Neuroendocrine tumors, or more properly gastro-entero-pancreatic or gastroenteropancreatic neuroendocrine tumors (GEP-NETs), are cancers of the interface between the endocrine (hormonal) system and the nervous system. Tumor (American English) or tumour (British English) originally means swelling, and is sometimes still used with that meaning. ...

The Neuroendocrine System

The endocrine system is a communication system in which hormones act as biochemical messengers to regulate physiological events in living organisms. The nervous system is a communication system in which electrical impulses act as messengers to regulate events in living organisms. The neuroendocrine system is the combination of those two systems, or more specifically, the various interfaces between the two systems. A GEP-NET is a tumor of any such interface. Hormone is also the NATO reporting name for the Soviet/Russian Kamov Ka-25 military helicopter. ... Neuroendocrinology is the study of the interactions between the nervous system and the endocrine system. ...

More concretely, the endocrine system is primarily a network of glands that produce and secrete hormones, usually into the bloodstream. But it also includes cells that are not part of glands: the diffuse neuroendocrine system, scattered throughout other organs. Most GEP-NETs begin in the diffuse neuroendocrine system.

A hormone is a chemical that delivers a particular message to a particular organ, typically remote from the hormone's origin. For example, the hormone insulin, secreted by the pancreas, acts primarily to allow glucose to enter the body's cells for use as fuel. The hormone gastrin is secreted by the stomach to tell the stomach to produce acids to digest food. The structure of insulin. ... The pancreas is an organ in the digestive system that serves two major functions: exocrine - it produces pancreatic juice containing digestive enzymes. ... In humans, gastrin is a hormone that stimulates secretion of gastric acid by the stomach. ... In anatomy, the stomach (in ancient Greek στόμαχος) is an organ in the gastrointestinal tract used to digest food. ...

Hormones can be divided into subtypes such as peptides, steroids, and neuroamines. For some researchers, there is no clear distinction between peptide hormones and peptides; the hormones are simply longer than other peptides. In the context of GEP-NETs, the terms hormone and peptide are often used interchangeably. Peptides are the family of molecules formed from the linking, in a defined order, of various amino acids. ... In chemistry and biology, Steroids are a type of lipid, characterized by a carbon skeleton with four fused rings. ... Ammonia Amines are organic compounds and a type of functional group that contain nitrogen as the key atom. ...

Classification of GEP-NETs by Site of Origin and by Symptom

According to Rufini et alia, GEP-NETs "originate from pancreatic islet cells, [from] gastroenteric tissue (from diffuse neuroendocrine cells distributed throughout the gut), [from] neuroendocrine cells within the respiratory epithelium, and [from] parafollicullar cells distributed within the thyroid (the tumours being referred to as medullary carcinomas of the thyroid). Pituitary, parathyroid, and adrenomedullary neoplasms have certain common characteristics with these tumours but are considered separately" (PMID 16762613). Some researchers, however, do not consider the last groups separately.

Note that some GEP-NETs do not arise from the gastro-entero-pancreatic system; for example, one type that Rufini mentions arises from the lungs. Those tumors are included under the GEP-NET label because of their similarity to what we may call "true" GEP-NET tumors.

Subtypes of the GEP-NETs by site of origin include

• carcinoid
• pancreatic endocrine tumor (PET)
• medullary carcinoma of the thyroid
• Merkel cell cancer (trabecular cancer)
• neuroendocrine lung tumors, including small-cell lung cancer (SCLC) and large-cell neuroendocrine carcinoma
• neuroendocrine carcinoma of the cervix
• Multiple Endocrine Neoplasia type 1 (MEN-1 or MEN1)
• neuroendocrine cancer of the liver (a disease of dogs)
• Devil facial tumor disease (a disease of Tasmanian Devils)
• other, rare forms

(see more detail in the summary below). Carcinoid is a potentially malignant tumour that occurs in the mucosa of the lungs and digestive tract and potentially in other organs. ... Merkel cell cancer, also called Merkel cell carcinoma or neuroendocrine cancer or trabecular cancer, is a rare and highly aggressive cancer where malignant cancer cells develop on or just beneath the skin and in hair follicles. ... Schematic frontal view of female anatomy The cervix (from Latin neck) is the lower, narrow portion of the uterus where it joins with the top end of the vagina. ... Devil Facial Tumor Disease is a fatal disease of the Tasmanian Devil. ... Binomial name Sarcophilus laniarius (Boitard, 1841) Synonyms Sarcophilius harrisii The Tasmanian Devil (Sarcophilus laniarius), also referred to simply as the devil, is a carnivorous marsupial now found only in the Australian island state of Tasmania. ...

The vast majority of GEP-NETs are in the first two categories. Originally only one category was recognized, and in 1907 Oberndorfer gave it the name carcinoid because the tumors were so slow-growing that he considered them to be "cancer-like" rather than truly cancerous -- thus he distinguished what we now call GEP-NETs from adenocarcinoma. In 1929, he reported that some such tumors were not so indolent -- thus he distinguished PETs from carcinoids. (Still, even in 2006, many physicians, including oncologists, persist in calling all GEP-NETs "carcinoid", in effect failing to advance beyond Oberndorfer's pre-1929 terminology. This persistence results from similarities in appearance of PET cells and carcinoid cells under the microscope.) In medicine, carcinoma is any cancer that arises from epithelial cells. ...

Pancreatic endocrine tumors (PETs) are also known as endocrine pancreatic tumors (EPTs) or islet cell tumors. PETs are assumed to originate generally in the islets of Langerhans within the pancreas (or, Arnold suggests, from endocrine pancreatic precursor cells), though they may originate outside of the pancreas. (The term pancreatic cancer almost always refers to adenopancreatic cancer, also known as exocrine pancreatic cancer. Adenopancreatic cancer is not a neuroendocrine cancer. About 95 percent of tumors occurring in the pancreas are adenopancreatic; about 1 or 2 percent are GEP-NETs.) The endocrine (i. ... Pancreatic cancer (also called cancer of the pancreas) is represented by the growth of a malignant tumour within the small pancreas organ. ...

PETs may secrete hormones (as a result, perhaps, of impaired storage ability), and those hormones can wreak symptomatic havoc on the body. Those PETs that do not secrete hormones are called nonsecretory or nonfunctioning or nonfunctional tumors. Secretory tumors are classified by the hormone most strongly secreted — for example, insulinoma, which produces excessive insulin, and gastrinoma, which produces excessive gastrin (see more detail in the summary below).

Carcinoid tumors are further classified, depending on the point of origin, as foregut (lung, thymus, stomach, and duodenum) or midgut (distal ileum and proximal colon) or hindgut (distal colon and rectum). Less than one percent of carcinoid tumors originate in the pancreas. But for many tumors, the point of origin is unknown. The lungs flank the heart and great vessels in the chest cavity. ... In human anatomy, the thymus is a ductless gland located in the upper anterior portion of the chest cavity. ... In anatomy, the stomach (in ancient Greek στόμαχος) is an organ in the gastrointestinal tract used to digest food. ... In anatomy of the digestive system, the duodenum is a hollow jointed tube connecting the stomach to the jejunum. ... Grays Fig. ... Colon has several meanings: colon (anatomy) colon (punctuation) colon (rhetoric) See also Colón This is a disambiguation page — a navigational aid which lists other pages that might otherwise share the same title. ... The posterior aspect of the rectum exposed by removing the lower part of the sacrum and the coccyx. ...

Carcinoid tumors tend to grow much more slowly than PETs. A carcinoid tumor may produce serotonin (5-HT), a biogenic amine that causes a specific set of symptoms including Serotonin (5_hydroxytryptamine, or 5_HT) is a monoamine neurotransmitter synthesised in serotonergic neurons in the central nervous system and enterochromaffin cells in the gastrointestinal tract. ... Ammonia Amines are organic compounds and a type of functional group that contain nitrogen as the key atom. ...

• facial flushing
• diarrhea
• congestive heart failure (CHF)
• asthma
• acromegaly
• Cushing's syndrome

This set of symptoms is called carcinoid syndrome. Although this serotonin secretion is entirely different from a secretory PET's hormone secretion, carcinoid tumors with carcinoid syndrome are nevertheless sometimes called functioning, adding to the frequent confusion of carcinoids with PETs. Carcinoid syndrome is primarily associated with midgut carcinoids. A severe episode of carcinoid syndrome is called carcinoid crisis; it can be triggered by surgery or chemotherapy, among other factors. Congestive heart failure (CHF), also called congestive cardiac failure (CCF) or just heart failure, is a condition that can result from any structural or functional cardiac disorder that impairs the ability of the heart to fill with or pump a sufficient amount of blood throughout the body. ... Acromegaly (from Greek akros high and megas large - extremities enlargement) is a hormonal disorder that results when the pituitary gland produces excess growth hormone (hGH). ...

The mildest of the carcinoids are discovered only upon surgery for unrelated causes. These coincidental carcinoids are fairly common: for example, for roughly every 250 appendices removed by surgery for unrelated reasons, one is found.

Neuroendocrine tumors other than coincidental carcinoids are rare. Incidence of PETs is estimated at 0.4 to 1.5 new cases per 100,000 per year; incidence of carcinoids is twice that. Thus the total incidence of GEP-NETs in the United States would be about 9,000 new cases per year. But researchers differ widely in their estimates of incidence — especially at the level of the secretory subtypes (the various "-omas").

Rufini summarizes: "Neuroendocrine tumors (NETs) are a heterogeneous group of neoplasms originating from endocrine cells, which are characterized by the presence of secretory granules as well as the ability to produce biogenic amines and polypeptide hormones. These tumors originate from endocrine glands such as the adrenal medulla, the pituitary, and the parathyroids, as well as endocrine islets within the thyroid or the pancreas, and dispersed endocrine cells in the respiratory and gastrointestinal tract. The clinical behavior of NETs is extremely variable; they may be functioning or not functioning, ranging from very slow-growing tumors (well-differentiated NETs), which are the majority, to highly aggressive and very malignant tumors (poorly differentiated NETs)". (Note that the definition of well-differentiated may be counterintuitive: a tumor is well-differentiated if its cells are similar to normal cells, which have a well-differentiated structure of nucleus, cytoplasm, membrane, etc.)

Summary of Human GEP-NETs by Site of Origin and by Symptom

• carcinoids (about 66 percent of GEP-NETs)
  • with carcinoid syndrome (about 10 percent of carcinoids)
  • without carcinoid syndrome (about 90 percent of carcinoids)
• PETs (about 33 percent of GEP-NETs)
  • nonfunctioning (15 to 30 percent of PETs)
  • functioning (70 to 85 percent of PETs)
    • gastrinoma, producing excessive gastrin and causing Zollinger-Ellison Syndrome (ZES)
    • insulinoma, producing excessive insulin
    • glucagonoma, producing excessive glucagon
    • vasoactive intestinal peptideoma (VIPoma), producing excessive vasoactive intestinal peptide (VIP)
    • PPoma, producing excessive pancreatic polypeptide (often classed with nonfunctioning PETs)
    • somatostatinoma, producing excessive somatostatin
    • watery diarrhea, hypokalemia-achlorhydria (WDHA)
    • CRHoma, producing excessive corticotropin-releasing hormonse (CRH)
    • calcitoninoma, producing excessive calcitonin
    • GHRHoma, producing excessive growth-hormone-releasing hormone (GHRH)
    • neurotensinoma, producing excessive neurotensin
    • ACTHoma, producing excessive adrenocorticotropic hormone (ACTH)
    • GRFoma, producing excessive growth-hormone release factor (GRF)
    • parathyroid hormone–related peptide tumor
• medullary carcinoma of the thyroid
• Merkel cell cancer (trabecular cancer)
• small-cell lung cancer (SCLC)
• large-cell neuroendocrine carcinoma (of the lung)
• neuroendocrine carcinoma of the cervix
• Multiple Endocrine Neoplasia type 1 (MEN-1 or MEN1) (usually nonfunctioning) (also causing ZES)
• Multiple Endocrine Neoplasia type 2 (MEN-2 or MEN2)
• neurofibromatosis type 1
• tuberous sclerosis
• von Hippel-Lindau (VHL) disease
• neuroblastoma
• pheochromocytoma (phaeochromocytoma)
• paraganglioma
• neuroendocrine tumor of the anterior pituitary
• Carney's complex
• etc.

In humans, gastrin is a hormone that stimulates secretion of gastric acid by the stomach. ... In humans, gastrin is a hormone that stimulates secretion of gastric acid by the stomach. ... Zollinger-Ellison syndrome is a disorder where increased levels of the hormone gastrin are produced, causing the stomach to produce excess hydrochloric acid. ... An insulinoma is a tumour of the pancreas derived from the beta cells which while retaining the ability to synthesize and secrete insulin is autonomous of the normal feedback mechanisms. ... The structure of insulin. ... A glucagonoma is a rare tumor of the alpha cells of the pancreas that results in up to a 1000-fold overproduction of the hormone glucagon. ... Glucagon ball and stick model Glucagon is a 29-amino acid polypeptide acting as an important hormone in carbohydrate metabolism. ... VIP is a peptide hormone containing 28 amino acid residues. ... Pancreatic polypeptide is an enzyme secreted by PP cells in the tail of pancreas. ... Somatostatin is a hormone. ... CRH can refer to: 1. ... Calcitonin is a a 32 amino acid polypeptide hormone that is produced in humans primarily by the C cells of the thyroid, and in many other animals in the ultimobranchial body. ... Adrenocorticotropic hormone (ACTH or corticotropin) is a polypeptide hormone synthesised (from POMC, pre-opiomelanocortin) and secreted from corticotropes in the anterior lobe of the pituitary gland in response to the hormone corticotropin-releasing hormone (CRH) released by the hypothalamus. ... Categories: Anatomy stubs | Endocrine system ... Merkel cell cancer, also called Merkel cell carcinoma or neuroendocrine cancer or trabecular cancer, is a rare and highly aggressive cancer where malignant cancer cells develop on or just beneath the skin and in hair follicles. ... Schematic frontal view of female anatomy The cervix (from Latin neck) is the lower, narrow portion of the uterus where it joins with the top end of the vagina. ... Neuroblastoma is the most common extracranial solid cancer in infancy and childhood. ... A pheochromocytoma (also phaeochromocytoma, English spelling) is a tumor of the medulla of the adrenal glands originating in the chromaffin cells, which secretes excessive amounts of catecholamines, usually epinephrine and norepinephrine. ... A paraganglioma is a rare neoplasm that can be found in the head and neck region and other less common areas. ... Located at the base of the skull, the pituitary gland is protected by a bony structure called the sella turcica. ...

Classification of GEP-NETs by Cell Characteristics

The diverse and amorphous nature of GEP-NETs has led to a confused, overlapping, and changing terminology. In general, aggressiveness (malignancy), secretion (of hormones), and anaplasia (dissimilarity between tumor cells and normal cells) tend to go together, but there are many exceptions, which have contributed to the confusion in terminology. For example, the term atypical carcinoid is sometimes used to indicate an aggressive tumor without secretions, whether anaplastic or well-differentiated.

In 2000, the World Health Organization (WHO) revised the classification of GEP-NETs, abandoning the term carcinoid in favor of neuroendocrine tumor (NET) and abandoning islet cell tumor or pancreatic endocrine tumor for neuroendocrine carcinoma (NEC). Judging from papers published into 2006, the medical community is accepting this new terminology with great sluggishness. (Perhaps one reason for the resistance is that the WHO chose to label the least aggressive subclass of neuroendocrine neoplasm with the term — neuroendocrine tumor — widely used previously either for the superclass or for the generally aggressive noncarcinoid subclass.) The overview by Klöppel et alia clarifies the WHO classification and bridges the gap to the old terminology. In this article we conform to the older terminology.

Summary of Classification by Cell Characteristics

• Superclass:
  • Öberg, WHO, Klöppel et alia: gastro-entero-pancreatic neuroendocrine tumor (GEP-NET)

• Subclass 1 (less malignant)
  • Öberg: carcinoid
  • WHO: neuroendocrine tumor (NET)
  • Klöppel et alia: well-differentiated neuroendocrine tumor (NET) (carcinoid)
  • this article: carcinoid

• Subclass 2 (more malignant)
  • Öberg: endocrine pancreatic tumor
  • WHO: neuroendocrine carcinoma (NEC)
  • Klöppel et alia: well-differentiated neuroendocrine carcinoma (NEC) (malignant carcinoid)
  • this article: pancreatic endocrine tumor (PET) or endocrine pancreatic tumor (EPT) or islet cell tumor or noncarcinoid GEP-NET

• Subclass 3 (most malignant)
  • WHO: poorly-differentiated neuroendocrine carcinoma
  • Klöppel et alia: poorly-differentiated neuroendocrine carcinoma (high-grade malignant carcinoid)

• Subclass 4 (mixed)
  • WHO: mixed endocrine/exocrine tumor

• Subclass 5 (miscellaneous)
  • WHO: rare neuroendocrine-like lesions

GEP-NETs are also sometimes called APUDomas, but that term is now considered to be misleading, since it is based on a discredited theory of the development of the tumors.

Metastases and Malignancy

In the context of GEP-NETs, the terms metastatic and malignant are generally used as synonyms. Metastasis (Greek: change of the state) is the spread of cancer from its primary site to other places in the body. ... In medicine, malignant is a clinical term that is used to describe a clinical course that progresses rapidly to death. ...

GEP-NETs are often malignant, since the primary site often eludes detection for years, sometimes decades -- during which time the tumor has the opportunity to metastasize. Researchers differ widely in their estimates of malignancy rates, especially at the level of the secretory subtypes (the various "-omas").

The most common metastatic sites are the liver, the lymph nodes, and the bones. Liver metastases are so frequent and so well-fed that for many patients, they dominate the course of the cancer. For a patient with a nonsecretory PET, for example, the primary threat to life may be the sheer bulk of the tumor load in the liver.

The term lesion is a synonym for tumor; in particular, lesion means original tumor or metastasis.

Diagnosis

CT-scans, MRIs, sonography (ultrasound), and endoscopy (including endoscopic ultrasound) are common diagnostic tools. Symptoms from hormone secretions or from carcinoid syndrome, or measures of the corresponding hormones in the blood, can aid in diagnosis. CT-scans using contrast medium can detect 95 percent of tumors over 3 cm in size, and no tumors under 1 cm. CAT apparatus in a hospital Computed axial tomography (CAT), computer-assisted tomography, computed tomography, CT, or body section roentgenography is the process of using digital processing to generate a three-dimensional image of the internals of an object from a large series of two-dimensional X-ray images taken around... The Menopausal Research & Info Service is a British medical research charity dedicated to the research into the menopause. ... Night writing was a system of code that used symbols of twelve dots (2 wide and 6 high) designed by Charles Barbier in response to Napoleons demand for a code that soldiers could use to communicate silently and without light at night. ... Endoscopic images of a duodenal ulcer Endoscopy means looking inside and refers to looking inside the human body for medical reasons. ...

"Noteworthy, many tumors are asymptomatic even in the presence of metastases", according to Arnold.

Cells that receive hormonal messages do so through receptors on the surface of the cells. For reasons that are not understood, many neuroendocrine tumor cells possess especially strong receptors; for example, PETs often have strong receptors for somatostatin, a very common hormone in the body. We say that such tumor cells overexpress the somatostatin receptors (SSTRs) and are thus avid for the hormone; their uptake of the hormone is strong. This avidity for somatostatin is a key for diagnosis — and it makes the tumors vulnerable to certain targeted therapies, described below. Somatostatin is a hormone. ...

However, the half-life of somatostatin in circulation is under three minutes, making it useless for diagnosis and targeted therapies. For this reason, synthetic forms of somatostatin are used instead; the earliest was octreotide, first marketed, by Sandoz, in 1988. The synthetic forms are typically called somatostatin analogs (somatostatin analogues), but according to the US Food and Drug Administration (FDA), the proper term is somatostatin congeners. (In this article we conform to the old terminology, as the medical community has been slow to adopt the term congener.) The analogs have a much longer half-life than somatostatin, and other properties that make them more suitable for diagnosis and therapy. Somatostatin is a hormone. ... Sandoz is the generics subsidiary of Novartis, one of the Big Pharma pharmaceutical companies. ... This article or section is in need of attention from an expert on the subject. ... A congener (from Latin roots meaning born together or within the same race or kind) is applied in biology to mean organisms within the same genus; in chemistry to mean a chemical that is in some way related to another e. ...

The diagnostic procedure that utilizes a somatostatin analog is the OctreoScan, also called somatostatin receptor scintigraphy (SRS or SSRS): a patient is injected with octreotide chemically bound to a radioactive substance, typically indium-111; for those patients whose tumor cells are avid for octreotide, a radiation-sensitive scan can then indicate the locations of the larger lesions. General Name, Symbol, Number indium, In, 49 Chemical series poor metals Group, Period, Block 13, 5, p Appearance silvery lustrous gray Atomic mass 114. ...

An OctreoScan is a relatively crude test that generates subjective results. A Gallium-68 receptor PET-CT, integrating a PET image with a CT image, is approximately one thousand times as sensitive as an OctreoScan, and it generates objective (quantified) results. General Name, Symbol, Number gallium, Ga, 31 Chemical series poor metals Group, Period, Block 13, 4, p Appearance silvery white   Atomic mass 69. ... Image of a typical positron emission tomography (PET) facility Positron emission tomography (PET) is a nuclear medicine medical imaging technique which produces a three dimensional image or map of functional processes in the body. ...

Fluorodeoxyglucose (FDG)-PET is not useful in diagnosis of GEP-NETs. As Warner says, "Most GEP NETs do not image with fluorodeoxyglucose PET". According to Öberg, new PET "tracers such as C-5-hydroxy-L-tryptophan show very high sensitivity for detection of tumors, higher than for somatostatin receptor scintigraphy" (PMID 15933475).

The list of potential markers for GEP-NETs is long. Aside from the hormones of secretory tumors, the most important markers are

• chromogranin A (CgA)
• urine 5-hydroxy indole acetic acid (5-HIAA) (grade C)
• neuron-specific enolase (NSE, gamma-gamma dimer)
• synaptophysin (P38)

and other markers include

• synaptobrevin (VAMP-1)
• synapsin (1A, 1B, 2A, 2B)
• SV2
• protein P65
• protein S-100
• protein gene product (PGP) 9.5
• intermediate filaments (cytokeratins, vimentin, neurofilaments)
• protein 7B2
• chromogranin B (secretogranin I)
• chromogranin C (secretogranin II)
• pancreastatin
• vasostatin
• cytochrome b561
• leu-7 (HNK-1)
• calcitonin
• human chorionic gonadotropin-alpha (HCG-α)
• human chorionic gonadotropin-beta (HCG-β)
• thyroid function tests (TFTs)
• parathyroid hormone (PTH)
• calcium
• prolactin
• {alpha}-fetoprotein
• carcinoembryonic antigen (CEA)
• ß-human chorionic gonadotrophin (ß-HCG) (grade D)
• CGRP
• GRP
• PYY
• hCGα
• N Peptide K
• neurokinin A
• serotonin
• neurotensin
• motilin
• substance P
• histamine
• catecholamines
• dopa
• various rarer peptide hormones
• synaptotagmin
• HISL-19

and newer (as of 2005) markers include

• N-terminally truncated variant of heat shock protein 70 (Hsp70)
• CDX-2, a homeobox gene product
• neuroendocrine secretory protein-55

Aside from their use in diagnosis, some markers can track the progress of therapy while the patient avoids the detrimental side-effects of CT-scan contrast.

Therapy

According to Warner, the best care, at least for noncarcinoid GEP-NETs, is provided by "an active [as opposed to wait-and-see] approach using sequential multimodality treatment" delivered by a "multidisciplinary team, which also may include a surgeon, endocrinologist, oncologist, interventional radiologist, and other specialists". This recommendation is based on his view that, except for most insulinomas, "almost all" PETs "have long-term malignant potential" — and in sixty percent of cases, that potential is already manifest. "Indeed, the most common cause of death from PETs is hepatic [that is, liver] failure".

Surgery and Chemotherapy

Surgery is the only therapy that can cure GEP-NETs. However, the typical delay in diagnosis, giving the tumor the opportunity to metastasize, makes most GEP-NETs ineligible for surgery (non-resectable).

There is "no established standard therapy for the liver metastasis of pancreatic endocrine tumors", according to Sato et alia (PMID 10791232). The most common nonsurgical therapy for all GEP-NETs is chemotherapy, although chemotherapy is reported to be largely ineffective for carcinoids, not particularly durable (long-lasting) for PETs, and inappropriate for PETs of nonpancreatic origin.

When chemotherapy fails, the most common therapy, in the United States, is more chemotherapy, with a different set of agents. Some studies have shown that the benefit from one agent is not highly predictive of the benefit from another agent, except that the long-term benefit of any agent is likely to be low.

Strong uptake of somatostatin analogs is a negative indication for chemo.

Symptomatic Relief

There are two major somatostatin-analog-based targeted therapies. The first of the two therapies provides symptomatic relief for patients with secretory tumors. In effect, somatostatin given subcutaneously or intramuscularly "clogs up" the receptors, blocking the secretion of hormones from the tumor cells. Thus a patient who might otherwise die from severe diarrhea caused by a secretory tumor can gain additional years of life.

Specific counter-hormones or other hormone-blocking medications are sometimes also used to provide symptomatic relief.

Hormone-Delivered Radiotherapy

The second of the two major somatostatin-analog-based targeted therapies is called peptide receptor radionuclide therapy (PRRT), though we might simply call it hormone-delivered radiotherapy. In this therapy, radioactive substances (called radionuclides or radioligands) are chemically bound to hormones (peptides or neuroamines); the combination is given intravenously to a patient who has good uptake of the chosen hormone. The tumor cells pull the hormone to them, and the attached radiation kills nearby cells. In patients with strongly overexpressing tumor cells, nearly all the radiation is either excreted in urine or sticks to the tumors. As Rufini says, GEP-NETs "are characterized by the presence of neuroamine uptake mechanisms and/or peptide receptors at the cell membrane, and these features constitute the basis of the clinical use of specific radiolabeled ligands, both for imaging and therapy". (Nonmedullary thyroid tumors -- which are not GEP-NETs -- tend to be avid for iodine, and the iodine-131 isotope is a standard therapy for such tumors. The use of PRRT for GEP-NETs is analogous to that use of iodine, with the somatostatin analog playing the role of iodine's uptake properties and the radionuclide playing the role of its tumoricidal properties. In both therapies, hormonal targeting delivers a much higher dose of radiation than external beam radiation could safely deliver.) Radiation therapy (or radiotherapy) is the medical use of ionizing radiation as part of cancer treatment to control malignant cells (not to be confused with radiology, the use of radiation in medical imaging and diagnosis). ... A radionuclide is an atom with an unstable nucleus. ... General Name, Symbol, Number iodine, I, 53 Chemical series halogens Group, Period, Block 17, 5, p Appearance violet-dark gray, lustrous Atomic mass 126. ...

As of 2006, PRRT is available in at least twelve institutions in Europe and South America. In the USA it is FDA-approved, and available at the MD Anderson Cancer Center, but using a radionuclide, indium-111, that is vastly weaker than the lutetium-177 and the even stronger yttrium-90 used on the European continent. In the UK, only the iodine-131 radionuclide metaiodobenzylguanidine (I-MIBG) is licensed (but pancreatic tumors are rarely avid for MIBG). PRRT with lutetium or yttrium is nowhere an "approved" therapy, but the German health insurance system, for example, covers the cost for German citizens. General Name, Symbol, Number indium, In, 49 Chemical series poor metals Group, Period, Block 13, 5, p Appearance silvery lustrous gray Atomic mass 114. ... General Name, Symbol, Number lutetium, Lu, 71 Chemical series lanthanides Group, Period, Block n/a, 6, d Appearance silvery white Atomic mass 174. ... General Name, Symbol, Number yttrium, Y, 39 Chemical series transition metals Group, Period, Block 3, 5, d Appearance silvery white Atomic mass 88. ...

MIBG therapy was developed in the 1980s and PRRT in the 1990s, and practitioners continue to refine their choices of radionuclides to maximize damage to tumors, of somatostatin analogs to maximize delivery, of chelators to bind the radionuclides with the hormones (and chelators can also increase uptake), and of protective mechanisms to minimize damage to healthy tissues (especially the kidneys).

Other Therapies

Another therapy for GEP-NETs is hepatic artery embolization (HAE). According to Dr. Larry Kvols of Lee H. Moffitt Cancer Center, "hepatic artery embolization . . . has been quite successful. During that procedure a catheter is placed in the groin and then threaded up to the hepatic artery that supplies the tumors in the liver. We inject a material called embospheres into the artery and it occludes the blood flow to the tumors, and in more than 80% of patients the tumors will show significant tumor shrinkage". HAE is based on the observation that tumor cells get about 90 percent of their nutrients from the hepatic artery, while the normal cells of the liver get about 90 percent of their nutrients from the portal vein, and thus can survive with the hepatic artery effectively blocked.

Hepatic artery chemoembolization (HACE) is a variation on hepatic artery embolization: the spheres are bound with chemotherapy drugs before administration. The targeting of the hepatic artery delivers a higher effective dose of chemotherapy than systemic chemotherapy can deliver.

Radioactive microsphere therapy (RMT) is another variation on hepatic artery embolization: spheres of glass or resin are bound with radionuclides before administration. In contrast with PRRT, there is no requirement for the tumor cells to overexpress peptide receptors; however, the treatment affects liver metastases only, not the primary site or other metastases. Because of the targeting provided by the arterial embolization, the yttrium-labeled microspheres "are selectively taken up by the tumors, thus preserving normal liver", according to Salem et alia (http://pubmed.org PMID 12354840).

Radiofrequency ablation (RFA) is used when a patient has relatively few tumor sites, whether original sites or metastases. In RFA, a needle is inserted into the center of the tumor and is vibrated at high frequency to generate heat; the tumor cells are killed by cooking. RFA is especially suited for large tumors, which can be cooked about as easily as small tumors (though some researchers disagree on the lack of a size limitation).

Cryoablation is similar to RFA; a endothermic substance is injected into the tumors to kill by freezing. Cryoablation has been considerably less successful for GEP-NETs than RFA.

Interferon is sometimes used to treat GEP-NETs; its use was pioneered by Dr. Kjell Öberg at Uppsala. For GEP-NETs, Interferon is often used at low doses and in combination with other agents (especially somatostatin analogs such as octreotide). But some researchers have stated that Interferon provides little value aside from symptom control.

As described above, somatostatin analogs have been used for about two decades to alleviate symptoms by blocking the production of hormones from secretory tumors. They are also integral to PRRT. In addition, some doctors claim that, even without radiolabeling, even patients with nonsecretory tumors can benefit from somatostatin analogs, which purportedly can shrink or stabilize GEP-NETs. But some researchers have stated that this "cold" octreotide provides little value aside from symptom control.

Two tricky issues in evaluating test data are durability and stasis. For example, one trial therapy might give good initial results -- but within months the benefit evaporates. And another trial therapy might be disparaged by some for causing very little tumor shrinkage, but be championed by others for causing significant tumoristasis.

Finally, therapies based on growth factor inhibitors are in the experimental stage. These inhibitors of epidermal growth factor receptors (EGFRs), of vascular endothelial growth factor receptors (VEGFRs), and of angiopoietin-related growth factor (AGF) include imatinib, sunitinib, temozolide, thalidomide, sorafenib, and panitumumab. Imatinib is a drug used to treat certain types of cancer. ... Sunitinib (marketed as Sutent, previously known as SU11248) is a small molecule receptor tyrosine kinase inhibitor that is used in the treatment of gastrointestinal stromal tumor (GIST) as well as renal cell carcinoma (RCC). ... It has been suggested that Neurosedyn be merged into this article or section. ... Sorafenib (marketed as Nexavar by Bayer) is a drug used for the treatment of advanced renal cell cancer. ...

External links

If you can't open the .ppt pages listed below, download and install (free) OpenOffice from http://openoffice.org, and the page will then be readable.

• http://www.neuroendocrine.net
  • http://www.neuroendocrine.net/rel/upload/ENETS_2006_English0606.pdf
• http://www.carcinoid.org (with information on noncarcinoid GEP-NETs as well)
• http://www.cancer.gov/cancertopics/pdq/treatment/isletcell
• http://www.netpatientfoundation.com (UK)
  • http://www.netpatientfoundation.com/powerpoint/Dr%20M%5B1%5D.Caplin%20-%20Patient%20Support%20Meeting.ppt
  • http://www.netpatientfoundation.com/powerpoint/Dr%20J%5B1%5D.Ramage%20-%20Patient%20Support%20Meeting.ppt
• http://www.med.umich.edu/lrc/presentation/endo/islet.htm (overview in tabular format)