NETs arise from cells of the neuroendocrine system, which produce and secrete regulatory hormones. 1[Doherty-44.6, 1721a] Most NETs are slow growing and malignant, with metastatic potential. 1[Doherty-44.6, 1723Table44.6.2] 2[Pinochot2008, 1257e] 3[NCCN NET v2.2010, MS-1c] The exception is insulinomas, which are usually benign. NETs can arise nearly anywhere in the body, although the most common sites of origin are the: 4[Yao2008, 3066Table 1] Gastrointestinal (GI) tract, including the small intestine, rectum, large bowel, stomach, appendix, and liver Lungs Pancreas References: Doherty GM. Cancer of the Endocrine System: Carcinoid Tumors and the Carcinoid Syndrome. In: DeVita Jr V, Lawrence T, Rosenberg S, eds. DeVita, Hellman, and Rosenberg's Cancer Principles & Practice of Oncology. 8th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2008:1721-1735. Pinchot SN, Holen K, Sippel RS, et al. Carcinoid tumors. Oncologist . 2008;13(12):1255-1269. Clark OH, Benson AB, III, Berlin JD et al. NCCN Clinical Practice Guidelines in Oncology: Neuroendocrine Tumors. National Comprehensive Cancer Network. 2010. Yao JC, Hassan M, Phan A, et al. One hundred years after "carcinoid": epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. J Clin Oncol . 2008;26(18):3063-3072. Image source: 4[Yao2008, 3066Table 1]
Tumour classification is based on the different characteristics of the tumour, such as primary site, biologic behavior, hormone or peptide secretions and symptoms. Tumour grade refers to the biologic aggressiveness and how likely the tumour is to spread. It is predictive of prognosis. This is based on what the pathologist detects, such as mitotic rate and Ki-67 index. It is important to note that low-grade NET can still metastasize. References: Klöppel G, et al. Ann Ny Acad Sci . 2004;1014:13-27. Rindi G, et al. Virchows Arch. 2007;451:757-762.
NETs have been traditionally classified based on the sites where they originate: 1[Oberg2004a, 293a], 2[NCCN NET v2.2010, MS-2d] Foregut tumors: Thymus Esophagus Lung Stomach Duodenum Pancreas Midgut tumors: Appendix Small bowel (ileum and cecum) Ascending colon Hindgut tumors: Distal large bowel (tranverse and descending colon) Rectum A new tumor-based classification developed by the World Health Organization (WHO) is replacing this site-based method. Although the new WHO classification is more comprehensive, some clinical studies still use the traditional method. 1[Oberg2004a, iv293ab] References: Oberg K. Management of neuroendocrine tumours. Ann Oncol . 2004;15 Suppl 4:iv293-iv298. Clark OH, Benson AB, III, Berlin JD et al. NCCN Clinical Practice Guidelines in Oncology: Neuroendocrine Tumors. National Comprehensive Cancer Network. 2010. Image source: 1[Oberg2004a, 293a], 2[NCCN NET v2.2010, MS-2d]
The WHO classification defines NETs by degree of tumor differentiation, taking into consideration specific clinicopathological features. 1[Kloppel2004, 16b, Table 1] The WHO classification system is based on the following criteria: 1[Kloppel2004, 25Table 7, Table 8] 2[Scholzen2000, 311c, 312b, 318c] Biological behavior (malignancy) Metastases Ki-67 index Ki-67 is a protein that correlates to cell division. A high Ki-67 index indicates a high rate of cell proliferation and is correlated with tumor proliferation. Angioinvasion Tumor size Histological differentiation Hormonal syndrome References: Kloppel G, Perren A, Heitz PU. The gastroenteropancreatic neuroendocrine cell system and its tumors: the WHO classification. Ann N Y Acad Sci . 2004;1014:13-27. Scholzen T, Gerdes J. The Ki-67 protein: from the known and the unknown. J Cell Physiol . 2000;182(3):311-322.
WHO distinguishes the three classifications based on tumour size, metastases, Ki67 and biological behavior. Well-differentiated benign tumours typically indolent If less than 2 cm, they are not likely to have spread beyond the primary site Low-grade tumours on examination will usually demonstrate low to no mitotic activity in 10/HPFs with a Ki-67 of < 2% Well-differentiated carcinoma are associated with malignant biologic behavior are associated with higher Ki-67 indexes and are more likely to metastasize. The primary tumour is typically greater than 2 cm Poorly differentiated carcinomas are most often associated with high mitotic activity, with Ki-67% of greater than 30%, and are aggressive. This slide is a general overview, in the following two slides specific examples of WHO classification will be reviewed. References: 1. Strosberg JR, Nasir A, Hodul P, Kvols L. GI Cancer Res. 2008; 2:113-125. 2. Klöppel G, Perren A, Heitz PU. Ann Ny Acad Sci. 2004;1014:13-27.
The WHO classification is clinically and prognostically useful for newly diagnosed neuroendocrine tumours as it takes into consideration the site of origin, the malignant potential and the functional activity of the tumour. Reference: Ong SL, et al. Pancreatology . 2009;9:583-600.
The incidence has been rising in the last three decades. This might be due to greater awareness, improved diagnostic capabilities, improved reporting to registries, or a change in nomenclature from carcinoid. With new successful treatments to control or slow the progression of the disease, the prevalence of cancer will increase. We will discuss these treatments in NET modules 3 and 4.
Clinical features of GI NETs vary widely. 1[Ghevariya2009, 1033b] They may remain asymptomatic for years, and most cases are discovered incidentally. Symptoms occur mainly from: 1[Ghevariya2009, 1033b] Mechanical problems secondary to tumor bulk Fibrosis Secretion of various hormones The most common substance secreted from GI NETs is serotonin. 2[Pinchot2008, 1256d] The release of serotonin into the bloodstream can cause the classic symptoms of carcinoid syndrome. Image shows a dissection of a serotonin-producing NET in the ileum. References: Ghevariya V, Malieckal A, Ghevariya N, et al. Carcinoid tumors of the gastrointestinal tract. South Med J . 2009;102(10):1032-1040. Pinchot SN, Holen K, Sippel RS, et al. Carcinoid tumors. Oncologist . 2008;13(12):1255-1269. Image source: Novartis.
Symptoms associated with typical carcinoid syndrome include: 1[Barakat2004, 3c] 2[Ghevariya2009, 1033bcd] Hypotension Cutaneous flushing (redness and warmth of the face, neck, and upper chest) Rapid heard beat Heart disease Wheezing Severe diarrhea with abdominal cramping The liver inactivates the secretions of GI NETs, preventing carcinoid syndrome. However, if GI NETs metastasize outside of the GI tract, such as to the liver, then the secretions can enter the main bloodstream and reach other parts of the body, resulting in symptoms. 2[Ghevariya2009, 1033b] 3[Jensen-344, 2348Table 344.2] As a result, most cases (95%–100%) of carcinoid syndrome are due to metastatic disease. References: Barakat MT, Meeran K, Bloom SR. Neuroendocrine tumours. Endocr Relat Cancer . 2004;11(1):1-18. Ghevariya V, Malieckal A, Ghevariya N, et al. Carcinoid tumors of the gastrointestinal tract. South Med J . 2009;102(10):1032-1040. Jensen RT. Endocrine Tumors of the Gastrointestinal Tract and Pancreas. In: Braunwald E, Fauci AS, Kasper DL, et al, eds. Harrison's Principles of Internal Medicine. 15th ed. New York, NY: McGraw-Hill; 2001:2347-2358. Image source: 1[Barakat2004, 3c] 2[Ghevariya2009, 1033bcd]
Pancreatic NETS (pNETs) are rare and usually slow-growing neoplasms, with symptoms resulting from excess hormone production or mechanical problems secondary to tumor bulk. 1[Ong2009, 584a] 2[Yao-44.5, 1702c] 3[Yao2008, 3066Table 1] 6.4% of all NETs are found in the pancreas The incidence rate of pNETs in the US is about 0.4 cases per 100,000 persons. 1[Ong2009, 583b] Incidence is thought to be increasing over the past 2 decades. pNETs may or may not have secretory symptoms. 4[Jensen-344, 2347d] Secretory symptoms are related to the specific hormone released. Tumors without secretory symptoms (nonfunctional) may still secrete peptides; however, they cause no specific clinical symptom. Presence of symptoms is due to the tumor bulk. References: Ong SL, Garcea G, Pollard CA, et al. A fuller understanding of pancreatic neuroendocrine tumours combined with aggressive management improves outcome. Pancreatology . 2009;9(5):583-600. Yao JC, Rindi G, Evans DB. Cancer of the Endocrine System: Pancreatic Endocrine Tumors. In: DeVita Jr V, Lawrence T, Rosenberg S, eds. DeVita, Hellman, and Rosenberg's Cancer Principles & Practice of Oncology. 8th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2008:1702-1721. Yao JC, Hassan M, Phan A, et al. One hundred years after "carcinoid": epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. J Clin Oncol . 2008;26(18):3063-3072. Jensen RT. Endocrine Tumors of the Gastrointestinal Tract and Pancreas. In: Braunwald E, Fauci AS, Kasper DL, et al, eds. Harrison's Principles of Internal Medicine. 15th ed. New York, NY: McGraw-Hill; 2001:2347-2358.
There are several subtypes of pNETs. These are dependent on which islet cell type is affected and consequently, which hormone is over-produced. 1[Jensen-334, 2348Table 344.2] 2[Tortora-18, 646b] 3[Ong2009, 584Table 1] Review table with participants. Note: Most cases of PPoma are asymptomatic, although rare cases have been associated with watery diarrhea, diabetes, ulcers, or skin rash. 4[Yao-44.5, 1706b] The relative frequency of pNETs are: 5[Metz2008, 1470b] Asymptomatic > Insulinoma > Gastrinoma > Glucagonoma > VIPomas > Somatostatinoma > Others References: Jensen RT. Endocrine Tumors of the Gastrointestinal Tract and Pancreas. In: Braunwald E, Fauci AS, Kasper DL, et al, eds. Harrison's Principles of Internal Medicine. 15th ed. New York, NY: McGraw-Hill; 2001:2347-2358. Tortora GJ, Derrickson B. The endocrine system. In: Principles of Anatomy and Physiology. 11th ed. Hoboken, NJ: John Wiley & Sons Inc; 2006:616-665. Ong SL, Garcea G, Pollard CA, et al. A fuller understanding of pancreatic neuroendocrine tumours combined with aggressive management improves outcome. Pancreatology . 2009;9(5):583-600. Yao JC, Rindi G, Evans DB. Cancer of the Endocrine System: Pancreatic Endocrine Tumors. In: DeVita Jr V, Lawrence T, Rosenberg S, eds. DeVita, Hellman, and Rosenberg's Cancer Principles & Practice of Oncology. 8th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2008:1702-1721. Metz DC, Jensen RT. Gastrointestinal neuroendocrine tumors: pancreatic endocrine tumors. Gastroenterology . 2008;135(5):1469-1492.
Tumors without secretory symptoms are not associated with a hormonal syndrome. 1[Metz2008, 1475a] 2[Jensen-344, 2356h] Because of this, they may be present as an incidental finding at surgery or be detected radiographically when investigating for nonspecific abdominal pain. Patients usually present late in the disease course with large primary malignancies or advanced disease. Symptoms are due to tumor growth or spread. 2[Jensen-344, 2356i] 3[Yao-44.5, 1706b] Abdominal pain Jaundice Diarrhea Indigestion Weight loss References: Metz DC, Jensen RT. Gastrointestinal neuroendocrine tumors: pancreatic endocrine tumors. Gastroenterology . 2008;135(5):1469-1492. Jensen RT. Endocrine Tumors of the Gastrointestinal Tract and Pancreas. In: Braunwald E, Fauci AS, Kasper DL, et al, eds. Harrison's Principles of Internal Medicine. 15th ed. New York, NY: McGraw-Hill; 2001:2347-2358. Yao JC, Rindi G, Evans DB. Cancer of the Endocrine System: Pancreatic Endocrine Tumors. In: DeVita Jr V, Lawrence T, Rosenberg S, eds. DeVita, Hellman, and Rosenberg's Cancer Principles & Practice of Oncology. 8th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2008:1702-1721.
Neuroendocrine tumours can remain asymptomatic for a long period of time. Vague abdominal symptoms may be associated with primary tumour growth. These are not usually identified until they have metastasized and spread. Symptoms from syndromes secondary to hormone/peptide secretion such as diarrhea and flushing seen with carcinoid syndrome often does not appear until metastatic spread. Reference: Vinik A, et al. Pancreas . 2009 Nov;38(8):876-89.
Neuroendocrine tumours can present with a variety of nonspecific and generalized symptoms. Clinical presentation depends on the site of the primary tumour and whether the peptides secreted produce symptoms. Reference: Aggarwal G, Obideen K, Wehbi M, et al. Cleve Clin J Med . 2008;75(12):849-855.
Since the incidence is increasing and the prevalence is high, it is important for physicians to have NET in their differential diagnosis and suspect it over other more common ailments. It is also important to understand the vague difference in presentation For example, flushing of NET is slightly different than the flushing from menopause which is a typical misdiagnosis. Flushing with NET is unrelated to time or day, warmth, or perspiration Because CgA is usually elevated in NET, it should be ordered when there is even a small suspicion of NET. Reference: Peracchi M, Gebbia C, Basilisco G, et al. Eur J Endocrinol . 2003;148(1):39-43.
A good history of physical examinations is important to the diagnosis of NET. Characteristic symptoms are present in 8% to 35% of metastatic NET and include dry flushing, cramps, nocturnal diarrhea, erythematous to purplish skin, telangiectasias, hepatomegaly, cardiac murmurs, edema, hypoglycemia, confusion, dyspepsia, and GI bleeding. Lab tests for biochemical markers should include: Serum CgA and other biomarkers as appropriate for symptoms (eg, if glucagonoma is suspected, glucagon levels should be tested) Tissue Once a biopsy is performed, the specimen should be stained for Ki-67, CgA, synaptophisin, and neuron specific enolase Urine 5-HIAA if patient has symptoms consistent with carcinoid syndrome Imaging Should include CT scan with contrast or MRI Nuclear imaging with Octreoscan and PET scan Endoscopic ultrasound is useful for diagnosing pNET References: Rorstad O. J Surg Oncol. 2005;89(3):151-160. Toth-Fejel S, Pommier RF. Am J Surg . 2004;187(5):575-579. Ferolla P, et al. J Endocrinol Invest . 2008;31(3):277-286. Barakat MT, Meeran K, Bloom SR. Endocr Rel Cancer . 2004;11(1):1-18.
Depending on the results obtained from a workup, a patient’s NET is classified as local 5 , regional 5 , or advanced. 3,5,6 Treatment goals should be curative where possible, with the use of pharmacological management as necessary. 3 Local Regional NET The treatment goal for localized NETs is curative, which is most often accomplished with surgery. 3,7,8 Advanced NET The treatment goal for advanced NETs is also curative surgery if possible, followed by pharmacological treatment. 3,7
Radiation therapy (RT) involves the use of high-energy radiation from x-rays, gamma rays, neutrons, protons, and other sources to kill cancer cells and shrink tumors. 6 In general, the management of NETs with therapies, including radiation, is determined by the specific endocrine gland(s) involved, grade of differentiation, aggressiveness and stage of the tumor, amount of hormone produced, and specific patient needs. 3 PRRT represents a new advance in the treatment of NETs. It is based upon the presence of a greater number of somatotrophin release-inhibiting hormone receptors (also known as somatostatin receptors [SSTRs]) on NETs (compared with other tissues). 15 Radioembolization combines embolization with radiation therapy. This is done by injecting small radioactive beads into a main artery. The beads travel to the tumor and give off small amounts of radiation only at the tumor sites. 13
SSAs are currently approved for the relief of certain symptoms associated with symptomatic (functional) GI NETs and pNETs. 3,16,17 In addition, recent data from the PROMID clinical trial is being submitted to regulatory authorities. In patients with GI or Lung NETs, chemotherapy is considered a viable treatment option if not other treatments are feasible and the patient presents with unresectable liver metastases, symptomatic lung metastases, or metastasis to the regional lymph nodes. It is an option when no other treatments are feasible because of the poor efficacy and toxicity of chemotherapy. However, single-agent therapies and combination therapy with doxorubicin, 5-fluorouracil, dacarbazine, actinomycin-D, cisplatin, alkylating agents, etoposide, streptozotocin, and carboplatin have reported response rates ranging from 20% to 50%. 3 Systemic chemotherapy is recommended for patients with pNETs when they have unresectable liver or lung metastases. Trials using chemotherapeutic drugs including doxorubicin, streptozocin, 5-FU, temozolomide, and dacarbazine have established cytotoxic effects in pNETs. 3 Biological therapies include interferon. 18 Interferons are hormone-like proteins normally made by white blood cells to help the immune system fight infections. 18 Interferon-alpha is sometimes helpful in shrinking or slowing the growth of advanced NETs and improving symptoms of carcinoid syndrome. 19
Targeted therapies - these drugs are designed to attack some specific aspect of cancer cells. 20 A number of investigational therapies have shown preliminary evidence of activity in patients with advanced NETs, creating an opportunity to advance beyond traditional cytotoxic chemotherapy. 3,21 These include mTOR inhibitors (everolimus (AFINITOR)), as well as Tyrosine Kinase and VEGF pathway inhibitors (sunitinib, sorafenib, bevacizumab). 3,22,23,24 Pasireotide (SOM230), a multiligand somatstatin analogue, is currently in phase III development. 19,25,26
Somatostatin (SST) receptors are highly expressed on the surface of GI NETs. 1[Grotzinger2004, 10b] 2[Mougey2007, 15e] More than 80% of all NETs express somatostatin receptors. This overexpression provides the basis for regulation by somatostatin and its stable analogs. 1[Grotzinger2004, 10b] SST receptor activation inhibits secretory and proliferative activity. 3[Susini2006, 1734b, 1736b] References: Grotzinger C. Tumour biology of gastroenteropancreatic neuroendocrine tumours. Neuroendocrinology . 2004;80 Suppl 1:8-11. Mougey AM, Adler DG. Neuroendocrine Tumors: Review and Clinical Update. Hospital Physician . 2007;43(11):12-51. Susini C, Buscail L. Rationale for the use of somatostatin analogs as antitumor agents. Ann Oncol . 2006;17(12):1733-1742. Low MJ. Neuroendocrinology. In: Williams Textbook of Endocrinology. 11th ed. Philadelphia, PA: Saunders Elsevier; 2008:85-154. Image source:4[Low-7, 123e, 124a]
This diagram is a generalized representation of the intracellular signalling pathways that may be used by sst receptors to mediate the direct effects of sst on cell growth and proliferation, depending on the make-up of the cell: Not all cells contain all pathways or all sst receptors Not all sst receptors use all pathways New pathways continue to be identified Pathways used by sst receptors often overlap All sst receptors activate phosphotyrosine phosphatases (SHP-1, SHP-2, PTP- η ), and modulate mitogen-activated protein kinase (MAPK). sst receptor stimulation can block the effects of growth factor receptor stimulation. sst receptor stimulation can result in increased production of the cell cycle inhibitor p27. Pathways used by sst receptors overlap with pathways used by chemotherapeutic agents: For example, in vitro findings suggest that both sst receptors and the mTOR inhibitor everolimus act through a similar pathway and inhibit Akt-mTOR-p70S6 kinase References Grozinsky-Glasberg S et al. Neuroendocrinology 2008;87:168–181 Jacobs S & Schulz S. Mol Cell Endocrinol 2008;286:58–62 Lahlou H et al. J Biol Chem 2003;278:39356–39371 Lopez F et al. FASEB J 2001;15:2300–2302 Patel YC. Front Neuroendocrinol 1999;20:157–198 Weckbecker G et al. Nat Rev Drug Discov 2003;2:999–1017
The mammalian target of rapamycin (mTOR) plays a central role in a number of cell proliferation pathways. Mutation or loss of genes involved in the phosphoinositide 3-kinase (PI3K)/Akt/mTOR pathway may cause resistance to apoptosis (cell death) and increased cell proliferation in NETs. 1[Yao2007, 168def], 2[Stedman’s, 121 apoptosis] mTOR is downstream of signaling pathways often deregulated in cancers such as NETs. 1[Yao2007, 168def] mTOR signaling promotes: Cell growth and proliferation Angiogenesis Angiogenesis is the development/proliferation of blood vessels in tissue, which is very important in NETs because the tumors are highly vascularized. 3[vonMarschall2003, 437c] 4[Dorland’s, 83 angiogenesis] References: Yao JC. Neuroendocrine tumors. Molecular targeted therapy for carcinoid and islet-cell carcinoma. Best Pract Res Clin Endocrinol Metab . 2007;21(1):163-172. Stedman's Medical Dictionary . 28th ed. Philadelphia, PA: Lippincott, Williams, and Wilkins; 2006. von Marschall Z, Scholz A, Cramer T, et al. Effects of interferon alpha on vascular endothelial growth factor gene transcription and tumor angiogenesis. J Natl Cancer Inst . 2003;95(6):437-448. Dorland WAN. Dorland's Illustrated Medical Dictionary. 30th ed. Philadelphia, PA: Saunders; 2003. Faivre S, Kroemer G, Raymond E. Current development of mTOR inhibitors as anticancer agents. Nat Rev Drug Discov . 2006;5(8):671-688. Image source:5[Faivre2006, 685Figure 6]
Everolimus is a novel targeted therapy that acts as a signal transduction inhibitor . Its target is mTOR (mammalian target of rapamycin), a key protein kinase regulating cell growth, proliferation, and survival. The mTOR pathway activity is modulated by the phosphatidylinositol 3-kinase (PI3K)/protein kinase-B (AKT) pathway Pathway is known to be dysregulated in numerous human cancers. A role for everolimus in the treatment of NET is suggested by the observation that the PI3K/mTOR pathway is activated by insulin-like growth factor-1 (IGF-1) in NET 3,4 . Data suggest that everolimus may have a role in inhibiting cell growth, and tumour proliferation in NET by interrupting the IGF-1/PI3K/mTOR signaling cascade. The understanding of the anti-tumour activity of somatostatin analogs (in addition to their proven antisecretory activity) is expanding 5 There is new evidence that these compounds reduce the expression of tumour growth factors, including IGFs and epidermal growth factor (EGF). These observations suggest that everolimus may work synergistically with octreotide LAR to arrest cell growth and control hypersecretory activity in NET through the dual inhibition of mTOR and growth factors . The loss of negative feedback inhibition of PI3K, which occurs when mTOR is inhibited, can be reversed with the addition of octreotide Octreotide LAR works upstream of mTOR, and when combined with everolimus, may reverse the inhibited negative feedback loop by decreasing IGF-1 References: O ’ Reilly T, McSheehy PM. Transl Oncol . 2010;3(2):65-79. Meric-Bernstam F, Gonzalez-Angulo AM. J Clin Oncol . 2009;27:2278-2287. Faivre S, Kroemer G, Raymond E. Nat Rev Drug Disc . 2006;5:671-688. Susini C, Buscail L. Ann Oncol . 2006;17:1733-1742. 5. Yao JC, Phan AT, Chang DZ, et al. J Clin Oncol. 2008;26:4311-4318. Rinke A, Müller HH, Schade-Brittinger C, et al. J Clin Oncol . 2009;27:4656-4663 Gorshtein A, Rubinfeld H, Kendler E, Theodoropoulou M, Cerovac V, et al. Endocr Relat Cancer. 2009; 16(3): 1017-27.
After randomization, patients received octreotide LAR 30 mg or placebo every 28 days until tumour progression, documented by CT or MRI, or death. Octreotide LAR 30 mg or placebo were administered by a study nurse or physician not involved in further patient care. Patients were blinded and all clinical assessments were performed without knowledge of the assigned treatment. During the study, additional antiproliferative therapy was not allowed. Post-study treatment in patients with tumour progression was at the discretion of the investigator. All patients will be followed-up until death. Tumour progression was evaluated using the WHO criteria. Importantly, CT and/or MRI scans were evaluated by a blinded central reader. In the event of progression, patients were unblinded to the investigator, who could then decide further treatment options for the patient. Once the study is finished, the investigator is unblinded with regard to the treatment. In patients who progressed while receiving placebo, octreotide LAR or a different treatment could have been administered. Patients enrolled in the PROMID study were treatment-naïve with locally inoperable or metastatic well-differentiated NETs with a midgut primary tumour without curative therapeutic options. Patients could have either a functioning or non-functioning tumour. Patients with symptoms of carcinoid syndrome and increased urinary 5-hydroxyindole acetic acid (5-HIAA) were classified as having a functioning tumour. Only those patients with carcinoid syndrome who tolerated flushing without intervention or responded to treatment with loperamide and/or cholestyramine in case of diarrhoea were included. Patients with a tumour of unknown origin were believed to have a midgut tumour if a primary within the pancreas, chest and elsewhere was excluded by multiphasic CT and/or MRI. Only those patients with measurable disease by CT or MRI were included. Progressive metastatic disease was not required for enrolment, however, all patients were required to demonstrate metastatic or inoperable disease measurable by CT or MRI. Although this does not necessarily mean that patients had progressive disease on entry, it would certainly have included patients with significant disease burden. Additional notes The term treatment-naïve means no treatment with, for example, drugs, cytotoxics, chemoembolization or radiotherapy, before study entry. It does not exclude surgical resection of the primary tumour. 69% of patients in the octreotide LAR 30 mg arm had resection of the primary tumour, but had liver metastases. 31% of patients had locally inoperable disease because of the size of the tumour or large lymph nodes. In total, 86% of patients had liver metastases. 75% of patients in the study had a hepatic tumour load of ≤10%. One of the strengths of the PROMID study is that in order to include a homogeneous patient population, only one group of tumours was included. Midgut NETs represent the largest subgroup of NETs, and by targeting these patients, the PROMID study addressed the question of the antiproliferative effects of octreotide LAR 30 mg in the largest homogeneous NET patient population.
Baseline characteristics of the patients were well balanced between treatment arms. The median time between diagnosis and randomization for the whole group was 4.3 months, however that seen in the placebo group was 3.3 months compared with 7.5 months in the octreotide LAR 30 mg group. Although the time since diagnosis appears to be nearly twice as long in the octreotide LAR 30 mg group, this is due largely in part to the inclusion of two patients in the octreotide LAR 30 mg treatment arm with a much longer time since diagnosis than patients in the placebo arm which skewed the results. About 40% of all patients had functioning tumours (carcinoid syndrome). 75% of patients had low tumour load (tumour load ≤10%). Tumour load ≤10% was seen in 32/42 (76%) patients in the octreotide LAR 30 mg group and 32/43 (74%) patients in the placebo group. The primary tumour had been removed in 66% of patients. Ki-67 was below 2% in 97.6% of octreotide LAR 30 mg recipients and in 93% of patients receiving placebo. CgA was elevated in 62% of the octreotide LAR 30 mg arm and in 70% of the placebo arm. These criteria indicate that, at randomization, all midgut NETs were comparable in their classification. Rinke A, Müller HH, Schade-Brittinger C, et al. J Clin Oncol . 2009;27:4656-4663.
In this study, 61.2% of patients had a non-functioning midgut NET and 38.8% of patients had a functioning tumour (carcinoid syndrome). Only those patients with mild carcinoid syndrome who tolerated flushing without intervention or responded to treatment with loperamide and/or cholestyramine in cases of diarrhoea were included. In patients with non-functioning NETs, there were 9/25 tumour progressions or tumour-related deaths in the octreotide LAR 30 mg group (TTP 28.8 months), compared with 24/27 events in the placebo group (TTP 5.91 months) [HR=0.25; P =0.0008]. There were fewer patients with functioning NETs than non-functioning NETs enrolled in the study. In patients with functioning NETs in the octreotide LAR 30 mg group, there were 11/17 events with a median TTP of 14.26 months. In the placebo group there were 14/16 events and a median TTP of 5.45 months (HR=0.23; P =0.0007). This analysis tells us is that while all patients in the PROMID study benefited from octreotide LAR 30 mg therapy, those patients with non-functioning NETs experienced the most benefit. This is a key finding of the PROMID study. Recent treatment guidelines are being updated to recommend octreotide LAR 30 mg as a therapeutic option in patients with non-functioning NETs which are progressive and metastatic.
RADIANT-3 is a prospective, double-blind, randomized, placebo-controlled phase III trial assessing the efficacy and safety of everolimus plus best supportive care vs. placebo plus best supportive care in patients with advanced pNET. This is the largest phase III randomized trial ever to be conducted in advanced pNET The trial accrued more rapidly than anticipated, meeting full enrollment in less than 2 years. In total, 410 patients were enrolled. The study was designed to detect a hazard ratio of 0.67 with 282 events needed to achieve 92% power. The primary endpoint of this trial was progression-free survival per investigator assessment. Secondary endpoints include safety and overall survival. Patients with advanced pNET and radiological progression within the preceding 12 months were randomized 1:1 to everolimus plus best supportive care versus placebo plus best supportive care. Best supportive care may include the use of somatostatin analogs. There are two stratification factors: Prior cytotoxic chemotherapy WHO performance status at baseline (0 vs. 1-2) Multi-phasic CTs and/or MRIs were performed every 12 weeks for response evaluation. Treatment continued until progression, unacceptable toxicity, or withdrawal. The patient may have discontinued participation in the study for any of the following reasons: Disease progression Adverse event(s) Abnormal laboratory value(s) Abnormal test procedure result(s) Protocol deviation Subject withdrew consent Lost to follow-up Administrative problems New cancer therapy Death At progression, patients were unblinded and if on placebo allowed to crossover to open label everolimus. Ninety-one percent (91%) of eligible patients who had progressed (148 out of 163) on the placebo arm received open label everolimus at the time of progression. Reference: Yao JC, Shah M, Ito T, et al. 35 th ESMO Congress 2010; Milan, Italy. Abstract #LBA9
Results of the PFS analysis as per central review were consistent with and support those generated from the local investigator assessment. Central review resulted in a hazard ratio of 0.34 and P -value of less than 0.0001, reflecting a 66% PFS risk reduction Median PFS values were also consistent with those reported for the local investigator assessment. The median PFS was 11.4 months with everolimus and 5.4 months with placebo. The prolongation in median PFS was 6.0 months. Reference: Yao JC, Shah M, Ito T, et al. 35 th ESMO Congress 2010; Milan, Italy. Abstract # LBA9
Median OS was not reached for either treatment group. The final analysis of OS will take place when approximately 250 deaths are reached. As expected when this trial was designed to allow crossover at the time of progression, no statistically significant difference was observed between the two treatment groups (HR= 1.05; 95% CI [0.71-1.55]; P =0.594). Crossover occurred for 148 (73%) of the 203 patients initially randomized to placebo prior to the data cut-off date. When considering placebo patients who had disease progression and were thus eligible for crossover, 148 out of 163 patients (91%) received open label everolimus. Subsequent use of other anti-neoplastic therapies after discontinuation of the study medication and crossover treatment with open label everolimus further confounded OS. There were a total of 101 deaths at the time of the data cut-off (February 28, 2010). Reference: Yao JC, Shah M, Ito T, et al. 35 th ESMO Congress 2010; Milan, Italy. Abstract #LBA9
This is a summary as presented by Dr Yao at the 35th European Society for Medical Oncologist Congress.
Median overall survival varies by primary site as well as stage of disease (SEER data excludes all benign malignancies). The primary tumour site was found to be a powerful predictor of survival duration ( P < 0.001). In NET locations such as the lung, cecum, appendix, and small bowel there is little difference between local and regional spread in respect to poor prognosis. In contrast, prognosis is greatly affected in locations such as the colon, gastric, pancreas and rectum in relation to localized or regional NET. Overall, distant metastasis correlate with poor prognosis irrespective of the site of NET origin. In summary, disease site and disease spread alone are independent factors influencing prognosis but this varies dependent on location of NET. Reference: 1. Yao JC, Hassan M, Phan A, et al. J Clin Oncol. 2008;26:3063–3072.
Introduction to NETs NETs arise from cells which produce and secrete hormones Most NETs are slow growing and malignant, with metastatic potential Common sites of origin are: GI tract Lungs Pancreas 2
Definitions: Classification, Grade, and Stage Classification = origin, tumor characteristics, behavior Different NET classification systems (WHO, ENET, AJCC) take into consideration different tumor characteristics Grade = inherent biological aggressiveness1 For example: low-grade malignant, intermediate-grade malignant, high-grade malignant Prognostic; may be independent from tumor stage Stage = extent of disease2 For example, organ confined, locally invasive, metastatic, etc. Prognostic; may be independent from tumour grade1. Klöppel G, et al. Ann Ny Acad Sci. 2004;1014:13-272. Rindi G, et al. Virchows Arch. 2007;451:757-762. 3
ClassificationTraditional Method NETs have been traditionally classified as foregut, midgut, or hindgut, depending on site of origin Replaced by new tumor-based classification method developed by World Health Organization (WHO) 4
ClassificationWorld Health Organization MethodWHO classification defines NETs by degree of tumor differentiation,with specific clinicopathological featuresThe WHO classification system is basedon the following criteria: Biological behavior (malignancy) Metastases Ki-67 index Angioinvasion Tumor size Histological differentiation Hormonal syndrome 5
WHO Classification: NET Grouped By Prognostic Factors Prognosis of Patients With NET Good Poor a pancreatic NETStrosberg JR, et al. GI Cancer Res. 2008;2:113-125.Klöppel G, et al. Ann Ny Acad Sci. 2004;1014:13-27. 6
WHO Classification for NET Neuroendocrine Tumours Malignant Potential Site of Origin •Benign •GI tract •Benign or low •Pancreas Functional Activity malignant potential •Functioning •Lungs (uncertain) •Non-Functioning •Thyroid •Low malignant •Pituitary potential •Others •Highly malignant 7Ong SL, et al. Pancreatology. 2009;9:583-600.
The Pancreas Is the Most Common Primary Location of NET Breakdown in Middle East & Asia Pacific RegionBile duct and gallbladder 3%Omentum/abdominal lining 1%Rectum 1%Ovary 1%Lung 1% Liver 4% Stomach 6% Hwang T, et al. Presented at: 8th Annual ENETS Conference; March 9-11, 2011; Lisbon, Portugal. Abstract C48.
Potential Reasons for Increased Incidence and Prevalence in NET• Exact reasons are unknown but may include: – Potential underdiagnoses and underreporting in the past – Improved diagnostic techniques – Increased awareness of NET in the community 9
GI NETs Clinical PresentationClinical presentation of GI NETs varies widely Often discovered incidentallySymptoms due to: Mechanical bulk Fibrosis Secretion of various hormonesSerotonin is most commonsubstance secreted from GI NET Serotonin-producing GI NET (ileum) Serotonin release can cause carcinoid syndrome 10
GI NETs Carcinoid Syndrome Symptoms of carcinoid syndrome include: Hypotension Flushing Heart disease Rapid heart beat Wheezing DiarrheaCarcinoid syndrome is associated with metastatic disease 11
Pancreatic NETs OverviewpNETs are rare, slow-growingneoplasms Symptoms from excess hormone production or mechanical problems 6.4% of all NETs are found in pancreasIncidence rate of 0.4 cases per100,000 persons Incidence is increasingpNETs may or may not havesecretory symptoms Secretory symptoms related to specific hormones Tumors (nonfunctional) may secrete peptides but cause no clinical symptoms 12
Pancreatic NETs Types Islet cell Predominant hormone Malignant Tumor type produced potentialGastrinoma Gamma Gastrin Very highInsulinoma Beta Insulin LowGlucagonoma Alpha Glucagon Very highVIPoma Delta Vasoactive intestinal peptide HighSomatostatinoma Delta Somatostatin Very highPPoma PP cells Pancreatic polypeptide Very highRelative frequency: Asymptomatic >Insulinoma > Gastrinoma >Glucagonoma > VIPomas > Somatostatinoma > Others 13
Pancreatic NETsClinical Presentation—Asymptomatic pNETs Tumors without secretory symptoms are not associated with a hormonal syndrome Often found incidentally Patients present late with large malignancies or advanced disease Symptoms due to tumor growth or spread Abdominal pain Jaundice Diarrhea Indigestion Weight loss 14
Natural History of Neuroendocrine Tumours Estimated time to diagnosis: 5 to 7 years Death Diarrhea * Vague abdominal symptoms Flushing * Metastases Primary tumour growth 1 2 3 4 5 6 7 8 9 Time, years *Symptoms of carcinoid syndromeVinik A, et al. Pancreas. 2009 Nov;38(8):876-89 15
Nonspecific Symptoms Are Common to Multiple Diagnoses Menopause Functional Bowel Disease Symptoms Food Allergy • Sweating • Flushing Irritable Bowel • Diarrhea Syndrome • Intermittent abdominal pain Neurosis • Hypoglycemia • Confusion • Bronchoconstriction • Dyspepsia • GI bleeding Alcoholism NET • Cardiac disease Peptic Ulcer Asthma Thyrotoxicosis AnxietyAggarwal G, et al. Cleve Clin J Med. 2008;75(12):849-855. 16
Importance of Raising the Index of Suspicion Incidence of NET is increasing More prevalent than other cancers (ie, stomach, pancreas, esophagus) Associations between these symptoms suggest the presence of NET over more common ailments Flushing with NET is unrelated to time or day, warmth, or perspiration Hormone production differs from menopause, which is a typical misdiagnosis Elevated chromogranin A (CgA) is the generally accepted marker for NET 80% to 100% of NET, regardless of symptoms, secrete CgA 17Peracchi M, et al. Eur J Endocrinol. 2003;148(1):39-43.
Systematic Approach to Diagnosing NET Is Needed History and physical exam Biochemical markers (serum, tissue, urine) 1 Serum Tissue Urinary Imaging2 Computed tomography scan (CT)/ Magnetic Resonance Imaging (MRI) Nuclear Imaging Endoscopic ultrasound (pNET only)1. Ferolla P, et al. J Endocrinol Invest. 2008;31(3):277-286. 182. Barakat MT, et al. Endocr Rel Cancer. 2004;11(1):1-18.
General NET Treatment Goals Depending on the results obtained from a workup, a patient’s NET is classified as local, regional, or advanced. Treatment goals should be curative where possible, with the use of pharmacological management as necessary. General Treatment Goals: Local Regional NET The treatment goal for localized NETs is curative, which is most often accomplished with surgery. Advanced NET The treatment goal for metastatic tumors is also curative surgery if possible, followed by pharmacological treatment.
Current Systemic Treatment Options for Patients With Advanced NETs Somatostatin analogues Interferon-alfa Chemotherapy Peptide receptor–targeted therapy Molecular-targeted therapies
Pharmacological Treatment of NET Several types: Somatostatin analogues Currently approved for the relief of certain symptoms associated with symptomatic (functional) GI NETs and pNETs Cytotoxic therapy GI and Lung NETs: An option when no other options are feasible because of the poor efficacy and toxicity. Single-agent and combination therapies with doxorubicin, 5-FU, dacarbazine, actinomycin-D, cisplatin, alkylating agents, etoposide, streptozotocin, and carboplatin have resulted in response rates from 20-50%. pNETs: Systemic chemotherapy is recommended for patients with unresectable liver or lung metastases. Trials using doxorubicin, streptozocin, 5-FU, temozolomide, and dacarbazine have established cytotoxic effects in pNETs. Biological Treatment Interferon Hormone-like proteins normally made by white blood cells to help the immune system fight infections Sometimes helpful in shrinking or slowing growth of advanced NETs and improving symptoms of carcinoid syndrome
Pharmacological Treatment of NET (Continued) Several types: Targeted Therapies Designed to attack some specific aspect of cancer cells A number of investigational therapies have shown preliminary evidence of activity in patients with advanced NETs Targeted Therapies: mTOR Inhibitors everolimus (AFINITOR) Tyrosine Kinase Inhibitors sunitinib, sorafenib VEGF Inhibitors bevacizumab Other Agents Pasireotide, a multiligand somatstatin analogue, is currently in phase III development for NET
PathophysiologySignificance of Somatostatin Signaling Somatostatin (SST) receptors are highly expressed on the surface of GI NETs More than 80% of all NETs express SST receptors Overexpression provides basis for regulation by SST SST receptor activation inhibits secretory and proliferative activity 27
Octreotide May Have a Direct Antitumour Effect via sst2 and sst5 sst2 sst2 sst5 • sst2 and sst5 both downregulate MAPK G protein PI3K G protein PDK1 • sst2 binding effects the SHP2 SHP1 Src G protein P13K/Akt/mTOR Akt pathway and SHP1 PTPŋ SHP1 ↓ cGMP signalling NF-KB GSK3β mTOR MAPK ↓PKG p53 JNK p70S6K • Antiproliferative effect ↑Zac1 p27 also mediated via protein tyrosine phosphatase (PTPase) ↑ Apoptosis ↓ Cell growth modulationFlorio T et al. Front Biosci 2008;13:822–840Grozinsky-Glasberg S et al. Neuroendocrinology 2008;87:168–181Theodoropoulou M et al. Cancer Res 2006;66:1576–1582
PathophysiologySignificance of the mTOR Pathway Alterations in the mTOR pathway result in the development of some NETs 29
Rationale for Combining Everolimus and Octreotide LAR mTOR is a central regulator of ↓secretion IGF-1 ↓ligands VEGF growth, proliferation, metabolism, K+ IGF-1 IGF-1R sst analog sstr1-5 IGF-1R VEGFR and angiogenesis1-3 Ca2· NET have been linked to genetic cAMP PI3K alterations that activate the PTEN ↓signaling mTOR pathway2,3 SHP1 cGMP AKT mTOR TSC1/2 inhibitor Everolimus inhibits mTOR3 Caspase 8 p53 Bax NFcb MAP K NF1 mTOR Octreotide downregulates IGF-1, X X HI F1 VHL Survival Growth and X X a an upstream activator of the proliferation Metabolism Angiogenesis PI3K/AKT/mTOR pathway4 Everolimus + octreotide LAR has shown activity in a phase II trial51. O’Reilly T, McSheehy PM. Transl Oncol. 2010;3(2):65-79. 2. Meric-Bernstam F, Gonzalez-Angulo AM. J Clin Oncol. 2009;27:2278-2287. 3. Faivre S,Kroemer G, Raymond E. Nat Rev Drug Disc. 2006;5:671-688. 4. Susini C, Buscail L. Ann Oncol. 2006;17:1733-1742. 5. Yao JC, Phan AT, Chang DZ,et al. J Clin Oncol. 2008;26:4311-4318.
PROMID: Evaluation of the Antiproliferative Effect of Octreotide LAR 30 mg Phase III randomized, double-blind, placebo-controlled study Patients with midgut NETs Octreotide LAR RANDOMIZATION (1:1) • Treatment naïve 30 mg im Treatment • Histologically confirmed every 28 days until CT/MRI • Locally inoperable documented or metastatic tumour • Well differentiated progression • Measurable (CT/MRI) Placebo im or death • Functioning or non- every 28 days functioning Month 3 6 9 12 15 18 Primary endpoint: Time to tumour progression (blinded central review) Secondary endpoints: objective response rate, survival, quality of life, safetyRinke A et al. J Clin Oncol 2009;27:4656–4663
PROMID Patient Demographics Octreotide LAR Placebo Total 30 mg (n=42) (n=43) (n=85) Median age, years (range) 63.5 (38–79) 61.0 (39–82) 62.0 (38–82) Sex male (%) 47.6 53.5 50.6 female (%) 52.4 46.5 49.4 Time since diagnosis, months (range) 7.5 (0.8–271.2) 3.3 (0.8–109.4) 4.3 (0.8–271.2) Karnofsky score ≤80 (%) 16.7 11.6 14.1 >80 (%) 83.3 88.4 85.9 Carcinoid syndrome* (%) 40.5 37.2 38.8 Resection of primary (%) 69.1 62.8 65.9 Hepatic tumour load 0% 16.7 11.6 14.1 0–10% 59.5 62.8 61.2 10–25% 7.1 4.7 5.9 25–50% 11.9 9.3 10.6 50% 4.8 11.6 8.2 Octreoscan positive (%) 76.2 72.1 74.1 Ki-67 up to 2% (%) 97.6 93.0 95.3 CgA elevated (%) 61.9 69.8 65.9 * not requiring octreotide for symptom controlRinke A, Müller HH, Schade-Brittinger C, et al. J Clin Oncol. 2009;27:4656-4663.
Octreotide LAR 30 mg Extends TTP in Patients with Functioning and Non-functioning Tumours Patients with non-functioning tumours Patients with functioning tumours Octreotide LAR 30 mg: 25 pts / 9 events Octreotide LAR 30 mg: 17 pts / 11 events Median TTP 28.8 months Median TTP 14.26 months Placebo: 27 patients / 24 events Placebo: 16 patients / 14 events 1 1 Median TTP 5.91 months Median TTP 5.45 monthsProportion without progression Proportion without progression 0.75 0.75 0.5 0.5 0.25 0.25 0 0 0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 Time (months) Time (months) P=0.0008; HR=0.25 [95% CI: 0.10–0.59] P=0.0007; HR=0.23 [95% CI: 0.09–0.57] Based on the per protocol analysisArnold R. Abst #4508 presented at ASCO 2009, Orlando FLRinke A et al. J Clin Oncol 2009;27:4656–4663
Phase III Randomized Trial of Everolimus (RAD001) vs Placebo in Advanced Pancreatic NET (RADIANT-3) James Yao1, Manisha Shah2, Tetsuhide Ito3, Catherine Lombard-Bohas4, Edward Wolin5, Eric Van Cutsem6, David Lebwohl7, Sakina Hoosen7, Carolin Sachs8, Jeremie Lincy8, Timothy Hobday9 and Kjell Öberg10 for the RADIANT-3 study group
RADIANT-3 Study Design Phase III Double Blind Placebo Controlled Trial Everolimus 10 mg/d + R best supportive care* Patients with A advanced pNET, n = 207 N N = 410 D 1:1 Treatment Stratified by: O until disease •WHO PS M Crossover progression •Prior I Z Placebo + Chemotherapy E best supportive care* n = 203 Multi-phasic CT or MRI performed every 12 weeks Primary endpoint: Secondary endpoints: • PFS (RECIST) • Response, OS, biomarkers, safety, and PK* Concurrent somatostatin analogs allowedRandomization August 2007 - May 2009Yao JC, Shah M, Ito T, et al. 35th ESMO Congress 2010; Milan, Italy. Abstract #LBA9
PFS by Central Review* Kaplan-Meier medians PFS Everolimus: 11.4 months Placebo: 5.4 months Hazard ratio = 0.34; 95% CI [0.26-0.44] Percentage event-free P-value: <0.0001 No. of patients still at risk Everolimus Placebo * Independent adjudicated central review committee • P-value obtained from stratified one-sided log rank test • Hazard ratio is obtained from stratified unadjusted Cox modelYao JC, Shah M, Ito T, et al. 35th ESMO Congress 2010; Milan, Italy. Abstract #LBA9
Overall Survival Everolimus 10mg Placebo N = 207 N = 203 No. of events – n (%) 51 (24.6%) 50 (24.6%) HR = 1.05; 95% CI [0.71-1.55]; P = 0.594 No. censored – n (%) 156 (75.4%) 153 (75.4%) Kaplan-Meier estimates [95% CI] at: 3 months 97.1 [93.6-98.7] 98.5 [95.5-99.5] 6 months 93.1 [88.7-95.9] 91.6 [86.8-94.7] 12 months 82.3 [76.0-87.0] 82.6 [76.5-87.3] 18 months 73.1 [65.1-79.6] 73.9 [66.1-80.2] 24 months 57.3 [43.0-69.2] 62.8 [51.1-72.4] 148 placebo patients crossed over to receive everolimus Hazard ratio is obtained from the unadjusted stratified Cox model P-value is obtained from the stratified one-sided log rank testYao JC, Shah M, Ito T, et al. 35th ESMO Congress 2010; Milan, Italy. Abstract #LBA9
Summary Everolimus provided a 65% reduction in risk for progression compared to placebo (HR = 0.35, P < 0.0001)• Everolimus therapy resulted in a significant 6.4 month increase in median PFS – 4.6 months to 11.0 months• 18 months PFS rate of 34% vs 9% placebo demonstrates that everolimus provides a durable benefit Disease control rate (CR+PR+SD) was 77.7% with a significant response difference, P < 0.0001 Everolimus showed a consistent benefit in all subgroups Everolimus has an acceptable safety profile
Sunitinib Phase III Trial: SummaryInvestigator, algorithmic, and central analysis of PFS showed a mediandifference in PFS of 5.9 to 7.2 months (HR, 0.32-0.42) favoring sunitinib The increase in PFS was not statistically significant Though there is evidence of a clinically meaningful benefit, the magnitude of this benefit remains unclear due to the study being terminated early These PFS results may be an overestimate because of early looks at the data and premature study terminationThe FDA did an additional analysis, and found a median PFS of 10.2 monthsfor sunitinib and 5.4 months for placebo; these data were used in the Sutentprescribing informationThere was no statistically significant improvement in OS(43% event rate; 69% crossover)There was an increased risk for serious AEs associated with sunitinib,including 2 deaths from cardiac failureMedian exposure to treatment and follow up were 4.6 months and 10.2months in the sunitinib arm and 3.7 months and 5.4 months in the placeboarm 40
SummaryThe sunitinib trial and RADIANT-3 are both phase III,randomized, double-blind studies that assessed theeffects of treatment on PFS in patients with advancedpNET However, the trials differ substantially in design, patient population, and study conduct and, therefore, can not be directly compared 42