Treatment algorithm

Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer

ONGOING

localized disease

1st line – surgical resection

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ONGOING
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localized disease
1st line – 

surgical resection

Surgery should be considered in patients with localized disease (i.e., no evidence of regional nodal involvement) or with lymph node involvement but no distal metastases. Large resections with associated mesenteric resection may be required.[64] With appendiceal tumors, carcinoid syndrome does not occur unless distal metastases are present. Localized appendiceal carcinoid is somewhat unrelated to carcinoid syndrome.[65]

In patients with resectable bronchial carcinoids, surgery should be considered as first-line therapy in those with a good functional status.[27] Specific guidance for surgical involvement requires referral to cardiothoracic surgeons. There is a low operative mortality of <1% for published surgical series, and the benefit is a possible curative resection.[27] Complications depend on the type of procedure performed and previous functional status.

Midgut carcinoids involving the small bowel should be resected if the patient is fit enough to undergo surgery. Occasionally, these patients present with small bowel obstruction and require emergency surgery.

Plus – perioperative octreotide infusion

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ONGOING
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localized disease
Plus – 

perioperative octreotide infusion

Treatment recommended for ALL patients in selected patient group

Prior to surgery patients with carcinoid syndrome should be commenced on octreotide infusion to prevent carcinoid crisis.[2]​ It is commenced at least 2 hours prior to surgery and given until 48 hours after surgery.[26]

Primary options

octreotide: consult specialist for guidance on dose

metastatic disease

1st line – surgical resection

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ONGOING
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metastatic disease
|
suitable for resection
1st line – 

surgical resection

Resection of liver metastases can rectify hormonal markers and resolve symptoms. The type of surgery performed depends on the location, size, and number of liver lesions.

Plus – perioperative octreotide infusion

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ONGOING
|
metastatic disease
|
suitable for resection
Plus – 

perioperative octreotide infusion

Treatment recommended for ALL patients in selected patient group

Prior to surgery patients with carcinoid syndrome should be commenced on octreotide infusion to prevent carcinoid crisis.[2]​ It is commenced at least 2 hours prior to surgery and given until 48 hours after surgery.[26]

Primary options

octreotide: consult specialist for guidance on dose

Consider – radiofrequency ablation

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ONGOING
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metastatic disease
|
suitable for resection
Consider – 

radiofrequency ablation

Treatment recommended for SOME patients in selected patient group

Radiofrequency ablation may sometimes be used at the time of surgery.

1st line – somatostatin analog or interferon alfa

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ONGOING
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metastatic disease
|
not suitable for resection or symptomatic following resection
1st line – 

somatostatin analog or interferon alfa

Symptoms (flushing, diarrhea, wheeze) are usually controlled with somatostatin analogs and interferon alfa.[30]

All patients with carcinoid syndrome are suitable for therapy with somatostatin analogs.[32][34][66] They reduce carcinoid symptoms, especially flushing and diarrhea.

Octreotide is available as a short-acting, subcutaneous formulation and a long-acting, intramuscular formulation. Patients should be started on the short-acting formulation and switched to the long-acting only once their dose has been stabilized.

Lanreotide is available as a long-acting, subcutaneous formulation.

Long-acting formulations are given once every 4 weeks. Long-term use is associated with development of gallstones in 60% of cases. Occasionally patients may develop intolerance upon initial injection. Steatorrhea can occur with sustained use of these agents and is best treated with a pancreatic enzyme supplement.

Interferon alfa has previously been used in patients with carcinoid syndrome who are intolerant of somatostatin analogs. Symptomatic response is observed in approximately 40% of patients.[32][35][60] In addition to its symptom control effects, it has antiproliferative and antiangiogenic actions.[61] The most commonly used interferon is interferon alfa-2b. The biochemical response varies between 15% and 45%. The pegylated interferon preparations are also available for use as weekly injections.[62]

Primary options

octreotide: 100-600 micrograms/day subcutaneously given in 2-4 divided doses; 20-30 mg intramuscularly every 4 weeks

OR

lanreotide: 60-120 mg subcutaneously every 4 weeks

Secondary options

interferon alfa 2b: consult specialist for guidance on dose

Consider – telotristat ethyl

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ONGOING
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metastatic disease
|
not suitable for resection or symptomatic following resection
Consider – 

telotristat ethyl

Treatment recommended for SOME patients in selected patient group

Telotristat ethyl, a tryptophan hydroxylase inhibitor, is recommended in combination with a somatostatin analog in patients with carcinoid syndrome-related diarrhea who are not adequately controlled on a somatostatin analog.[40]

It is not recommended in patients who are on interferon alfa.

Should be administered at least 30 minutes before short-acting octreotide.

Primary options

telotristat ethyl: 250 mg orally three times daily

2nd line – hepatic transarterial embolization or selective internal radiation therapy

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ONGOING
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metastatic disease
|
not suitable for resection or symptomatic following resection
2nd line – 

hepatic transarterial embolization or selective internal radiation therapy

Liver metastases are often the cause of carcinoid syndrome and, therefore, if symptoms progress despite optimal medical management with biotherapy, there may be a role for hepatic embolization.[41] The technique involves identifying the arterial blood supply to the hepatic metastases. If bilobar disease is present, then usually only 1 lobe is embolized at a time. Symptomatic improvement occurs in 40% to 80% and a biochemical response in 7% to 75% of cases.[42][43] The duration of response may last for 6 to 8 months, sometimes much longer.[41] Embolization can be repeated, although its effectiveness diminishes with repeated episodes.

Prior to surgery patients with carcinoid syndrome should be commenced on octreotide infusion to prevent carcinoid crisis.[2]​ It is commenced at least 2 hours prior to surgery and given until 48 hours after surgery.[26]

Patients should be given intravenous fluids and allopurinol (to prevent tumor lysis syndrome) prior to procedure and hospitalized for 24 to 72 hours postprocedure. Appropriate intravenous antibiotics should be commenced prior to procedure.

Overall mortality is <5% and side effects include postembolization syndrome (fever, abdominal pain, nausea, vomiting), hepatic abscess, and ischemic necrosis of the gallbladder and small bowel.

Selective internal radiation therapy (SIRT) is a method of combining embolization and radionuclide therapy to liver metastases. The radiation therapy is delivered by resin microsphere labeled with yttrium (Y)-90. The Y-90 labeled microspheres are selectively delivered to the metastases via infusion through a catheter in the hepatic artery.[44]

3rd line – radionuclide-targeted therapy

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ONGOING
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metastatic disease
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not suitable for resection or symptomatic following resection
3rd line – 

radionuclide-targeted therapy

Radiolabeled somatostatin analogs can be given for inoperable or metastasized neuroendocrine tumors. Symptomatic improvement has been reported in 60% to 80% of cases. Partial tumor response of greater than 50% tumor load is seen in 9% to 33% of patients, while disease stabilization is reported in approximately two thirds of cases. Both agents described have similar efficacy.

Somatostatin receptors are present in the majority of carcinoid tumors, and these can be visualized in patients using indium-(In)-111 diethylenetriaminepentaacetic acid (DTPA)-octreotide. Patients to be considered for this therapy need to have a positive somatostatin receptor positron emission tomography (SSTR-PET) result, commonly performed with gallium (Ga)-68 dotatate, Ga-68 dotatoc, or Ga-68 dotanoc, or a positive Octreoscan®. Patients need to be able to provide self-care, because for 24 hours they will be alone in a radioactive room. Inclusion criteria include: good tumor uptake on In-111 DTPA-octreotide scintigrams (tumor uptake > liver uptake); Hb >8 g/dL; WBC count >3.5 x 10⁹/L; platelet count >80 x 10⁹/L; and creatinine clearance >40 mL/minute.

An amino acid infusion is administered pre- and postprocedure to protect the kidneys. Acute side effects: nausea, vomiting, and increased pain in tumor sites. Minor side effects: hair loss, hematologic toxicity, renal toxicity, and liver toxicity.

4th line – chemotherapy

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ONGOING
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metastatic disease
|
not suitable for resection or symptomatic following resection
4th line – 

chemotherapy

Generally, chemotherapy has disappointing results in management of symptoms in patients with carcinoid syndrome. The commonly used regimens depend in part on the histology and site of the primary tumor. For bronchial tumors, etoposide and cisplatin can be used as first-line chemotherapy, while other centers recommend capecitabine and temozolomide.[41][50] Temozolomide is an oral alkylating agent used for the treatment of neuroendocrine tumors (NETs) as monotherapy. Results from one study showed a 14% radiological response, 53% had stable disease, and the overall median time to progression was 7 months.[51] For midgut carcinoid tumors, the best clinical response rate identified was in a study using doxorubicin and streptozotocin, where a 40% response rate was reported.[52] Other studies report response rates of usually <25% following a number of different chemotherapy regimens for well-differentiated midgut NETs.[30] The response rate for poorly differentiated NETs with etoposide and cisplatin has been shown to be between 40% and 67%.[53] This response rate does not necessarily correlate with improvement in carcinoid symptoms and often is related to tumor-related symptoms such as weight loss and tiredness.[54] Protocols, dosing and combination of agents tend to vary, and chemotherapy should only be used in specialist centers.

5th line – everolimus or sunitinib

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ONGOING
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metastatic disease
|
not suitable for resection or symptomatic following resection
5th line – 

everolimus or sunitinib

Everolimus and sunitinib are licensed for use in pancreatic neuroendocrine tumors (NETs).[30][55] Around 1% to 2% of pancreatic NETs cause carcinoid syndrome. Therefore, there is very limited evidence for improvement of carcinoid syndrome specifically with either of these agents. However, there is excellent evidence demonstrating delayed time to progression using these agents compared with placebo.[56] Everolimus is a protein kinase inhibitor of mTOR (mammalian target of rapamycin) that has demonstrated prolonged progression-free survival in the RADIANT-3 study.[57] Sunitinib inhibits cellular signalling by targeting multiple tyrosine kinase receptors including: platelet-derived growth factor receptor (PDGF-R), vascular endothelial growth factor receptor (VEGF-R), KIT, and RET.[59]

Primary options

everolimus (oncologic): consult specialist for guidance on dose

OR

sunitinib: consult specialist for guidance on dose

6th line – palliative debulking

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ONGOING
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metastatic disease
|
not suitable for resection or symptomatic following resection
6th line – 

palliative debulking

Massive hepatomegaly can cause symptoms that are difficult to manage. Debulking surgery should be considered for improving quality of life. Ideally, >90% of the tumor load should be resectable.

Cholecystectomy should also be performed in view of the high incidence of gallstones.

Prior to surgery patients with carcinoid syndrome should be commenced on octreotide infusion to prevent carcinoid crisis.[2]​ It is commenced at least 2 hours prior to surgery and given until 48 hours after surgery.[26]

Plus – perioperative octreotide infusion

Back
ONGOING
|
metastatic disease
|
not suitable for resection or symptomatic following resection
Plus – 

perioperative octreotide infusion

Treatment recommended for ALL patients in selected patient group

Prior to surgery patients with carcinoid syndrome should be commenced on octreotide infusion to prevent carcinoid crisis.[2]​ It is commenced at least 2 hours prior to surgery and given until 48 hours after surgery.[26]

Primary options

octreotide: consult specialist for guidance on dose

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Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups. See disclaimer

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