Sandostatin LAR Depot Text

Epidemiology and Pathophysiology of
Carcinoid Syndrome

This section contains the following information on carcinoid tumors and carcinoid syndrome:

• Epidemiology and Pathophysiology
• Serotonin Metabolism in Carcinoid Syndrome
• Clinical Symptoms of Carcinoid Syndrome
• VIPomas

Epidemiology and Pathophysiology of Carcinoid Tumors

Carcinoid tumors originate from the diffuse neuroendocrine system, specifically the enterochromaffin (EC) cells. EC cells are widely distributed throughout the body, but are most prevalent in the submucosa of the intestine and main bronchi¹. Carcinoid tumors—the most frequently occurring NETs of the gastrointestinal tract—are generally characterized by their ability to produce peptides that lead to hormonal syndromes^2,3. As such, they can be both symptomatic and asymptomatic⁴. Clinically, tumors are considered to be "functioning" when their hormone secretions produce symptoms such as severe diarrhea and flushing. When they do not, they are considered to be "nonfunctioning" tumors⁴. The majority of carcinoid tumors originate in the gastroenteric system. Carcinoid tumors are generally classified as foregut, midgut, or hindgut depending on their embryonic origin⁴.

Carcinoid Syndrome

Malignant carcinoid syndrome, the predominant clinical feature of carcinoid tumors, results from excessive secretion of hormone products into the systemic circulation. These hormones (peptides and amines) cause the extreme symptoms of the disease, such as severe diarrhea and flushing, and a reduction in their circulating blood concentrations through treatment is a therapeutic goal^4,7,8,10.

Gastrointestinal peptides and amines secreted by carcinoid tumors⁹:

• ACTH
• Gastrin
• Pancreatic polypeptide
• Insulin
• Tachykinins
• Vasoactive intestinal polypeptide (VIP)
• Serotonin

Serotonin Metabolism in Carcinoid Syndrome

Many of the symptoms of carcinoid syndrome are produced by serotonin or its metabolites. Serotonin metabolism in carcinoid disease is illustrated below⁹.

Serotonin Metabolism in Carcinoid Disease

Functioning carcinoid tumors hypersecrete serotonin that is converted to 5-HT, processed by the kidneys, and secreted as 5-HIAA in the urine⁹.

The Clinical Symptoms of Carcinoid Syndrome

Malignant carcinoid tumors can metastasize to distant sites. Small-bowel carcinoids most frequently metastasize to the liver. Secretions of hormones and bioactive amines by the malignant carcinoid cells may lead to development of carcinoid syndrome resulting in characteristic symptoms, the most frequent of which are listed below^3,9,13:

• Arthritis
• Bronchospasms/wheezing
• Carcinoid heart disease
• Cutaneous flushing
• Severe diarrhea
• Fibrosis
• Increased skin pigmentation

Diagnosis and Treatment

• Although it is the most common systemic clinical manifestation of carcinoid tumors, carcinoid syndrome occurs in fewer than 10% of patients with carcinoid tumors¹¹
• Many cases of carcinoid tumors are discovered incidentally during routine appendectomy or during GI endoscopy and abdominal computed tomography (CT)^4,8
• Surgical removal of the tumors is the primary therapeutic option; chemotherapy is less effective¹
• The most common initial diagnosis is irritable bowel syndrome^6,12
• Frequently, carcinoid syndrome is diagnosed only with the sudden onset of severe symptoms that accompany metastases^6,12
• Octreotide is the primary medical therapy for the management of severe diarrhea and flushing associated with carcinoid syndrome^13,14

Octreotide may alter absorption of dietary fats. Monitoring of vitamin B₁₂ levels is recommended during therapy with Sandostatin^® LAR Depot. Patients on total parenteral nutrition (TPN) and octreotide should have periodic monitoring of zinc levels.

The 2 most prominent symptoms of carcinoid syndrome:

Flushing^4,9,18:

• Flushing, the most frequent symptom, may occur spontaneously or be precipitated by stress, alcohol, certain foods, exercise, or pharmacologic agents
• Flushing episodes may be brief (2 to 5 minutes) or last for several hours, particularly in later stages of the disease
• Flushing caused by carcinoid tumors is often not associated with sweating (dry flushing), which is unlike menopausal flushing, which is neurally activated and frequently associated with sweating (wet flushing)

Severe Diarrhea⁹:

• Severe diarrhea usually accompanies flushing but occurs alone in approximately 15% of cases; abdominal pain or cramping may be associated with severe diarrhea
• Other symptoms include a unique type of endocardial fibrosis and wheezing or asthma-like symptoms
• Myopathy, arthritis, arthralgias, and changes in mental state are reported, although only rarely

VIPomas

VIPomas are rare endocrine tumors that occur with an annual incidence of 1 per 10 million ¹⁶. VIPomas are:

• Often large, solitary tumors that occur primarily (80% to 90%) in the pancreas¹
• Characterized by severe symptoms^1,5

• Associated with secretory diarrhea, a major marker of VIPoma syndrome, which is severe and of a high volume, ie, usually more than 3 L/day^1,16
• Diagnosed based on the demonstration of elevated vasoactive intestinal peptide (VIP) in plasma and presence of large volume secretory diarrhea¹
• Associated with VIPoma syndrome, often referred to as pancreatic cholera, Verner-Morrison syndrome, or watery diarrhea, hypokalemia, and achlorhydria (WDHA)^1,16

INDICATIONS AND USAGE

Sandostatin^® LAR Depot (octreotide acetate for injectable suspension) is indicated for patients in whom initial treatment with immediate release Sandostatin^® (octreotide acetate) Injection has been shown to be effective and tolerated for:

• Long-term maintenance therapy in acromegalic patients who have had 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).
• Long-term treatment of the severe diarrhea and flushing episodes associated with metastatic carcinoid tumors.
• Long-term treatment of the profuse watery diarrhea associated with VIP-secreting tumors.

In patients with carcinoid syndrome and VIPomas, the effect of Sandostatin Injection and Sandostatin LAR Depot on tumor size, rate of growth and development of metastases has not been determined.

IMPORTANT SAFETY INFORMATION

Warnings and Precautions:

• Gallbladder abnormalities may occur: Patients should be monitored periodically.
• Glucose Metabolism: Hypoglycemia or hyperglycemia may occur. Blood glucose levels should be monitored when Sandostatin LAR Depot treatment is initiated or when the dose is altered. Antidiabetic treatment should be adjusted accordingly.
• Thyroid Function: Hypothyroidism may occur. Baseline and periodic assessment of thyroid function (TSH, total and/or free T4) is recommended.
• Cardiac Function: Bradycardia, arrhythmia, conduction abnormalities, and other EKG changes may occur. The relationship of these events to octreotide acetate is not established because many of these patients have underlying cardiac disease. Use with caution in at-risk patients.
• Nutrition: Octreotide may alter absorption of dietary fats. Monitoring of vitamin B₁₂ levels is recommended during therapy with Sandostatin LAR Depot. Patients on total parenteral nutrition (TPN) and octreotide should have periodic monitoring of zinc levels.

Drug Interactions: The following drugs require monitoring and possible dose adjustment when used with Sandostatin LAR Depot: cyclosporine, insulin, oral hypoglycemic agents, beta-blockers, bromocriptine. Octreotide has been associated with alterations in nutrient absorption, so it may have an effect on absorption of orally administered drugs. Drugs mainly metabolized by CYP3A4 and which have a low therapeutic index should be used with caution.

Adverse Reactions: The most common adverse reactions occurring in patients receiving Sandostatin LAR Depot are:

• Acromegaly: biliary abnormalities (52%), diarrhea (36-48%), cholelithiasis (13-38%), abdominal pain or discomfort (11-29%), flatulence (26%), influenza-like symptoms (20%), constipation (19%), headache (15%), anemia (15%), hyperglycemia (15%), injection site pain (2-14%), hypertension (13%), dizziness (12%), fatigue (11%), nausea (10%), vomiting (7%), hypothyroidism (2%), hypoglycemia (2%), and goiter (2%).
• Carcinoid Tumors and VIPomas: biliary abnormalities (62%), injection site pain (20-50%), nausea (24-41%), abdominal pain (10-35%), fatigue (8-32%), headache (16-30%), hyperglycemia (27%), back pain (8-27%), constipation or vomiting (15-21%), dizziness (18-20%), sinus bradycardia (19%), pruritus (18%), URTI (10-18%), myalgia (4-18%), flatulence (9-16%), arthropathy (8-15%), rash (15%), generalized pain (4-15%), sinusitis (5-12%), conduction abnormalities (9%), hypoglycemia (4%), and arrhythmia (3%).

References