Management of the hormonal syndrome of neuroendocrine tumors
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Submission date: 2015-08-16
Final revision date: 2016-04-03
Acceptance date: 2016-04-07
Online publication date: 2016-06-01
Publication date: 2017-04-20
Arch Med Sci 2017;13(3):515-524
Gastroenteropancreatic neuroendocrine tumors (GEP/NET) are unusual and relatively rare neoplasms that present many clinical challenges. They characteristically synthesize, store and secrete a variety of peptides and neuroamines which can lead to the development of distinct clinical syndromes, including the carcinoid syndrome, insulinoma, glucagonoma or VIPoma, although many are clinically silent until late presentation with mass effects. Management strategies include surgery and cytoreduction with chemotherapy and the use of somatostatin analogues to control symptoms from peptide neurotransmitter release. Somatostatin have a broad range of biological actions that include inhibition of exocrine and endocrine secretions, gut motility, cell proliferation, cell survival and angiogenesis. Five G-protein-coupled somatostatin receptors (SSTR1-SSTR5) have been cloned and characterized. Clinically used somatostatin analogues including octreotide and lanreotide are effective medical tools in treatment and show selectivity for SSTR2 and SSTR5. During treatment, disappearance of flushing, normalization of bowel movements and reduction of serotonin and 5-hydroxyindole acetic acid (5-HIAA) secretion are observed. The addition of interferon (INF) to somatostatin analogues may improve the antiproliferative effects. Patients who received the combination therapy had a significantly lower risk of progressive disease. On the other hand, the major toxicity of INF including temporary flu-like symptoms, tiredness, anorexia and leukopenia should be considered. Telotristat etiprate is an orally bioavailable, tryptophan hydroxylase (TPH) inhibitor with potential antiserotoninergic activity. Telotristat represents a novel approach by specifically inhibiting serotonin synthesis and, as such, is a promising potential new treatment for patients with carcinoid syndrome. Pancreatic functioning neuroendocrine tumors include insulinoma, gastrinoma, glucagonoma and VIPoma. Medical management in patients with insulinoma and severe hypoglycemic attacks includes diazoxide, which suppresses insulin release. Also mTOR inhibitors may inhibit insulin secretion. Treatment of gastrinoma includes both proton pump inhibitors (PPIs) and histamine H2-receptor antagonists. Octreotide and lanreotide can also control acid hypersecretion. In patients with glucagonomas hyperglycemia can be controlled using insulin and oral blood glucose lowering drugs. In malignant glucagonomas somatostatin analogues are effective in controlling necrolytic migratory erythema. Severe cases of the VIPoma syndrome require supplementation of fluid losses. Octreotide reduces tumoral VIP secretion and controls secretory diarrhea. Further control of diarrhea can be achieved with loperamide, opiates and glucocorticoids.
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