Neuroendocrine tumors

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Neuroendocrine tumors
ICD-9 209
ICD-O: M8013/3, M8041/3, M8246/3, M8247/3, M8574/3
MedlinePlus 000393
MeSH D018358

Neuroendocrine tumors Microchapters

Patient Information

Overview

Historical Perspective

Classification

Pathophysiology

Causes

Epidemiology and Demographics

Risk factors

Natural History, Complications and Prognosis

History and Symptoms

Laboratory Findings

CT scan

PET scan

Medical Therapy

Surgery

For patient information, click here

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [9] Associate Editor(s)-in-Chief: Sara Mohsin, M.B.B.S.[10] Ramyar Ghandriz MD[11]

Overview

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.

Historical Perspective

Classification

Human GEP-NETs by Site of Origin and by Symptom

Human GEP-NETs by Site of Origin and by Symptom Percentage
Carcinoids (about two thirds of GEP-NETs)
PETs (about one third of GEP-NETs)
  • Nonfunctioning
Rare GEP-NETs

Simplified classification according to anatomic distribution

Simplified classification of Neuroendocrine tumors according to anatomic distribution
Involved organ Name/type of neuroendocrine tumor
Pituitary gland
Thyroid gland
Parathyroid glands
Thymus and mediastinum
Lungs
Extrapulmonary
GIT
Adrenal gland
Peripheral nervous system Peripheral nervous system tumors, such as:
Mammary gland
Genitourinary tract
Skin
Multiple organs involvement in inherited conditions

Classification of GEP-NETs by cell characteristics

Summary of classification by cell characteristics (the WHO classification)

  • This classification was done due to peripheral receptors.
  • GEP-NETs receptors (APUDomas) are the main detected receptors.
  • That term is now misleading, since it is based on a discredited theory of the development of the tumors.
  • It is now known that this receptor may not be indicator of cell origin.[1]
Superclass:Öberg, WHO, Klöppel et alia: Gastro-entero-pancreatic neuroendocrine tumor (GEP-NET)
Subclass 1 (less malignant) Subclass 2 (more malignant) Subclass 3 (most malignant) Subclass 4 (mixed) Subclass 5 (miscellaneous)

2010 WHO Classification Of NET

2010 World Health Organization International Classification and Distribution of Diseases for Oncology (3rd Ed. (ICD-O-3) Codes of Neuroendocrine Tumors (NETs) in the Gastrointestinal and Pancreatobiliary Tracts)
NET (Neuroendocrine Tumor) Classification Location ICD-O-3 Code
NET G1 (Grade 1) All organs 8240/3
NET G2 (Grade 2) All organs 8249/3
Neuroendocrine carcinoma All organs 8246/3
Large cell NEC All organs 8013/3
Small cell NEC All organs 8041/3
Enterochromaffin cell serotonin-producing NET All organs 8241/3
Gastrin-producing NET (gastrinoma) Stomach, ampulla, small intestine, pancreas 8153/3
Glucagon-producing NET (glucagonoma) Pancreas 8152/3
Gangliocytic paraganglioma Ampulla, small intestine 8683/0
Somatostatin-producing NET (somatostatinoma) Ampulla, small intestine, pancreas 8156/3
Insulin-producing NET (insulinoma) Pancreas 8151/3
VIPoma Pancreas 8155/3
L cell, Glucagon-like peptide, and PP/PYY-producing NETs Small intestine, appendix, colorectum 8152/1
Goblet cell carcinoid Appendix, extrahepatic bile duct 8241/3
Tubular carcinoid Appendix, extrahepatic bile duct 8245/1
Mixed adenoneuroendocrine carcinoma (MANEC) All organs 8244/3
Neuroendocrine microadenoma Pancreas 8150/0

WHO Grading criteria for neuroendocrine neoplasms

2017 World Health Organization Classification of Neuroendocrine Tumors (NETs) in the GIT and Pancreatobiliary Tracts (PanNETs)
Grade/Classification Mitotic Count/ 10 HPFs (High-Power Field) Ki-67 Labeling Index, % Traditional
Neuroendocrine neoplasm GX Grade cannot be assessed
Well-differentiated GIT NETs & PanNENs: Pancreatic neuroendocrine tumors (PanNETs)
Neuroendocrine tumor, Grade 1 and PanNET G1 (low grade) <2 <3
Neuroendocrine tumor, Grade 2 and PanNET G2 (intermediate grade) 2–20 3–20
PanNET G3 >20 >20 _
Poorly differentiated PanNENs: Pancreatic neuroendocrine carcinomas (PanNECs)
Neuroendocrine carcinoma, Grade 3 and

PanNEC G3 (high grade)

>20 >20 Small cell carcinoma
Large cell neuroendocrine carcinoma
Mixed neuroendocrine-non-neuroendocrine neoplasm (MiNEN)
Classification of Gastric Enterochromaffin-Like Cell Histamine-Producing Neuroendocrine Tumors
Classification I II III
Incidence, % 55–88 8–13 12–23
Multifocality Multiple Multiple Single
Peritumoral oxyntic mucosa Atrophic Hypertrophic Normal
Size, cm 0.5–1 <2 >2
Location Corpus Corpus Any
Sex M < F M = F M > F
Hypergastrinemia Yes Yes No
Antral G-cell hyperplasia Yes No No
Associated disease No
Precursor lesion Yes Yes No
WHO 2010 classification Grade 1 Grades 1 or 2 Grades 1–3
Lymph node metastasis, % 5 30 70


Comparison of the WHO classifications of pancreatic neuroendocrine neoplasms
WHO 1980 WHO 2000/2004 WHO 2010 WHO 2017
Islet cell tumor (adenoma/carcinoma) Well-differentiated endocrine tumor/carcinoma (WDET/WDEC) NET G1/G2 NET G1/G2/G3 (well-differentiated NEN)
Poorly differentiated endocrine carcinoma Poorly differentiated endocrine carcinoma/small cell carcinoma (PDEC) NEC (G3), large cell or small cell type NEC (G3), large cell or small cell type (poorly differentiated NEN)
_ Mixed exocrine-endocrine carcinoma (MEEC) Mixed adenoneuroendocrine carcinoma Mixed neuroendocrine-non-neuroendocrine neoplasm
Pseudotumor lesions Tumor-like lesions (TLLs) Hyperplastic and preneoplastic lesions _

Pathophysiology

Neuroendocrine system

Causes

Hereditary Syndromes Associated With Gastrointestinal (GI) and Pancreatobiliary Tract Neuroendocrine Tumors (NETs)
Name of the syndrome Pattern of inheritance Chromosomal Band Location Gene/ Protein Involved GIT and Pancreatobiliary Tract NETs Other Tumors of GIT and Pancreatobiliary Tract Clinical Presentation Outside GIT and Pancreatobiliary Tract
Multiple endocrine neoplasia 1 (MEN 1)
  • 11q13.1
  • Nonfunctional

Maybe associated with multiple:

More commonly:

Less commonly:

von Hippel-Lindau disease/syndrome (VHL)
  • 3p25.3
Neurofibromatosis 1

(von Recklinghausen disease)

  • 17q11.2
Tuberous sclerosis
  • 9q34.13
  • 16p13.3

Other familial syndromes associated with neuroendocrine neoplasms are:

Epidemiology and Demographics

Lung NETs

Digestive system NETs

Disease/Syndrome % chance of developing Pancreatic NET
Multiple endocrine neoplasia 1 (MEN 1) 80-100%
von Hippel-Lindau disease/syndrome (VHL) 20%
Neurofibromatosis 1

(von Recklinghausen disease)

10%
Tuberous sclerosis 1%

Risk factors

Few of the risk factors for neuroendocrine tumors include:

Natural History, Complications and Prognosis

Complications

Prognosis

History and Symptoms

Carcinoid tumor

Pancreatic NETs

Laboratory Findings

List of potential markers for GEP-NETs apart from hormones of secretory tumors
Most important markers Other markers Newer (as of 2005) markers

CT Scan

  • CT scan is one of the most common diagnostic tool used for diagnosing of Neuroendocrine tumors.
  • CT scan with contrast medium can detect 95% of the tumors with size of >3 cm in size, and no tumors under 1 cm (University of Michigan Medical School n. d., [12]).

PET Scan

A gallium-68 receptor PET-CT, integrating a PET image with a CT image, is much more senstitive than an OctreoScan, and it generates objective (quantified) results in the form of a standardized uptake value (SUV).

Octreoscan

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, often 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.

An OctreoScan is a relatively crude test that generates subjective results.

Images courtesy of RadsWiki

OctreoScan demonstrates abnormal uptake in the liver and abdominal lymph nodes


OctreoScan demonstrates abnormal uptake in the liver and abdominal lymph nodes


OctreoScan demonstrates abnormal uptake in the head of the pancreas


OctreoScan demonstrates abnormal uptake in the head of the pancreas


OctreoScan demonstrates abnormal uptake in the head of the pancreas


Medical Therapy

Approach

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" (Warner 2005, 4).

Two tricky issues in evaluating therapies are durability (is the therapy long-lasting?) and stasis (are the tumors neither growing nor shrinking?). For example, one therapy might give good initial results – but within months the benefit evaporates. And another therapy might be disparaged by some for causing very little tumor shrinkage, but be championed by others for causing significant tumoristasis.

The half-life of somatostatin in circulation is under three minutes, making it useless for diagnosis and targeted therapies. For this reason, 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.

Chemotherapy

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. [29]

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 – PRRT

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 form of radioisotope therapy (RIT), radioactive substances (called radionuclides or radioligands) are chemically conjugated with hormones (peptides or neuroamines); the combination is given intravenously to a patient who has good uptake of the chosen hormone. The radioactive labelled hormones enter the tumor cells, and the attached radiation damages the tumor- and nearby cells. Not all cells are immediately killed this way. The process of tumor cells dying as result of this therapy can go on for several months, even up to two years. In patients with strongly overexpressing tumor cells, nearly all the radiation either gets into the tumors or is excreted in urine. As Rufini et alia say, 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" (Rufini, Calcagni, and Baum 2006, [13]).

The use of PRRT for GEP-NETs is similar to the use of iodine-131 as a standard therapy (in use since 1943) for nonmedullary thyroid tumors (which are not GEP-NETs). Thyroid cells (whether normal or neoplastic) tend to be avid for iodine, and nearby cells are killed when iodine-131 is infused into the bloodstream and is soon attracted to thyroid cells. Similarly, overexpressing GEP-NET cells (neoplastic cells only) are avid for somatostatin analogs, and nearby cells are killed when radionuclides attached to somatostatin analogs are infused into the bloodstream and are soon attracted to the tumor cells. In both therapies, hormonal targeting delivers a much higher dose of radiation than external beam radiation could safely deliver.

As of 2006, PRRT is available in at least dozen medical centers in Europe. In the USA it is FDA-approved, and available at the MD Anderson Cancer Center, but using a radionuclide, indium-111, that is much weaker than the lutetium-177 and the even stronger yttrium-90 used on the European continent. In the UK, only the radionuclide metaiodobenzylguanidine (I-MIBG) is licensed (but GEP-NETs are rarely avid for MIBG). Most patients (from all over the world) are treated (with lutetium-177) in The Netherlands, at the Erasmus Medical Center. PRRT with lutetium or yttrium is nowhere an "approved" therapy, but the German health insurance system, for example, covers the cost for German citizens.

PRRT using yttrium or lutetium was first applied to humans about 1999. 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).


Hepatic artery-delivered therapies

  • One therapy for liver metastases of GEP-NETs is hepatic artery embolization (HAE). Larry Kvols, of the Moffitt Cancer Center and Research Institute in Tampa, Florida, says that "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 [tiny spheres of glass or resin, also called microspheres] 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" (Kvols 2002, [14]). HAE is 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 75 percent of their nutrients (and about half of their oxygen) from the portal vein, and thus can survive with the hepatic artery effectively blocked.

[30]

  • Another therapy is hepatic artery chemoinfusion, the injection of chemotherapy agents into the hepatic artery. Compared with systemic chemotherapy, a higher proportion of the chemotherapy agents are (in theory) delivered to the lesions in the liver.

[31]

  • 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 a much better targeting leverage than chemoinfusion provides.
  • Radioactive microsphere therapy (RMT) combines hepatic artery embolization with radiation therapy – microspheres bound with radionuclides, injected into the hepatic artery, lodge (as with HAE and HACE) in downstream capillaries. This therapy is also called selective internal radiation therapy, or SIRT. In contrast with PRRT, the lesions need not overexpress peptide receptors. (But PRRT can attack all lesions in the body, not just liver metastases.) Due to the mechanical targeting, the yttrium-labeled microspheres "are selectively taken up by the tumors, thus preserving normal liver" (Salem et al. 2002, [15]).

[32]

Other Therapies

  • Radiofrequency ablation (RFA) is used when a patient has relatively few metastases. In RFA, a needle is inserted into the center of the lesion and is vibrated at high frequency to generate heat; the tumor cells are killed by cooking.
  • Cryoablation is similar to RFA; an 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 claim 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 claim that this "cold" octreotide provides little value aside from symptom control.

Surgery

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).

Case Studies

Case #1

External links

Acknowledgements

The content on this page was first contributed by: C. Michael Gibson, M.S., M.D.

References

  1. "The APUD concept led to the belief that these cells arise from the embryologic neural crest. This hypothesis eventually was found to be incorrect" (Warner 2005, 2).

    "The APUD-concept is currently abandoned" (Öberg 1998, 2, [1]).

  2. Tang LH, Basturk O, Sue JJ, Klimstra DS (2016). "A Practical Approach to the Classification of WHO Grade 3 (G3) Well-differentiated Neuroendocrine Tumor (WD-NET) and Poorly Differentiated Neuroendocrine Carcinoma (PD-NEC) of the Pancreas". Am J Surg Pathol. 40 (9): 1192–202. doi:10.1097/PAS.0000000000000662. PMC 4988129. PMID 27259015.
  3. Inzani F, Petrone G, Rindi G (2018). "The New World Health Organization Classification for Pancreatic Neuroendocrine Neoplasia". Endocrinol Metab Clin North Am. 47 (3): 463–470. doi:10.1016/j.ecl.2018.04.008. PMID 30098710.
  4. 4.0 4.1 Sorbye H, Welin S, Langer SW, Vestermark LW, Holt N, Osterlund P; et al. (2013). "Predictive and prognostic factors for treatment and survival in 305 patients with advanced gastrointestinal neuroendocrine carcinoma (WHO G3): the NORDIC NEC study". Ann Oncol. 24 (1): 152–60. doi:10.1093/annonc/mds276. PMID 22967994.
  5. Heetfeld M, Chougnet CN, Olsen IH, Rinke A, Borbath I, Crespo G; et al. (2015). "Characteristics and treatment of patients with G3 gastroenteropancreatic neuroendocrine neoplasms". Endocr Relat Cancer. 22 (4): 657–64. doi:10.1530/ERC-15-0119. PMID 26113608.
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  10. 10.0 10.1 Basturk O, Tang L, Hruban RH, Adsay V, Yang Z, Krasinskas AM; et al. (2014). "Poorly differentiated neuroendocrine carcinomas of the pancreas: a clinicopathologic analysis of 44 cases". Am J Surg Pathol. 38 (4): 437–47. doi:10.1097/PAS.0000000000000169. PMC 3977000. PMID 24503751.
  11. Oladejo AO (December 2009). "GASTROENTEROPANCREATIC NEUROENDOCRINE TUMORS (GEP-NETs) - APPROACH TO DIAGNOSIS AND MANAGEMENT". Ann Ib Postgrad Med. 7 (2): 29–33. PMC 4111010. PMID 25161467.
  12. "The main two groups of neuroendocrine GEP tumours are so-called carcinoid tumours and endocrine pancreatic tumours" (Öberg 2005a, 90, ).

    "Less than 1% of carcinoids arise in the pancreas" (Warner 2005, 9).

    Arnold et alia in effect define carcinoids as "extra-pancreatic endocrine gastronintestinal tumors" (Arnold et al. 2004, 196).

    Some doctors believe that there is significant overlap between PETs and carcinoids. For example, endocrine surgeon Rodney Pommier says that "there are pancreatic carcinoids" (Pommier 2003, [2]). However, Pommier made his statement in a talk at a conference on carcinoids, not in a peer-reviewed journal; and in his talk he did not define the word carcinoid.

    Another way to classify GEP-NETs is to separate those that begin in the glandular neuroendocrine system from those that begin in the diffuse neuroendocrine system. "Neuroendocrine tumors generally may be classified into two categories. The first category is an organ-specific group arising from neuroendocrine organs such as pituitary gland, thyroid, pancreas, and adrenal gland. The second group arises from the diffuse neuroendocrine cells/Kulchitsky cells that are widely distributed throughout the body and are highly concentrated in the pulmonary and gastrointestinal systems" (Liu et al. 2001, [3]).

  13. 13.0 13.1 13.2 Dasari A, Shen C, Halperin D, Zhao B, Zhou S, Xu Y; et al. (2017). "Trends in the Incidence, Prevalence, and Survival Outcomes in Patients With Neuroendocrine Tumors in the United States". JAMA Oncol. 3 (10): 1335–1342. doi:10.1001/jamaoncol.2017.0589. PMC 5824320. PMID 28448665.
  14. Quaedvlieg PF, Visser O, Lamers CB, Janssen-Heijen ML, Taal BG (2001). "Epidemiology and survival in patients with carcinoid disease in The Netherlands. An epidemiological study with 2391 patients". Ann Oncol. 12 (9): 1295–300. doi:10.1023/a:1012272314550. PMID 11697843.
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  18. Skuladottir H, Hirsch FR, Hansen HH, Olsen JH (2002). "Pulmonary neuroendocrine tumors: incidence and prognosis of histological subtypes. A population-based study in Denmark". Lung Cancer. 37 (2): 127–35. PMID 12140134.
  19. Cao C, Yan TD, Kennedy C, Hendel N, Bannon PG, McCaughan BC (2011). "Bronchopulmonary carcinoid tumors: long-term outcomes after resection". Ann Thorac Surg. 91 (2): 339–43. doi:10.1016/j.athoracsur.2010.08.062. PMID 21256263.
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  26. Froudarakis M, Fournel P, Burgard G, Bouros D, Boucheron S, Siafakas NM; et al. (1996). "Bronchial carcinoids. A review of 22 cases". Oncology. 53 (2): 153–8. doi:10.1159/000227552. PMID 8604242.
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  28. Oliveira AM, Tazelaar HD, Wentzlaff KA, Kosugi NS, Hai N, Benson A; et al. (2001). "Familial pulmonary carcinoid tumors". Cancer. 91 (11): 2104–9. doi:10.1002/1097-0142(20010601)91:11<2104::aid-cncr1238>3.0.co;2-i. PMID 11391591.
  29. Ramage et alia say that "response to chemotherapy in patients with strongly positive carcinoid tumours was of the order of only 10% whereas patients with SSRS negative tumours had a response rate in excess of 70%. The highest response rates with chemotherapy are seen in the poorly differentiated and anaplastic NETs: response rates of 70% or more have been seen with cisplatin and etoposide based combinations. These responses may be relatively short lasting in the order of only 8–10 months. Response rates for pancreatic islet cell tumours vary between 40% and 70% and usually involve combinations of streptozotocin (or lomustine), dacarbazine, 5-fluorouracil, and adriamycin. However, the best results have been seen from the Mayo clinic where up to 70% response rates with remissions lasting several years have been seen by combining chemoembolisation of the hepatic artery with chemotherapy. The use of chemotherapy for midgut carcinoids has a much lower response rate, with 15–30% of patients deriving benefit, which may only last 6–8 months (Ramage et al. 2005, [4]).

    For 125 patients with histologically proven unresectable islet-cell carcinomas, "median duration of regression was 18 months for the doxorubicin combination and 14 months for the 5-FU combination" (Arnold et al. 2004, 230).

  30. "The liver gets about 80% of its blood and half the oxygen from the portal vein, and only 20% of the blood and the other 50% of the oxygen from the artery.... The liver gets 80% of its blood from the portal vein and 20% from that little hepatic artery. But tumors get 100% of their blood off the hepatic artery, and this has been shown by multiple lines of evidence (Pommier 2003, [5]).

    "The normal liver gets its blood supply from two sources; the portal vein (about 70%) and the hepatic artery (30%)" (Fong and Schoenfield n. d., [6]).

  31. "The theoretical advantage is that higher concentrations of the agents can be delivered to the tumors without subjecting the patients to the systemic toxicity of the agents.... In reality, however, much of the chemotherapeutic agents does end up in the rest of the body" (Fong and Schoenfield, [7]).
  32. The "microspheres preferentially cluster around the periphery of tumor nodules with a high tumor:normal tissue ratio of up to 200:1". The SIRT-spheres therapy is not FDA-approved for GEP-NETs; "it is FDA approved for liver metastases secondary to colorectal carcinoma and is under investigation for treatment of other liver malignancies, such as hepatocellular carcinoma and neuroendocrine malignancies" (Welsh, Kennedy, and Thomadsen 2006, [8]).

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