Sandostatin LAR Depot Text

Carcinoid Diagnosis

The diagnosis of carcinoid syndrome is complicated by the fact that many of the symptoms—at least in the early stages—are nonspecific, mimicking those of conditions such as irritable bowel syndrome¹.

This section will cover both detection and testing methods for carcinoid syndrome, including:

• Initial Diagnosis
• Chromogranin A (CgA) Testing
• 5-hydroxyindoleacetic Acid (5-HIAA) Testing
• Diagnostic Imaging
• Ki-67 Testing

Detection of Carcinoid Tumors or Carcinoid Syndrome

Detection of carcinoid tumors or carcinoid syndrome may occur in a variety of ways.

• In the majority of cases, the flushing, diarrhea, and other symptoms of carcinoid syndrome trigger recognition of this condition¹
• In about 20% of patients with carcinoid disease, the presenting symptoms may be due to heart disease²
• In some cases, intestinal symptoms caused by primary tumors (eg, abdominal pain or intestinal bleeding) are the presenting complaint³
• In other cases, tumors are found incidentally during unrelated surgical procedures, such as an appendectomy³

Initial Diagnosis

Initial staging of the disease involves the following:

• Patients with carcinoid syndrome have significantly elevated serum levels of serotonin or its metabolites, of which the most important is 5-HIAA³
• Thus, measurement of urinary 5-HIAA is the most commonly used diagnostic test for carcinoid syndrome with a sensitivity of 73% and a specificity of 88%^3,4
• Other molecules that may be increased in carcinoid syndrome are substance P (sensitivity: 32%, specificity: 85%) and CgA (sensitivity: 10% to 100%, specificity: 68% to 100%). CgA, in particular, may be a useful biochemical marker for carcinoid tumors^3,5,6
• The diagnosis and management of patients with neuroendocrine cancer has been enhanced through the application of somatostatin receptor scintigraphy (SRS), using OctreoScan™* (indium In ¹¹¹), a radiolabeled analogue of somatostatin⁵
  • 88% of carcinoid tumors have high-affinity receptors for somatostatin³
  • SRS is recommended as the initial imaging procedure to use to stage carcinoid tumors due to its sensitivity and ability to detect metastases throughout the body^3,7
• A number of imaging modalities contribute to tumor localization³:
  • Imaging studies such as computed tomography (CT) scan, magnetic resonance imaging (MRI), ultrasound, and GI endoscopy
• Since right-sided heart disease is a frequent complication, echocardiography is useful for detecting the presence of cardiac abnormalities²

*OctreoScan is a trademark of Covidien AG or one of its affiliates.

Plasma CgA

CgA is ubiquitous in endocrine tissues and the measurement of CgA is considered the gold standard of biochemical tests for confirming the diagnosis of carcinoid and neuroendocrine tumors and following their course. There is a clear correlation between tumor burden and serum CgA concentrations. High levels of CgA in carcinoid patients are indicative of high tumor burden^5,8.

The highest levels of serum CgA (up to 1000 times the upper limit of the normal range) have been found in patients with metastatic carcinoid tumors. In patients with midgut carcinoid tumors, an elevated CgA level is an independent predictor of death. The survival at 5 years in patients with high CgA is 22%, while it is 63% in patients with low CgA. As such, CgA measurements have become the most important parameter for monitoring disease spread and are used to follow the results of treatment. CgA is a stable molecule and no special precaution is needed to handle or store the serum or plasma. Most assays are sensitive enough to measure CgA in normal patients. Elevations can be seen in conditions other than carcinoid tumors such as renal or hepatic failure, and only slight elevations may be seen in inflammatory conditions of the bowel, such as ulcerative colitis and Crohn's disease^9-11.

How the CgA Test Works¹²

A typical CgA test measures serum CgA using enzyme immunoassay technology. Measurements may vary with meal consumption and should be drawn fasting.

• An enzyme-conjugated antibody, also specific to CgA, is incubated with the serum specimen that allows the 2 antibodies to bind the CgA protein as a "sandwich"
• After unbound materials are washed away, a substrate is added
• The conjugated enzyme uses this substrate to produce color
• The intensity of color is proportional to the specimen's CgA concentration

What to Expect:

Elevated CgA levels are detected in approximately 8 of 10 patients with carcinoid tumors⁸. Although this test does not differentiate carcinoid tumors from other neuroendocrine tumors (NETs) or gastroenteropancreatic (GEP) tumors, it is an accurate but not very sensitive test for NETs and GEPs, with a sensitivity and specificity varying between 10% to 100% and 68% to 100%, respectively⁵.

When to Test^5,10,13,14

CgA tests should be performed every 3 to 6 months.

Urinary 5-HIAA³

Urinary 5-HIAA—the primary biochemical marker for midgut carcinoid tumors and, less often, foregut tumors—is the metabolite of serotonin that is broken down by the liver and excreted via the kidneys.

An elevated 5-HIAA level is associated with a classic carcinoid syndrome of flushing, diarrhea, and carcinoid heart disease. The 24-hour urinary 5-HIAA as a measure of the biochemical activity of these tumors is preferred over plasma serotonin, which is highly variable over a 24-hour period. Elevated levels of urinary 5-HIAA generally occur at advanced stages of disease and generally indicate the presence of liver metastases¹⁴. Elevated urinary 5-HIAA levels have been associated with shorter survival than those with normal levels. The severity of elevation of urinary 5-HIAA also correlates with the severity of carcinoid syndrome, and the highest levels of the metabolites are observed in patients with heart failure¹⁵. Urinary 5-HIAA is a useful biochemical marker that is widely available; however, false positive results are still possible. 5-HIAA testing has a specificity of approximately 88%. Certain serotonin-rich foods (bananas, avocados, plums, eggplant, tomatoes, plantains, pineapples, and walnuts) can increase urinary 5-HIAA levels and should be avoided during specimen collection¹⁴.

How the 5-HIAA Test Works^5,15:

Serotonin synthesized by carcinoid tumors is secreted into the circulation, taken up by platelets, and stored in granules. Most of the serotonin remaining in plasma is converted to 5-HIAA, which is excreted into the urine. The testing then proceeds as follows¹⁶:

• Dietary and medicinal intake controlled
• Assessment of 5-HIAA by high-performance liquid chromatography with electrochemical detection
• Total serotonin production is analyzed

What to Expect:

5-HIAA testing has a sensitivity of 73% and a specificity of 88% for carcinoid tumors³.

When to Test:

5-HIAA tests should be performed every 3 to 6 months¹⁴.

 

Diagnostic Imaging

Diagnostic imaging plays a key role in diagnosing and monitoring NETs. There are multiple imaging techniques available to diagnose, stage, and monitor the progression of NETs¹⁶:

 

 

OctreoScan™ (somatostatin receptor scintigraphy) of a patient with liver metastasis from a carcinoid tumor. The primary tumor located in the distal ileum also is present in the figure.

Ultrasonography of liver metastases from a patient with carcinoid tumor. Ultrasound-guided biopsy can be taken during this procedure. CT picture of liver metastases in a patient with an endocrine pancreatic tumor.

Somatostatin Receptor Scintigraphy (SRS) Testing Using OctreoScan™

Clinical experience has established SRS as one of the imaging techniques of choice for carcinoid tumors⁵. High-affinity somatostatin receptors, including somatostatin receptor subtype 2 (sst-2) are found on 88% to 100% of carcinoid tumors. These receptors are found on both the primary tumor and the metastases^5,23,25-27. Because the somatostatin analogue octreotide binds with high specificity to sst-2 and sst-5 receptors⁷,radiolabeled octreotide probes for initial whole body imaging have been useful^3,25. SRS will not detect the ~10% of tumors that fail to express somatostatin receptors²⁸. Additionally, the detection limit is about 0.5 cm. The advantage of SRS over conventional computed tomography or magnetic resonance imaging—which are localized to the suspected disease sites—is the ability to image all body regions with high sensitivity and selectivity, allowing evaluation of tumors for potential octreotide palliation therapy^8,23. An additional advantage is that SRS testing allows for estimation on somatostatin receptor density²⁹.

In addition to imaging somatostatin-rich tumors, the normal pituitary gland, thyroid gland, liver, spleen, urinary bladder, and bowels may also be visualized³⁰.

SRS Whole-Body Scan (OctreoScan™*)

Image acquired 24 hours postinjection, revealing multiple
carcinoid tumors in the liver, pelvis, abdomen, and brain.

*OctreoScan™ is a trademark of Covidien AG or one of its affiliates.

How SRS Testing Works²⁵:

• Intravenous administration
• Planar images taken 4 hours postinjection (40-minute duration)
• Planar and single photon emission computed tomography images obtained 24 hours postinjection (2-hour duration)
• Additional images may be needed 48 hours postinjection

Determining the extent of cell proliferation

The Ki-67 protein (also known as antigen identified by monoclonal antibody Ki-67 or MKI67) is a cellular marker for proliferation. This proliferation index can be used to determine the rate of tumor cell growth fraction. A high Ki-67 index, coupled with a high mitotic count, may call for more aggressive treatment alternatives like chemotherapy and interferon-alpha in most cases^5,32.

Important Safety Information

Carcinoid Syndrome:

Sandostatin^® LAR Depot (octreotide acetate for injectable suspension) is indicated for long-term treatment of the severe diarrhea and flushing episodes associated with metastatic carcinoid tumors and for the long-term treatment of the profuse watery diarrhea associated with VIP-secreting tumors in patients in whom initial treatment with immediate release Sandostatin^® (octreotide acetate) Injection has been shown to be effective and tolerated.

Important Safety Information:

As with immediate release Sandostatin^® Injection, the most frequently reported drug-related adverse events were biliary disorders (62%), gastrointestinal disorders (14% to 38%), and injection-site pain (20% to 50%). Hypoglycemia (4%), hyperglycemia (27%), sinus bradycardia (19%), conduction abnormalities (9%), and arrhythmias (3%) have been reported.

The controlled clinical trials that support the marketing clearance for Sandostatin^® LAR Depot did not include determination of effect on tumor size or rate of growth. Sandostatin^® LAR Depot is not indicated for tumor shrinkage.

Acromegaly

Sandostatin^® LAR Depot (octreotide acetate for injectable suspension) is indicated for long-term maintenance therapy in acromegalic patients who have had an inadequate response to surgery and/or radiotherapy, or for whom surgery and/or radiotherapy is not an option. The goal of treatment in acromegaly is to reduce GH and IGF-1 levels to normal.

Important Safety Information:

As with immediate release Sandostatin^® Injection, the most frequently reported drug-related adverse events were biliary disorders (52%), gastrointestinal disorders (7% to 36%), and injection-site pain (2% to 11%). Hypoglycemia (2%), hyperglycemia (15%), and hypothyroidism (2%) have been reported. While not measured in acromegalic patients receiving Sandostatin^® LAR Depot, ECG changes have been reported in patients receiving immediate release Sandostatin^® Injection; the degree to which these abnormalities are related to octreotide acetate is not clear, as many acromegalics have cardiovascular disease. You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch or call 1-800-FDA-1088.

References