the disease in sixty-five percent of patients treated with lanreotide in the study had not progressed or caused death at 96 weeks, the same was true of 33% of patients on placebo. this represented a 53% reduction in risk of disease progression or death with lanreotide based on a hazard ratio of .47. lanreotide is the first and only fda approved antitumor therapy demonstrating a statistically significant progression-free survival benefit in a combined population of patients with gep-nets. other medications that block particular secretory effects can sometimes relieve symptoms. chemotherapy interferon is sometimes used to treat gep-nets. its effectiveness is somewhat uncertain, but low doses can be titrated within each person, often considering the effect on the blood leukocyte count; interferon is often used in combination with other agents, especially somatostatin analogs such as octreotide. gastrointestinal neuroendocrine tumors most gastrointestinal carcinoid tumors tend not to respond to chemotherapy agents, showing 10 to 20% response rates that are typically less than 6 months. combining chemotherapy medications has not usually been of significant improvement showing 25 to 35% response rates that are typically less than 9 months. the exceptions are poorly differentiated (high-grade or anaplastic) metastatic disease, where cisplatin with etoposide may be used and somatostatin receptor scintigraphy (ssrs) negative tumors which had a response rate in excess of 70% compared to 10% in strongly positive srss carcinoid tumors. pannets main article: pancreatic neuroendocrine tumor § treatment targeted therapy with everolimus (afinitor) and sunitinib (sutent) is approved by the fda in unresectable, locally advanced or metastatic pannets. some pannets are more responsive to chemotherapy than gastroenteric carcinoid tumors. several agents have shown activity and combining several medicines, particularly doxorubicin with streptozocin and fluorouracil (5-fu or f5u), is often more effective. although marginally effective in well-differentiated pets, cisplatin with etoposide is active in poorly differentiated neuroendocrine cancers (pdnecs). radionuclide therapy peptide receptor radionuclide therapy (prrt) is a type of radioisotope therapy (rit) in which a peptide or hormone conjugated to a radionuclide or radioligand is given intravenously, the peptide or neuroamine hormone previously having shown good uptake of a tracer dose, using somatostatin receptor imaging as detailed above. this type of radiotherapy is a systemic therapy and will impact somatostatin positive disease. the peptide receptor may be bound to lutetium-177, yttrium-90, indium-111 and other isotopes including alpha emitters. this is a highly targeted and effective therapy with minimal side effects in tumors with high levels of somatostatin cell surface expression, because the radiation is absorbed at the sites of the tumor, or excreted in the urine. the radioactively labelled hormones enter the tumor cells which, together with nearby cells, are damaged by the attached radiation. not all cells are immediately killed; cell death can go on for up to two years. prrt was initially used for low grade nets. it is also very useful in more aggressive nets such as grade 2 and 3 nets provided they demonstrate high uptake on sstr imaging to suggest benefit. hepatic artery main article: hepatic artery embolization metastases to the liver can be treated by several types of hepatic artery treatments based on the observation that tumor cells get nearly all their nutrients from the hepatic artery, while the normal cells of the liver get about 70–80 percent of their nutrients and 50% their oxygen supply from the portal vein, and thus can survive with the hepatic artery effectively blocked. hepatic artery embolization (hae) occludes the blood flow to the tumors, achieving significant tumor shrinkage in over 80%. in hepatic artery chemotherapy, the chemotherapy agents are given into the hepatic artery, often by steady infusion over hours or even days. compared with systemic chemotherapy, a higher proportion of the chemotherapy agents are (in theory) delivered to the lesions in the liver. hepatic artery chemoembolization (hace), sometimes called transarterial chemoembolization (tace), combines hepatic artery embolization with hepatic artery chemoinfusion: embospheres bound with chemotherapy agents, injected into the hepatic artery, lodge in downstream capillaries. the spheres not only block blood flow to the lesions, but by halting the chemotherapy agents in the neighborhood of the lesions, they provide much better targeting leverage than chemoinfusion provides. selective internal radiation therapy (sirt) for neuroendocrine metastases to the liver delivers radioactive microsphere therapy (rmt) by injection into the hepatic artery, lodging (as with hae and hace) in downstream capillaries. in contrast to hormone-delivered radiotherapy, the lesions need not overexpress peptide receptors. the mechanical targeting delivers the radiation from the yttrium-labeled microspheres selectively to the tumors without unduly affecting the normal liver. this type of treatment is fda approved for liver metastases secondary to colorectal carcinoma and is under investigation for treatment of other liver malignancies, including neuroendocrine malignancies. other therapies advince, a type of gene therapy using a genetically modified oncolytic adenovirus and supported by the crowdfunding campaign icancer was used in a phase 1 trial against net in 2016. further efforts towards more personalized therapies in neuroendocrine tumors are undertaken i.a. combining drug screening platforms and patient-derived ex vivo cell cultures that mimic relevant aspects of the original tumors. epidemiology although estimates vary, the annual incidence of clinically significant neuroendocrine tumors is approximately 2.5–5 per 100,000; two thirds are carcinoid tumors and one third are other nets. the prevalence has been estimated as 35 per 100,000, and may be considerably higher if clinically silent tumors are included. an autopsy study of the pancreas in people who died from unrelated causes discovered a remarkably high incidence of tiny asymptomatic nets. routine microscopic study of three random sections of the pancreas found nets in 1.6%, and multiple sections identified nets in 10%. as diagnostic imaging increases in sensitivity, such as endoscopic ultrasonography, very small, clinically insignificant nets may be coincidentally discovered; being unrelated to symptoms, such neoplasms may not require surgical excision. history small intestinal neuroendocrine tumors were first distinguished from other tumors in 1907. they were named carcinoid tumors because their slow growth was considered to be "cancer-like" rather than truly cancerous. however, in 1938 it was recognized that some of these small bowel tumors could be malignant. despite the differences between these two original categories, and further complexities due to subsequent inclusion of other nets of pancreas and pulmonary origin, all nets are sometimes (incorrectly) subsumed into the term "carcinoid". enterochromaffin cells, which give rise to carcinoid tumors, were identified in 1897 by nikolai kulchitsky and their secretion of serotonin was established in 1953 when the "flushing" effect of serotonin had become clinically recognized. carcinoid heart disease was identified in 1952, and carcinoid fibrosis in 1961. neuroendocrine tumors were sometimes called apudomas because these cells often show amine precursor (l-dopa and 5-hydroxytryptophan) uptake and decarboxylation to produce biogenic amines such as catecholamines and serotonin. although this behavior was also part of the disproven hypothesis that these cells might all embryologically arise from the neural crest, neuroendocrine cells sometimes produce various types of hormones and amines, and they can also have strong receptors for other hormones to which they respond. there have been multiple nomenclature systems for these tumors, and the differences between these schema have often been confusing. nonetheless, these systems all distinguish between well-differentiated (low and intermediate-grade) and poorly differentiated (high-grade) nets. cellular proliferative rate is of considerable significance in this prognostic assessment.