Carcinoid syndrome medical therapy

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Parminder Dhingra, M.D. [2]

Overview

The predominant therapy for carcinoid syndrome is surgical resection. Supportive therapy for carcinoid syndrome includes somatostatin analogs, interferons, and radionuclides.

Medical Therapy

Standard treatments for patients with gastrointestinal (GI) carcinoid tumors include the following:

• Somatostatin analogs
• Telotristat
• Interferons
• Treatment of hepatic metastases
• Radionuclides
• Management of carcinoid-related fibrosis
• Surgery

Somatostatin Analogs

• Somatostatin acts by binding to somatostatin receptors expressed on the majority of carcinoid tumors
• Flushing and diarrhea are significantly improved in over 80 percent of patients with the carcinoid syndrome with somatostatin therapy.
• Experimentally, somatostatin has been shown to have a cytostatic effect on tumor cells. This effect involves hyperphosphorylation of the retinoblastoma gene product and G1 cell cycle arrest, in addition to somatostatin receptor (SSTR) subtype 3 [sst(3)]-mediated (and to a lesser extent, SSTR subtype [sst(2)]-mediated) apoptosis.

• Somatostatin also appears to have some antiangiogenic properties. However, only a small number of patients treated with somatostatin analog therapy experience partial tumor regression.
• Octreotide, a short-acting somatostatin analog and the first biotherapeutic agent used in the management of carcinoid tumors, exhibits beneficial effects that are limited to symptom relief, with about 70% of patients experiencing resolution of diarrhea or flushing.
• Lanreotide, a long-acting somatostatin analog administered every 10 to 14 days, has an efficacy similar to that of octreotide and an agreeable formulation for patient use. The effects of lanreotide on symptom relief are comparable to those of octreotide, with 75% to 80% of patients reporting decreased diarrhea and flushing. However, there appears to be little improvement in tumor responses over shorter-acting octreotide.
• Depot formulations include long-acting repeatable (LAR) octreotide and a slow-release depot preparation of lanreotide.
• The typical duration of treatment with somatostatin analogs is approximately 12 months because of the development of tachyphylaxis (reported less frequently with long-acting formulations) and/or disease progression.

Adverse effects of somatostatin analog administration include:

• Nausea
• Cramping
• Loose stools
• Steatorrhea
• Cardiac conduction abnormalities and arrhythmias
• Endocrine disturbances (e.g., hypothyroidism, hypoglycemia, or hyperglycemia)
• Gastric atony

Telotristat

• Telotristat is a oral inhibitor of tryptophan hydroxylase which catalyzes the conversion of l-tryptophan into serotonin.
• Tryptophan hydroxylase is an aromatic amino acid hydroxylase and is the rate-limiting enzyme in serotonin synthesis.
• Somatostatin analogs (SSAs) are the mainstay of treatment, but are unable to ameliorate symptoms in all patients due to dose-limiting side effects and tachyphylaxis.
• Telotristat represents a significant advance in the treatment of carcinoid syndrome diarrhea in patients who have inadequate control on long-acting SSAs and should be considered for patients with >4 bowel motions per day on SSAs.

Interferons

• The most researched interferon in the treatment of carcinoid disease is interferon-alpha (IFN-alpha); comparable to somatostatin analogs, the most pronounced effects of IFN-alpha are inhibition of disease progression and symptom relief, with approximately 75% of patients reporting the resolution of diarrhea or flushing.

• IFN-alpha may show greater anti-tumor activity than somatostatin analogs. Both single-agent and multiagent chemotherapeutics appear to have little role in the management of these essentially chemoresistant tumors, no protocol has shown objective tumor response rates greater than 15%.

Treatment of Hepatic Metastases

The management of hepatic metastases may include:

• Surgical resection
• Hepatic artery embolization
• Cryoablation and Radiofrequency ablation (RFA)
• Orthotopic liver transplantation

Radionuclides

The four radionuclide conjugates most commonly used in the treatment of carcinoid disease are:

• 131I-MIBG (iodine-131-meta-iodobenzylguanidine)
• Indium-111
• Yttrium-90
• Lutetium-177

Management of Carcinoid-Related Fibrosis

Currently, there is no effective pharmacologic therapy for bowel obstruction and heart failure secondary to peritoneal fibrosis and right-sided valvular fibrosis respectively. In the instance of bowel obstruction, surgical lysis of the adhesions often is technically demanding because of the cocoon-like effects of extensive fibrosis stimulated by the various tumor-derived growth factors. Valvular replacement usually is required to manage carcinoid heart disease.

Symptomatic Therapy

• In addition to the use of long-acting depot formulations of somatostatin analogs as the principal agents in the amelioration of carcinoid symptoms, the nonspecific supportive care of patients includes, advising them to avoid factors that induce flushing or bronchospastic episodes including the following:

• Ingestion of alcohol, certain cheeses, capsaicin-containing foods, and nuts
• Stressful situations
• Physical activity

• Diarrhea may be treated with conventional anti-diarrheal agents such as loperamide or diphenoxylate, more pronounced diarrhea may be treated with the 5-HT receptor subtype 2 antagonist cyproheptadine, which is effective in as many as 50% of patients and may also help alleviate anorexia or cachexia in patients with a malignant carcinoid syndrome.

• Histamine 1 receptor blockade with fexofenadine, loratadine, terfenadine, or diphenhydramine may be of benefit in treating skin rashes, particularly in histamine-secreting gastric carcinoid tumors.

• Bronchospasm can be managed with theophylline or beta-2 adrenergic receptor agonists such as albuterol.

References

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