Approach

Management of symptoms related to carcinoid syndrome is based on reducing hormonal secretion. Tumors 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.[26] Surgery, embolization of metastases, radiofrequency ablation, or radiolabeled 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 tumor without evidence of metastatic spread). Surgery should be considered when both the primary and secondary lesions can be resected. Prior to surgery, patients should be commenced on octreotide infusion to prevent carcinoid crisis. It is commenced at least 2 hours prior to surgery and given until 48 hours after surgery.[27]

  • Bronchial carcinoid tumors: a significant number of these cases present with localized tumors and, thus, curative resection of the primary tumor 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 tumor. 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 postoperatively.

  • Midgut tumors: occasionally midgut carcinoid tumors without or with limited liver involvement are suitable for curative resection. Midgut carcinoids involving the small bowel should be resected if that 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. Other than resection, radiofrequency ablation may also be performed and may sometimes be used at the time of surgery.

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/radiologic progression of disease. In these cases, if resection of >90% of the tumor load is possible, then surgery may provide better symptom control and possibly longer survival.[29][30]

Medical management

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

Somatostatin analogs

Somatostatin analogs are suitable for all patients with carcinoid syndrome. Octreotide was the first developed somatostatin analog.[32] This can be administered as a subcutaneous or intravenous injection. However, due to the short half-life, a 3-times-daily regimen was previously required to maintain steady levels.[33] As a result, long-acting preparations have been developed that last for 28 days. Both long-acting preparations have similar comparable binding profiles and bind with a high affinity to somatostatin receptor types 1 and 4.[34][35][36][Figure caption and citation for the preceding image starts]: Octreotide planar image showing uptake in the liver from tumorFrom the collection of Dr R. Srirajaskanthan and Dr M. Caplin; used with permission [Citation ends].com.bmj.content.model.Caption@3c880264

A randomized placebo-controlled prospective study demonstrated that somatostatin analogs inhibited tumor growth and delayed time to progression in patients with metastatic midgut tumors.[37] A further study including small-bowel neuroendocrine tumors (NETs) has confirmed these findings.[38]

Somatostatin analogs also inhibit release of hormones from the pancreas. Steatorrhea can occur with sustained use of these agents and is best treated with a pancreatic enzyme supplement.

Telotristat ethyl

Telotristat ethyl (formulated as telotristat etiprate, the hippurate salt of telotristat ethyl) is an orally delivered small molecule that acts by inhibiting the enzyme tryptophan hydroxylase (TPH), the rate-limiting enzyme responsible for serotonin production. Telotristat ethyl was specifically designed to be absorbed into the bloodstream without crossing the blood-brain barrier so as not to affect brain serotonin levels. Results from a placebo-controlled, phase 2 study in patients with metastatic carcinoid syndrome who were refractory to currently available therapy indicated that telotristat ethyl was well tolerated and demonstrated positive response in key measures, including reduction in bowel movements and in patient-reported adequate relief of carcinoid symptoms.[39][40] The results of one study comparing telotristat ethyl with placebo in patients with high bowel frequency on the background of carcinoid syndrome has demonstrated a reduction in bowel frequency of patients receiving telotristat ethyl versus placebo.[41] The European Medicines Agency (EMA) has recommended approval of telotristat ethyl in patients with carcinoid syndrome-related diarrhea in combination with a somatostatin analog. The Food and Drug Administration (FDA) has approved the drug for use in patients with carcinoid syndrome-related diarrhea who are not adequately controlled on a somatostatin analog.

Hepatic transarterial embolization

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.[42] 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.[43][44] The duration of response may last for 6 to 8 months, sometimes much longer.[42] Embolization can be repeated, although its effectiveness diminishes with repeated episodes. 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 the procedure. Patients also require octreotide infusion to prevent carcinoid crisis, commenced at least 2 hours prior to surgery and given until 48 hours after surgery.

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-90. The 90-Y labeled microspheres are selectively delivered to the metastases via infusion through a catheter in the hepatic artery.[45]

Radionuclide therapies

The high-intensity expression of somatostatin receptors in NETs is demonstrated by a positive octreoscan, which involves the use of indium 111-In-diethylenetriaminepentaacetic acid (DTPA)-octreotide or Ga-68 DOTATATE or DOTATOC positive emission tomography (PET) imaging. Somatostatin receptors are present in the majority of carcinoid tumors. This facilitates the use of radionuclide therapies composed of a radiolabeled ligand attached to a somatostatin analog, producing localized radionuclide activity. Radiolabeled somatostatin analogs can be given for inoperable or metastasized NETs. Patients to be considered for this therapy need to have a positive octreoscan or Ga-68 PET imaging. 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 tumor uptake on 111-In-DTPA-octreotide scintigrams (tumor uptake > liver uptake)

  • Hemoglobin >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 yttrium Y-90-DOTA-octreotate and lutetium Lu-177-DOTA-octreotate.[46][47] Symptomatic improvement has been reported in 60% to 80% of cases. Partial tumor response of >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. Results of the first phase 3 randomized controlled trial examining Lu-177-DOTA-octreotate therapy in small bowel NET with carcinoid syndrome demonstrated an improved progression-free survival and possible overall survival benefit of Lu-177-DOTA-octreotate compared with octreotide (depot formulation).[48] The use of radionucleotide therapies should be limited to specialist centers.

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 tumor. For bronchial tumors, etoposide and cisplatin can be used as first-line chemotherapy, while other centers recommend capecitabine and temozolomide.[42][49] 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.[50] 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.[51] 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%.[52] 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.[53] Protocols, dosing and combination of agents tend to vary, and chemotherapy should only be used in specialist centers.

Everolimus and sunitinib are licensed for use in pancreatic NETs.[31][54] 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.[54] However, there is excellent evidence demonstrating delayed time to progression using these agents compared with placebo.[55] Everolimus is a protein kinase inhibitor of mTOR (mammalian target of rapamycin) that has demonstrated prolonged progression-free survival in the RADIANT-3 study.[56] Results from one RADIANT-4 study have demonstrated a progression-free survival benefit in patients with gastrointestinal and bronchial NETs.[57] Sunitinib inhibits cellular signaling by targeting multiple tyrosine kinase receptors including: platelet-derived growth factor receptor (PDGF-R), vascular endothelial growth factor receptor (VEGF-R), KIT, and RET.[58]

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.[33][36][59] The effects of interferon alfa are mediated via the interferon type 1 receptors. In addition to its symptom control effects, it has antiproliferative and antiangiogenic actions.[60] 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.[61]

Cyproheptadine has been used only on rare occasions where somatostatin analogs and interferon alfa are unable to control diarrhea. It appears to be effective in the management of diarrhea associated with malignant carcinoid syndrome. However, its biochemical and antitumoral effects are minimal.[62]

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