The Foundation Dedicated to Discovering a Cure for Neuroendocrine Cancer

Caring for Carcinoid Foundation

Treatment and Drugs

Treatment

Due to their varied nature and primary locations, carcinoid cancers can be very difficult to treat.  Carcinoid 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).

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 well-versed in treating neuroendocrine tumor patients.

Surgery

The surgical treatment of carcinoid tumors depends on the tumor type, location, extent of metastases, as well as other factors.  Surgery can often be curative for individuals whose tumors are localized (have not spread) and do not cause syndrome (Norton, 2005).  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). A multimodal approach combining surgery with embolization or other treatment methods may also be possible for patients with liver metastases.  For all patients who undergo surgery, continued and extensive follow up is recommended.

Appendix

Carcinoid tumors are the most common appendiceal tumor and most frequently are benign (Akerstrom, Hellman, Hessman, & Osmak, 2007).  These tumors are often incidentally discovered during surgery and are usually removed by an appendectomy (Kulke, 2007).  An appendectomy is the complete removal of the appendix, which can be done either laparoscopically or as an open procedure.  Low incidence of metastasis has been observed in patients undergoing appendectomy with tumors smaller than two cm (Kulke, 2007).

Intestine

The majority of carcinoid tumors originate in the gastrointestinal tract.  Of these, intestinal carcinoids are the most common (Modlin, Lye, & Kidd, 2003). After diagnosis of an intestinal carcinoid, a small bowel resection may be preformed.  A small bowel resection is the surgical removal of one or more parts of the small intestine.  The extent of the resection depends on a variety of factors, including tumor size, number, and extent of metastasis.  If the tumor has metastasized to the surrounding tissues and liver, a more invasive surgery may be conducted.  In certain cases, the removal of these tumors can help to decrease Carcinoid Syndrome, alleviate abdominal pain, prevent further metastases and increase survival.   (Norton, Kivlen, Li, Schneider, Chuter & Jensen, 2003).

Liver

The liver is the most common site for carcinoid tumors to metastasize but it is rare for the liver to be the primary site of carcinoid development. (Norton, Warren, Kelly, Zuraek, & Jensen, 2003; Steinmuller et al., 2008). 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 (Reidy, Tang, & Saltz, 2009). 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.  Presence of liver metastasis is a major prognostic factor with presence of liver metastasis indicating worse outcome (Norton, 2005).

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. (Kianmanesh, Sauvanet, Hentic, Couvelard, Levy, Vilgrain, Rusziewski, & Belghiti, 2008). 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 carcinoid 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.

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 (van Vilsteren, Baskin-Bey, Nagorney, Sanderson, Kremers, Rosen, Gores, Hobday, 2006; Blonski, Reddy, Shaked, Siegelman, & Metz, 2005).

Lung

Bronchial carcinoid tumors can develop almost anywhere in the lungs.  Surgical management is the recommended treatment for most bronchial carcinoids. The type and extent of the surgery depends on the nature, location and size of the tumor(s) (Fiala, Petraskova, Cernohorsky, Kinkor,  Krepela, & Zatloukal, 2003). A lobectomy, which is the surgical removal of one lung lobe, is the most common surgical method used to treat bronchial carcinoids. If more than one lobe is affected and surgery is possible, an individual may undergo a bilobectomy, which is the surgical removal of two lung lobes or a pneumonectomy, which is the surgical removal of a lung. A sleeve resection, which is the surgical removal of a section of bronchus or trachea along with the infected lobe, may also be used to remove bronchial carcinoids. A wedge resection, which is the surgical removal of the affected lung tissue and the surrounding margins, may be used to remove the tumor and leave the lung lobe.  A wedge resection is less invasive than a lobectomy and is the preferred treatment method when clinically possible (Chughtai, Morin, Sheiner, Wilson, & Mulder, 1997).

Lymph Nodes

Lymph nodes are often the site of carcinoid metastases.  When an individual is diagnosed with carcinoid 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. 

Rectal Carcinoids

Rectal carcinoids represent just over 10% of all carcinoids and are most commonly incidentally found during routine endoscopic cancer screenings.  Treatment of rectal carcinoids depends on the size and invasiveness of the tumor.  Tumors that are < 1 cm can usually be treated by an endoscopic excision, a minimally invasive surgical procedure which involves the removal of the tumor and the surrounding tissues.  However the histological features of these tumors should still be examined to make sure they have not invaded the surrounding tissue (Kulke, 2007). Tumors that are ≥1 cm will need further investigation and depending on size and invasiveness may require a rectal resection, the surgical removal of a portion of the rectum (Kulke, 2007).

Stomach

The surgical removal of gastric carcinoids will depend on their type, size, quantity, extent of invasiveness and response to somatostatin analogues.  Endoscopic excision, a minimally invasive surgical procedure, can be used for smaller type I and II gastric carcinoids. A gastric resection (gastrectomy), the partial or complete surgical removal of the stomach, may be done for individuals who have large and multiple type I or II gastric carcinoids as well as for nearly all type III gastric carcinoids (Borch, Ahren, Ahlman, Falkmer, Granerus, & Grimelius, 2005).  

Non-Surgical Therapies

If curative surgery is not possible, other treatment options are available to individuals with carcinoid cancer. 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.                

Somatostatin Analogues             

The excess of hormones produced and secreted into the body by carcinoid tumors can cause several symptoms, which when grouped together may be classified as a syndrome, such as Carcinoid Syndrome or Cushing’s Syndrome.  Most neuroendocrine tumors, including carcinoid, 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 carcinoid tumors (Oberg, Reubi, Kwekkeboom, & Krenning, 2010).  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).  These somatostatin analogues have been proven to control, decrease and prevent symptoms associated with carcinoid. 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 (Rinke, Muller, Schade-Brittinger, Lose, Barth, Weid, Mayer, Aminossadati, Pape, Blacker, Harder, Arnold, Gress, Arnold, & PROMID Study Group, 2009).

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 carcinoid tumors.

Interferon-α

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 in combination with somatostatin analogue for symptom management in individuals whose symptoms are not controlled by somatostatin analogues (Janson, Holmberg, Stridsberg, Eriksson, Theodorsson, Wilander, & Oberg, 1997). 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            

Cytotoxic chemotherapy is the use of anticancer drugs that target and kill rapidly proliferating (dividing) cells.  Thus far, there has been little clinical evidence for the use of chemotherapeutic drugs in the treatment of well-differentiated (typical) carcinoid tumors (Kulke 2007). However, studies have demonstrated that poorly-differentiated (atypical) carcinoid tumors are more responsive to chemotherapeutic drugs, especially the combination of cisplatin and etoposide (Toumpanakis, Meyer, & Caplin, 2007).

Ablative Therapies

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. 

Radioembolization

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 (Reidy, Tang, & Saltz, 2009).

Common side-effects of radioembolization can include fever, abdominal pain, fatigue, nausea and vomiting.  The severity of these varies for each individual. 

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 carcinoid 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 (Poncet, Faucheron, & Walter, 2010).

Peptide Receptor Radionuclide Therapy (PRRT)

Most neuroendocrine tumors, including carcinoid, 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.  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 (Kwekkeboom, de Herder, van Eijck,  Kam, van Essen, Teunissen, Krenning, 2010).

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, Bouterfa, Li, Kacena, LaFrance, & Pauwels, 2010).

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 (Haug, Auernhammer, Wangler, Schmidt, Uebleis, Goke, Cumming, Bartenstein, Tiling, &  Hacker, 2010) and have inoperable carcinoid tumors that are growing or individuals whose symptoms are not well managed by somatostatin analogues may be candidates for PRRT. However, the extent of tumor growth, kidney function, liver function, prior treatments, and many other factors must also be considered.  (Bushnell et al., 2010; Haug et al, 2010).

Molecular Targeted Therapies

Carcinoid 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 Endothelia 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 carcinoid, 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 carcinoid tumors, this signal is over expressed. Targeted therapies called angiogenic inhibitors are currently being investigated to see if they can effectively suppress VEGF in carcinoid or inhibit pathways that would disrupt its production or effects.  Bevacizumab and sunitinib malate are two drug therapies that interrupt VEGF and their effects on carcinoid are being investigated. To learn more about these therapies and other investigational trials, please visit the clinical trials section of the Caring for Carcinoid Foundation’s website. 

Mammalian Target of Rapamycin (mTOR) Inhibitors

Normally, cells that have unfixable mutations in the genetic code will undergo apoptosis (programmed cell death).  Carcinoid tumors cells, like other cancer cells, do not do this.  Instead, their growth and death is unregulated (Chan & Kulke, 2009). The mammalian target of rapamycin (mTOR) is a protein that is involved in many cellular pathways including cell growth and death (Reidy, Tang, & Saltz, 2009; Vignot, Feliberti, Perry & Nakave, 2008). In carcinoid, mTOR is not regulated and consequently promotes tumor cell growth.  Targeted therapies called mTOR inhibitors deactivate mTOR and prevent cellular growth and replication.  Everolimus (RAD001) is drug therapy that inhibits mTOR.  Its effects on carcinoid are being investigated.  To learn more about this therapy and other investigational trials, please visit the clinical trials section of the Caring for Carcinoid Foundation’s website.

References

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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.

Borch, K., Ahren, B., Ahlman, H., Falkmer, S., Granerus, G., Grimelius, L., (2005). Gastric carcinoids: biologic behavior and prognosis after differentiated treatment in relation to type. Annals of Surgery, 242(1), 64-73. Retrieved from: http://www.ncbi.nlm.nih.gov/pubmed/15973103.

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Janson E., Holmberg, L., Stridsberg, M., Eriksson, B., Theodorsson, E., Wilander, E. and Oberg, K. (1997). Carcinoid tumors: analysis of prognostic factors and survival in 301 patients from a referral center. Annals of Oncology, 8(7), 685-690. Retrieved from: http://www.ncbi.nlm.nih.gov/pubmed/9296223.

Kianmanesh, R., Sauvanet, A., Hentic, O., Couvelard, A., Levy, P., Vilgrain, V., Rusziewski, P., Belghiti, J. (2008). Two-step surgery for synchronous bilobar liver metastases from digestive endocrine tumors : a safe approach for radical resection. Annals of Surgery, 247(4), 659-665. Retrieved from: http://www.ncbi.nlm.nih.gov/pubmed/18362629.

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.

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.

Modlin, I., Lye, K., Kidd, M. (2003) A 5-decade analysis of 13,715 carcinoid tumors. Cancer, 97(4), 934-959. Retrieved from: http://www.ncbi.nlm.nih.gov/pubmed/12569593.

Norton, J., Kivlen, M., Li, M., Schneider, D., Chuter, T., and Jensen, R. (2003). Morbidity and mortality of aggressive resection in patients with advanced neuroendocrine tumors. Archives of Surgery, 138(8), 859-866. Retrieved from: http://www.ncbi.nlm.nih.gov/pubmed/12912744.

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. (2005). Endocrine tumours of the gastrointestinal tract. Surgical treatment of neuroendocrine metastases. Best Practice and Research. Clinical Gastroenterology, 19(4), 577-583. Retrieved from: http://www.ncbi.nlm.nih.gov/pubmed/16183528.

Oberg, K. E., Reubi, J. C., Kwekkeboom, D. J., Krenning, E. P. (2010) Role of somatostatins in gastroenteropancreatic neuroendocrine tumor development and therapy. Gastroenterology, 139(3), 742-753. Retrieved from: http://www.ncbi.nlm.nih.gov/pubmed/20637207.

Poncet, G., Faucheron, J., and Walter, T. (2010). Recent trends in the treatment of well-differentiated endocrine carcinoma o the small bowel. World Journal of Gastroenterology, 16(14), 1696-1706. Retrieved from: http://www.ncbi.nlm.nih.gov/pubmed/20380000.

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

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.

Rinke, A., Muller, H., Schade-Brittinger, C., Lose, J., Barth, P., Weid, M., Mayer, C., Aminossadati, B., Pape, U., Blacker, M., Harder, J., Arnold, C., Gress, T., Arnold, R., PROMID Study Group. (2009). Placebo-controlled, double-blind, prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors: a report from the PROMID Study Group. Journal of Clinical Oncology, 27(28), 4656-4663. Retrieved from: http://www.ncbi.nlm.nih.gov/pubmed/19704057.

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/.

Toumpanakis, C., Meyer, T., Caplin, M. (2007) Cytotoxic treatment including embolization/chemoembolization for neuroendocrine tumours. Best Practice and Research, Clinical Endocrinology and Metabolism, 21(1), 131-144. Retrieved from: http://www.ncbi.nlm.nih.gov/pubmed/17382269.

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.

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.

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