Version July 2025
INTRODUCTION —
Carcinoid syndrome is the term applied to a constellation of symptoms that are mediated by various hormones that are secreted by some neuroendocrine tumors (NETs).
This topic will discuss treatment of the carcinoid syndrome as well as prevention and treatment of carcinoid crisis. The clinical features and diagnosis of the carcinoid syndrome and other relevant topics related to gastroenteropancreatic NETs are discussed separately.
●(See "Clinical features of carcinoid syndrome".)
●(See "Diagnosis of carcinoid syndrome and tumor localization" and "Metastatic gastroenteropancreatic neuroendocrine tumors: Local options to control tumor growth and symptoms of hormone hypersecretion".)
●(See "Pathology and classification of gastroenteropancreatic neuroendocrine neoplasms".)
●(See "Diagnosis of carcinoid syndrome and tumor localization" and "Metastatic gastroenteropancreatic neuroendocrine tumors: Local options to control tumor growth and symptoms of hormone hypersecretion".)
DEFINITION —
Carcinoid syndrome is the term applied to a constellation of symptoms that are mediated by various hormones that are secreted by some neuroendocrine tumors (NETs) (table 1) [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. 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). (See "Clinical features of carcinoid syndrome" and "Pathology and classification of gastroenteropancreatic neuroendocrine neoplasms", section on 'Pathology and tumor classification'.)
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. Carcinoid crisis may be triggered by tumor manipulation (eg, biopsy, embolization, surgery) or anesthesia, and occurs mostly in patients with markedly elevated serum serotonin or urine 5-hydroxyindoleacetic acid. (See 'Prevention and treatment of carcinoid crisis' below.)
TREATMENT OF CARCINOID SYNDROME
Initial management — For patients who are symptomatic from carcinoid syndrome, we recommend initiating treatment with a somatostatin analog (SSA). Options include octreotide and lanreotide, which are highly effective in controlling carcinoid symptoms associated with neuroendocrine tumors (NETs).
Somatostatin-analog therapy
Treatment of carcinoid syndrome — Somatostatin is a 14-amino acid peptide that inhibits the secretion of a broad range of hormones. It acts by binding to somatostatin receptors (SSTRs), which are expressed on the majority of NETs [2]. The majority of well-differentiated gastrointestinal NETs express SSTRs, as determined using SSTR-based diagnostic positron emission tomography (PET) imaging, typically with gallium Ga-68 dotatate. However, it is controversial whether imaging with SSTR-based imaging studies is necessary before a trial of SSA therapy for patients who are symptomatic from carcinoid syndrome. (See "Clinical presentation, imaging and biomarker monitoring, and prognosis of metastatic well-differentiated gastroenteropancreatic neuroendocrine tumors", section on 'Somatostatin receptor-based imaging studies'.)
Because the SSAs octreotide and lanreotide bind to SSTRs on the tumor cells, they are highly effective at inhibiting the release of serotonin and other vasoactive substances. Flushing and diarrhea are significantly improved in over 80 percent of patients with the carcinoid syndrome [3].
The standard dose of octreotide long-acting release (LAR) is 30 mg intramuscularly every four weeks, and the standard dose of lanreotide is 120 mg administered as a deep subcutaneous injection every four weeks [4]. These doses also have a proven inhibitory effect on tumor growth [5,6]. (See 'Treatment of tumor growth' below.)
Lower doses (eg, octreotide LAR 20 or 10 mg every four weeks) or lanreotide (90 or 60 mg every four weeks) are also an option, particularly in patients who experience side effects. Octreotide also exists as a short-acting subcutaneous injection, typically administered at doses of 100 to 500 mcg every eight hours as needed. Supplementary short-acting octreotide can be used for breakthrough symptoms.
Treatment of tumor growth — The SSAs octreotide and lanreotide were initially developed for control of the carcinoid syndrome. Both drugs have also been proven to inhibit tumor growth in randomized phase III trials [5,6]. This subject is addressed separately. (See "Systemic therapy for metastatic well-differentiated low-grade (G1) and intermediate-grade (G2) gastrointestinal neuroendocrine tumors", section on 'SSAs (octreotide LAR and lanreotide)'.)
Side effects — SSA therapy is usually well tolerated, and side effects are generally mild. Potential side effects include the following:
●Symptoms of pancreatic malabsorption – Approximately one-third of patients treated with SSAs may develop nausea, abdominal discomfort or bloating, weight loss, loose stools, and/or steatorrhea [7,8]. Pancreatic malabsorption may be a contributing factor to these symptoms, as SSAs reversibly inhibit secretion of pancreatic enzymes and bile acids [9]. Such symptoms often occur during the first several weeks of therapy, after which they subside in most patients without intervention. Any symptoms of pancreatic malabsorption that subsequently persist or worsen may be treated with pancreatic enzyme supplementation.
●Mild glucose intolerance – Mild glucose intolerance rarely occurs, due to transient inhibition of insulin secretion.
●Gallstones – SSAs reduce postprandial gallbladder contractility and delay gallbladder emptying. This can lead to the development of gallstones or sludge in up to 25 percent of patients during the first 18 months of therapy [8]. For that reason, a prophylactic cholecystectomy is sometimes performed for patients who are undergoing abdominal surgery for other reasons.
Liver-directed therapies — Liver-directed therapies, including surgical resection or hepatic embolization, can be highly palliative for patients with carcinoid syndrome and liver-dominant disease.
●Hepatic resection – Hepatic resection is often used to treat potentially resectable liver metastases in the absence of diffuse bilobar involvement, compromised liver function, or widespread extrahepatic metastases. Hepatic resection can also provide palliation for patients who are symptomatic from tumor bulk or the carcinoid syndrome. Although preoperative and intraoperative short-acting octreotide therapy was previously deemed essential to protect against carcinoid crises that can arise from anesthesia and/or tumor manipulation, subsequent studies have challenged this viewpoint [10]. (See 'Prevention and treatment of carcinoid crisis' below.)
Hepatic resections are generally restricted to patients in whom 70 percent or more of the disease bulk can be successfully resected or ablated. These issues are all addressed in more detail separately. (See "Metastatic gastroenteropancreatic neuroendocrine tumors: Local options to control tumor growth and symptoms of hormone hypersecretion", section on 'Surgical resection'.)
●Hepatic transarterial embolization – Hepatic transarterial embolizations are often performed for patients with surgically unresectable liver-dominant metastases. In patients with widespread liver metastases, the embolizations are often lobar rather than highly selective. Embolization of the entire liver can usually be undertaken in two to three separate procedures. In uncontrolled trials, up to 75 percent of patients with neuroendocrine tumor hepatic metastases have marked symptomatic improvement in flushing and diarrhea [11-14]. Embolizations can be performed using microparticles alone (bland embolization) or with admixed chemotherapy (chemoembolization). There is no evidence that chemoembolization results in superior outcomes compared with bland embolization, particularly in the treatment of metastases from midgut NETs, which are generally chemoresistant (as compared with pancreatic NETs). Short-term side effects of liver embolization include abdominal pain, fever, nausea/vomiting, and fatigue. In patients with carcinoid syndrome, prophylactic octreotide pre- and postembolization is an option to reduce the risk of carcinoid crisis.
●Hepatic radioembolization – Experience with hepatic radioembolization using yttrium Y-90-labeled resin or glass microspheres is limited but growing. Radioembolization using Y-90-labeled resin or glass microspheres reduces symptoms in approximately one-half of patients with functioning NETs [15,16]. However, in the absence of randomized trials, it is difficult to know when to choose this technique over other embolization techniques. In particular, the risk of long-term radioembolization-induced liver disease (REILD) has not been well-characterized. (See "Metastatic gastroenteropancreatic neuroendocrine tumors: Local options to control tumor growth and symptoms of hormone hypersecretion", section on 'Hepatic arterial embolization'.)
Management of refractory symptoms
Escalating the somatostatin analog — Escalation of the dose or frequency of a somatostatin analog (SSA) may be necessary for patients with refractory symptoms [4,17]. For example, patients who complain of exacerbation of symptoms at the end of their four-week SSA cycle may benefit from drug administration every three weeks. It is unclear whether there is benefit to escalation of dose beyond double the label dose.
Telotristat — For patients with carcinoid syndrome diarrhea that is refractory to SSA therapy, we suggest the addition of telotristat ethyl to an SSA. Telotristat ethyl is administered 250 mg orally three times daily with food.
The carcinoid syndrome is thought to be caused in large part by secretion of serotonin. Telotristat ethyl is an oral inhibitor of the enzyme tryptophan hydroxylase, which catalyzes a rate-limiting step in the conversion of the amino acid tryptophan to serotonin (figure 1). By inhibiting tryptophan hydroxylase, telotristat reduces the production of serotonin production, thus reducing symptoms associated with the carcinoid syndrome.
In a double-blind, placebo-controlled phase III trial (TELESTAR), 135 patients with a history of carcinoid syndrome who were receiving treatment with an SSA and had uncontrolled diarrhea (≥4 bowel movements daily) were randomly assigned to treatment over 12 weeks at one of two doses of oral telotristat ethyl (250 mg and 500 mg, each taken three times daily) or placebo [18].
●Relative to placebo, telotristat ethyl at either dose reduced bowel movement frequency over time (at week 12, the mean reduction in daily bowel movement frequency from baseline was -1.7 and -2.1 with telotristat 250 and 500 mg, respectively, versus -0.9 for placebo).
●Telotristat ethyl also reduced levels of urinary 5-hydroxyindoleacetic acid (a metabolite of serotonin). By week 12, mean urinary 5-hydroxyindoleacetic acid levels decreased by 40 and 57.7 mg per 24 hours with telotristat 250 and 500 mg, respectively, while levels increased by 11.5 mg per 24 hours with placebo.
●Too few patients had flushing or abdominal discomfort to ascertain changes in these endpoints.
●Overall, telotristat ethyl was best tolerated at the 250 mg dosing. The 500 mg dose caused more nausea compared with either the 250 mg dose or placebo (31 versus 13 and 11 percent, respectively) and depression-related adverse events (16 versus 7 percent each for the 250 mg dose and placebo, respectively).
Telotristat is approved by the US Food and Drug Administration in combination with SSA therapy for the treatment of adults with diarrhea related to carcinoid syndrome that is inadequately controlled by SSA therapy alone [9].
It is unclear whether telotristat ethyl has any significant impact on flushing in patients with carcinoid syndrome, which is associated with production of multiple vasoactive substances.
The use of telotristat in patients with carcinoid heart disease is discussed separately. (See "Carcinoid heart disease", section on 'Telotristat ethyl'.)
Antidiarrheal therapy — Antidiarrheal agents (eg, loperamide, diphenoxylate, and atropine) can be used for control of refractory diarrhea due to the carcinoid syndrome. For more severe diarrhea, options include tincture of opium and paregoric (where available). Serotonin receptor antagonists, such as ondansetron, can alleviate diarrhea in patients with the carcinoid syndrome for whom treatment with SSAs is not successful [19-21].
Other causes of diarrhea (with different treatments) are also possible. As examples:
●Symptomatic fat malabsorption and steatorrhea from chronic SSA therapy may respond to pancreatic enzyme supplementation. (See 'Side effects' above.)
●Patients who have undergone resection of the distal small bowel frequently develop bile malabsorption and bile salt-induced diarrhea that can be treated with bile acid sequestrants, such as cholestyramine or colestipol [22]. A trial of a bile acid sequestrant is reasonable in any patient who has refractory diarrhea after right hemicolectomy.
Everolimus — There are few data addressing the benefit of everolimus, a mechanistic (previously called mammalian) target of rapamycin (mTOR) inhibitor, for control of symptoms related to carcinoid syndrome. Most of the information comes from small retrospective series and case reports [23,24]. It is important to note that diarrhea is a frequent side effect of everolimus.
A phase III trial (RADIANT-2) compared everolimus plus octreotide LAR with placebo plus octreotide LAR in patients with metastatic NETs and a history of carcinoid syndrome. In this study, improvements in urinary excretion of 5-hydroxyindoleacetic acid occurred at a slightly higher frequency in the everolimus arm of this study (61 versus 54 percent), but information was not provided on symptoms attributed to carcinoid syndrome [25]. The study fell short of meeting its primary endpoint, which was a significant improvement in progression-free survival with everolimus. (See "Systemic therapy for metastatic well-differentiated low-grade (G1) and intermediate-grade (G2) gastrointestinal neuroendocrine tumors", section on 'Everolimus'.)
Peptide receptor radionuclide therapy — For patients with SSTR-expressing tumors, one option is peptide receptor radionuclide therapy with lutetium Lu-177 dotatate, which is associated with high symptomatic response rates in patients with octreotide-refractory carcinoid syndrome. However, due to treatment-related risks, this treatment is typically reserved for patients with radiographic tumor progression.
Radiolabeled SSAs can be used to deliver targeted radiation to somatostatin receptor-expressing tumors. Single-arm studies of the radiolabeled SSAs have demonstrated high symptomatic response rates in patients with carcinoid syndrome who were refractory to octreotide [26].
A phase III trial (NETTER-1) of 231 patients with progressive metastatic midgut NETs compared Lu-177 dotatate plus octreotide LAR 30 mg versus a higher dose octreotide (60 mg every four weeks). Analysis of health-related quality of life (HRQOL) outcomes based on European Organisation for Research and Treatment of Cancer (EORTC) questionnaires demonstrated clinically and statistically significant delays in time to deterioration of HRQOL in global health, physical functioning, role functioning, and in clinically relevant symptoms, notably diarrhea [27]. No significant change was seen in time to deterioration of flushing. (See "Systemic therapy for metastatic well-differentiated low-grade (G1) and intermediate-grade (G2) gastrointestinal neuroendocrine tumors", section on 'Peptide receptor radionuclide therapy (initial therapy)'.)
CARCINOID HEART DISEASE —
Carcinoid heart disease occurs in a minority of patients with the carcinoid syndrome. High-circulating concentrations of serotonin are thought to be the major underlying factor. Carcinoid heart lesions are characterized by plaque-like fibrous endocardial thickening that classically involves the right side of the heart, and often causes retraction and fixation of the leaflets of the tricuspid and pulmonary valves (picture 1). Tricuspid regurgitation is a nearly universal finding; tricuspid stenosis, pulmonary regurgitation, and pulmonary stenosis may also occur. The resulting right-sided heart failure produces significant morbidity and mortality. (See "Carcinoid heart disease", section on 'Clinical manifestations'.)
Among patients with the carcinoid syndrome, individuals with carcinoid heart disease exhibit higher levels of serum serotonin and urinary 5-hydroxyindoleacetic acid excretion than do those without heart disease. (See "Carcinoid heart disease", section on 'Pathophysiology'.)
It is likely that somatostatin analogs (SSAs) and other therapies that reduce circulating serotonin levels can reduce the risk of developing carcinoid heart disease and inhibit progression of existing disease, as evidence suggests a pathogenic role for serotonin or one of its metabolites in the development of carcinoid heart disease. However, there is no evidence that medical therapy for carcinoid syndrome can reverse valvular damage. (See "Carcinoid heart disease", section on 'Valve intervention'.)
In patients with carcinoid syndrome without valvular heart disease or heart failure, the guidelines for screening for carcinoid heart disease are discussed in detail separately. (See "Carcinoid heart disease", section on 'Initial testing for carcinoid heart disease'.)
Management of patients with diagnosed carcinoid heart disease is discussed separately. (See "Carcinoid heart disease", section on 'Treatment of carcinoid syndrome'.)
PREVENTION AND TREATMENT OF CARCINOID CRISIS —
Carcinoid crisis is a life-threatening form of the carcinoid syndrome that results from the release of an overwhelming amount of biologically active compounds from the tumor (table 1). Carcinoid crisis may be triggered by tumor manipulation (eg, biopsy, surgery) or by anesthesia [28]. It is less commonly reported after hepatic arterial embolization or radionuclide therapy, mostly in patients with extensive tumor bulk [29-36]. It occurs mostly in patients with markedly elevated serum serotonin or urine 5-hydroxyindoleacetic acid. The predominant symptom is wide blood pressure fluctuations with a predominance of hypotension.
In our view, prophylactic preoperative use of octreotide is optional in patients with carcinoid syndrome (especially in patients who are already receiving a long-acting somatostatin analog [SSA]) and is almost certainly unnecessary in patients without carcinoid syndrome.
For patients with carcinoid syndrome who develop hemodynamic instability during surgery, in addition to standard management with intravenous fluids and vasopressors, intravenous octreotide should be available intraoperatively for use as needed. Octreotide doses of 500 mcg can be used intravenously (IV), potentially followed by an IV infusion of 50 to 200 mcg per hour. (See "Evaluation of and initial approach to the adult patient with undifferentiated hypotension and shock", section on 'Hemodynamic support'.)
Although data in patients with carcinoid syndrome previously suggested that prophylactic administration of octreotide prior to surgical procedures reduced the incidence of carcinoid crisis [37-40], subsequent studies have demonstrated limited benefit for prophylactic octreotide in preventing intraoperative carcinoid crisis [10,41-43]. In a prospective observational study of 195 operations (primarily bowel and/or hepatic metastasis resection) in 171 patients with NETs with no prophylactic octreotide, an intraoperative carcinoid crisis developed in only 49 operations (25 percent), and was predominantly characterized by profound hypotension and tachycardia [41]. Patients were managed with IV fluids and vasopressors, the duration of each episode was short (median duration of the first and second episodes were three and two minutes, respectively), and there were no postoperative complications associated with the development of carcinoid crisis.
SOCIETY GUIDELINE LINKS —
Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Neuroendocrine neoplasms".)
INFORMATION FOR PATIENTS —
UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topics (see "Patient education: Carcinoid syndrome (The Basics)")
SUMMARY AND RECOMMENDATIONS
●Definition – Carcinoid syndrome is the term applied to a constellation of symptoms mediated by various hormones that are elaborated by some neuroendocrine tumors (NETs) (table 1) [1]. Two of the most common manifestations are flushing and diarrhea (table 2). More than 90 percent of patients with the carcinoid syndrome have metastatic disease, typically to the liver, and primary tumors in the distal small intestine or proximal colon (midgut). (See "Clinical features of carcinoid syndrome".)
●Initial treatment of carcinoid syndrome
•Somatostatin analogs – For patients who are symptomatic from carcinoid syndrome, we recommend initiating treatment with a somatostatin analog (SSA) (Grade 1A). Options include octreotide and lanreotide, which are highly effective in controlling carcinoid symptoms associated with NETs. (See 'Somatostatin-analog therapy' above.)
-Dosing – We usually begin therapy with octreotide long-acting release (LAR) 30 mg intramuscularly every four weeks or lanreotide 120 mg via deep subcutaneous injection every four weeks; however, lower starting doses are also an option (eg, octreotide 20 mg or lanreotide 90 mg), particularly in patients who experience side effects. (See 'Treatment of carcinoid syndrome' above.)
•Liver-directed therapies – Liver-directed therapies, including surgical resection or hepatic embolization, can be highly palliative for patients with carcinoid syndrome and liver-dominant disease. (See 'Liver-directed therapies' above.)
●Management of refractory disease
•Escalating the SSA – Patients with persistence or recurrence of flushing and/or diarrhea may benefit from higher doses or more frequent administration of long-acting SSAs. (See 'Management of refractory symptoms' above.)
•Telotristat ethyl – For patients with carcinoid syndrome diarrhea that is refractory to SSA therapy, we suggest the addition of telotristat ethyl to an SSA (Grade 2A). (See 'Telotristat' above.)
•Peptide receptor radionuclide therapy – For patients with somatostatin receptor (SSTR)-expressing tumors, one option is peptide receptor radionuclide therapy with lutetium Lu-177 dotatate, which is associated with high symptomatic response rates in patients with octreotide-refractory carcinoid syndrome. However, due to treatment-related risks, this treatment is typically reserved for patients with radiographic tumor progression. (See 'Peptide receptor radionuclide therapy' above.)
•Antidiarrheal agents – Patients with refractory diarrhea may benefit from use of an antidiarrheal agent, such as loperamide or diphenoxylate and atropine. Other causes of diarrhea are also possible, such as fat malabsorption and steatorrhea from chronic SSA therapy which responds to pancreatic enzyme supplementation. (See 'Antidiarrheal therapy' above.)
●Carcinoid heart disease
•Clinical presentation – Carcinoid heart disease can occur in patients with severe, longstanding elevations of circulating serotonin and is typically characterized by fibrosis of the right-sided (tricuspid and pulmonary) heart valves. (See 'Carcinoid heart disease' above.)
•Prevention – It is likely that SSAs and other therapies that reduce circulating serotonin levels can reduce the risk of developing carcinoid heart disease and inhibit progression of existing disease, as evidence suggests a pathogenic role for serotonin or one of its metabolites in the development of carcinoid heart disease. However, there is no evidence that medical therapy for carcinoid syndrome can reverse valvular damage.
•Management – The management of carcinoid heart disease is discussed separately. (See "Carcinoid heart disease", section on 'Management'.)
●Carcinoid crisis
•Definition – 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. Carcinoid crisis may be triggered by tumor manipulation (eg, biopsy, embolization, surgery) or anesthesia. It occurs mostly in patients with markedly elevated serum serotonin or urine 5-hydroxyindoleacetic acid. The predominant symptom is wide blood pressure fluctuations with a predominance of hypotension. (See 'Prevention and treatment of carcinoid crisis' above.)
•Prevention – For patients undergoing surgery for metastatic NET who have a history of carcinoid syndrome, prophylactic preoperative use of octreotide is optional, especially in those who are already receiving a long-acting SSA, and is almost certainly unnecessary in patients without carcinoid syndrome. (See 'Prevention and treatment of carcinoid crisis' above.)
•Treatment – For patients with carcinoid syndrome who develop hemodynamic instability during surgery, in addition to standard management with intravenous fluids and vasopressors, intravenous octreotide should be available intraoperatively for use as needed. Octreotide doses of 500 mcg can be used intravenously (IV), potentially followed by an IV infusion of 50 to 200 mcg per hour. (See 'Prevention and treatment of carcinoid crisis' above and "Evaluation of and initial approach to the adult patient with undifferentiated hypotension and shock", section on 'Hemodynamic support'.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Stephen Goldfinger, MD, who contributed to an earlier version of this topic review.
