Background     The carcinoid syndrome (CS) is a symptom complex resulting from hormone secretion in patients with carcinoid tumors.  Carcinoid tumors typically grow slowly, and patients may live for many years following diagnosis.  CS becomes manifested only when sufficient concentration of hormones reaches the systemic circulation, most commonly in the presence of liver metastases.  This Fast Fact will focus on managing the symptoms of CS.

Symptoms and causes     The CS includes the complex of: flushing, diarrhea, abdominal cramping, cyanosis, bronchoconstriction, and symptoms of right heart failure. Compared with the general population and other cancer patients, CS sufferers may also be at increased risk for cognitive impairment.  Other specific symptoms depend on the hormones the tumor secretes.  Serotonin-secreting tumors cause diarrhea and abdominal cramping; bradykinin and histamine secretion lead to flushing and cyanosis. Carcinoid tumors may also produce somatostatin, norepinephrine, dopamine, gastrin, vasoactive intestinal peptide, and other hormones. Drugs that block the hormonal secretion can help to control the symptoms of carcinoid syndrome.

Diagnosis:  Usually CS is diagnosed clinically.  Supportive diagnostic tests include 24-hour urinary excretion of 5-hydroxyindoleacetic acid (5-HIAA) and tumor localization through imaging and endoscopy.

Somatostatin Analogs     These drugs are the treatment of choice for CS. Three formulations are available: short-acting octreotide (continuous infusion or 50-500 mcg TID, IV or subcutaneously); depot octreotide (standard dose is 30 mg intramuscularly every 4 weeks; however, doses up to 40 to 60 mg every 4 weeks may offer added benefit); and lanreotide (standard dosing is 30 mg every other week intramuscularly). 50-70% of patients experience a significant reduction of diarrhea and flushing episodes within seven days.  Efficacy and side effect profiles for the three preparations are similar. Side effects include pain at the injection site, abdominal bloating, fatigue, transient fever, elevated serum glucose, and asymptomatic biliary lithiasis. Annual cost varies between $25,000-$60,000, but most insurances cover it.

Interferon     Interferon alpha is effective in controlling both diarrhea and flushing, although it is inferior to the somatostatin analogs.  The dose is 3-9 mU subcutaneously three to seven times per week.  Interferon alpha therapy is often limited by its side effects: fever, anemia, thrombocytopenia, neutropenia, fatigue, depression, and flu-like symptoms.

Telotristat:  this medication is an oral tryptophan hydroxylas inhibitor.  It has been approved in the United States for the treatment of refractory diarrhea in adults with CS that is inadequately controlled by somatostatin therapy alone.  The recommended dose is 250 mg three times a day with food.  Nausea and depression are common side effects at higher doses.  Annual cost averages around $90,000 but most insurances will cover it.

Other symptom-specific treatments 

• Diarrhea:  Besides somatostatin analogs, interferon, and telostristat, cyproheptadine is an alternative treatment for carcinoid-associated diarrhea.  60% of patients report improvement within one week.  The dosage is 4 mg TID given orally as a tablet; it can be titrated up to 0.5 mg/kg per day.  Side effects include sedation, dry mouth, dizziness, mild blurring of vision, nausea, and vomiting.  Loperamide and opioids are non-specific anti-diarrheal agents that can be used for mild symptoms.
• Wheezing: bronchodilators. 
• Heart failure: diuretics; tricuspid valve replacement.

Non-Drug Treatments     Patients should be counseled to identify and eliminate stressors that reproducibly cause symptoms—this may include specific stressful situations, foods, or alcohol.

Other     Other treatments for refractory symptoms include systemic chemotherapy, hepatic artery embolization, hepatic chemoembolization, or debulking surgery of hepatic metastases. Radiolabeled somatostatin analog 177-Lutetium Dotatate can be used for patients with somatostatin receptor expressing tumors. (13).

References 

1. Kulke, MH, Mayer, RJ. Medical progress: carcinoid tumors. N Engl J Med. 1999; 340:858-68.
2. Pasieka JL, Longman RS, et al. Cognitive impairment associated with carcinoid syndrome. Annals of Surgery 2014; 259:355-359.
3. di Bartololmeo M, Bajetta E, Buzzoni R, et al. Clinical efficacy of octreotide in the treatment of metastatic neuroendocrine tumors. A study by the Italian Trials in Medical Oncology Group. Cancer. 1996; 77:402-8.
4. Ruszniewski P, Ducreux M, Chayvialle J, et al. Treatment of carcinoid syndrome with the longacting somatostatin analogue lanreotide: a prospective study in 39 patients. Gut. 1996; 39:279-83.
5. Garland J, Buscombe JR, Bouvier C, et al. Sandostatin LAR (long-acting octreotide acetate) for malignant carcinoid syndrome: a 3-year experience. Aliment Pharmacol Ther. 2003; 17:437-44.
6. Strosberg JR, Benson AB, et al. Clinical benefits of above-standard dose of octreotide LAR in patients with neuroendocrine tumors for control of carcinoid syndrome symptoms: a multicenter retrospective chart review study. The Oncologist 2014; 19:930-936.
7. Moertel CG, Kvols LK, Rubin J. A study of cyproheptadine in the treatment of metastatic carcinoid tumor and the malignant carcinoid syndrome. Cancer. 1991; 67:33-6.
8. Oberg K, Funa K, Alm G. Effects of leukocyte interferon on clinical symptoms and hormone levels in patients with mid-gut carcinoid tumors and carcinoid syndrome. N Engl J Med. 1983; 309:129-33.
9. Sitaraman SV, Goldfinger SE. Treatment of carcinoid tumors and the carcinoid syndrome. In: Basow DS, ed. UpToDate. Waltham, MA; UpToDate; 2004.
10. Kunz PL, Reidy-Lagunes D, Anthony LB, Bertino EM, Brendtro K, Chan JA, Chen H, Jensen RT, Kim MK, Klimstra DS, Kulke MH, Liu EH, Metz DC, Phan AT, Sippel RS, Strosberg JR, Yao JC; North American Neuroendocrine Tumor Society. Consensus guidelines for the management and treatment of neuroendocrine tumors. Pancreas. 2013 May;42(4):557-77. doi: 10.1097/MPA.0b013e31828e34a4. PMID: 23591432; PMCID: PMC4304762.
11. TELESTAR (Telotristat Etiprate for Somatostatin Analogue Not Adequately Controlled Carcinoid Syndrome). CTG Labs – NCBI. (n.d.). https://www.clinicaltrials.gov/study/NCT01677910?term=telestar&checkSpell=false&rank=1&tab=results
12. https://documents.tersera.com/xermelo/XermeloPrescribingInformation.pdf.
13. Bushnell DL Jr, O’Dorisio TM, O’Dorisio MS, Menda Y, Hicks RJ, Van Cutsem E, Baulieu JL, Borson-Chazot F, Anthony L, Benson AB, Oberg K, Grossman AB, Connolly M, Bouterfa H, Li Y, Kacena KA, LaFrance N, Pauwels SA. 90Y-edotreotide for metastatic carcinoid refractory to octreotide. J Clin Oncol. 2010 Apr 1;28(10):1652-9. doi: 10.1200/JCO.2009.22.8585. Epub 2010 Mar 1. PMID: 20194865; PMCID: PMC4872330.
14. Pharmacoeconomic Review Report: Telotristat ethyl (Xermelo®): Indication: refractory carcinoid syndrome diarrhea, in combination with somatostatin analogue therapy (SSA) in patients inadequately controlled by SSA therapy alone.  Ottawa (ON): Canadian Agency for Drugs and Technologies in Health; 2019 July.

Version History:  This Fast Fact was originally edited by David E Weissman MD and published in May 2005. Version re-copy-edited in April 2009; revised again July 2015 by Sean Marks MD with references #2 and #6 added and incorporated into the text. Revised again significantly in September 2023 by Arun Ghoshal MD.