Sandostatin LAR Depot Text

Epidemiology and Pathophysiology of NETs
and Carcinoid Tumors

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

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

Neuroendocrine tumors

Tumors arising from enterochromaffin cells located in neuroendocrine tissue throughout the body are commonly referred to as neuroendocrine tumors (NETs). NETs present with a variety of functional and nonfunctional symptoms and include a heterogeneous group of neoplasms^1,2:

• Multiple endocrine neoplasia, type 1 and type 2/medullary thyroid carcinoma
• Carcinoid tumor
• Islet cell tumors
• Pheochromocytoma/paraganglioma
• Poorly differentiated/small cell/atypical lung carcinoid
• Small cell carcinoma of the lung
• Merkel cell carcinoma

Survival rates based on tumor classification^3-5

The survival probability associated with the incidence of NETs is dependent on the classification of the tumor at the time of diagnosis. In the case of localized and regional tumors, the median survival rates have not changed much since 1973; however, in the case of distant NETs, there has been some improvement in the median survival rate since 1973, and this may be due to improved diagnostic and monitoring techniques.

Carcinoid tumors—the most frequently occurring
gastrointestinal NETs^1,6,7

Generally defined as slow-growing tumors, carcinoid tumors—the most frequently occurring NETs of the gastrointestinal tract—can be both symptomatic and asymptomatic. Nonfunctioning carcinoid tumors generally do not produce the range of symptoms associated with functioning carcinoid tumors, though they may still be active. Nonfunctioning carcinoid tumors can be harder to diagnose, due to the vague nature of subtle symptoms that often mirror other gastrointestinal disorders, such as irritable bowel syndrome.

Active carcinoid tumors lead to carcinoid syndrome

After the onset of clinical symptoms, median survival times of 3.5 to 8.5 years have been reported; 5-year survival has ranged from 30% to 67%⁸.

• The prognosis for poor patient outcome generally correlates inversely with increasing levels of urinary 5-HIAA excretion⁹
• Other biochemical indicators of a bad prognosis are high levels in the plasma of neuropeptide K and chromogranin A (CgA)⁹
• Patients with fewer liver metastases have longer life expectancies^{4, 9}
• Patients with extensive liver metastases should be treated more aggressively since they have a worse prognosis⁹
• Factors associated with an increased risk of poor prognosis are the following^5,9:
  • Advanced stage of the disease
  • Tumors located in the large bowel
  • Occurrence of another malignancy

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 bronchi⁸.

Carcinoid tumors have an overall incidence rate of 2.5 to 5 cases per 100,000 in the United States. Carcinoid tumors are generally characterized by their ability to produce peptides that lead to hormonal syndromes. Carcinoid lesions comprise about 50% of all gastrointestinal (GI) neuroendocrine tumors and their presence may be undetected for years without obvious signs or symptoms^5-7,10.

The majority of carcinoid tumors originate in the gastroenteric system. Carcinoid tumors are generally classified as foregut, midgut, or hindgut depending on their embryonic origin^11,12:

• Foregut tumors develop in the respiratory tract, thymus, stomach, duodenum, and pancreas
• Midgut tumors develop in the small bowel, appendix, and ascending colon
• Hindgut tumors develop in the transverse colon, descending colon, or rectum
• Primary occurrence in the appendix (38%), ileum (23%), rectum (13%), and bronchus (11.5%)⁸
• Occurrence with an incidence of less than 1% in the pancreas, gallbladder, liver, ovaries, larynx, and testes, but these tumors have a high incidence of metastases⁸

In women, the primary tumor sites are the lungs, stomach, appendix, and rectum, while in men the primary tumor sites are the stomach, duodenum, pancreas, jejunum/ileum, or rectum⁵.

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, and a reduction in their circulating blood concentrations through targeted 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 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:

• Although it is the most common systemic clinical manifestation of carcinoid tumors, carcinoid syndrome occurs in fewer than 10% of patients with carcinoid tumors¹⁴
• The likelihood of occurrence and the associated severity of carcinoid syndrome depend on several factors: tumor size, tumor location, and the degree of metastasis³
• Many cases of carcinoid tumors are discovered incidentally during routine appendectomy or during GI endoscopy and abdominal computed tomography (CT)^6,9
• Due to their slow-growing nature and the constellation of vague symptoms associated with these tumors, diagnosis often occurs after the disease becomes metastatic⁹
• The incidence of metastases in carcinoid tumors is less than 2% in tumors smaller than 1 cm and almost 100% in tumors greater than 2 cm^6,7
• Surgical removal of the tumors is the primary therapeutic option; chemotherapy is less effective⁸
• Octreotide is the primary medical therapy for the management of certain symptoms associated with carcinoid syndrome^15,16
• Patient age at diagnosis ranges widely—from 10 to 93 years; however, carcinoid tumors are most frequently reported between 50 and 70 years with a mean of approximately 55 years⁸
• Patients presenting with vague or nonspecific abdominal symptoms can often go 5 to 7 years before receiving an accurate diagnosis⁶
• The most common initial diagnosis is irritable bowel syndrome^7,17
• Generally, carcinoid syndrome is diagnosed only with the sudden onset of severe symptoms that accompany metastases^7,17

Once considered rare, carcinoid tumors are slowly becoming an increasing threat in the United States, creating an urgent need for earlier diagnosis, timely intervention, and symptom control⁶.

The delay in diagnosis spans 2 to 20 years and reflects the diffuse features of the disease and the need for early symptom recognition and continual monitoring⁹.

A slow onset of symptoms can often lead to a delay in diagnosis⁷

Courtesy of Aaron I. Vinik, MD, PhD, FCP, MACP

Clinical Symptoms of Carcinoid Syndrome

A variety of different symptoms are associated with carcinoid syndrome:

Clinical Presentation of Carcinoid Syndrome

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)

Diarrhea⁹:

• Diarrhea usually accompanies flushing but occurs alone in approximately 15% of cases; abdominal pain or cramping may or may not be associated with 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

Carcinoid heart disease: A dangerous complication^2,9,14,19

Carcinoid heart disease, caused by the exposure of the heart to elevated concentrations of serotonin and other vasoactive substances, occurs in up to two-thirds of patients with carcinoid syndrome and is responsible for one-third of patient deaths.

• Lesions are characterized by plaque-like, fibrous endocardial thickening, involving predominantly the right side of the heart (tricuspid and pulmonic valves)
• Right-sided heart failure is irreversible and can lead to significant morbidity/mortality
• Patients with carcinoid heart disease have a 5-year survival of approximately 20% versus approximately 50% for those without carcinoid heart disease

Tricuspid valve

VIPomas

VIPomas are rare endocrine tumors that occur with an annual incidence of 1 per 10 million (20). VIPomas are:

• Often large, solitary tumors that occur primarily (80% to 90%) in the pancreas⁸
• Characterized by severe symptoms^4,8

• 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^8,20
• Diagnosed based on the demonstration of elevated vasoactive intestinal peptide (VIP) in plasma and presence of large volume secretory diarrhea⁸
• Associated with VIPoma syndrome, often referred to as pancreatic cholera, Verner-Morrison syndrome, or watery diarrhea, hypokalemia, and achlorhydria (WDHA)^8,20

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