Treatment of the carcinoid syndrome
- Jonathan R Strosberg, MD
Jonathan R Strosberg, MD
- Associate Professor
- Department of Gastrointestinal Oncology
- H. Lee Moffitt Cancer Center
- Section Editors
- Kenneth K Tanabe, MD
Kenneth K Tanabe, MD
- Section Editor — Gastrointestinal Malignancies
- Professor of Surgery
- Harvard Medical School
- David C Whitcomb, MD, PhD
David C Whitcomb, MD, PhD
- Section Editor — Pancreatic Diseases
- Professor of Medicine
- University of Pittsburgh School of Medicine
Carcinoid tumors are neuroendocrine tumors that originate in the digestive tract, lungs, or rare primary sites, such as kidneys or ovaries. The term "carcinoid" usually implies a well-differentiated histology and is rarely used to describe high-grade or poorly differentiated neuroendocrine cancers. (See "Pathology, classification, and grading of neuroendocrine tumors arising in the digestive system", section on 'Pathology, tumor classification, and nomenclature'.)
Carcinoid syndrome is the term applied to a constellation of symptoms that are mediated by various hormones that are secreted by some carcinoid tumors (table 1) . Two of the most common manifestations are flushing and diarrhea (table 2). Symptoms are associated with elevations in serum serotonin or its metabolite urinary 5-hydroxyindoleacetic acid (5-HIAA). (See "Clinical features of the carcinoid syndrome".)
Carcinoid crisis is a life-threatening form of carcinoid syndrome that results from the release of an overwhelming amount of biologically active compounds from the tumor that may be triggered by tumor manipulation (biopsy or surgery) or by anesthesia.
More than 90 percent of patients with the carcinoid syndrome have metastatic disease, typically involving the liver, with primary tumors in the distal small intestine or proximal colon (midgut). Rare exceptions are bronchial and ovarian carcinoids, which can rarely release hormones directly into the systemic circulation, thereby producing symptoms without metastases. When it does occur, carcinoid syndrome associated with bronchial carcinoids is often atypical; episodes of flushing and/or diaphoresis may be accompanied by other symptoms, such as tremor, periorbital edema, lacrimation, salivation, and edema. (See "Clinical features of the carcinoid syndrome", section on 'Lung NET variant syndrome'.)
This topic provides an overview of treatment for patients with symptoms of the carcinoid syndrome. Diagnosis of the carcinoid syndrome, radiologic staging, tumor localization, histologic assessment of carcinoid tumors, and presentation, treatment, prognosis, and posttreatment surveillance of patients with localized and metastatic carcinoid are discussed in detail elsewhere. (See "Diagnosis of the carcinoid syndrome and tumor localization" and "Pathology, classification, and grading of neuroendocrine tumors arising in the digestive system", section on 'Pathology, tumor classification, and nomenclature' and "Staging, treatment, and posttreatment surveillance of nonmetastatic, well-differentiated gastrointestinal tract neuroendocrine (carcinoid) tumors" and "Metastatic well-differentiated gastroenteropancreatic neuroendocrine tumors: Presentation, prognosis, imaging, and biochemical monitoring" and "Metastatic gastroenteropancreatic neuroendocrine tumors: Local options to control tumor growth and symptoms of hormone hypersecretion", section on 'Surgical resection'.)
- Kulke MH, Mayer RJ. Carcinoid tumors. N Engl J Med 1999; 340:858.
- Reubi JC, Kvols LK, Waser B, et al. Detection of somatostatin receptors in surgical and percutaneous needle biopsy samples of carcinoids and islet cell carcinomas. Cancer Res 1990; 50:5969.
- Kvols LK, Moertel CG, O'Connell MJ, et al. Treatment of the malignant carcinoid syndrome. Evaluation of a long-acting somatostatin analogue. N Engl J Med 1986; 315:663.
- Rubin J, Ajani J, Schirmer W, et al. Octreotide acetate long-acting formulation versus open-label subcutaneous octreotide acetate in malignant carcinoid syndrome. J Clin Oncol 1999; 17:600.
- Strosberg J, Weber J, Feldman M, et al. Above-Label Doses of Octreotide-LAR in Patients With Metastatic Small Intestinal Carcinoid Tumors. Gastrointest Cancer Res 2013; 6:81.
- Ruszniewski P, Ducreux M, Chayvialle JA, et al. Treatment of the carcinoid syndrome with the longacting somatostatin analogue lanreotide: a prospective study in 39 patients. Gut 1996; 39:279.
- Faiss S, Räth U, Mansmann U, et al. Ultra-high-dose lanreotide treatment in patients with metastatic neuroendocrine gastroenteropancreatic tumors. Digestion 1999; 60:469.
- Wymenga AN, Eriksson B, Salmela PI, et al. Efficacy and safety of prolonged-release lanreotide in patients with gastrointestinal neuroendocrine tumors and hormone-related symptoms. J Clin Oncol 1999; 17:1111.
- O'Toole D, Ducreux M, Bommelaer G, et al. Treatment of carcinoid syndrome: a prospective crossover evaluation of lanreotide versus octreotide in terms of efficacy, patient acceptability, and tolerance. Cancer 2000; 88:770.
- Ducreux M, Ruszniewski P, Chayvialle JA, et al. The antitumoral effect of the long-acting somatostatin analog lanreotide in neuroendocrine tumors. Am J Gastroenterol 2000; 95:3276.
- Faiss S, Pape UF, Böhmig M, et al. Prospective, randomized, multicenter trial on the antiproliferative effect of lanreotide, interferon alfa, and their combination for therapy of metastatic neuroendocrine gastroenteropancreatic tumors--the International Lanreotide and Interferon Alfa Study Group. J Clin Oncol 2003; 21:2689.
- Khan MS, El-Khouly F, Davies P, et al. Long-term results of treatment of malignant carcinoid syndrome with prolonged release Lanreotide (Somatuline Autogel). Aliment Pharmacol Ther 2011; 34:235.
- Vinik AI, Wolin EM, Liyanage N, et al. EVALUATION OF LANREOTIDE DEPOT/AUTOGEL EFFICACY AND SAFETY AS A CARCINOID SYNDROME TREATMENT (ELECT): A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED TRIAL. Endocr Pract 2016; 22:1068.
- Strosberg JR, Cheema A, Kvols LK. A review of systemic and liver-directed therapies for metastatic neuroendocrine tumors of the gastroenteropancreatic tract. Cancer Control 2011; 18:127.
- Rinke A, Müller HH, Schade-Brittinger C, et al. Placebo-controlled, double-blind, prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors: a report from the PROMID Study Group. J Clin Oncol 2009; 27:4656.
- Caplin ME, Pavel M, Ćwikła JB, et al. Lanreotide in metastatic enteropancreatic neuroendocrine tumors. N Engl J Med 2014; 371:224.
- Ruszniewski P, Malka D. Hepatic arterial chemoembolization in the management of advanced digestive endocrine tumors. Digestion 2000; 62 Suppl 1:79.
- Strosberg JR, Choi J, Cantor AB, Kvols LK. Selective hepatic artery embolization for treatment of patients with metastatic carcinoid and pancreatic endocrine tumors. Cancer Control 2006; 13:72.
- Gupta S, Yao JC, Ahrar K, et al. Hepatic artery embolization and chemoembolization for treatment of patients with metastatic carcinoid tumors: the M.D. Anderson experience. Cancer J 2003; 9:261.
- Eriksson BK, Larsson EG, Skogseid BM, et al. Liver embolizations of patients with malignant neuroendocrine gastrointestinal tumors. Cancer 1998; 83:2293.
- King J, Quinn R, Glenn DM, et al. Radioembolization with selective internal radiation microspheres for neuroendocrine liver metastases. Cancer 2008; 113:921.
- Cao CQ, Yan TD, Bester L, et al. Radioembolization with yttrium microspheres for neuroendocrine tumour liver metastases. Br J Surg 2010; 97:537.
- Oberg K, Kvols L, Caplin M, et al. Consensus report on the use of somatostatin analogs for the management of neuroendocrine tumors of the gastroenteropancreatic system. Ann Oncol 2004; 15:966.
- Strosberg JR, Fisher GA, Benson AB, et al. Systemic treatment in unresectable metastatic well-differentiated carcinoid tumors: consensus results from a modified delphi process. Pancreas 2013; 42:397.
- Strosberg JR, Benson AB, Huynh L, 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. Oncologist 2014; 19:930.
- Woltering EA, Mamikunian PM, Zietz S, et al. Effect of octreotide LAR dose and weight on octreotide blood levels in patients with neuroendocrine tumors. Pancreas 2005; 31:392.
- Kulke MH, O'Dorisio T, Phan A, et al. Telotristat etiprate, a novel serotonin synthesis inhibitor, in patients with carcinoid syndrome and diarrhea not adequately controlled by octreotide. Endocr Relat Cancer 2014; 21:705.
- Pavel M, Hörsch D, Caplin M, et al. Telotristat etiprate for carcinoid syndrome: a single-arm, multicenter trial. J Clin Endocrinol Metab 2015; 100:1511.
- Kulke MH, Hörsch D, Caplin ME, et al. Telotristat Ethyl, a Tryptophan Hydroxylase Inhibitor for the Treatment of Carcinoid Syndrome. J Clin Oncol 2017; 35:14.
- https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm544035.htm (Accessed on March 03, 2017).
- http://www.xermelo.com/Media/Default/pdfs/Product_Info_telotristat_etiprate.pdf (Accessed on March 03, 2017).
- 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.
- Frank M, Klose KJ, Wied M, et al. Combination therapy with octreotide and alpha-interferon: effect on tumor growth in metastatic endocrine gastroenteropancreatic tumors. Am J Gastroenterol 1999; 94:1381.
- Yao JC, Guthrie K, Moran C, et al. SWOG S0518: Phase III prospective randomized comparison of depot octreotide plus interferon alpha-2b versus depot octreotide plus bevacizumab (NSC #704865) in advanced, poor prognosis carcinoid patients (NCT00569127). (abstr). J Clin Oncol 33, 2015 (suppl; abstr 4004).
- Wymenga AN, de Vries EG, Leijsma MK, et al. Effects of ondansetron on gastrointestinal symptoms in carcinoid syndrome. Eur J Cancer 1998; 34:1293.
- Kiesewetter B, Raderer M. Ondansetron for diarrhea associated with neuroendocrine tumors. N Engl J Med 2013; 368:1947.
- Westergaard H. Bile Acid malabsorption. Curr Treat Options Gastroenterol 2007; 10:28.
- Bainbridge HE, Larbi E, Middleton G. Symptomatic Control of Neuroendocrine Tumours with Everolimus. Horm Cancer 2015; 6:254.
- Capdevila J, Díez Miranda I, Obiols G, Tabernero J. Control of carcinoid syndrome with everolimus. Ann Oncol 2011; 22:237.
- Pavel ME, Hainsworth JD, Baudin E, et al. Everolimus plus octreotide long-acting repeatable for the treatment of advanced neuroendocrine tumours associated with carcinoid syndrome (RADIANT-2): a randomised, placebo-controlled, phase 3 study. Lancet 2011; 378:2005.
- Bushnell DL Jr, O'Dorisio TM, O'Dorisio MS, et al. 90Y-edotreotide for metastatic carcinoid refractory to octreotide. J Clin Oncol 2010; 28:1652.
- Woodside KJ, Townsend CM Jr, Mark Evers B. Current management of gastrointestinal carcinoid tumors. J Gastrointest Surg 2004; 8:742.
- Warner RR, Mani S, Profeta J, Grunstein E. Octreotide treatment of carcinoid hypertensive crisis. Mt Sinai J Med 1994; 61:349.
- Davì MV, Bodei L, Francia G, et al. Carcinoid crisis induced by receptor radionuclide therapy with 90Y-DOTATOC in a case of liver metastases from bronchial neuroendocrine tumor (atypical carcinoid). J Endocrinol Invest 2006; 29:563.
- Majeed F, Porter TR, Tarantolo S, et al. Carcinoid crisis and reversible right ventricular dysfunction after embolization in untreated carcinoid syndrome. Eur J Echocardiogr 2007; 8:386.
- Gillams A, Cassoni A, Conway G, Lees W. Radiofrequency ablation of neuroendocrine liver metastases: the Middlesex experience. Abdom Imaging 2005; 30:435.
- Kharrat HA, Taubin H. Carcinoid crisis induced by external manipulation of liver metastasis. J Clin Gastroenterol 2003; 36:87.
- Vaughan DJ, Brunner MD. Anesthesia for patients with carcinoid syndrome. Int Anesthesiol Clin 1997; 35:129.
- Gates J, Hartnell GG, Stuart KE, Clouse ME. Chemoembolization of hepatic neoplasms: safety, complications, and when to worry. Radiographics 1999; 19:399.
- Lewis MA, Jaramillo S, Roberts L, et al. Hepatic artery embolization for neuroendocrine tumors: postprocedural management and complications. Oncologist 2012; 17:725.
- Kinney MA, Warner ME, Nagorney DM, et al. Perianaesthetic risks and outcomes of abdominal surgery for metastatic carcinoid tumours. Br J Anaesth 2001; 87:447.
- Veall GR, Peacock JE, Bax ND, Reilly CS. Review of the anaesthetic management of 21 patients undergoing laparotomy for carcinoid syndrome. Br J Anaesth 1994; 72:335.
- Boudreaux JP, Klimstra DS, Hassan MM, et al. The NANETS consensus guideline for the diagnosis and management of neuroendocrine tumors: well-differentiated neuroendocrine tumors of the Jejunum, Ileum, Appendix, and Cecum. Pancreas 2010; 39:753.
- Ramage JK, Davies AH, Ardill J, et al. Guidelines for the management of gastroenteropancreatic neuroendocrine (including carcinoid) tumours. Gut 2005; 54 Suppl 4:iv1.
- Massimino K, Harrskog O, Pommier S, Pommier R. Octreotide LAR and bolus octreotide are insufficient for preventing intraoperative complications in carcinoid patients. J Surg Oncol 2013; 107:842.
- Condron ME, Pommier SJ, Pommier RF. Continuous infusion of octreotide combined with perioperative octreotide bolus does not prevent intraoperative carcinoid crisis. Surgery 2016; 159:358.
- Déry R. Theoretical and clinical considerations in anaesthesia for secreting carcinoid tumors. Can Anaesth Soc J 1971; 18:245.
- Memon MA, Nelson H. Gastrointestinal carcinoid tumors: current management strategies. Dis Colon Rectum 1997; 40:1101.
- Dobson R, Valle JW, Burgess MI, et al. Variation in Cardiac Screening and Management of Carcinoid Heart Disease in the UK and Republic of Ireland. Clin Oncol (R Coll Radiol) 2015; 27:741.
- Davar J, Connolly HM, Caplin ME, et al. Diagnosing and Managing Carcinoid Heart Disease in Patients With Neuroendocrine Tumors: An Expert Statement. J Am Coll Cardiol 2017; 69:1288.
- SOMATOSTATIN-ANALOG THERAPY
- Antiproliferative effects
- LIVER-DIRECTED THERAPIES
- MANAGEMENT OF REFRACTORY SYMPTOMS
- Additional octreotide
- Antidiarrheal therapy
- Systemic therapies
- - Cytotoxic chemotherapy
- - Everolimus
- Peptide receptor radioligand therapy
- PREVENTION AND MANAGEMENT OF CARCINOID CRISIS
- CARCINOID HEART DISEASE
- SUMMARY AND RECOMMENDATIONS