Approach

Management of symptoms related to carcinoid syndrome is based on reducing hormonal secretion. Tumours normally secrete biogenic amines into the circulation. However, when the primary site is within the gut, the secreted amines are degraded by the liver and symptoms do not generally occur. When liver metastases are present, these amines drain into the circulation prior to being broken down and hence cause carcinoid syndrome.

Nearly all patients with carcinoid syndrome have liver metastases and many have unresectable disease. Consequently, symptomatic medical management is the initial mainstay of treatment.[23] Surgery, embolisation of metastases, radiofrequency ablation, or radiolabelled octreotide is appropriate in some patients.

Surgical management

Curative surgical therapy should always be considered. However, most patients have advanced disease. Surgery is an option in patients with a resectable primary lesion (e.g., a bronchial carcinoid tumour without evidence of metastatic spread). Surgery should be considered when both the primary and secondary lesions can be resected.

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 the administration of prophylactic octreotide as timeframes for administration can vary.

Bronchial carcinoid tumours

A significant number of these cases present with localised tumours and, thus, curative resection of the primary tumour is an option. Surgery should be considered as first-line therapy in those with a good functional status.[28] The type of surgery undertaken depends on the location, size, and extent of the tumour. In well-circumscribed lesions, wedge resection can be performed; other cases may require lobectomies and, occasionally, pneumonectomy. There is a low operative mortality of <1% for published surgical series, and the benefit is a possible curative resection.[28] Complications of surgery after initial resection relate to the type of procedure performed and previous functional status. Wedge excision and lobectomy leave a good residual lung volume, but pneumonectomy may impair quality of life post-operatively.

Midgut tumours

Occasionally midgut carcinoid tumours without or with limited liver involvement are suitable for curative resection. 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. 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. Radiofrequency ablation may also be performed (in combination with surgery, or alone) when lesions are small and limited in number.[24]​

Debulking surgery for liver disease

Should be considered as a palliative option in patients with symptoms related to carcinoid syndrome refractory to medical therapy, or in whom there is evidence of clinical/radiological progression of disease. In these cases, if resection of >90% of the tumour load is possible, then surgery may provide better symptom control and possibly longer survival.[29][30]

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

Medical management

Symptoms (flushing, diarrhoea, wheeze) are usually controlled with somatostatin analogues.[31] Second-line treatment for management of symptoms involves the use of radionuclide-targeted therapy or hepatic transarterial embolisation and possibly chemotherapy.[2]​[24]​ However, chemotherapy for midgut carcinoids lacks efficacy, with response rates of <25%.[31]

Somatostatin analogues

Somatostatin analogues are suitable for all patients with carcinoid syndrome. They inhibit tumour growth and delay time to progression in patients with metastatic midgut tumours.[32]​[33]​

Octreotide, the first somatostatin analogue to be developed, can be administered as a subcutaneous, intramuscular, or intravenous injection. Long-acting octreotide formulations allow administration at longer intervals.

Somatostatin analogues can cause steatorrhoea by inhibiting the release of pancreatic digestive enzymes. Treatment is with pancreatic enzyme supplement.[24]​

[Figure caption and citation for the preceding image starts]: Octreotide planar image showing uptake in the liver from tumourFrom the collection of Dr R. Srirajaskanthan and Dr M. Caplin; used with permission [Citation ends].com.bmj.content.model.Caption@2839e1fb

Telotristat ethyl

Guidelines from the American Society for Clinical Oncology (ASCO) and The European Neuroendocrine Tumor Society (ENETS) recommend telotristat ethyl, in conjunction with a somatostatin analogue, for use in patients with carcinoid syndrome-related diarrhoea who are not adequately controlled on a somatostatin analogue.[19]​[24]​

Telotristat ethyl, an oral small molecule tryptophan hydroxylase inhibitor, reduced bowel movements and improved patient-reported relief of carcinoid symptoms in placebo-controlled phase 2 and phase 3 trials.[34][35][36] 

Hepatic transarterial embolisation

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 the procedure and hospitalised for 24 to 72 hours post-procedure. Appropriate intravenous antibiotics should be commenced prior to procedure. 

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 the administration of prophylactic octreotide as timeframes for administration can vary.

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]

Radionuclide therapies

Somatostatin receptors are present in the majority of carcinoid tumours. This facilitates the use of radionuclide therapies composed of a radiolabelled ligand attached to a somatostatin analogue, producing localised radionuclide activity. Radiolabelled somatostatin analogues can be given for inoperable or metastasised NETs. Patients to be considered for this therapy need to have a positive somatostatin receptor positron emission tomography PET (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 are:

  • Good tumour uptake on indium-(In)-111-DTPA-octreotide scintigrams (tumour uptake > liver uptake)

  • Haemoglobin >80 g/L (8 g/dL)

  • WBC count >3.5 x 10⁹/L

  • Platelet count >80 x 10⁹/L

  • Creatinine clearance >40 mL/minute

The commonly used radionuclide therapies are Y-90-DOTA-octreotate and lutetium (Lu)-177-DOTA-octreotate.[41][42]​ 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. Results of phase 3 randomised controlled trials examining Lu-177-DOTA-octreotate therapy in patients with advanced midgut and gastroenteropancreatic NETs demonstrate an improved progression-free survival and possible overall survival benefit of Lu-177-DOTA-octreotate compared with octreotide (depot formulation).[43][44][45]​​​ The use of radionucleotide therapies should be limited to specialist centres.

Other treatments

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 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.

Everolimus and sunitinib are licensed for use in pancreatic 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.[51] 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] Results from one RADIANT-4 study have demonstrated a progression-free survival benefit in patients with gastrointestinal and bronchial NETs.[54] 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]

Peginterferon alfa has been used as an alternative to somatostatin analogues in these patients, but is rarely used in practice and is not included as a standard therapy in current guidelines.

Cyproheptadine is another alternative on rare occasions where somatostatin analogues have been unable to control diarrhoea. It appears to be effective in the management of diarrhoea associated with malignant carcinoid syndrome. However, its biochemical and antitumoural effects are minimal.[56]

Use of this content is subject to our disclaimer