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

localised disease

1st line – surgical resection

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ONGOING
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localised disease
1st line – 

surgical resection

Surgery should be considered in patients with localised 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.[57] With appendiceal tumours, carcinoid syndrome does not occur unless distal metastases are present. Localised appendiceal carcinoid is somewhat unrelated to carcinoid syndrome.[58]

In patients with resectable bronchial carcinoids, surgery should be considered as first-line therapy in those with a good functional status.[28] 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.[28] 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.

Consider – peri-operative octreotide

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ONGOING
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localised disease
Consider – 

peri-operative octreotide

Additional treatment recommended for SOME patients in selected patient group

Prophylactic octreotide should be considered prior to surgery, but evidence for the prevention of carcinoid crisis is limited.[2][19][24][25][26]​ European guidelines recommend that octreotide is commenced 12 hours prior to surgery, and continued post-operatively until the patient is clinically stable.​[19]​ Standard protocols are, however, lacking.[27]​ Refer to local protocols regarding administration of prophylactic octreotide as timeframes for administration can vary.

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.

Consider – peri-operative octreotide

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ONGOING
|
metastatic disease
|
suitable for resection
Consider – 

peri-operative octreotide

Additional treatment recommended for SOME patients in selected patient group

Prophylactic octreotide should be considered prior to surgery, but evidence for the prevention of carcinoid crisis is limited.[2][19][24][25][26]​ European guidelines recommend that octreotide is commenced 12 hours prior to surgery, and continued post-operatively until the patient is clinically stable.[19]​ Standard protocols are, however, lacking.[27]​ Refer to local protocols regarding administration of prophylactic octreotide as timeframes for administration can vary.

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

Additional treatment recommended for SOME patients in selected patient group

Radiofrequency ablation may sometimes be used in combination with surgery, or alone when lesions are small and limited in number.[24]

1st line – somatostatin analogue

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

somatostatin analogue

Symptoms (flushing, diarrhoea, wheeze) are usually controlled with somatostatin analogues.[31]

All patients with carcinoid syndrome are suitable for therapy with somatostatin analogues.[59][60][61]​ They reduce carcinoid symptoms, especially flushing and diarrhoea.

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 stabilised.

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. Steatorrhoea can occur with sustained use of these agents. Treatment is with a pancreatic enzyme supplement.

Primary options

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

OR

lanreotide: 120 mg subcutaneously every 4 weeks

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

Additional treatment recommended for SOME patients in selected patient group

Telotristat ethyl, a tryptophan hydroxylase inhibitor, is recommended in combination with a somatostatin analogue in patients with carcinoid syndrome-related diarrhoea who are not adequately controlled on a somatostatin analogue.[19][24]​​

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 embolisation or selective internal radiotherapy treatment

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

hepatic transarterial embolisation or selective internal radiotherapy treatment

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 embolisation.[37] The technique involves identifying the arterial blood supply to the hepatic metastases. If bilobar disease is present, then usually only 1 lobe is embolised at a time. Symptomatic improvement occurs in 40% to 80% and a biochemical response in 7% to 75% of cases.[38][39]​ The duration of response may last for 6 to 8 months, sometimes much longer.[37] Embolisation can be repeated, although its effectiveness diminishes with repeated episodes.

Patients should be given intravenous fluids and allopurinol (to prevent tumour lysis syndrome) prior to procedure and hospitalised for 24 to 72 hours post-procedure. Appropriate intravenous antibiotics should be commenced prior to procedure.

Overall mortality is less than 5% and adverse effects include post-embolisation syndrome (fever, abdominal pain, nausea, vomiting), hepatic abscess, and ischaemic necrosis of the gallbladder and small bowel.

Selective internal radiotherapy treatment (SIRT) is a method of combining embolisation and radionuclide therapy to liver metastases. The radiotherapy is delivered by resin microsphere labelled with yttrium (Y)-90. The Y-90 labelled microspheres are selectively delivered to the metastases via infusion through a catheter in the hepatic artery.[40]

Consider – perioperative octreotide

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

perioperative octreotide

Additional treatment recommended for SOME patients in selected patient group

Prophylactic octreotide should be considered prior to surgery, but evidence for the prevention of carcinoid crisis is limited.[2][19][24][25][26]​ European guidelines recommend that octreotide is commenced 12 hours prior to surgery, and continued post-operatively until the patient is clinically stable.[19]​ Standard protocols are, however, lacking.[27]​ Refer to local protocols regarding administration of prophylactic octreotide as timeframes for administration can vary.

Primary options

octreotide: consult specialist for guidance on dose

3rd line – radionuclide-targeted therapy

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

radionuclide-targeted therapy

Radiolabelled somatostatin analogues can be given for inoperable or metastasised neuroendocrine tumours. Symptomatic improvement has been reported in 60% to 80% of cases. Partial tumour response of >50% tumour load is seen in 9% to 33% of patients, while disease stabilisation is reported in approximately two-thirds of cases. Both agents described have similar efficacy.

Somatostatin receptors are present in the majority of carcinoid tumours, and these can be visualised 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 tumour uptake on In-111 DTPA-octreotide scintigrams (tumour uptake > liver uptake); Hb >80 g/L (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 post-procedure to protect the kidneys. Acute adverse effects: nausea, vomiting, and increased pain in tumour sites. Minor adverse effects: hair loss, haematological 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 tumour. For bronchial tumours, etoposide, and cisplatin can be used as first-line chemotherapy, while other centres recommend capecitabine and temozolomide.[37][46] Temozolomide is an oral alkylating agent used for the treatment of neuroendocrine tumours (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.[47] For midgut carcinoid tumours, the best clinical response rate identified was in a study using doxorubicin and streptozocin, where a 40% response rate was reported.[48] Other studies report response rates of usually <25% following a number of different chemotherapy regimens for well-differentiated midgut NETs.[31] The response rate for poorly differentiated NETs with etoposide and cisplatin has been shown to be between 40% and 67%.[49] This response rate does not necessarily correlate with improvement in carcinoid symptoms and often is related to tumour-related symptoms such as weight loss and tiredness.[50] Protocols, dosing and combination of agents tend to vary, and chemotherapy should only be used in specialist centres.

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 tumours (NETs).[31][51] 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.[52] Everolimus is a protein kinase inhibitor of mTOR (mammalian target of rapamycin) that has demonstrated prolonged progression-free survival in the RADIANT-3 study.[53] 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.[55]

Primary options

everolimus: 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 tumour load should be resectable.

Prophylactic cholecystectomy should also be considered in those already undergoing abdominal surgery, in view of the high incidence of gallstones.[24]

Consider – perioperative octreotide

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

perioperative octreotide

Additional treatment recommended for SOME patients in selected patient group

Prophylactic octreotide should be considered prior to surgery, but evidence for the prevention of carcinoid crisis is limited.[2][19][24][25]​​[26]​ European guidelines recommend that octreotide is commenced 12 hours prior to surgery, and continued post-operatively until the patient is clinically stable.[19]​ Standard protocols are, however, lacking.[27]​ Refer to local protocols regarding administration of prophylactic octreotide as timeframes for administration can vary.

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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