIST is currently being evaluated in two Phase III clinical trials, one in the United States and the other in Europe. Both trials are comparing imatinib treatment to no adjuvant treatment in patients with intermediate or high-risk GIST (determined by tumor size and mitotic rate) that has been completely removed by surgery. The goal of adjuvant therapy is to reduce the risk of disease recurrence. Results from these studies are not yet available. As noted above, neoadjuvant therapy with imatinib is also a strategy frequently used for GISTs that are very large at initial presentation.

 Localized Advanced or Metastatic

The standard treatment of patients with locally advanced or metastatic GIST is targeted therapy with imatinib. The rate of tumor shrinkage with imatinib is in the range of 60 to 70 percent. If patients progress on imatinib, the dose of imatinib is increased or the patients are switched to treatment with sunitinib (Sutent). Patients who exhibit an excellent response to treatment and have isolated sites of residual disease may benefit from surgical exploration to resect these areas, but the long-term advantages of such an approach have yet to be proven.

Five-Year Survival 10 to 20 percent

Investigational Other novel targeted-therapy agents are being evaluated in clinical trials in patients with unresectable GIST that is resistant to imatinib treatment. These include sorafenib (Nexavar) and PTK/ZK (vatalanib), both of which are tyrosine kinase inhibitors that block vascular endothelial growth factor (VEGF). VEGF plays a key role in tumor blood vessel formation, which in turn is important in tumor growth and metastasis. Another clinical trial is evaluating the combination of imatinib and bevacizumab (Avastin), which is an antibody directed against VEGF.

Recurrent Cancer

Patients whose GIST recurs after surgery may undergo a repeat operation if the recurrence is localized and the individual is a good candidate for surgery. If the recurrent disease is more extensive, patients are typically treated with imatinib mesylate (Gleevec) and sunitinib (Sutent) as in the case of metastatic disease.

Prevention

Because GIST is so rare and is not associated with any known risk factors, there are no recommended preventive measures against GIST.

The Most Important Questions You Can Ask

• Is my GIST removable by surgery? If not, why not?

• Is there a role for imatinib either before or after my planned surgery to remove the tumor?

• Based on the pathology of the tumor, is my GIST high, low, or intermediate risk and what does that mean?

• Does my GIST express the c-Kit protein?

• Can the tumor be analyzed for its mutational status (e.g., exon 11 or 9 mutation)?

• If the tumor is not removable by surgery, can I take imatinib or sunitinib (Sutent)?

• Is there a clinical trial available for my condition?

Carcinoids of the Gastrointestinal Tract – Common Signs and Symptoms, Diagnosis and Treatment

Carcinoid tumors are uncommon cancers. Although they can develop in other organs, especially the lung, they generally arise in the intestinal tract, including the stomach, pancreas, small bowel, appendix, and rectum. They are the most common tumors of the appendix, occurring in 1 out of every 300 appendectomies. They make up 30 percent of small bowel tumors but less than 2 percent of all gastrointestinal malignancies.

In their early stages, carcinoid tumors are highly treatable and often curable. They are usually slow growing, and the risk of metastasis is related to the size of the primary tumor. Because these tumors are indolent in their behavior and the patient is usually asymptomatic early in the disease, the tumor often goes undetected for many years. Consequently, the disease is often in a more advanced stage at the time of diagnosis.

Small bowel carcinoids may occur in multiple sites (about 25 percent of patients have multiple tumors) and, except for those of rectal origin, may produce biologically active hormones and peptides. In many cases, there are no symptoms, so some carcinoid tumors are discovered incidentally during abdominal operations performed for other reasons. The survival of most people with carcinoid tumors is quite good, although symptoms may develop when the tumor cannot be removed, when it recurs after treatment, or when there is metastatic disease.

Manifestations of the carcinoid syndrome

Types There are no meaningful cell type (histologic) variations that help predict the clinical course of these tumors. Carcinoids are broadly defined as neuroendocrine or APUD (amine precursor uptake and decarboxylation) tumors. They are classified as foregut, midgut, or hindgut, according to site of primary tumor. Foregut tumors include lung, gastric, duodenal, and pancreatic tumors; midgut tumors include those in the small bowel, appendix, and the first portion of the large intestine; and hindgut tumors are from the remainder of the large intestine and the rectum. Each classification of carcinoid tumors represents not only differences in location of the primary tumor, but also where the tumor is likely to spread and differences in hormone production. Malignant midgut carcinoids may produce at least two hormones, serotonin and substance P, but some carcinoid tumors are nonfunctional and do not release any substances.

How It Spreads Carcinoid tumors spread by direct invasion of the underlying layers of tissue (submucosally). They can also spread via lymphatics to regional lymph nodes and through the bloodstream to the liver, lung(s), bones, or other organs.

The site of origin and size of the primary tumor are important in determining whether the carcinoid tumor is likely to spread. A tumor less than 1/2 inch (1 cm) rarely metastasizes. But 88 percent of patients with tumors larger than 3/4 inch (2 cm) have metastases, and 18 percent of these develop the carcinoid syndrome (see “Common Signs and Symptoms,” below).

What Causes It Unknown

Risk Factors

Factors that put an individual at risk have not been identified. It is exceedingly rare for carcinoids to be hereditary. However, there are certain genetic mutations found to be associated with the development of the disease. The majority of mutations associated with carcinoid tumors appear to be spontaneous mutations rather than a result of an inherent risk.

Screening

There are no effective screening methods.

Common Signs and Symptoms

Symptoms are unusual in the early stages. The tumors are small and grow slowly and the symptoms so vague, any changes noticed are considered normal. When pronounced symptoms do occur, the tumor has already spread in 90 percent of patients. The most common symptoms associated with gastrointestinal tumors are periodic abdominal pain, intermittent intestinal obstruction, and kinking of the bowel. Gastrointestinal bleeding is uncommon and ulcerations of the tumor are rare.

In addition to the symptoms caused by the tumor, there may be symptoms of the carcinoid syndrome. This is characterized by facial flushing, wheezing, diarrhea, and cardiac valvular disease. Midgut carcinoid tumors are more likely to be associated with the syndrome compared to foregut tumors. Hindgut tumors are usually asymptomatic. The syndrome is associated with abnormal amounts of the two hormones produced by malignant carcinoids, serotonin and substance P. The syndrome occurs in approximately 10 percent of patients with carcinoid tumors, almost always because of carcinoid metastases in the liver.

Diagnosis

Physical Examination

• Palpating the abdomen to identify an abdominal mass and/or an enlarged liver.

• Examination of the facial skin to identify prominent skin veins (telangiectasis) and flushing.

• Listening with a stethoscope for signs that may be associated with carcinoid syndrome—heart murmur and wheezing on expiration.

Blood and Other Tests

• Chromogranin A (CgA) is a general biochemical marker for neuroendocrine tumors. Not all carcinoid tumors overproduce and secrete measurable CgA, but most do. If levels are abnormal, it provides a marker for the disease.

• Metastatic carcinoid tumors may be diagnosed by the twenty-four-hour urine 5-hydroxyindoleacetic acid (5-HIAA) test, which detects elevated levels of 5-HIAA, a metabolic product of the serotonin produced by the tumor. Plasma serotonin levels represent only the level at the time of blood sampling, but the 5-HIAA urine sample provides a twenty-four-hour picture of the serotonin levels, thus providing a more accurate measure for abnormal serotonin production. False positive 5-HIAA tests can be caused by foods such as bananas, avocados, and pineapple and by certain drugs. The laboratory should provide a complete list of foods to be avoided during urine collection.

Imaging

• X-rays of the chest and gastrointestinal tract (small bowel and barium enema).

• Endoscopic evaluation of the stomach may include endoscopic ultrasound (EUS), bronchoscopy for lung tumors, enteroclysis (small bowel enema) for tumors of the small intestine, and colonoscopy to detect large intestinal or rectal tumors.

• CT or MRI scans (with contrast) of the abdomen to detect primary tumors and liver metastases.

• Octreoscan is a nuclear medicine test to determine where the tumor has spread. This test uses a radio-labeled somatostatin analogue that binds to receptors in a lock-and-key fashion. These receptors are located on the tumor cell surface and allow the tumor to be detected through imaging by a nuclear medicine camera. This imaging is used for initial staging of disease and restaging when disease progression is suspected. Since this test reveals somatostatin receptors, it also provides a means for evaluation if the tumor cells would be responsive to somatostatin analogue therapy.

Biopsy Tissue biopsy is the most definitive means of diagnosing the disease. Biopsies may be done of the primary tumor and/or the metastatic lesions.

Staging

There are no specific staging criteria for carcinoids. The tumors are usually referred to as local, local/regional, or metastatic, with emphasis on the extent and location of metastatic disease.

Treatment Overview

Surgery is the standard therapy. The extent of disease spread is important in deciding treatment options.

Surgery Surgical removal of the tumor is the standard treatment for cure. If the primary tumor is localized and can be removed, the five-year survival rate is in the range of 70 to 90 percent. Since carcinoid tumors are usually slow growing, even patients with tumors that can’t be removed have an average survival of several years. Surgery often offers excellent relief from symptoms—for example, by removing the liver metastases causing the carcinoid syndrome or by resecting or bypassing intestinal obstructions. Such surgery may add years to a patient’s life, an uncommon result of surgery for other types of liver metastases.

Radiation Radiation therapy may be used for symptomatic treatment of bone metastases.

Chemotherapy There has been modest success with chemotherapy. Drug combinations of 5-fluorouracil and streptozocin (Zanosar) have had responses of 10 to 30 percent. Clinical trials evaluating newer drugs are preferable.

Palliation Drugs such as Periactin (cyproheptadine), alpha- and beta adrenergic blockers, chlorpromazine (Thorazine), and corticosteroids may be used to alleviate the symptoms related to the carcinoid syndrome.

Octreotide (Sandostatin), a somatostatin analogue, is very effective in decreasing the secretion of serotonin and can help relieve symptoms of the carcinoid syndrome such as flushing, diarrhea, and wheezing. Interferon-alpha may alleviate symptoms and arrest tumor growth.

Treatment of Localized Tumors by Site

Appendiceal Carcinoids

Appendiceal tumors account for 22 percent of all carcinoids. They are treated by appendectomy and, in fact, are usually diagnosed for the first time at surgery. Lesions less than 3/4 inch (2 cm) in diameter are essentially 100 percent curable.

Appendiceal tumors larger than 3/4inch (2 cm) are rare and treated like a carcinoma of the colon. For these larger tumors, removal of the right side of the colon and the lymphatics is recommended.

Five-Year Survival 99 to 100 percent

Rectal Carcinoids

These account for a quarter of all carcinoids. Rectal carcinoids less than 1/2 inch (1 cm) can be treated adequately by local excision (fulguration), with cure rates approaching 100 percent.

Carcinoid lesions larger than 3/4 inch (2 cm) are treated surgically. As with carcinoma, an abdominal-perineal resection may be necessary, but sphincter-preserving surgery may be performed in some cases.

Lesions between 1/2 and 3/4 inch (1 to 2 cm) are in a “gray zone” and receive individualized treatment depending on age, operative risk, and acceptability of a colostomy. The cure rate is excellent.

Five-Year Survival 76 to 83 percent

Small Bowel Carcinoids

Small bowel tumors make up 28 percent of all carcinoids. Conservative local excision is sufficient for tumors less than 1/2 inch (1 cm) in diameter. For larger tumors, a wedge of the tissues supporting the bowel (mesentery) containing the regional lymph nodes should also be removed.

Anyone with a tumor larger than 3/4 inch (2 cm) should be followed closely for a minimum of ten years. The follow-up program should include quarterly or semiannual CT scan of the abdomen and measurements of CgA and urinary 5-HIAA levels.

Five-Year Survival 54 to 67 percent

Treatment of Invasive and Metastatic Carcinoids

Regional Gastrointestinal Carcinoids

Carcinoid tumors with regional metastasis or local extension should be treated by aggressive surgery. If all visible malignant disease can be removed, long-term survival rates will be excellent.

No surgical adjuvant treatment is known to be helpful.

If the regional disease cannot be removed, palliative surgery—to remove all the accessible disease, for example—should be carried out.

Chemotherapy is not required; these patients frequently have many months or even years of comfortable life without further treatment.

Metastatic Carcinoid Tumors

A number of standard treatment options are available for metastatic carcinoid tumors.

Surgery This has considerable value when there are large liver metastases involving surgically accessible areas of the liver. Liver metastases that recur after surgery should be considered for another resection if they are in an area where the operation can be done with minimal complications. Since these tumors are often slow growing, such surgery may result in significant improvement in life span.

• Radiofrequency ablation of liver metastasis is an option for multiple smaller tumors (less than 2?3/4 inches [7 cm]) and it is often used in conjunction with surgical removal of larger liver tumors. A needle is placed in the tumor, and radiofrequency current is transmitted. This current heats the tumor tissue, causing tumor cell death. The heat also closes up small blood vessels, thereby minimizing the risk of bleeding.

• For very carefully selected patients with slowly progressive disease and symptomatic carcinoid heart disease, heart valve replacement may be indicated.

Hepatic Artery Embolization This is an option for bulky or symptomatic liver metastases that are not surgically resectable. Hepatic artery embolization is used to reduce the blood flow through the hepatic artery, the artery that feeds most liver cancer cells. A material that can plug up the artery is injected. Most of the healthy liver cells will be unaffected because they get their blood supply from the portal vein. A catheter is inserted into an artery in the groin area and threaded up into the liver. A dye is usually injected into the bloodstream at this time to allow the doctor to see the path of the catheter by a special type of X-ray called angiography. Once the catheter is in place and it is confirmed that the portal vein is not blocked, small particles are injected into the artery, cutting off the blood supply to the tumor cells.

Embolization may be done with or without chemotherapy. This can lead to substantial tumor regression. It can also cause significant side effects—abdominal pain, fever, nausea, and a short-term worsening of the syndrome—but many patients do experience substantial relief from symptoms.

Embolizations are often performed over several procedures until the desired effect is appreciated, usually one month apart. This procedure can be repeated years later in the course of disease management.

Radiation The role of radiation therapy in managing carcinoid tumors with distant metastasis is restricted to relief of symptoms, most commonly from bone involvement. However, localized metastasis will occasionally respond to radiation therapy.

Supportive Therapy There are a number of ways to manage symptoms from metastatic disease with medication:

• Diarrhea, if not severe, will frequently respond to standard antidiarrheal medications such as Lomotil, Imodium, or tincture of opium and to dietary changes such as restricting consumption of foods high in fat.

• The somatostatin analogue octreotide (Sandostatin) has been shown to be useful in improving symptoms of the carcinoid syndrome and may be life saving in carcinoid crisis (sudden exacerbation of symptoms). It targets the cell receptors that control the abnormal production and release of the hormones that cause the syndrome and carcinoid heart disease. This method of therapy is the standard for reducing elevated levels of 5-HIAA.

• Interferon-alpha preparations may have a role in controlling symptoms of the carcinoid syndrome and/or in arresting tumor growth.

• Acute symptoms—carcinoid crisis—may be prevented by pretreatment, and an active crisis can be reversed with short-acting octreotide. Some specific drugs are to be avoided in these patients because of the risk of causing the release of vasoactive substances. This is especially true during surgery and in the treatment of low blood pressure.

Chemotherapy Although activity with a variety of single agents and drug combinations has been reported—5-fluorouracil (5-FU), doxorubicin (Adriamycin), and dacarbazine (DTIC) or 5-FU + streptozocin—response rates seldom exceed 30 percent. Complete responses are uncommon, and the duration of the response may be short, if chemotherapy is used alone.

Chemotherapy should be used for palliation in patients with symptoms and in the case of liver metastases, after blocking the hepatic (liver) artery and then giving chemotherapy (chemoembolization).

Investigational A novel approach has been introduced recently where octreotide is tagged with a radionuclide that kills tumor cells. This is given intravenously and targets tumor cells with somatostatin receptors. Newer drugs that target other molecular pathways are also being investigated.

Treatment Follow-Up

Patients should be evaluated every three to twelve months. The evaluation should include

• physical examination;

• twenty-four-hour urine 5-HIAA levels;

• chromogranin A;

• octreoscan, if required;

• chest X-ray, if required; and

• abdominal MRI or CT scan, if required. If a CT scan is used, it is preferable to use a three-phase scan.

Recurrent Cancer

The selection of further treatment depends on many factors, including the therapy initially used, the site of the recurrence, and individual considerations.

Since some tumors grow rather slowly, attempts to remove them again or multiple operations to remove liver metastases are worthy of consideration. Reducing tumor volume may provide long-term relief of symptoms.

Investigational treatments are appropriate and should be considered when standard treatment fails.

The Most Important Questions You Can Ask

• How are carcinoids different from the usual cancers of the bowel?

• What tests are needed to follow my progress after surgery?

• What does a rising urine 5-HIAA mean?

• What are the toxic side effects of chemotherapy?

• What is the role of repeated surgeries for recurrent carcinoid cancers?

• Am I eligible for any research or investigational protocols?