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Treatment of the carcinoid syndrome

Treatment of the carcinoid syndrome
Literature review current through: Jan 2024.
This topic last updated: Oct 19, 2023.

INTRODUCTION — Carcinoid tumors are neuroendocrine tumors (NETs) 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 neoplasms 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 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".)

By contrast, 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.

This topic provides an overview of treatment for patients with symptoms of the carcinoid syndrome, and recommendations for prevention and treatment of carcinoid crisis. Diagnosis of the carcinoid syndrome, radiologic staging, tumor localization, histologic assessment of NETs arising at different sites, and presentation, treatment, prognosis, and posttreatment surveillance of patients with localized and metastatic NETs are discussed separately. (See "Diagnosis of carcinoid syndrome and tumor localization" and "Pathology, classification, and grading of neuroendocrine neoplasms arising in the digestive system", section on 'Pathology, tumor classification, and nomenclature' and "Staging, treatment, and post-treatment surveillance of non-metastatic, 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'.)

INITIAL TREATMENT OF CARCINOID SYNDROME

Somatostatin-analog therapy — Somatostatin is a 14-amino acid peptide that inhibits the secretion of a broad range of hormones. It acts by binding to somatostatin receptors, which are expressed on the majority of neuroendocrine tumors (NETs) [2]. Nearly 80 percent of well-differentiated gastrointestinal NETs express somatostatin receptors, as determined using somatostatin receptor-based diagnostic imaging with a radiolabeled form of the somatostatin analog octreotide (indium-111 [111-In] pentetreotide [OctreoScan]) or gallium Ga-68 DOTATATE (or gallium Ga-68 DOTATOC) positron emission tomography (PET)/computed tomography (CT). However, whether imaging with any of these modalities is necessary before a trial of somatostatin analog therapy for patients who are symptomatic from carcinoid syndrome is controversial. (See "Metastatic well-differentiated gastroenteropancreatic neuroendocrine tumors: Presentation, prognosis, imaging, and biochemical monitoring", section on 'Somatostatin receptor-based imaging techniques'.)

Because the somatostatin analogs octreotide and lanreotide bind to somatostatin receptors 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].

Treatment for symptomatic carcinoid syndrome may be initiated with short-acting octreotide, administered subcutaneously. An octreotide pen (2500 mcg/mL) for self- or caregiver administration of short-acting octreotide has been approved for initial treatment of severe diarrhea/flushing episodes associated with carcinoid syndrome. However, unless patients are severely symptomatic, we generally initiate therapy with octreotide long-acting release (LAR) rather than short-acting subcutaneous octreotide. We typically initiate depot octreotide (Sandostatin LAR) at a dose of 20 to 30 mg intramuscularly every four weeks [4].

Escalation of the dose or frequency of a somatostatin analog, or supplementation with doses of short-acting octreotide may be necessary for patients with refractory symptoms [4,5]. For example, patients who complain of exacerbation of symptoms at the end of their four-week somatostatin analog 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. Typical doses of short-acting octreotide range from 200 to 500 mcg up to three times a day. Short-acting octreotide is also available in a prefilled pen at a concentration of 2500 mcg/mL.

A long-acting formulation of lanreotide (Somatuline Depot) is also available for monthly injections at doses ranging from 60 to 120 mg every four weeks [6]. Lanreotide appears to have similar clinical efficacy and tolerability as octreotide for treatment of the carcinoid syndrome [7-14]. In a randomized phase III trial of depot lanreotide versus placebo in patients with carcinoid syndrome, lanreotide significantly reduced the need for short-acting somatostatin analog injections compared with placebo [13,14].

Both octreotide and lanreotide are usually well tolerated. Rarely, patients may develop nausea, abdominal discomfort, bloating and/or steatorrhea, often during the first several weeks of therapy, after which the symptoms subside. Pancreatic malabsorption may be a contributing factor, which can be alleviated with pancreatic enzyme supplementation. Another effect of somatostatin analogs is inhibition of gallbladder contractility, which can lead to gallstones or sludge. For that reason, a prophylactic cholecystectomy is sometimes recommended for patients who are undergoing abdominal surgery for other reasons [15].

Antiproliferative effects — The somatostatin analogs 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 [16,17]. This subject is addressed separately. (See "Metastatic well-differentiated gastrointestinal neuroendocrine (carcinoid) tumors: Systemic therapy options to control tumor growth", section on 'Somatostatin analogs' and "Metastatic well-differentiated gastrointestinal neuroendocrine (carcinoid) tumors: Systemic therapy options to control tumor growth".)

Liver-directed therapies — Hepatic resection is often considered for the treatment of 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. Preoperative and intraoperative octreotide therapy are essential to protect against carcinoid crises that can arise from anesthesia and/or tumor manipulation. (See 'Carcinoid crisis: prevention and management' below.)

Hepatic resections are generally restricted to patients in whom 90 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 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 [18-21]. 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. Patients with the carcinoid syndrome should receive prophylactic octreotide pre- and postembolization in order to reduce risk of carcinoid crisis.

Experience with radioembolization using yttrium-90 (90Y)-labeled resin or glass microspheres is limited but growing. Radioembolization using 90Y-labeled resin or glass microspheres reduces symptoms in approximately one-half of patients with functioning NETs [22,23]. 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

Telotristat — The carcinoid syndrome is thought to be caused in large part by secretion of serotonin. A rate-limiting step in the conversion of the amino acid tryptophan to serotonin is mediated by the enzyme tryptophan hydroxylase (figure 1). An oral tryptophan hydroxylase inhibitor, telotristat ethyl, can be used in combination with somatostatin analog therapy in order to control diarrhea associated with the carcinoid syndrome. Approval was based on the TELESTAR trial, a three-arm study evaluating two doses of oral telotristat (250 mg and 500 mg, each taken three times daily) against placebo over a 12-week period) that was conducted in 135 patients with history of carcinoid syndrome who were receiving treatment with a somatostatin analog and who had uncontrolled diarrhea (≥4 bowel movements daily) [24]. Treatment with telotristat at either dose was associated with a statistically significant reduction in bowel movement frequency over time compared with placebo. At week 12, the arithmetic mean reduction in daily bowel movement frequency from baseline was -1.7 and -2.1 with telotristat 250 and 500 mg, respectively, compared with -0.9 for placebo. Urinary 5-hydroxyindoleacetic acid (5-HIAA; a metabolite of serotonin) was also significantly decreased with telotristat; by week 12, mean urinary 5-HIAA levels decreased by 40 and 57.7 mg per 24 hours with telotristat 250 and 500 mg, respectively, while levels increased in the placebo group by 11.5 mg per 24 hours in this same time period. Too few patients had flushing or abdominal discomfort to ascertain changes in these endpoints. Overall, the drug was well tolerated. There was a higher incidence of nausea with the 500 mg dose of telotristat as compared with either the lower 250 mg dose or placebo (31 versus 13 and 11 percent, respectively), and depression-related adverse events were also more frequent at the higher dose (16 versus 7 percent each for the telotristat 250 mg and placebo groups, respectively).

Largely based upon these results, telotristat has been approved in the United States in combination with somatostatin analog therapy for the treatment of adults with diarrhea related to carcinoid syndrome that is inadequately controlled by somatostatin analog therapy alone [25]. The recommended dose is 250 mg three times daily with food [26].

Flushing in patients with carcinoid syndrome is associated with production of multiple vasoactive substances, and it is unclear whether telotristat has a significant impact upon this symptom. On the other hand, carcinoid heart disease is thought to be directly related to high levels of circulating serotonin. Although evidence of inhibition of carcinoid heart disease with telotristat is purely anecdotal at this time, use of the drug in patients with early evidence of carcinoid heart disease and high levels of circulating serotonin is reasonable, even if their diarrhea is otherwise controlled.

Interferon — Another option for control of refractory symptoms of the carcinoid syndrome in patients treated with somatostatin analogs is interferon alfa (IFNa) [27]. Interferons can exert antitumor effects via stimulation of T cells, induction of cell cycle arrest, and inhibition of angiogenesis.

In retrospective series, low-dose IFNa alone (ie, 3 to 5 million units up to three to five times weekly) reduces symptoms of hormonal hypersecretion (flushing, diarrhea) in 40 to 50 percent of patients who are refractory to somatostatin analogs [28]. Objective tumor regression is rare [29]. Unfortunately, the benefits of IFNa for neuroendocrine tumors (NETs) are counterbalanced by sometimes debilitating toxicities, which can include fatigue, depression, and flu-like symptoms. As a result, IFNa is rarely used and typically only for otherwise refractory NETs. (See "Metastatic well-differentiated gastrointestinal neuroendocrine (carcinoid) tumors: Systemic therapy options to control tumor growth", section on 'Interferon'.)

Antidiarrheal therapy — Antidiarrheal agents, such as loperamide and/or diphenoxylate-atropine (Lomotil), can be used for control of refractory diarrhea. For more severe diarrhea, the opiates paregoric (where available) and tincture of opium may be prescribed. Paregoric has been discontinued in the United States but is available in other countries. A few reports demonstrate that serotonin receptor antagonists, such as ondansetron, can alleviate diarrhea in patients with the carcinoid syndrome in whom treatment with somatostatin analogs is not successful [30-32].

Other causes of diarrhea should be considered. As noted above, symptomatic fat malabsorption and steatorrhea from chronic somatostatin analog therapy may respond to pancreatic enzyme supplementation. (See 'Somatostatin-analog therapy' 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 [33]. A trial of a bile acid sequestrant is reasonable in any patient who has refractory diarrhea after right hemicolectomy.

Systemic therapies

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 [34,35]. It is important to note that diarrhea is a frequent side effect of everolimus.

In the phase III RADIANT 2 study comparing everolimus plus octreotide long-acting release (LAR) with placebo plus octreotide LAR in patients with metastatic NETs and a history of carcinoid syndrome, improvements in urinary excretion of 5-HIAA 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 [36]. The study fell short of meeting its primary endpoint, which was a significant improvement in progression-free survival with everolimus. (See "Metastatic well-differentiated gastrointestinal neuroendocrine (carcinoid) tumors: Systemic therapy options to control tumor growth", section on 'Molecularly targeted therapy'.)

177-Lutetium (Lu) dotatate (Peptide receptor radioligand therapy) — Radiolabeled somatostatin analogs can be used to deliver targeted radiation to somatostatin receptor-expressing tumors. Single-arm studies of the radiolabeled somatostatin analogs have demonstrated high symptomatic response rates in patients with carcinoid syndrome who were refractory to octreotide [37].

The phase III NETTER-1 study randomized 231 patients with progressive metastatic midgut NETs to receive 177-Lu-dotatate plus octreotide LAR 30 mg versus high-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 [38]. No significant change was seen in time to deterioration of flushing. (See "Metastatic well-differentiated gastroenteropancreatic neuroendocrine tumors: Presentation, prognosis, imaging, and biochemical monitoring", section on 'Somatostatin receptor-based imaging techniques' and "Metastatic well-differentiated pancreatic neuroendocrine tumors: Systemic therapy options to control tumor growth and symptoms of hormone hypersecretion", section on 'Radiolabeled somatostatin analogs' and "Metastatic well-differentiated gastrointestinal neuroendocrine (carcinoid) tumors: Systemic therapy options to control tumor growth", section on 'Radiolabeled somatostatin analogs'.)

CARCINOID HEART DISEASE — Carcinoid heart disease occurs in fewer than one-half 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'.)

Because evidence suggests a pathogenic role for serotonin or one of its metabolites in the development of carcinoid heart disease, it is likely that somatostatin analogs and other therapies that reduce circulating serotonin levels can reduce the risk of developing carcinoid heart disease, and they may inhibit progression of existing disease. However, there is no evidence that medical therapy of carcinoid syndrome can reverse valvular damage. (See "Carcinoid heart disease", section on 'Treatment of carcinoid syndrome'.)

Guidelines for screening for carcinoid heart disease in at-risk patients without valvular heart disease or heart failure are evolving, with differing recommendations in various major society guidelines [39]. For most patients with carcinoid syndrome, periodic echocardiography is recommended, although the optimal frequency is not established. Another alternative is monitoring of serum levels of N-terminal brain natriuretic peptide. This subject is discussed in detail separately. (See "Carcinoid heart disease", section on 'When and how to initially test for carcinoid heart disease'.)

Management of patients with diagnosed carcinoid heart disease is discussed separately. (See "Carcinoid heart disease", section on 'Valve intervention'.)

CARCINOID CRISIS: PREVENTION AND MANAGEMENT — Carcinoid crisis is a life-threatening form of the carcinoid syndrome that may be triggered by tumor manipulation (eg biopsy, surgery) or by anesthesia [40]. It is less commonly reported after chemotherapy, hepatic arterial embolization, or radionuclide therapy, mostly in patients with extensive tumor bulk [41-48].

Carcinoid crisis results from the release of an overwhelming amount of biologically active compounds from the tumor (table 1). The predominant symptom is wide blood pressure fluctuations with a predominance of hypotension.

Octreotide should be available during any surgical procedure, particularly the resection of hepatic metastases. Until recently, prophylactic administration of octreotide prior to resection (300 to 500 mcg intravenously or subcutaneously) was routinely recommended to reduce the incidence of carcinoid crisis in patients with a history of carcinoid syndrome who require surgical procedures [49-52]. However, intraoperative complications can still occur despite the use of preoperative prophylactic octreotide, and the routine use of prophylactic octreotide has been called into question [53]. In this report of 195 operations (primarily bowel and/or hepatic metastasis resection) on 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. Patients were managed with intravenous (IV) fluids and vasopressors, the duration of each episode was short (median duration of the first episode three minutes, and of the second episode two minutes), and there were no postoperative complications associated with the development of carcinoid crisis. Citing these data and other studies demonstrating a lack of benefit for preoperative octreotide in preventing intraoperative carcinoid crisis [49,54-56], the authors concluded that use of prophylactic octreotide may be safely discontinued and that treatment of crisis with octreotide should be replaced with intravenous fluids and vasopressors.

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), and is almost certainly unnecessary in patients without carcinoid syndrome. We recommend that octreotide be available intraoperatively for "as needed" intravenous use for patients with carcinoid syndrome who develop hemodynamic instability during surgery. Doses of 500 mcg can be used IV, potentially followed by an IV infusion of 50 to 200 mcg per hour.

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: Well-differentiated gastroenteropancreatic neuroendocrine tumors".)

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.

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Basics topics (see "Patient education: Carcinoid syndrome (The Basics)")

SUMMARY AND RECOMMENDATIONS

Definitions

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 midgut. (See "Clinical features of 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; it 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 'Carcinoid crisis: prevention and management' above.)

Initial treatment of carcinoid syndrome

The somatostatin analogs octreotide and lanreotide are highly effective in controlling the symptoms associated with NETs. For patients who are symptomatic from carcinoid syndrome, we recommend initiating treatment with a somatostatin analog (Grade 1A). (See 'Somatostatin-analog therapy' above.)

We usually begin therapy with octreotide long-acting release (LAR) 30 mg every four weeks or depot lanreotide 120 mg every four weeks; however, lower starting doses can be considered (eg, octreotide 20 mg or lanreotide 90 mg).

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

Patients with persistence or recurrence of flushing and/or diarrhea may benefit from higher doses or more frequent administration of long-acting somatostatin analogs. (See 'Management of refractory symptoms' above.)

For patients with somatostatin receptor expressing tumors, one option is radiolabeled somatostatin analog 177-Lutetium Dotatate, which is associated with high symptomatic response rates in patients with carcinoid syndrome who were refractory to octreotide. (See '177-Lutetium (Lu) dotatate (Peptide receptor radioligand therapy)' above.)

Patients with refractory diarrhea may benefit from use of an antidiarrheal agent, such as loperamide. (See 'Antidiarrheal therapy' above.)

For patients with carcinoid syndrome diarrhea that is refractory to somatostatin analog therapy and other treatments, we suggest telotristat (Grade 2A). (See 'Telotristat' above.)

Carcinoid heart disease

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.

The available evidence suggests a pathogenic role for serotonin or one of its metabolites in the development of carcinoid heart disease, and it is likely that somatostatin analogs and other therapies that reduce circulating serotonin levels can reduce the risk of developing carcinoid heart disease, and possibly inhibit progression of existing disease. However, there is no evidence that medical therapy of carcinoid syndrome can reverse valvular damage. (See 'Carcinoid heart disease' above.)

Prevention and treatment of carcinoid crisis

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 somatostatin analog, and is almost certainly unnecessary in patients without carcinoid syndrome. (See 'Carcinoid crisis: prevention and management' above.)

Octreotide should be available intraoperatively for "as needed" intravenous use for patients with carcinoid syndrome who develop hemodynamic instability during surgery. Doses of 500 mcg can be used intravenously (IV), potentially followed by an IV infusion of 50 to 200 mcg per hour.

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Stephen Goldfinger, MD, who contributed to an earlier version of this topic review.

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Topic 16638 Version 50.0

References

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