Could It Be a NET? - The Net Alliance HCP · Could it be a pancreatic NET? The basics ... neoplasia type 1 (MEN-1), von Hippel-Lindau syndrome (VHL), von Recklinghausen disease (neurofibromatosis

Neuroendocrine Tumors

Could It Be a NET?Detecting and diagnosing an uncommon cancer

An uncommon cancer

A word about neuroendocrine nomenclature

This brochure uses the nomenclature established in the 2010 WHO Classification of Tumours of the Digestive System, which establishes 2 broad types of neuroendocrine neoplasms1:

• Neuroendocrine tumors (NET): well-differentiated neuroendocrine neoplasms that can be divided into grade 1 (G1) and grade 2 (G2) depending on proliferation and histology

• Neuroendocrine carcinomas: poorly differentiated grade 3 (G3) neuroendocrine neoplasms

NET may be referred to using a variety of terms, such as “carcinoids,” “carcinoid tumors,” or “endocrine tumors.” These terms can be used interchangeably with “NET” as defined above.1 NET may also be referred to by the hormones they secrete, such as gastrinoma (gastrin) or glucagonoma (glucagon).

Neuroendocrine neoplasms are a family of malignancies that are believed to originate in neuroendocrine cells found throughout the body.1-3 These include well-differentiated grade 1 (G1) and grade 2 (G2) neuroendocrine tumors (NET). Traditionally regarded as an indolent, slow-growing cancer, attention has been heightened around the rising incidence and malignant potential of these tumors.2

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Overview of 3 types of NETThis brochure focuses on NET arising in 3 key anatomic locations (gastrointestinal [GI] tract, lungs, and pancreas), providing an overview of their varying clinical presentations, techniques for their identification and evaluation, and diagnostic clues to help clinicians recognize them in practice.

NET are an uncommon cancer that can elude diagnosis for years, at which time disease often has metastasized, negatively impacting patient outcomes. Thus, a key unmet need is diagnosing patients earlier in the course of disease.

Regional Distant

Lungs 23 28 193

Pancreas 22 64 42

Stomach 9 15 124

Appendix 28 12 Not reached

Duodenum 10 9 99

Jejunum/ileum 41 30 88

Cecum 42 44 83

Colon 23 32 121

Rectum 4 5 240

Life-threatening potentialDiagnosis is often delayedWell-differentiated NET can produce nonspecific symptoms that are easily mistaken for those of other conditions.4,5 This can delay the diagnosis of certain NET by up to 5 to 7 years.4

Disease may be metastatic at diagnosisNET often metastasize before they are diagnosed.6 In fact, 50% of all patients in whom disease stage is reported have either regional or distant metastases at diagnosis.2 Notably, more than 60% of patients with pancreatic NET have distant metastases at diagnosis. Frequent sites of metastasis include the lymph nodes, liver, and bones.7

3

Even small GI and pancreatic NET (<2 cm) can be aggressive and metastasize.8,9

Source: SEER data (1973-2004). Adapted from Yao JC et al. J Clin Oncol. 2008;26(18):3066.2

% of Patients With Metastatic Disease at Diagnosis Median Survival Times (all disease stages, months)

Primary NET Location

Life-threatening potential (cont)Prognosis is poor with advanced diseaseLong-term data (1973-2004) from the National Cancer Institute (NCI) Surveillance, Epidemiology, and End Results (SEER) database reveal the malignant potential of all neuroendocrine neoplasms. Survival rates vary according to disease stage, and even G1 and G2 NET have the potential to metastasize to distant sites, negatively impacting patient prognosis.

Grade also impacts prognosisAlong with disease stage, the grade of the neoplasm can also provide prognostic information.10 Grade estimates the biologic aggressiveness (ie, potential for metastatic spread) of the neoplasm. For example, G3 neuroendocrine carcinomas are highly aggressive, with a 5-year survival probability of 4% for patients with distant metastases. But even for well-differentiated G1 and G2 NET, the 5-year survival probability for patients with distant metastases is 35%.2

4

aTerminology used in reference characterized well-differentiated G1 and G2 NET as well- to moderately differentiated NET.Source: SEER data (1973-2004).Adapted with permission. ©2008 American Society of Clinical Oncology. All rights reserved. Yao JC et al. J Clin Oncol. 2008;26(18):3067.2

Median survival as a function of extent of disease (all NET locations)2,a

Localized

Regional

Distant

1.0

0.8

0.6

0.4

0.2

00 12 24 36 48 60 72 84 96 108 120

P<0.001

Sur

viva

l Pro

bab

ility

Months

33months

Recognizing and evaluating NETA disguised diseaseNET are more prone to secrete hormones and overexpress biomarkers, such as chromogranin A and synaptophysin, than are high-grade neuroendocrine carcinomas.4,10,11 Some of the symptoms and syndromes associated with NET are due to excessive secretion of hormones and other bioactive substances.5

Other NET symptoms are due to neoplasm size or growth.4

aTumor biomarkers typically are more strongly expressed in NET than in other neuroendocrine neoplasms.4,10,11

CgA, chromogranin A; 5-HIAA, 5-hydroxyindoleacetic acid; NSE, neuron-specific enolase; SNAP, synaptophysin; VIP, vasoactive intestinal peptide.

Detect and Diagnose

Symptoms/Conditions

Raise index of suspicion5

Biochemical testing

Aid in differential diagnosis12

• Abdominal pain/cramping

• Diarrhea/steatorrhea

• Constipation/abdominal pain

• Anorexia, nausea, vomiting

• Wheezing

• Zollinger-Ellison syndrome (ZES)

• Hypoglycemia

• Dermatitis

• Cushing disease

Hormone tests

— 5-HIAA (24-hour urine sample)13

— Glucose and insulin (72-hour fasting glucose)12

— Fasting serum gastrin/ gastric pH12

— Plasma glucagon, VIP, somatostatin14

Tumor biomarkersa

— CgA15

— NSE16

— SNAP17

5

NET are more prone to secrete hormones and overexpress biomarkers, such as CgA and SNAP, than are high-grade neuroendocrine carcinomas4,10,11

Because these symptoms often are associated with more common conditions, identifying and diagnosing a NET may be challenging.5 However, tools are available to help establish a diagnosis and monitor existing NET.

For diagnostic accuracy — as well as continued disease management — preliminary biomarker results should be confirmed with imaging and endoscopic techniques, along with histopathologic analysis, when appropriate.7,18

Localize and Characterize

ImagingLocalize primary neoplasm

and metastases11,18

EndoscopyLocate neoplasms,

collect biopsy samples11,18

PathologyIdentify and grade NET19

• Triple-phase CT

• MRI

• Somatostatin receptor scintigraphy (Octreoscan™)

• MIBG scintigraphy

• PET

• Endoscopy

• Endoscopic ultrasound

• Immunohistochemical staininga

—CgA

—SNAP

Definitive diagnosis requires tissue confirmation, when appropriate

6

Recognizing and evaluating NET (cont)

aTumor biomarkers typically are more strongly expressed in NET than in other neuroendocrine neoplasms.4,10,11

CT, computed tomography; MIBG, metaiodobenzylguanidine; MRI, magnetic resonance imaging; PET, positron emission tomography.

Octreoscan is a trademark of Covidien AG or one of its affiliates.

Could it be a lung NET?The basicsG1 and G2 NET of the lung — called typical and atypical lung carcinoids — account for approximately 2% of all primary lung tumors.20,21 About one-third of diagnosed lung NET exhibit atypical histologic features.20

Hormones secreted include adrenocorticotropic hormone (ACTH), growth hormone–releasing hormone (GHRH), and antidiuretic hormone (ADH).11 Carcinioid syndrome is a rare manifestation, but can occur in the presence of metastatic disease.22,23

Lung NET are slightly more prevalent in women vs men and in whites vs other ethnicities, and are the most common primary lung tumor in children and adolescents.23

Typical carcinoid

• Usually present in the fifth decade of life

• Most often central in location

• Rarely associated with the classic carcinoid syndrome; have been associated with ectopic ACTH secretion, resulting in Cushing syndrome

Atypical carcinoid

• Occur most commonly in the sixth decade of life

• More common in smokers

• Tend to be larger in size and more commonly peripheral in location than typical carcinoids

• Often found incidentally

• Characterized by the presence of frequent mitoses or areas of necrosis

Typical vs Atypical Carcinoids20

Clinical presentationPatients are often asymptomatic for long periods, or may present with nonspecific symptoms, including coughing and wheezing.20 Other symptoms include dyspnea, hemoptysis, recurrent obstructive pneumonia, pleuritic pain, and atelectasis. Related syndromes due to hormonal secretion are Cushing syndrome, acromegaly, and hyponatremia.24

Respiratory symptoms are typically only encountered with centrally located lung NET.23

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Diagnostic considerationsNonspecific symptoms such as coughing and wheezing can prompt initial suspicion of asthma, contributing to delayed diagnosis.25

Radiologic investigations should focus on the major bronchi (main-stem and lobar bronchi) and the peripheral lung (segmental bronchi or beyond).26

Immunohistochemical staining of select markers (eg, chromogranin A, synaptophysin) can help confirm the neuroendocrine nature of resected/biopsied tumor specimens, but do not distinguish typical and atypical histologies.23

For more information on lung NET, visit www.neuroendocrinetumor.com or ask your Novartis representative about Lung Neuroendocrine Tumors: An Overview of the Disease and Its Management.

Symptoms of Cushing syndrome are seen in approximately 2% of patients with lung NET.26

Evaluation for Cushing syndrome may be warranted in patients presenting with symptoms of hypercortisolemia.

Recommended tests include: overnight 1-mg dexamethasone suppression test with 8 am plasma cortisol; 2 to 3 midnight salivary cortisols; or free cortisol in a 24-hour urine sample.7

Importantly, assess serum ACTH in these patients because elevated levels indicate the excessive cortisol is not due to adrenal gland dysfunction and may point to an ectopic lung NET as the cause.7

8

Could it be a pancreatic NET?The basicsMost pancreatic NETs are well-differentiated G1 or G2 tumors27,28 that vary in clinical presentation and aggressiveness.14,29 They can be sporadic or associated with genetic syndromes such as multiple endocrine neoplasia type 1 (MEN-1), von Hippel-Lindau syndrome (VHL), von Recklinghausen disease (neurofibromatosis [NF-1]), and tuberous sclerosis complex (TSC).

Most pancreatic NETs are nonfunctional; however, they may be associated with symptoms and syndromes due to the oversecretion of specific hormones.14,30

Clinical presentationAbdominal pain is one of the most common presenting symptoms. Symptoms of hormone oversecretion typically are not part of the initial presentation and are usually indicative of metastatic disease.31

Diagnostic considerationsPatients with pancreatic NET are more likely to have advanced disease at diagnosis than patients with other types of NET.2

Liver metastases occur much more frequently with gastrinomas located in the pancreas (typically >1 cm) than in the duodenum (typically <1 cm).32

Elevated serum gastrin levels in some patients in whom a pancreatic NET is suspected (ie, gastrinoma) may be confounded by achlorhydria, antacids, or proton pump inhibitor (PPI) therapy.7

Endoscopic ultrasound can localize most pancreatic NET, although multiphase CT or MRI should be used to identify metastatic disease.7

For more information on pancreatic NET, visit www.neuroendocrinetumor.com or ask your Novartis representative about Pancreatic Neuroendocrine Tumors: An Overview of the Disease and Its Management.

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Pancreatic NET Signs and Symptoms7,14,29,33 Diagnostic Tests

Insulinoma Hypoglycemia A standard 72-hour fasting test should be used to measure glucose (<45 mg/dL) and insulin (>30 pmol/L) levels and to exclude all differential diagnoses of insulinoma, except for very rare conditions.11,12,34 Measurement of proinsulin and C-peptide levels may be helpful20

Gastrinoma Recurrent peptic ulcer, abdominal pain, diarrhea (Zollinger-Ellison syndrome, or ZES)

Diagnosis often begins with determination of fasting serum gastrin levels (≥1000 pg/mL) and gastric pH (<2.5).11 Over repeated testing, <0.5% of patients with ZES will have normal values.12,34 Note: PPI therapy can elevate serum gastrin levels and should be stopped at least 1 week before testing patients suspected of gastrinoma7

Glucagonoma Diabetes/glucose intolerance, rash (migratory necrolytic erythema), thromboembolic disease

Diagnosis can be made when plasma glucagon levels are increased to 500 pg/mL to 1000 pg/mL (normal range <50 pg/mL)14

VIPoma Severe watery diarrhea, electrolyte disturbances (Verner-Morrison syndrome, pancreatic cholera, or watery diarrhea, hypokalemia, and achlorhydria [WDHA] syndrome)

Diagnosis is based on elevated levels (>200 pg/mL) of plasma VIP in patients with large-volume secretory diarrhea (>700 mL/d)14,35

Somatostatinomas Diabetes, cholelithiasis, diarrhea Diagnosis can be confirmed by elevated plasma somatostatin levels in the setting of a histologically confirmed NET14

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Could it be a GI NET?The basicsWithin the GI tract, most NET arise in the small intestine (jejunum/ileum; 41.8%), rectum (27.4%), and stomach (8.7%).36

NET of the duodenum, jejunum/ileum, and rectum occur significantly more frequently in men than in women.2

Carcinoid syndrome can be a primary clinical manifestation of NET37 and is most frequently associated with NET of the small intestine.1

Some GI NET are often discovered incidentally during routine endoscopic procedures of the stomach, colon, rectum, and small intestines.38

Clinical presentationThe most common signs and symptoms experienced by patients with carcinoid syndrome are flushing, diarrhea, abdominal cramping, and cardiac disease caused by valvular heart lesions. Symptoms typically do not manifest until the tumor metastasizes.39

Carcinoid syndrome is also associated with skin changes such as telangiectasia, cyanosis, and, rarely, pellagra.3,11,40

For more information on GI NET, visit www.neuroendocrinetumor.com or ask your Novartis representative about Gastrointestinal Neuroendocrine Tumors: An Overview of the Disease and Its Management.

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Symptoms Patients With Symptoms, %

Flushing 90

Diarrhea 70

Abdominal pain 40

Valvular heart disease 40-45

Telangiectasia 25

Wheezing 15

Pellagra 5

Symptoms of Carcinoid Syndrome and Their Frequency11

Clues That Could Indicate Carcinoid Syndrome

Flushing in carcinoid syndrome is characteristically dry (not associated with perspiration) and usually pink to red in color, affecting the face, neck, and upper torso.11,43,44 Transient hypotension, headache, and bronchoconstriction may coincide with flushing.11,44

Carcinoid heart disease usually involves the right-side valves and develops later in the disease process. The right side of the heart is exposed to high levels of serotonin and other vasoactive substances released from hepatic metastases, causing the thickening, retraction, and fixation of the pulmonary and tricuspid valves. This can lead to valvular dysfunction and, eventually, right-sided heart failure.3,11,37,41,44-46

Abdominal pain in carcinoid syndrome typically is intermittent and crampy, and may not be relieved with defecation as it can be in irritable bowel syndrome (IBS).39,47

Diarrhea associated with carcinoid syndrome is typically chronic and may be nocturnal. It is characterized by increased gut motility and watery stools resulting from intestinal hypermotility and hypersecretion. Fasting typically does not alleviate the diarrhea.39,48,49

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Diagnostic considerationsAssessment of 24-hour urinary 5-HIAA is a useful diagnostic tool for NET associated with carcinoid syndrome11 and can be used to monitor response to treatment.7,41,42 Carcinoid heart disease has also been associated with elevated levels of urinary 5-HIAA.

The symptoms of carcinoid syndrome can have a major effect on quality of life, and earlier diagnosis can help patient outcomes.

Collaborative approach to patient care

NET may require collaboration among specialists from multiple disciplines The appropriate management of NET is dependent on factors such as7,50

• Location of neoplasm and specific glands involved

• Grade of neoplasm

• Differentiation of neoplasm cells

• Aggressiveness and stage of neoplasm

• Amount of hormones produced

• Specific patient needs

• Comorbidities/clinical manifestations involved

Because numerous health care professionals can contribute to the optimal care of patients with NET,51 the NCCN Clinical Practice Guidelines In Oncology (NCCN Guidelines®) state: “Appropriate diagnosis and treatment of neuroendocrine tumors often involves collaboration between specialists in multiple disciplines using specific biochemical, radiologic, and surgical methods.”7

The multidisciplinary team may include

• Dietitians • Oncologists51,52

• Endocrinologists51 • Pathologists52

• Gastroenterologists51,52 • Pulmonologists51,52

• Interventional radiologists51,52 • Social workers/case managers

• Nuclear medicine experts51,52 • Surgeons51,52

• Nurses

Furthermore, institutional studies show that outcomes are improved for patients who are managed at centers that specialize in NET.53

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1. Rindi G, Arnold R, Bosman FT, et al. Nomenclature and classification of neuroendocrine neoplasms of the digestive system. In: Bosman FT, Carneiro F, Hruban RH, et al, eds. WHO Classification of Tumours of the Digestive System. 4th ed. Lyon, France: International Agency for Research on Cancer (IARC); 2010:13-14.

2. 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.

3. Jensen RT, Doherty GM. Carcinoid tumors and the carcinoid syndrome. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds. Cancer: Principles & Practice of Oncology. 7th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2005:1559-1574.

4. Modlin IM, Oberg K, Chung DC, et al. Gastroenteropancreatic neuroendocrine tumours. Lancet Oncol. 2008;9(1):61-72.

5. Vinik AI, Woltering EA, O’Dorisio TM, Go VLW, Mamikunian G. Diagnosing and treating gastroenteropancreatic tumors, including ICD 9 codes. In: Neuroendocrine Tumors: A Comprehensive Guide to Diagnosis and Management. 5th ed. Inglewood, CA: Inter Science Institute; 2012:1-56.

6. Modlin IM, Kidd M, Latich I, Zikusoka MN, Shapiro MD. Current status of gastrointestinal carcinoids. Gastroenterology. 2005;128(6):1717-1751.

7. Referenced with permission from the NCCN Clinical Practice Guidelines In Oncology (NCCN Guidelines®) for Neuroendocrine Tumors. V.2.2016. © National Comprehensive Cancer Network, Inc 2016. All rights reserved. Accessed August 3, 2016. To view the most recent and complete version of the guideline, go online to www.nccn.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc.

8. Alexiev BA, Drachenberg CB, Papadimitriou JC. Endocrine tumors of the gastrointestinal tract and pancreas: grading, tumor size and proliferation index do not predict malignant behavior. Diagn Pathol. 2007;2:28.

9. Mullen JT, Wang H, Yao JC, et al. Carcinoid tumors of the duodenum. Surgery. 2005;138(6):971-978.

10. Klimstra DS, Modlin IR, Coppola, D, Lloyd RV, Suster S. The pathologic classification of neuroendocrine tumors. A review of nomenclature, grading, and staging systems. Pancreas. 2010;39(6):707-712.

11. Kaltsas GA, Besser GM, Grossman AB. The diagnosis and medical management of advanced neuroendocrine tumors. Endocr Rev. 2004;25(3):458-511.

12. Vinik AI, Silva MP, Woltering G, Go VLW, Warner R, Caplin M. Biochemical testing for neuroendocrine tumors. Pancreas. 2009;38(8):876-889.

13. Ferolla P, Faggiano A, Mansueto G, et al. The biological characterization of neuroendocrine tumors: the role of neuroendocrine markers. J Endocrinol Invest. 2008;31(2):277-286.

14. Kulke MH, Anthony LB, Bushnell DL, et al. NANETS treatment guidelines: well-differentiated neuroendocrine tumors of the stomach and pancreas. Pancreas. 2010;39(6):735-752.

15. Campana D, Nori F, Piscitelli L, et al. Chromogranin A: is it a useful marker of neuroendocrine tumors? J Clin Oncol. 2007;25(15):1967-1973.

16. Bajetta E, Ferrari L, Martinetti A, et al. Chromogranin A, neuron specific enolase, carcinoembryonic antigen, and hydroxyindole acetic acid evaluation in patients with neuroendocrine tumors. Cancer. 1999;86:(5)858-865.

17. Lloyd RV. Practical markers used in the diagnosis of neuroendocrine tumors. Endocr Pathol. 2003;14(4):293-301.

18. Modlin IM, Latich I, Zikusoka M, Kidd M, Eick G, Chan AKC. Gastrointestinal carcinoids: the evolution of diagnostic strategies. J Clin Gastroenterol. 2006;40(7):572-582.

19. Klimstra DS, Modlin IR, Adsay NV, et al. Pathology reporting of neuroendocrine tumors: application of the Delphic Consensus Process to the development of a minimum pathology data set. Am J Surg Pathol. 2010;34(3):300-313.

References

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20. Kulke MH. Clinical presentation and management of carcinoid tumors. Hematol Oncol Clin N Am. 2007;21:433-455.

21. Travis WD, Brambilla E, Nicholson AG et al, on behalf of the WHO Panel. The 2015 World Health Organization classification of lung tumors. J Thorac Oncol. 2015;10:1243-1260.

22. Beasley MB, Thunnissen FB, Hasleton PS. Carcinoid tumor. In: World Health Organization Classification of Tumours: Pathology and Genetics of Tumours of the Lung, Pleura, Thymus and Heart. Lyon, France: International Agency for Research on Cancer Press. 2004;59-62.

23. Caplin ME, Baudin E, Ferolla P, et al, the ENETS consensus conference participants. Pulmonary neuroendocrine (carcinoid) tumors: European Neuroendocrine Tumor Society expert consensus and recommendations for best practice for typical and atypical pulmonary carcinoids. Ann Oncol. 2015;26:1604-1620.

24. Krug LM, Kris MG, Rosenzweig K, Travis, WD. Small cell and other neuroendocrine tumors of the lung. In: DeVita, Hellman, and Rosenberg’s Cancer: Principles and Practice of Oncology. 8th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2008:946-971.

25. Phan AT, Oberg K, Choi J, et al. NANETS consensus guidelines for the diagnosis and management of neuroendocrine tumors. Well-differentiated neuroendocrine tumors of the thorax (includes lung and thymus). Pancreas. 2010;39(6):784-798.

26. Hage R, Brutel de la Riviere A, Seldenrijk CA, van den Bosch JMM. Update in pulmonary carcinoid tumors: a review article. Ann Surg Oncol. 2003;10(6):697-704.

27. Bilimoria KY, Tomlinson JS, Merkow RP, et al. Clinicopathologic features and treatment trends of pancreatic neuroendocrine tumors: analysis of 9,821 patients. J Gastrointest Surg. 2007;11(11)1460-1467.

28. Halfdanarson TR, Rabe KG, Rubin J, Petersen GM. Pancreatic neuroendocrine tumors (PNETs): incidence, prognosis and recent trend toward improved survival. Ann Oncol. 2008;19(10):1-7.

29. Metz DC, Jensen RT. Gastrointestinal neuroendocrine tumors: pancreatic endocrine tumors. Gastroenterology. 2008;135(5):1469-1492.

30. Jensen RT, Berna MJ, Bingham DB, Norton JA. Inherited pancreatic endocrine tumor syndromes: advances in molecular pathogenesis, diagnosis, management, and controversies. Cancer. 2008;113(7 suppl):1807-1843.

31. Ter-Minassian M, Chan JA, Hooshmand SM, et al. Clinical presentation, recurrence, and survival in patients with neuroendocrine tumors: results from a prospective institutional database. Endocr Relat Cancer. 2013;20(2):187-196.

32. Jensen RT, Cadiot G, Brandi ML, et al. ENETS consensus guidelines for the management of patients with digestive neuroendocrine neoplasms: functional pancreatic endocrine tumor syndromes. Neuroendocrinology. 2012;95(2):98-119.

33. Vagefi PA, Razo O, Deshpande V, et al. Evolving patterns in the detection and outcomes of pancreatic neuroendocrine neoplasms: the Massachusetts General Hospital experience from 1977 to 2005. Arch Surg. 2007;142(4):347-354.

34. Ehehalt F, Saeger HD, Schmidt CM, Grutzmann R. Neuroendocrine tumors of the pancreas. The Oncologist. 2009;14:456-467.

35. 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.

36. Modlin IM, Lye KD, Kidd M. A 5-decade analysis of 13,715 carcinoid tumors. Cancer. 2003;97(4):934-959.

37. Rorstad O. Prognostic indicators for carcinoid neuroendocrine tumors of the gastrointestinal tract. J Surg Oncol. 2005;89(3):151-160.

38. Lawrence B, Gustafsson BI, Chan A, Svejda B, Kidd M, Modlin IM. The epidemiology of gastroenteropancreatic neuroendocrine tumors. Endocrinol Metab Clin North Am. 2011;40(1):1-18.

39. Creutzfeldt W. Carcinoid tumors: development of our knowledge. World J Surg. 1996;20(2):126-131.

40. Vinik A, Thompson N, Eckhauser F, Moattari R. Clinical features of carcinoid syndrome and the use of somatostatin analogue in its management. Acta Oncologica. 1989;28:389-402.

41. Moller JE, Connolly HM, Rubin J, Seward JB, Modesto K, Pellikka PA. Factors associated with progression of carcinoid disease. N Engl J Med. 2003;348(11):1005-1015.

42. Jensen EH, Kvols L, McLoughlin JM, et al. Biomarkers predict outcomes following cytoreductive surgery for hepatic metastases from functional carcinoid tumors. Ann Surg Oncol. 2006;12(2):780-785.

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43. Martelli A, Ghiglioni D, Sarratud T, et al. Anaphylaxis in the emergency department: a Paediatric perspective. Curr Opin Allergy Clin Immunol. 2008;8:321-329.

44. McCormick D. Carcinoid tumors and syndrome. Gastroenterol Nurs. 2002;25(3):105-111.

45. Pellikka PA, Tajik AJ, Khandheria BK, et al. Carcinoid heart disease: clinical and echocardiographic spectrum in 74 patients. Circulation. 1993;87(4):1188-1196.

46. Westberg G, Wangberg B, Ahlman H, Bergh CH, Beckman-Suurkula, Caidahl K. Prediction of prognosis by echocardiography in patients with midgut carcinoid syndrome. Br J Surg. 2001;88:865-872.

47. International Foundation for Functional Gastrointestinal Disorders. Recognizing Symptoms. http://ww.aboutibs.org/site/sigs-symptoms/recognizing-symptoms. Accessed February 9, 2016.

48. von der Ohe MR, Camilleri M, Kvols LK, Thomforde GM. Motor dysfunction for the small bowel and colon in patients with the carcinoid syndrome and diarrhea. N Engl J Med. 1993;329(21):1592.

49. Wiedenmann B, Pape UF. From basic to clinical research in gastroenteropancreatic neuroendocrine tumor disease-the clinician- scientist perspective. Neuroendocrinology. 2004;80(suppl 1):94-98.

50. Modlin IM, Moss SF, Chung DC, Jensen RT, Snyderwine E. Priorities for improving the management of gastroenteropancreatic neuroendocrine tumors. J Natl Cancer Inst. 2008;100(18):1282-1289.

51. Caplin ME, Buscombe JR, Hilson AJ, Jones AL, Watkinson AF, Burroughs AK. Carcinoid tumour. Lancet. 1998;352(9130):799-805.

52. McStay MKG, Caplin ME. Carcinoid tumour. Minerva Med. 2002;93(5):389-401.

53. Strosberg J, Gardner N, Kvols L. Survival and prognostic factor analysis of 146 metastatic neuroendocrine tumors of the mid-gut. Neuroendocrinology. 2009;89(4):471-476.

Neuroendocrine Tumors: The unique challenges of a complex disease

Novartis Pharma AGCH-4002 Basel Switzerland © 2016 Novartis 6/16 G-NEA-1131368

Novartis Pharmaceuticals CorporationEast Hanover, New Jersey 07936-1080

A cancer on the rise1,2

• Incidence of all neuroendocrine neoplasms is increasing dramatically—fivefold over the past 30 years2

Life-threatening potential may be overlooked

• Because NET can produce vague, nonspecific symptoms,8 the estimated time to diagnosis can reach 5 to 7 years6

• Patients with distant metastases have a median survival of 33 months2

• The 5-year survival rate is 35% for patients diagnosed with well-differentiated grade 1 or grade 2 NET with distant metastases2

Detection and diagnosis are key

• Imaging techniques such as CT, MRI, and somatostatin receptor scintigraphy can help confirm an initial NET diagnosis and monitor disease status10

• Biochemical tests that detect bioactive substances secreted by NET have diagnostic and prognostic significance14

Multidisciplinary approach helps ensure optimal patient care

• Appropriate management of NET often involves collaboration between specialists in multiple disciplines using specific biochemical, radiologic, and surgical methods10