Carcinoid syndrome medical therapy

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Parminder Dhingra, M.D. [2] Anum Gull M.B.B.S.[3]

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

Standard treatments for patients with gastrointestinal carcinoid tumors include the following:^[1]

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

• Somatostatin analogs includes octreotide and lanreotide.
• 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.^[2]
• 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.^[3]
• 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.

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 is an oral inhibitor of tryptophan hydroxylase which catalyzes the conversion of l-tryptophan into serotonin..^[4]
• 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 somatostatin analogues and should be considered for patients with >4 bowel motions per day on somatostatin analogues.

• The most researched interferon in the treatment of carcinoid disease is interferon-alpha.
• Interferon-alpha (IFNα) is a cytokine that mediates anti-viral, anti-proliferative and anti-tumour activities.

• Side-effects includes

1. Flu-like symptoms
2. Chronic fatigue
3. Depression
4. Anemia
5. Neutropenia.

The management of hepatic metastases may include:

• Surgical resection
• Hepatic artery embolization especially when complemented by the addition of regional chemotherapy (trans-arterial chemoembolization or TACE)^[5]
• Cryoablation and Radiofrequency ablation (RFA)
• liver transplantation^[6]

• The use of somatostatin analogue radiolabeled peptide therapy (PRRT) provides radiation directed to the cells that express somatostatin receptors.^[7]
• 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
• It is mandatory to quantify cells with somatostatin receptors using imaging prior to PRRT therapy.

• 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.^[8]

• Nonspecific supportive care of patients is to avoid factors that induce flushing or bronchospastic episodes includes 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
• Severe 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.

• Treatment of skin rashes, particularly in histamine-secreting gastric carcinoid tumors can be done with histamine 1 receptor blockade with fexofenadine and loratadine

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

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