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Pancreatic Neuroendocrine Tumor Treatment and Drugs
Pancreatic Neuroendocrine Tumor Treatment
Pancreatic neuroendocrine tumors can be very difficult to treat. Pancreatic neuroendocrine tumors can be benign to highly malignant, indolent (slow growing) to very aggressive in development, and range from asymptomatic to causing debilitating syndromes. As a result, a multi-disciplinary team consisting of specialist physicians in NETs (gastroenterologists, oncologists, and endocrinologists), surgeons, radiologists, nuclear medicine specialists, histopathlogists, and clinical nurse specialists is often recommended (Ramage, Ahmed, Ardill, Bax, Breen, Caplin, Corrie, Davar, Davies, Lewington, Meyer, Newell-Price, Poston, Reed, Rockall, Steward, Thakker, Toubanakis, Valle, Verbeke, Grossman, and UK and Ireland Neuroendocrine Tumor Society, 2012).
Pancreatic Neuroendocrine Tumor treatment must be tailored to each patient’s tumor burden and symptoms. Treatments may be focused on inhibiting tumor growth or symptom relief. Often, this means that any given treatment plan may consist of a combination and/or series of several treatments. Be sure to discuss your treatment options thoroughly with your physician(s). Ultimately, all treatment decisions should be made by the patient. Please click here to visit the Caring for Carcinoid Foundation’s Doctor Database or call 617 948 2514 for help finding a physician.
Pancreatic Neuroendocrine Tumor Surgery
The surgical treatment of pancreatic neuroendocrine tumors depends on the tumor type, location, extent of metastases, as well as other factors. For individuals who have metastases, surgery can often increase survival and provide palliative care depending on tumor size and location (Steinmuller, Kianmanesh, Falconi, Scarpa, Taal, Kwekkeboom, Lopes, Perren, Nikou, Yao, Dell Fave, O’Toole, & Frascati Consensus Conference participants, 2008). For both local and metastatic tumors surgery can be helpful for reducing symptoms from tumor secretion (Akerstrom, Hellman, Hessman, & Osmak, 2005). Surgical resection of a functioning pancreatic neuroendocrine tumor should be considered when possible (Kulke, Anthony, Bushnell, de Herder, Goldsmith, Klimstra, Marx, Pasieka, Pommier, Yao, & Jensen, 2010). A multimodal approach combining surgery with embolization or other treatment methods may also be possible for patients with liver metastases (Steinmuller et al., 2005). For all patients who undergo surgery, continued and extensive follow up is recommended.
Insulinomas are frequently small with indolent behavior. In these cases treatment is indicated to relieve the characteristic syndrome from hormone hypersecretion. The type and extent of the surgery depends on the nature, location and size of the tumor(s). For small benign insulinomas enucleation can be preformed. Pancreatic enucleation is an operation when the tumor is removed from the pancreas without removing any pancreatic tissue. For cases where tumors are larger than 1 or 2 cm, where aggressive behavior is suspected, or where there is suspected local, liver, or lymph node invasion pancreatoduodenectomy or aggressive pancreatic resection may be indicated. Pancreatic-duodectonomy also known as a Whipple Procedure is an extensive surgical operation of the pancreas, duodenum and other organs.
Since the advent of medications such as Proton Pump Inhibitor’s (PPI’s) to control symptoms surgery for patients with gastrinoma has been considered controversial and different opinions exist. In certain cases removal of these tumors can help to decrease hormonal syndrome, alleviate pain, prevent future metastases and increase survival (Norton, Fraker, Alexander, Gibril, Liewehr, Venzon, & Jensen, 2006; Kulke et al., 2010).
The type and extent of the surgery depends on the nature, location and size of the tumor(s). Depending upon location and metastatic behavior gastrinoma may be removed by pancreatic enucleation, or more invasive pancreaticoduodenectomy. Pancreatic enucleation is an operation when the tumor is removed from the pancreas without removing any pancreatic tissue. Pancreaticduodectonomy also known as a Whipple Procedure is an extensive surgical operation of the pancreas, duodenum and other organs.
Glucagonomas are often large with metastasis to the liver. The type and extent of the surgery depends on the nature, location and size of the tumor(s). Surgical treatment may require distal pancreatectomy. A distal pancreatectomy is removal of the body and tail of the pancreas leaving the head intact.
The type and extent of the surgery depends on the nature, location and size of the tumor(s). Surgical treatment may require distal pancreatectomy. A distal pancreatectomy is removal of the body and tail of the pancreas leaving the head intact.
Non-functioning Pancreatic Neuroendocrine Tumors
These tumors do not causes characteristic hormonal symptoms but surgery may be indicated to prevent obstructive symptoms, manage symptoms of pain, jaundice, and weight loss or inhibit tumor growth. Because non-functioning neuroendocrine tumors are difficult to diagnosis they are usually large at diagnosis and may require pancreaticduodenectomy. Pancreaticduodectonomy also known as a Whipple Procedure is an extensive surgical operation of the pancreas, duodenum and other organs.
The liver is the most common site for pancreatic neuroendocrine tumors to metastasize but it is rare for the liver to be the primary site of neuroendocrine tumor development (Reidy, Tang, & Saltz, 2009). The type and extent of surgery for liver metastasis is contingent upon tumor type, size, location, disease progression, site of origin and other factors. Liver resection, the surgical removal of part of the liver, is a common treatment protocol for individuals for whom a complete resection is possible (Norton, Warren, Kelly, Zuraek, & Jensen, 2003; Cho, Labow, Tang, Klimstra, Loeffler, Leverson, Fong, Jarnagin, D’Angelica, Weber, Blumgart, & Dematteo, 2008).
For individuals for whom a complete resection is not possible, surgery, in combination with other treatment modalities, may be used to debulk (decrease) tumor burden. Resection and debulking (for individuals for whom the majority of tumor burden is removed) have resulted in increased survival and a decrease in disease symptoms (Norton et al., 2003).
Presence of liver metastasis is a major prognostic factor with presence of liver metastasis indicating worse outcome (Metz & Jenson, 2008). In certain cases, a two-stage surgical resection can be done for patients with extensive liver metastases. The first phase of a two-stage resection involves the radical resection of a portion of the left side of the liver with right portal vein ligation to encourage the left side of the liver to regenerate. After the liver is allowed to regenerate, the right side of the liver is then removed. One patient’s experience with this procedure and her treatment team are featured in CFCF’s Expert Interviews. Click here to learn more.
In a very small group of individuals with neuroendocrine tumor liver metastases, orthotopic liver transplantation (OLT) has been used. OLT is the process in which the diseased liver is completely removed and replaced with a healthy, donor liver (Steinmuller et al., 2008).
Currently, there is little clinical evidence on the results of radical, two-part liver resections and orthotopic liver transplantation. Due to the lack of clinical evidence, the benefit of these procedures, in particular OLT, has yet to be determined. (Lang, Oldhafer, Weimann, Schlitt, Scheumann, Flemming, Ringe, & Pichlmayr, 1997; van Vilsteren, Baskin-Bey, Nagorney, Sanderson, Kremers, Rosen, Gores, & Hobday, 2006; Blonski, Reddy, Shaked, Siegelman, & Metz, 2005)
Lymph nodes are often the site of neuroendocrine tumor metastases. When an individual is diagnosed with a pancreatic neuroendocrine tumor and is a surgical candidate, the lymph nodes surrounding the affected area should be examined for metastases and removed if affected. A lymphadenectomy is the surgical removal of one or more groups of lymph nodes (Akerstrom et al., 2005).
If curative surgery is not possible, other treatment options are available to individuals with pancreatic neuroendocrine tumors. Currently, there is no non-surgical curative treatment, but there are several non-surgical treatment options which can result in decreasing tumor bulk, halting tumor progression, and/or managing tumor symptoms. The type of treatment used is determined by tumor type, size, location, disease progression, as well as many other factors.
While there is currently no non-surgical curative treatment, progress in pancreatic neuroendocrine tumor treatment is being made through clinical trials. Please visit the Caring for Carcinoid Foundation’s Clinical Trials Resource for more information on clinical trials and to search clinical trials for pancreatic neuroendocrine tumors.
The excess of hormones produced and secreted into the body by pancreatic neuroendocrine tumors can cause characteristic syndromes from hormonal hypersecretion. Most neuroendocrine tumors, have five highly specialized receptors for the naturally occurring hormone somatostatin. (Reubi, Kvolz, Waser, Nagorney, Heitz, Chaboneau, Reading, & Moertel, 1990). When somatostatin is bound to these receptors, especially receptors two and five, it inhibits the release of the various hormones that cause many of the symptoms associated with hormonal hypersecretion (Oberg, 2009). Synthetic analogues (man-made versions) of somatostatin can mimic somatostatin by binding to receptors two and five and inhibiting hormone secretion. Currently, there are two synthetic somatostatin analogue products available: octreotide (Sandostatin) and lanreotide (Somatuline Depot) (Oberg, 2009). These somatostatin analogues have been proven to control, decrease and prevent symptoms associated with pancreatic neuroendocrine tumors (Oberg, 2009). Somatostatin analogs can be used for initial management of some patients with glucagonomas, VIPomas, and somatistatinomas (Kulke et al., 2010).
Somatostatin analogs may be used to manage hormone secretion from pancreatic neuroendocrine tumors and is approved for use in patients with VIPomas (Metz & Jensen, 2008). In patients with VIPomas somatostatin analogs can improve diarrhea but dose escalation may be necessary to maintain benefit (Metz & Jensen, 2008). Somatostatin analogs may be used to manage patients with insulinoma but patients should be monitored as somatostatin analogs can worsen symptoms of hypoglycemia. Somatostatin analogs can decrease glucagon levels and improve skin rash in patients with glucagonoma.
For patients with symptoms that are unresponsive to somatostatin analogs breakthrough medication, increased dosage or more frequent dosage can be considered (Kulke et al., 2010).
Side effects from somatostatin analogs include diarrhea, nausea, gallstones and glucose intolerance.
In a recent study, octreotide also demonstrated possible antitumor effects when compared to a placebo in patients with well-differentiated carcinoid tumors of midgut origin, limited hepatic tumor mass and a resected primary tumor. Similar studies do not yet exist for pancreatic neuroendocrine tumors.
Novel somatostatin analogs such as pasireteotide are currently in clinical trials to determine their role in treating characteristic syndromes from neuroendocrine tumors and/or for antitumor effects. Pasireotide is one somatostatin analog in clinical development which binds to somatostatin receptors one, two, three and five. Please visit the Caring for Carcinoid Foundation’s Clinical Trials Resource for more information on clinical trials and to search clinical trials for pancreatic neuroendocrine tumors.
Proton Pump Inhibitors (PPIs)
Gastrinomas secrete excess gastrin causing Zollinger-Ellison Syndrome. Proton Pump Inhibitors can effectively control the clinical symptoms of Zollinger-Ellison Syndrome and is the preferred non-surgical treatment (Metz & Jensen, 2008). Proton Pump Inhibitors (PPIs) are a group of drugs used to reduce production of gastric acid by blocking an enzyme in the wall of the stomach. All patients with Zollinger-Ellison Syndrome should work with a physician to manage PPI usage – treating symptoms may not be sufficient to neutralize the gastrin hypersecretion and a physician should follow acid output (Metz & Jensen, 2008). PPIs are most commonly given as oral tablets but can be given intravenously in patients who cannot tolerate oral therapy (Metz & Jensen, 2008).
In animal studies long-term exposure to high doses of PPIs has been shown to lead to development of gastric carcinoid tumors. However, in humans, there is no evidence of increased rates of gastric carcinoid tumors among patients with Zollinger-Ellison Syndrome on chronic PPI treatment (Metz & Jensen, 2008).
Insulinomas can secrete insulin causing hypoglycemia. Diazoxide can be used to treat hypoglycemia associated with insulinomas. Diazoxide is a benzothiadiazide that inhibits insulin release. Side effects include sodium/fluid retention and nausea.
Interferons are naturally occurring proteins that are secreted by specialized cells in the body to activate the body’s natural protective response to harmful substances including some tumors. There are many types of interferon produced by the body. A synthetic version of one type, interferon-α, can be used to stabilize tumor growth in pancreatic neuroendocrine tumors. (Metz & Jensen, 2008). However, interferon-α can have severe side effects, such as myelosuppression (the decrease in bone marrow activity resulting in lower blood cell levels), fatigue, depression and changes in thyroid function.
Cytotoxic chemotherapy is the use of anticancer drugs that target and kill rapidly proliferating (dividing) cells. Evidence has shown that well-differentiated pancreatic neuroendocrine tumors are more responsive to chemotherapeutic drugs than well-differentiated carcinoid tumors. Poorly differentiated neuroendocrine tumors have been shown to respond to chemotherapeutic drugs, especially the combination of cisplatin and etoposide (Moertel, Kvols, O’Connell, & Rubin, 1991; Metz & Jensen, 2008; Grabowski & Baum).
Pancreatic neuroendocrine tumors may respond to chemotherapeutics such as streptozocin. Streptozocin is approved by the Food and Drug Administration (FDA) to treat pancreatic neuroendocrine tumors. Temozolomide has also shown effectiveness in treatment pancreatic neuroendocrine tumors; in particular among patients with deficiency of the MGMT gene (0^6 methylguanine DNA methyl transferace deficiency and respnse to temozolomide based therapies in patients with neuroendocrine tumors (Kulke, Hornick, Frauenhoffer, Hooshmand, yan, Enzinger, Meyerhardt, Clark, Stuart, Fuchs, & Redston, 2009). MGMT is a DNA repair enzyme. Several chemotherapeutics are currently being investigated in combination with other chemotherapeutics and / or targeted agents to determine their effects on neuroendocrine tumors. Please see the Caring for Carcinoid Foundation’s Clinical Trials Resource for more information on ongoing studies.
Hepatic Artery Embolization
All cells require an adequate blood supply to survive. The human liver has two main sources of blood: the portal vein and hepatic artery. The portal vein supplies blood to most liver cells while tumor cells mostly depend on the hepatic artery for their blood supply. A hepatic embolization is a non-surgical procedure which involves the blockage of selective branches of the hepatic artery that supply tumor cells with blood. This blockage is made possible by the injection of embolic particles (specialized particles that cause a blockage) which travel to and cut off tumor blood supply. There are two types of embolization of the hepatic arteries: 1) bland embolization – the injection of just embolic particles, and 2) chemoembolization – the injection of embolic particles and chemotherapeutic agent (drug).
Individuals with liver metastases may be considered candidates for hepatic embolization or hepatic chemoembolization if they have non-resectable liver metastases, uncontrolled growth of liver metastases and/or uncontrolled symptoms (Reidy, Tang, & Saltz, 2009). However, other factors such as physical health and the extent of tumor growth must also be taken into consideration. These procedures can have very positive but short-term results of: a decrease in tumor size, a decrease in tumor symptoms, and a halt in tumor progression. Duration of response is highly variable (Reidy, Tang, & Saltz, 2009). Individuals who are candidates may undergo more than one embolization.
Common side-effects of either procedure can include fever, fatigue, abdominal pain, nausea and vomiting. The severity of these varies for each individual. For liver-directed therapies the order of treatments may matter and the decision to have one therapy may affect treatment options down the road (Kulke et al., 2010). Please discuss any limitations that embolizations may place on future treatment options with your physician.
Radioembolization is a form of selective internal radiation therapy (SIRT). It is a minimally invasive procedure that combines embolization and radiation therapy to target liver metastases. Radioembolization involves the injection of millions of radioactive microspheres (microscopic beads) into a branch of the hepatic artery which supplies blood to the tumor. From there, the microspheres travel to the tumor site where they inhibit the blood supply to the tumor and emit radiation effectively killing tumor cells.
Currently, there are two radioactive microsphere products available for patients with metastatic tumors to the liver, one made of glass and the other resin. Both products use Yttrium-90 (90Y), a beta emitting radionuclide.
Individuals with liver metastases may be considered candidates for hepatic embolization or hepatic chemoembolization if they have non-resectable liver metastases, uncontrolled growth of liver metastases and/or uncontrolled symptoms (Saxena, Chua, Bester, Kokandi, & Morris, 2010). Other factors such as physical health, extent of tumor burden and prior treatment therapies must also be taken into consideration. These procedures can have very positive but short-term results of: a decrease in tumor size, a decrease in tumor symptoms, and a halt in tumor progression. Currently, the role of radioembolization in combination with other therapies is not well understood.
Common side-effects of radioembolization can include fever, abdominal pain, fatigue, nausea and vomiting. The severity of these varies for each individual. For liver-directed therapies the order of treatments may matter and the decision to have one therapy may affect treatment options down the road (Kulke et al., 2010). Please discuss any limitations that these procedures may place on future treatment options with your physician.
Radiofrequency Ablation (RFA)
Radiofrequency ablation (RFA) is a minimally invasive procedure that uses a high frequency electrical current to destroy tumor cells. RFA involves placing a small probe into a tumor. Electrical currents (which are at the same range of radiofrequency) are sent through the probe. This effectively raises the temperature of the tumor tissue and destroys it. RFA can be done laparoscopically but is more commonly done in combination with liver resection.
Individuals with inoperable neuroendocrine tumors may be candidates for RFA. RFA has been shown to temporarily decrease tumor burden, stall tumor progression and temporarily relieve tumor symptoms. There are many limitations to RFA, including tumor size and tumor location. Tumors that are greater in diameter than 3 cm are difficult to eradicate and RFA cannot be used in tumors that are greater in diameter than 5 cm (Steinmuller et al., 2005).
Peptide Receptor Radionuclide Therapy (PRRT)
Most neuroendocrine tumors, including functioning and non-functioning pancreatic neuroendocrine tumors, have five highly specialized receptors that bind to the naturally occurring hormone somatostatin. Octreotide is a synthetic analogue (a man-made version) of somatostatin that is able to attach to two of these five somatostatin receptors.
Peptide receptor radionuclide therapy (PRRT) combines octreotide with a radionuclide (a radioactive substance) to form highly specialized molecules called radiolabeled somatostatin analogues or radiopeptides. These radiopeptides can be injected into a patient and will travel throughout the body binding to carcinoid tumor cells that have receptors for them. Once bound, these radiopeptides emit radiation and kill the tumor cells they are bound to.
There are three radionuclides that are attached to octreotide to create radiopeptides: indium 111 (111In), yttrium 90 (90Y) and lutetium 177 (177Lu). These radiopeptides differ in the type of radiation they emit as well as the depth of tissue into which they penetrate (Kwekkeboom, D., de Herder, W., van Eijck, C., Kam, B., van Essen, M., Teunissen, J., Krenning, E., 2010). Tissue penetration is an important factor since a certain range of radiation is necessary to kill tumor cells but not damage surrounding, healthy tissues. 111In emits both Auger electrons and γ-radiation and has the shortest range of tissue penetration (10 µm), 90Y emits β-radiation and has a range of 12 mm, and 177Lu emits both β-radiation and γ-radiation and has a range of 2 mm (Grabowski & Baum).
Studies have shown that in certain individuals, the short-term results of PRRT with 177Lu and 90Y (and 111In to a much lesser degree) are: a decrease in tumor size, a decrease in symptoms, and a halt in tumor progression (Bushnell, O’Dorisio, O’Dorisio, menda, Hicks, Van cutsem, Baulieu, Borson-Chazot, Anthony, Benson, Oberg, Grossman, Connolly, Bouterfra, Li, Kacena, LaFrance, & Pauwels, 2010). Among pancreatic neuroendocrine tumors Gastrinomas and glucagonomas seem to have the best results (Grabowski, & Baum).
Common side effects of radiopeptide therapy are nausea, vomiting and abdominal pain. Other less common side-effects are bone, liver and kidney toxicity, and mild hair loss (Bushnell et al., 2010).
Individuals whose tumors can be visualized by somatostatin receptor scintigraphy (SRS) or 68 GA –DOTATE PET/CT and have inoperable neuroendocrine tumors that are growing or individuals whose symptoms are not well managed by somatostatin analogues may be candidates for PRRT (Bushnell et al., 2010). However, the extent of tumor growth, kidney function, liver function, prior treatments, and many other factors must also be considered.
Molecular Targeted Therapies to Treat Pancreatic Neuroendocrine Tumors
Pancreatic neuroendocrine tumors are formed by an abnormal growth of cells within the body. Normally, the growth and replication of all cells within the body is strictly regulated at a molecular and genetic level. However, tumors are made up of cells that have undergone multiple mutations in their genetic code, which allow them to grow and replicate without the normal controls. By understanding what molecular and genetic mutations have occurred, scientists can develop drug therapies that target these mutations (targeted therapies) effectively stopping tumor cell growth and even promoting tumor cell death. At this time, there are two molecular pathways for which novel targeted therapies are being developed.
Vascular Endothelial Growth Factor (VEGF) Inhibitors
All cells require an adequate blood supply to survive. Cancer cells, since they tend to replicate faster than normal cells, require an even greater blood supply. In order to achieve this, many tumors, including pancreatic neuroendocrine tumors, undergo angiogenesis, the development of new blood vessels. Vascular endothelial growth factor (VEGF) is a highly specialized chemical signal that cells produce in order to stimulate new blood vessel growth. In pancreatic neuroendocrine tumors, this signal is over expressed (Kulke, 2007). Several targeted therapies called angiogenic inhibitors are currently being investigated to see if they can effectively suppress VEGF in pancreatic neuroendocrine tumors or inhibit pathways that would disrupt its production or effects.
One angiogenic inhibitor, Sunitinib malate (SUTENT), is approved by the US FDA for patients with progressive, well-differentiated pancreatic neuroendocrine tumors that are unresectable locally advanced, or metastatic (Raymond, 2011). The approval was based on a double-blind, randomized, placebo-controlled, phase III trial with progression free survival as the primary endpoint. This phase III trial was conducted at institutions worldwide and the results were published in the New England Journal of Medicine. Common side effects of sunitinib included diarrhea, nausea, asthenia (weakness), vomiting and fatigue (Raymond, 2011).
SUTENT is only the second therapy approved by the FDA to treat pancreatic neuroendocrine tumor patients since 1982.
Mammalian Target of Rapamycin (mTOR) Inhibitors
Normally, cells that have unfixable mutations in the genetic code will undergo apoptosis (programmed cell death). Neuroendocrine tumors cells, like other cancer cells, do not do this. Instead, their growth and death is unregulated (Kulke, 1999). The mammalian target of rapamycin (mTOR) is a protein that is involved in many cellular pathways including cell growth and death (Reidy, 2005). In neuroendocrine tumors, mTOR is not regulated and consequently promotes tumor cell growth. Targeted therapies called mTOR inhibitors deactivate mTOR and prevent cellular growth and replication. Everolimus (Afinitor) is drug therapy that inhibits mTOR.
Recently, CFCF-funded scientists at Johns Hopkins University identified mutations in the mTOR signaling pathway among patients with non-functioning pancreatic neuroendocrine tumors (Jiao, 2011).
Everolimus tablets (Afinitor) are approved by the US FDA to treat patients with progressive pancreatic neuroendocrine tumors that are unresectable, locally advanced or metastatic. The approval was based on a double-blind, randomized, placebo-controlled, phase III trial with progression free survival as the primary endpoint (Yao, 2011). This phase III trial was conducted at institutions worldwide and the results were published in the New England Journal of Medicine here. Common side effects of everolimus included stomatitis (inflammation in the mouth), rash, diarrhea, fatigue, and infections (Yao, 2011).
This 2011 approval marks the first FDA approval for pancreatic neuroendocrine tumor patients in nearly 30 years.
Everolimus' effects on other neuroendocrine tumors are being investigated. To learn more about this therapy for other indications, please visit the clinical trials section of the Caring for Carcinoid Foundation’s website.
For up to the minute information on novel clinical trials of chemotherapeutics and targeted therapies please visit the Caring for Carcinoid foundation’s clinical trials finder.
Akerstrom, G., Hellman, P., Hessman, O., and Osmak, L. (2005). Management of midgut carcinoids. Journal of Surgical Oncology, 1(89), 161-169. Retrieved from: http://www.ncbi.nlm.nih.gov/pubmed/15719373.
Blonski, W., Reddy, K., Shaked, A., Siegelman, E., Metz, D. (2005) Liver transplantation for metastatic neuroendocrine tumor: a case report and review of the literature. World Journal of Gastroenterology, 11(48), 7676-7683. Retrieved from: http://www.ncbi.nlm.nih.gov/pubmed/16437698.
Bushnell, D., O’Dorisio, T., O’Dorisio, M., Menda, Y., Hicks, R., Van Cutsem, E., Baulieu, J., Borson-Chazot, F., Anthony, L., Benson, A., Oberg, K., Grossman, A., Connolly, M., Bouterfa, H., Li, Y., Kacena, K., LaFrance, N., Pauwels, S. (2010). 90Y-edotreotide for metastatic carcinoid refractory to octreotide. Journal of Clinical Oncology, 28(10), 1652-1659. Retrieved from: http://www.ncbi.nlm.nih.gov/pubmed/20194865.
Cho, C., Labow, D., Tang, L., Klimstra, D., Loeffler, A., Leverson, G., Fong, Y., Jarnagin, W., D’Angelica, M., Weber, S., Blumgart, L., and Dematteo, R. (2008). Histologic grade is correlated with outcome after resection of hepatic neuroendocrine neoplasms. Cancer, 113(1), 126-134. Retrieved from: http://www.ncbi.nlm.nih.gov/pubmed/18457323.
Grabowski, P. & Baum, R. Differential Therapy for Neuroendocrine Tumors. Retrieved from: http://www.rhoen-klinikum-ag.com/rka/cms/zbb_2/deu/download/Differential_Therapy_for_Neuroendocrine_Tumors.pdf.
Jiao, Y., Shi, C., Edil, B., de Wilde, R., Klimstra, D., Maitra, A., Schulick, R., Tang, L., Wolfgang, C., Choti, M., Velculescu, V., Diaz, L., Vogelstein, B., Kinzler, K., Hruban, R., and Papadopoulos, N. (2011). AXX/ATRX, MEN1, and mTOR Pathway Genes Are Frequently Altered in Pancreatic Neuroendocrine Tumors. Science, 331(6021), 1199-1203. Retrieved from: http://www.sciencemag.org/content/331/6021/1199.
Kulke, M. H., Mayer, R. J. (1999). Carcinoid Tumors. New England Journal of Medicine, 340(11), 858-868. Retrieved from: http://www.ncbi.nlm.nih.gov/pubmed/10080850.
Kulke, M. H. (2007). Clinical Presentation and Management of Carcinoid Tumors. Hematology/Oncology Clinics of North America, 21, 433-455. Retrieved from: http://www.ncbi.nlm.nih.gov/pubmed/17548033.
Kulke, M., Lenz, H., Meropol, N., Posey, J., Ryan, D., Picus, J., Bergsland, E., Stuart, K., Tye, L., Huang, X., Li, J., Baum, C., and Fuchs, C. (2008). Activity of sunitinib in patients with advanced neuroendocrine tumors. Journal of Clinical Oncology, 26(20), 3403-3410. Retrieved from: http://www.ncbi.nlm.nih.gov/pubmed/18612155.
Kulke, M., Hornick, J., Frauenhoffer, C., Hooshmand, S., Ryan, D., Enzinger, P., Meyerhardt, J., Clark, J., Stuart, K., Fuchs, C., & Redston, M. (2009). O6-methylguanine DNA methyltransferase deficiency and response to temozolomide-based therapy in patients with neuroendocrine tumors. Clinical Cancer Research, 15(1), 338-345. Retrieved from: http://www.ncbi.nlm.nih.gov/pubmed/19118063.
Kulke, M. H., Anthony, L., Bushnell, D., de Herder, W., Goldsmith, S., Klimstra, D., Marx, S., Pasieka, J., Pommier, R., Yao, J., Jensen, R. (2010). NANETS Treatment Guidelines: Well-Differentiated Tumors of the Stomach and Pancreas. Pancreas, 39(6), 735-752. Retrieved from: http://nanets.net/pdfs/pancreas/04.pdf.
Kwekkeboom, D., de Herder, W., van Eijck, C., Kam, B., van Essen, M., Teunissen, J., Krenning, E. (2010). Peptide receptor radionuclide therapy in patients with gastroenteropancreatic neuroendocrine tumors. Seminars in Nuclear Medicine, 40(2), 78-88. Retrieved from: http://www.ncbi.nlm.nih.gov/pubmed/20113677.
Lang, H., Oldhafer, K., Weimann, A., Schlitt, H., Scheumann, G., Flemming, P. Ringe, B., and Pichlmayr, R. (1997). Liver transplantation for metastatic neuroendocrine tumors. Annals of Surgery, 225(4), 347-354. Retrieved from: http://www.ncbi.nlm.nih.gov/pubmed/9114792.
Moertel, C, Kvols, L, O’Connell, M., & Rubin, J. (1991). Treatment of neuroendocrine carcinomas with combined etoposide and cisplatin. Evidence of major therapeutic activity in the analplastic variants of these neoplasms. Cancer, 68(2), 227-232. Retrieved from: http://www.ncbi.nlm.nih.gov/pubmed/1712661.
Metz, D. and Jensen, R. (2008). Gastrointestinal neuroendocrine tumors, pancreatic endocrine tumors. Gastroenterology, 135(5), 1469-1492. Retrieved from: http://www.ncbi.nlm.nih.gov/pubmed/18703061.
Norton, J., Warren, R., Kelly, M., Zuraek, M., Jensen, R. (2003). Aggressive surgery for metastatic liver neuroendocrine tumors. Surgery, 134(6), 1057-1063. Retrieved from: http://www.ncbi.nlm.nih.gov/pubmed/14668741.
Norton, J., Fraker, D., Alexander, H., Gibril, F., Liewehr, D., Venzon, D., and Jensen, R. (2006). Surgery increases survival in patients with gastrinoma. Annals of Surgery, 244(3), 410-419. Retrieved from: http://www.ncbi.nlm.nih.gov/pubmed/16926567.
Oberg, K. (2009). Is it time to widen the use of somatostatin analogs in neuroendocrine tumors? Journal of Clinical Oncology, 27(28), 4635-4636. Retrieved from: http://www.ncbi.nlm.nih.gov/pubmed/19704053.
Ramage, J., Ahmed, A., Ardill, J., Bax, N., Breen, D.J, Caplin, M.E., Corrie, P., Davar, J., Davies, A.H., Lewington, V., Meyer, T., Newell-Price, J., Poston, G., Reed, N., Rockall, A., Steward, W., Thakker, R.V., Toubanakis, C., Valle, J., Verbeke, C., and Grossman, A.B., and UK and Ireland Neuroendocrine Tumor Society (2012) . Guidelines for the management of gastroenteropancreatic neuroendocrine (including carcinoid) tumours (NETs). Gut, 61(1):6-32. Retrieved from: http://www.ncbi.nlm.nih.gov/pubmed/22052063.
Raymond E., Dahan L., Raoul, J., Bang Y., Borbath I., Lombard-Bohas C., Valle J., Metrakos P., Smith D., Vinik A., Chen J., Hörsch D., Hammel P., Wiedenmann B., Van Cutsem E., Patyna S., Lu D., Blanckmeister C., Chao R., Ruszniewski P. (2011) Sunitinib Malate for the Treatment of Pancreatic. New England Journal of Medicine. Retrieved from: http://www.nejm.org/doi/full/10.1056/NEJMoa1003825#t=references
Reidy, D. L., Tang, L. H., Saltz, L. B. (2009). Treatment of advanced disease in patients with well-differentiated neuroendocrine tumors. Nature Clinical Practice, Oncology, 6(3), 143-152. Retrieved from: http://www.ncbi.nlm.nih.gov/pubmed/19190591.
Reubi, J., Kvolz, L., Waser, B., Nagorney, D., Heitz, P., Chaboneau, J., Reading, C., Moertel, C. (1990). Detection of somatostatin receptors in surgical percutaneous needle biopsy samples of carcinoids and islet cell carcinomas. Cancer Research, 50(18), 5969-5977. Retrieved from: http://www.ncbi.nlm.nih.gov/pubmed/2168286.
Saxena, A., Chua, T., Bester, L., Kokandi, A., Morris, D. (2010). Factors predicting response and survival after yttrium-90 radioembolization of unresectable neuroendocrine tumor liver metastases: a critical appraisal of 48 cases. Annals of Surgery, 251(5), 910-916. Retrieved from: http://www.ncbi.nlm.nih.gov/pubmed/20395859.
Steinmuller, T., Kianmanesh, R., Falconi, M., Scarpa, A., Taal, B., Kwekkeboom, D., Lopes, J., Perren, A., Nikou, G., Yao, J., Dell Fave, G., O’Toole, D., Frascati Consensus Conference participants. (2008). Consensus guidelines for the management of patients with liver metastases from digestive (neuro)endocrine tumors: foregut, midgut, hindgut, and unknown primary. Neuroendocrinology, 87(1), 47-62. Retrieved from: http://www.ncbi.nlm.nih.gov/pubmed/18097131/.
Vignot, S., Faivre, S., Aguirre, D., Raymond, E. (2005). mTOR-targeted therapy of cancer with rapamycin derivatives. Annals of Oncology, 16(4), 525-537. Retrieved from: http://www.ncbi.nlm.nih.gov/pubmed/15728109.
van Vilsteren, F., Baskin-Bey, E., Nagorney, D., Sanderson, S., Kremers, W., Rosen, C., Gores, G., Hobday, T. (2006). Liver transplantation for gasteroenteropancreatic neuroendocrine cancers: Defining selection criteria to improve survival. Liver Transplantation, 12(3), 448-456. Retrieved from: http://www.ncbi.nlm.nih.gov/pubmed/16498656.